Substituted bicyclic compounds

Abstract

The present invention relates to bicyclic compounds. These bicyclic compounds are useful as inhibitors of TEAD binding and / or YAP-TEAD and TAZ-TEAD protein-protein interactions or binding, and are useful in the prevention and / or treatment of cancer and other serious disorders and diseases.

Description

Invention 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 of the Invention 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 progenitor 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 its "on" state, the Hippo pathway involves a cytoplasmic kinase cascade (including Mst 1 / 2 and Lats 1 / 2) that induces 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 it in the cytoplasm and ultimately leads to its degradation. In contrast, when the Hippo pathway is "off" or dysfunctional, the unphosphorylated activated YAP / TAZ coactivators translocate to the nucleus. Its primary target transcription factors are four proteins (TEAD1-4) of the transcription enhancement-associated domain (TEAD) family of transcription factors. The binding and activation of TEAD (or other transcription factors) to YAP or TAZ have 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, it is believed that dysfunction or abnormal regulation of the Hippo pathway, as a tumor suppressor, is an important event in the development of various cancer types and diseases.

[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. It can also be applied to inhibit not only binding to a single member of the TEAD family, but also binding to two, three, and / or all four TEAD paralogs.

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

[0010] In one embodiment, the present invention relates to heteroaromatic compounds of formula I. I in Ring D and R 2 together or ; X 1 Indicates CR X1 Or N; R X1 Indicates H, halogen, straight-chain or branched C 1-4 -alkyl groups, which are unsubstituted or independently substituted with the following groups: 1, 2 or 3 halogens, and / or OH; R 1 This refers to straight-chain or branched C atoms that are not substituted or are independently substituted by one, two, or three halogens. 1-6 -alkyl, and the C 1-6 -In an alkyl group, 1, 2, 3, 4, 5, 6, or 7 H atoms may be replaced by deuterium (D-atom); or C atoms may be unsubstituted or independently substituted by 1, 2, or 3 halogens. 3-7 -cycloalkyl, and the C 3-7 In a cycloalkyl group, 1, 2, 3, 4, 5, 6, or 7 H atoms can be replaced by deuterium (D-atoms), especially unsubstituted C atoms. 3-5 -Cycloalkyl, especially cyclopropyl; R 2 Represents H, Alk 2 Ar 2 Hetar 2 Cyc 2 Hetcyc 2 -L 2 -Ar 2a ; R 3 Indicates H, halogen, or C 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently substituted with -OH or 1, 2 or 3 halogens (especially C). 1-4 -alkyl, C2-4 -Alkenyl or C 2-4 -Alynyl groups, each of which may be unsubstituted or monosubstituted with -OH); A represents a 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 a 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 or C 3-5 -Cycloalkyl mono- or di-substituted, the C 1-4 -The alkyl group is not substituted or is substituted with 1, 2 or 3 halogens, and the C 1-4 -alkyl or C 3-5 - In a cycloalkyl group, 1, 2, 3, 4, 5, 6 or 7 H atoms can be replaced by deuterium (D-atom); 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-, -NH-CH2-, -N(R 6 -CH2-, -NH-C(=O)-, -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 This 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 unsubstituted or independently converted to 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 unsubstituted or independently converted to 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 C10and / or R C11 replace; 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 not substituted or are independently substituted 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)2Rf -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 ; 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 connected to the same carbon atom of the carbon ring or the heterocycle B6 R B7 R B8 R B9 R B10 R B11 The two in the mixture form a divalent oxy group (=O); and / or R connected 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 a divalent oxo group or a divalent =NH or =NC group. 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 1, 2 or 3 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 1, 2 or 3 halogens -OC 1-4 -alkyl; Halogens are represented by F, Cl, Br, or I; 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.

[0011] In another embodiment, the present invention relates to heteroaromatic compounds of formula I. I in Ring D and R 2 together or ; X 1 CR X1 Or N; R X1 Indicates H, halogen, straight-chain or branched C 1-4 -alkyl groups, which are unsubstituted or independently substituted with the following groups: 1, 2 or 3 halogens, and / or OH; R 1 This refers to straight-chain or branched C atoms that are not substituted or are independently substituted by one, two, or three halogens. 1-6 -alkyl; R 2 Represents H, Alk 2 Ar 2 Hetar 2 Cyc 2 Hetcyc 2 -L 2 -Ar 2a ; R 3 Indicates H or halogen; A represents a 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 a 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 1, 2 or 3 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 This 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 unsubstituted or independently converted to R. C1 R C2 and / or R C3 replace; Ar a Ar 2 Ar 2aEach 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 unsubstituted or independently converted to 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 1This 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 not substituted or are independently substituted 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 ; Ra 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 B9R 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 connected to the same carbon atom of the carbon ring or the heterocycle B6 R B7 R B8 R B9 R B10 R B11 The two in the mixture form a divalent oxy group (=O); and / or R connected 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 a divalent oxo group or a divalent =NH or =NC group. 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 1, 2 or 3 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 1, 2 or 3 halogens -OC 1-4 -alkyl; Halogens are represented by F, Cl, Br, or I; 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.

[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... Ring D and R 2 together ; X 1 Indicates CR X1 Or N; R X1 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 Indicates CH; 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; Furthermore, 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 may also be described as a compound of Formula IB (see above). In another specific embodiment PE2 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... Ring D and R 2 together ; 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 other words, the compound of PE2 is a compound of formula IC: .

[0019] In another specific embodiment PE3 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... R 3 Indicates halogen; 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.

[0020] In another specific implementation of PE3, PE3a, wherein in formula I, R 3 Indicates I; 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 another specific implementation of PE3, PE3b, wherein in formula I, R 3 Indicate 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.

[0022] Compounds of PE3 and PE3a are particularly useful as starting materials for the preparation of I-type modified compounds, wherein R 3 It can be partially replaced by different functional groups, substituents, or structures, wherein such substitution can be achieved by CC- or CN- coupling reactions known in the art.

[0023] In another specific embodiment PE4 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... R 3 H 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.

[0024] In yet another specific embodiment PE5 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein R 1 C represents the unreplaced straight or branched chain. 1-6 -alkyl, the C 1-6 One, two, three, four, five, six or seven H atoms in the -alkyl group may be replaced by deuterium (D-atom), 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 implementation of PE5, PE5a, wherein in formula I, R 1 It represents CH3 or C2H5; 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] In another specific implementation of PE5 or PE5a, PE5aa, where R 1 CH3; 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] In another specific implementation of PE5, PE5b, wherein in formula I, R 1 This indicates CD3 or C2D5, especially (PE5ba) C2D5; 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 present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... R 2 Represents H, Alk 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a ; 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 implementation of PE6, PE6a, wherein in formula I, R 2 Represents H, Alk 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a ; Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl 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; L 2 This 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 Each of the above 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 unsubstituted or independently converted to R B1 and / or R B2 replace; Cyc 2a This refers to a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon rings are not substituted or are 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 Common replacement; R 2a1 R 2a2 R 2a3The 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 -SR 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 ; 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 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 replacement; 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 hEach 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 connected to the same carbon atom of the heterocycle B8 and R B9 Forming divalent oxygen (=O) groups; and / or R attached to the same sulfur (S) atom of the heterocycle B6 R B7 R B8 R B9 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 The other two in it form a divalent oxo group or a divalent =NH or =NC group. 1-4 -alkyl groups, thereby forming -S(=O)2, -S(=O)(=NH) or -S(=O)(=NC 1-4 -alkyl) moiety; 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 yet another specific embodiment of PE6 and PE6a, PE6aa, the compound of the present invention is a bicyclic compound of formula I, wherein R 2 Represents H, Alk 2 Hetar 2 Hetcyc 2 ; Alk 2 C represents a straight chain or a branch chain. 1-4 -alkyl groups, which may be unsubstituted or independently of each other, R2a1 and / or R 2a2 replace; Hetar a 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, the C 1-4 -The alkyl group may be unsubstituted or substituted with 1, 2 or 3 halogens; Cyc 2a This refers to a saturated monocyclic carbon ring having four ring carbon atoms, wherein the carbon ring is either unsubstituted or monosubstituted with -OH. Hetcyc 2 This refers to a saturated monocyclic heterocycle having 5 ring atoms, wherein one of the ring atoms is a heteroatom selected from O or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or monosubstituted by OH. Hetcyc 2a This refers to a saturated monocyclic heterocycle having 4, 5, or 6 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 to OH, -OC 1-4 -alkyl or C 1-4 -alkyl monosubstituted, wherein the C 1-4 -Alkyl groups may be unsubstituted or replaced with -OH or -OC. 1-4 -Alkyl monosubstituted; R 2a1 R 2a2 F, -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)(=NR) g )R f -C(=O)NH2, -C(=O)NHR a C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; R a R bEach can be represented independently as a straight chain or a branch C. 1-6 -alkyl; 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 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 replacement; R c C represents a straight chain or a branch chain. 1-4 -alkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f C represents a straight chain or a branch chain. 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 B6 R B7 Each represents OH independently; R connected to the same carbon atom of the heterocycle B8 and R B9 Forming divalent oxygen (=O) groups; In yet another specific embodiment of the present invention, PE6aaa, which is also a specific embodiment of any of the specific embodiments PE6, PE6a, or PE6aa, the compound of the present invention is a bicyclic compound of formula I, wherein... R 2Represents H; -CH3, -CH2-CN, -(CH2)2-CN, -(CH2)2-OH, -(CH2)3-OH, CH2-CH(CH3)-CH2-OH, -CH2-CHF-CH2-OH, -CH2-CH(OH)-CH2-OH, - CH(CH2OH)2, -CH2-CH(OH)-CH2-OCH3, -(CH2)3-S-CH3, -(CH2)2-S(=O)(=NH)CH3, -CH2-P(=O)(CH3)2, -CH2-C(=O)-NH2, -CH2-C (=O)-NHCH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-NH-C(=O)-H, -(CH2)2-NH-C(=O)-CH3, 2-(3-hydroxypyrrolidine-1-yl)ethyl, 2-(2-oxo-pyrrolidine-1-yl)-ethyl, (2-morpholin-4-yl-ethyl); 1-methyl-1H-imidazol-4-yl, 1-methyl-1H-imidazol-5-yl, 1,2-thiazolyl-2-yl, 1,3-thiazolyl-2-yl, 1,3-thiazolyl-4-yl, pyrazin-2-yl; (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (4-methyl-1H-imidazol-2-yl)methyl, 2-(1H-imidazol-4-yl)ethyl, (1H-pyrazol-4-yl)methyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)ethyl, 1-oxazol -2-ylmethyl, 1,3-thiazolyl-5-ylmethyl, 2-methyl-1,3-thiazolyl-4-ylmethyl, 2-methyl-1,3-thiazolyl-5-ylmethyl, 1H-1,2,3-triazol-4-ylmethyl, 1H-1,2,4-triazol-3-ylmethyl, pyrazin-2-ylmethyl, 3-methylpyrazin-2-ylmethyl, pyridazin-3-ylmethyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, 2-hydroxy-1-(pyrazin-2-yl)ethyl; 1-hydroxycyclobutylmethyl ( ), , , , [3-(hydroxymethyl)oxetane-3-yl]methyl( ), (3-hydroxyoxacyclopentan-3-yl)methyl ( ), (4-hydroxyoxacyclohexane-4-yl)methyl ( ); 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 yet another specific embodiment of the present invention, PE6aaaa, which is also a specific embodiment of any of the specific embodiments PE6, PE6a, PE6aa, or PE6aaa, wherein the compound of the present invention is a bicyclic compound of formula I, wherein R 2 Represents H; -CH3, -CH2-CN, -(CH2)2-CN, -(CH2)2-OH, -(CH2)3-OH, -CH(CH2OH)2, -(CH2)2-S(=O)(=NH)CH3, -CH2-P(=O)(C H3)2, -CH2-C(=O)-NH2, -CH2-C(=O)-NHCH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-NH-C(=O)-H, -( CH2)2-NH-C(=O)-CH3, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 1,3-thiazol-5-ylmethyl, 2-methyl-1,3-thiazol-5-ylmethyl, pyrazin-2-ylmethyl, 3-methylpyrazin-2-ylmethyl, pyrimidin-4-ylmethyl, 2-hydroxy-1-(pyrazin-2-yl)ethyl; -CH-(pyrazin-2-yl)-C(=O)OCH3; , , ; 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 another specific embodiment PE7 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... A represents , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or , in This indicates that ring A and compound of formula I The connection point of the double-ring system, and L represents the compound of formula I. 1 -B group connection points; 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 another specific embodiment P7a of PE7, the compound of the present invention is a bicyclic compound of formula I, wherein... A represents , , , , , , , , , , , , , ; in This indicates that ring A and compound of formula I The connection point of the double-ring system, and L represents the compound of formula I. 1 -B group connection points; 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 of PE7 or PE7a, PE7aa, the compound of the present invention is a bicyclic compound of formula I, wherein A represents , , , , , , , , , , ; in This indicates that ring A and compound of formula I The connection point of the double-ring system, and L represents the compound of formula I. 1 -B group connection points; 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] In another specific embodiment PE8 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 ; L 1 Represents -O-, -N(R) 4 -, -O-CH2-, -O-SO2-; R 4 Indicates H or 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 is divided by R C6 Single substitution or R C6 and R C7 Bisubstitution; R C1 It can be F, Cl, CH3, CHF2 or CF3; CF3 is optional. R C2 It represents CH3 or C2H5; R C6 Represents F, Cl; CH3, CHF2, CF3, -OCH3, -OCHF2, -OCF3; CF3 is optional; R C7 Indicate 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.

[0036] In yet another specific embodiment PE9 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-; 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 embodiment PE10 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... B indicates , , , , , , , , , , , , , , , , , , , , , , , , , ; , , , , , , , ; , , , , , , , , , , , , , , , or ; 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 another specific implementation of PE10, PE10a, wherein in formula I, B indicates , , , , , , , ; ; , ; , , , , , or ; 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] In another specific embodiment PE11 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... L 1 Indicates -O-; B indicates , , , , , , ; ; ; , , , , , or ; 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 another specific implementation of PE11, PE11a, wherein in formula I, L1 Indicates -O-; B indicates , , ; ; , , , , or ; 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] In another specific embodiment of PE11 or PE11a, PE11aa, wherein in formula I, A represents , , , , ; , , , , ; L 1 Indicates -O-; B indicates , , ; ; , , , , or ; 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] In yet another specific implementation of PE11, PE11a, or PE11aa, PE11aaa, wherein A represents , , , , ; , , ; L 1 Indicates -O-; B indicates , , ; ; , , , , or ; 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 PE12 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... A represents ; L 1 It represents -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.

[0044] In another specific embodiment PE13 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... L 1 It represents -O-CH2-; 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, PE13a, wherein in formula I, A represents , , , ; L 1 It represents -O-CH2-; 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 yet another specific embodiment of PE13 or PE13a, PE13aa, wherein in formula I, A represents , , ; L 1 It represents -O-CH2-; 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.

[0047] In another specific embodiment PE14 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.

[0048] In another specific implementation of PE14, PE14a, wherein in formula I 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.

[0049] In yet another specific implementation of PE14, PE14aa, wherein in formula I, 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.

[0050] In a specific embodiment PE15 of the present invention, the compound of the present invention is a bicyclic compound of formula I, wherein... Ring D together with R 2 express ; X 1 Indicates CH or N; R 1 It represents CH3; R 2 Represents H; -CH3, -CH2-CN, -(CH2)2-CN, -(CH2)2-OH, -(CH2)3-OH, -CH(CH2OH)2, -(CH2)2-S(=O)(=NH)CH3, -CH2-P (=O)(CH3)2, -CH2-C(=O)-NH2, -CH2-C(=O)-NHCH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-NH -C(=O)-H, -(CH2)2-NH-C(=O)-CH3, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 1,3-thiazol-5-ylmethyl, 2-methyl-1,3-thiazol-5-ylmethyl, pyrazin-2-ylmethyl, 2-methylpyrazin-3-ylmethyl, pyrimidin-4-ylmethyl, 2-hydroxy-1-(pyrazin-2-yl)ethyl; -CH-(pyrazin-2-yl)-C(=O)OCH3; , , ; R 3 H represents; 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.

[0051] In another specific implementation of PE15, PE15a, wherein in formula I, Ring D together with R 2 express ; X 1 Indicates CH or N; R 1 It represents CH3; R 2 It represents -(CH2)2-OH, 1H-imidazol-4-ylmethyl, and 1-methyl-1H-pyrazol-4-ylmethyl; R 3 H represents; 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.

[0052] In yet another specific embodiment, PE16, the compounds of the present invention are bicyclic compounds selected from those 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, PE16a, the compounds are selected from Tables 1 and 1a and are Formula I compounds described above and in 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, PE16aa, of PE16 or PE16a, the compounds are selected from Tables 1 and 1a, are Formula I compounds described above and in the claims, and are 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.

[0053] As used herein, the following limitations shall apply with respect to a particular substituent, group, residue, group or portion, unless otherwise specified or specifically defined elsewhere in the specification and / or claims.

[0054] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (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"), and generally (and unless otherwise defined in this specification or the appended claims) has a single connection point to the remainder of the molecule. Unless otherwise specified, an 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 (referred to as "C=C" in Chinese) 1-10 -Aliphatic", C 1-8 -Aliphatic" 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”).

[0055] 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. 5-8 Hydrocarbons (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, and 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, unless defined differently in specific cases, this term covers both unsubstituted and substituted hydrocarbon portions where chemically possible. 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.

[0056] 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, C1-2 -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 (C 2-4 -Alynyl) groups and mixtures thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0057] 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 -The alkyl group is methyl, ethyl, propyl, or isopropyl. The term "C" is used in this context. 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 (other than 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 (unless otherwise specified elsewhere in this specification and / or in the appended claims) be selected from the group consisting of: halogens, particularly F, cyano, hydroxyl, alkoxy, mercapto, thioalkoxy, dialkylphosphoryl, particularly -P(=O)(CH3)2, and unsubstituted, monosubstituted, or disubstituted amino groups. Sulfoxides, sulfones, iminoalkyl sulfones, especially -S(=O)(=NH)CH3, iminodialkyl sulfones, especially -N=S(=O)(CH3)2, carboxylic acids, carboxylic esters, carboxylic amides (primary, secondary, 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.

[0058] In some cases, C 1-3 -alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -alkyl, C 1-10 -alkyl (unbranched and branched) 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. Substitutions for other and / or different -CH- and -CH2- groups may be specified for particular alkyl substituents or groups used elsewhere in the specification and / or in 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 otherwise specified in this specification and / or in 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)3, CH2-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.

[0059] 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 carbon ring may be a monocyclic ring (C 3-15 ) or double ring (C 5-15 ) or three rings (C 8-15 It 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.

[0060] 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 or carbocyclic rings having 3, 4, 5, 6, or 7 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 (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 (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 group, halogen, unsubstituted or mono-substituted or di-substituted 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.

[0061] 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 oxy group" refers to an aliphatic oxy 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 oxy 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 alkyl groups may be straight-chain or (other than -O-C1 alkyl and -O-C2 alkyl) branched, and may be unsubstituted or substituted with one, two, or three substituents that may be the same or different and (unless otherwise specified in this specification) 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.

[0062] The term "alkylene" refers to a divalent aliphatic group, and specifically 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 chains," but also branched-chain alkylene. The term "C..." 1-6 "-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" refers to an alkylene moiety having 2, 3, 4, 5, or 6 carbon atoms. 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 is a group in which one or more methylene hydrogen atoms are replaced (or by) a substituent. Suitable substituents include those described herein 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-.

[0063] 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 substituted aliphatic groups. 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.

[0064] The term "halogen" refers to F, Cl, Br, or I. In particular, "halogen" refers to F.

[0065] 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 a substituted nitrogen of a basic nitrogen or 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).

[0066] 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 (pi) 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 in the aryl system or the entire ring system are 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 in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimide, naphthalimide, 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.

[0067] 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 other ring is a cycloaliphatic ring, aromatic ring, heteroaromatic ring, or heterocyclic (heteroaliphatic) ring; thus forming a ring system with at least two rings, 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; fused to pyridine, a quinoline or isoquinoline is obtained; fused to a cyclopentene ring, an indene ring is obtained.

[0068] 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 π (pi) electrons shared in a cyclic array; and having 1, 2, 3, 4, or 5 heteroatoms other than 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 heteroaromatic ring or ring system) can also be described as an aromatic heterocycle. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazolyl, pyridinyl, pyridinyl, pyrimidinyl, pyrazinyl, indoleyl, purinyl, naphthidyl, pteridinyl, and pyrrolopyridinyl, particularly pyrrolo[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, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazoleyl, dibenzofuranyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. 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 “heteroarylene group,” 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.

[0069] A heteroaryl ring can be attached to its side group at any of its heterocyclic or carbocyclic atoms, and this attachment produces a stable structure or molecule: either of the ring atoms may be unsubstituted or substituted.

[0070] 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.

[0071] 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 oxygen, sulfur, or nitrogen, 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).

[0072] 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 dioxathiohexacyclohexyl. 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 (saturated or unsaturated, but non-aromatic) fused with an aromatic or heteroaromatic ring system, wherein the "partially unsaturated heterocycle" is connected to the remainder of the molecule (its side groups) via a ring atom of the "heterocycle" portion of the system and not via the aromatic or heteroaromatic portion. This first type (i) of "partially unsaturated" heterocycles may also be referred to as "non-aromatic partially unsaturated" heterocycles. 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.

[0073] 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, thiohexyl, dioxathiohexyl, tetrahydrothiopheneyl, pyrroliyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxathiohexyl, dioxathiopentyl, diazaheptanyl, oxazaheptanyl, thiozaheptanyl, morpholinyl, and quininecycloyl. 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, chromanyl, phenanthridineyl, or tetrahydroquinolinyl, 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.

[0074] As used herein, the term "unsaturated" means that a part or group or substituent has one or more unsaturated units.

[0075] 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 or component; and (ii) bicyclic or tricyclic ring systems in which one ring is an aromatic or heteroaromatic ring fused with another ring that is neither an aromatic nor a heteroaromatic ring, 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.

[0076] 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-fused rings or spirocyclic rings. 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 ring. Such heteroatoms may be present at the ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as 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 carbocyclic or heterocyclic system, 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" systems requiring the presence of one or more heteroatoms in one or two rings of the tricyclic ring. Such heteroatoms may be present at ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as 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.

[0077] As described herein, certain compounds of the present invention contain a “substituted” or “optionally substituted” portion. Generally, the term “substituted” refers to the substitution of one or more hydrogens in the portion by a suitable substituent, whether preceded by the term “optionally”. “Substituted” applies to one or more hydrogens that are defined or implied in the structure. 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 substituted by more than one substituent selected from the prescribed group, the substituents at each position are the same or different. If a group, substituent, portion or group is “monosubstituted”, it carries one (1) substituent. If it is “disubstituted”, it carries two (2) identical or different substituents; if it is “trisubstituted”, it carries three (3) substituents, wherein all three are the same or two are the same and the third is different or all three are different from each other. 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 generated, detected, and in some embodiments, recovered, purified, and used for one or more of the purposes disclosed herein.

[0078] Unless otherwise specified elsewhere in this specification or in 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 o ; –(CH2) 0–4 OR o ; –O(CH2) 0-4 R o , –O–(CH2) 0–4 C(O)OR°; –(CH2) 0–4 CH(OR o )2; –(CH2) 0–4 SR o ; –(CH2) 0–4 Ph, which can be substituted 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 o )2; –(CH2) 0–4 N(R o)C(O)R o ; –N(R o )C(S)R o ; –(CH2) 0–4 N(R o )C(O)NR o 2; –N(R o )C(S)NR o 2; –(CH2) 0–4 N(R o )C(O)OR o ; –N(R o )N(R o )C(O)R o ; –N(R o )N(R o )C(O)NR o 2; –N(R o )N(R o )C(O)OR o ; –(CH2) 0–4 C(O)R o ; –C(S)R o ; –(CH2) 0–4 C(O)OR o ; –(CH2) 0–4 C(O)SR o ; –(CH2) 0–4 C(O)OSiR o 3; –(CH2) 0–4 OC(O)R o ; –OC(O)(CH2) 0–4 SR–, SC(S)SR°; –(CH2) 0–4 SC(O)R o ;–(CH2) 0–4 C(O)NR o 2; –C(S)NR o 2; –C(S)SR°; –SC(S)SR°, –(CH2) 0–4 OC(O)NR o 2; –C(O)N(OR o )R o ; –C(O)C(O)R o ; –C(O)CH2C(O)R o ; –C(NOR o )R o ;–(CH2) 0–4 SSR o ;–(CH2) 0–4 S(O)2Ro ; –(CH2) 0–4 S(O)2OR o ; –(CH2) 0–4 OS(O)2R o ; –S(O)2NR o 2;–S(O)(NR°)R°; –S(O)2N=C(NR°2)2; –(CH2) 0–4 S(O)R o ; –N(R o )S(O)2NR o 2; –N(R o )S(O)2R o ; –N(OR o )R o ; –C(NH)NR o 2; –P(O)2R o ; –P(O)R o 2; –OP(O)R o 2; –OP(O)(OR o )2; SiR o 3; –(C 1–4 (linear or branched alkylene) O–N(R o )2; or –(C 1–4 (straight-chain or branched alkylene)C(O)O–N(R) o 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.

[0079] Each R o 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 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, notwithstanding the foregoing, two independently occurring R o Together with the inserted atom, it forms a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted on the saturated carbon atom of R° by divalent substituents selected from =O and =S; or each R° may optionally be substituted by a monovalent substituent independently selected from: halogens, –(CH2). 0–2 ,-(halogen ), –(CH2) 0-2 OH, –(CH2) 0-2 –(CH2) 0-2 CH( )2;O(halogen) –CN, –N3, –(CH2) 0-2 C(O) –(CH2) 0-2 C(O)OH, –(CH2) 0–2 C(O) –(CH2) 0–2 –(CH2) 0-2 SH, –(CH2) 0-2 NH2、–(CH2) 0-2 –(CH2) 0–2 –NO2 – 、– C(O) 、 –(C 1-4 (Straight-chain or branched alkylene)C(O) or- 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.

[0080] each Selected independently from C 1–4 Aliphatic groups, -CH2Ph, -O(CH2) 0–1 Ph or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each It is either unsubstituted or, when preceded by a "halogen", substituted only by one or more halogens; or 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 R appears independently Selected from hydrogen, C 1–6 Aliphatic group or unsubstituted 5-6 member saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0081] When R C 1–6 When the aliphatic group is present, R Optional halogenation, – ,(halogen ), OH, – –O (halogen) ), –CN, –C(O)OH, –C(O) –NH2, – 、– Or –NO2 substitution, in which each Selected independently from C 1–4 Aliphatic groups, -CH2Ph, -O(CH2) 0–1 Ph or has a 5-6 membered saturated, partially unsaturated, or aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each It is not replaced, or when there is a "halogen" preceding it, it is replaced by one or more halogens.

[0082] 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 Aliphatic group, unsubstituted -OPh, or an unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or two independently occurring R groups. † Together with its inserted atoms, it forms an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; wherein when R † C 1–6 When the aliphatic group is present, R † Optional halogenation, – ,-(halogen ), –OH, – –O (halogen) ), –CN, –C(O)OH, –C(O) –NH2, – 、– , or –NO2 substitution, in which each Selected independently from C 1–4 Aliphatic groups, -CH2Ph, -O(CH2) 0–1 Ph or has a 5-6 membered saturated, partially unsaturated, or aryl ring with 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each It is not substituted, or when preceded by "halogen", it is substituted by one or more halogens. It should be understood that "Ph" refers to phenyl; and "halogen" refers to halogen.

[0083] 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.

[0084] 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).

[0085] 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, the present invention also relates to the optically active forms, enantiomers, racemates, diastereomerics, and mixtures thereof in all proportions, collectively referred to for the purposes of the invention as “stereoisomers.” Since the pharmaceutical activities of the racemates or stereoisomers of the compounds of the present 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 the present invention obtained in racemic form, or even their intermediates, 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 enriched or pure form utilizes stereoselective synthetic procedures, such as using starting materials in stereoisomerically enriched or pure form (e.g., using pure or enriched (R)- or (S)-enantiomers of a specific starting material carrying a chiral center) or utilizing chiral reagents or catalysts, particularly 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%.

[0086] 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 into their optically pure or enriched 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 chiral or achiral phases, or by recrystallization with an optionally 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 functional groups.

[0087] 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 mixtures in any ratio. The same applies to cis / trans isomers, E / Z isomers, conformational isomers, etc.

[0088] 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.

[0089] 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. Therefore, compounds of this invention containing acidic groups (such as carboxyl groups) can exist in salt form and can be used according to this invention as, for example, 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, calcium salts, magnesium salts, barium salts, or salts formed from ammonia or organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, 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 this invention containing one or more basic groups (e.g., protonable groups) may exist in salt form and may be used according to the invention as 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, pimelic 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, 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.

[0090] The compounds of the present invention containing basic nitrogen-containing groups can be quaternized using the following reagents: such as (C1-C4)alkyl halides, for example, 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.

[0091] 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.

[0092] Therefore, the following items also conform to this invention: (a) All stereoisomers or tautomers of the compound, including mixtures thereof in all ratios; (b) Compounds and pharmaceutically acceptable salts of the items mentioned in (a); (c) Compounds and pharmaceutically acceptable solvates of the items mentioned in (a) and (b); (d) Compounds and N-oxides of the items mentioned in (a), (b) and (c).

[0093] 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.

[0094] 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, sulfur, fluorine, and chlorine, respectively, for example… 2 H (D), 3 H, 13 C14 C 15 N、 18 O、 17 O、 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F and 36 Cl. Other isotopes of Formula I containing one or more of the isotopes mentioned above and / or 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, such as radioactive isotopes of C, are suitable for pharmaceutical and / or substrate tissue distribution analysis. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 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 a longer in vivo half-life or lower dosage, which in most cases represents a preferred embodiment of the invention. Isotope-labeled Formula I compounds can generally be prepared by replacing non-isotope-labeled reactants with readily available isotope-labeled reactants, following the procedures disclosed in the Examples and Preparation sections of this invention.

[0095] 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 chemical reaction rate caused by isotopic nuclear exchange, which in turn are caused by changes in the ground-state energy required for covalent bond formation after such isotopic exchange. Exchange of heavier isotopes usually leads to a decrease in the ground-state energy of chemical bonds and thus a decrease in the rate-limiting bond breaking rate. 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, then k M / k D A rate difference of 2-7 is typical. If this rate difference is successfully applied to easily oxidized Formula I compounds, the in vivo characteristics of these compounds can be significantly altered, leading to improvements in pharmacokinetic properties.

[0096] 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 characteristics are readily metabolized by oxidation. Currently available in vitro liver microsomal analysis provides valuable information about 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 characteristics 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.

[0097] The following aims to illustrate the above: Compounds of Formula I, possessing multiple potential attack sites for oxidative metabolism, such as benzyl hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared as a series of analogs in which various combinations of hydrogen atoms are substituted with deuterium atoms, such that some, most, or all of these hydrogen atoms are substituted with deuterium atoms. The determination of half-life allows for a favorable and accurate assessment of the degree of improvement in resistance to oxidative metabolism. In this manner, it can be determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

[0098] The deuterium-hydrogen 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 deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1995.

[0099] Furthermore, the present invention relates to pharmaceutical compositions comprising: at least one compound of formula I as an active ingredient, or an N-oxide, solvate, tautomer or stereoisomer thereof, and pharmaceutically acceptable salts thereof, including mixtures thereof in all proportions, and a pharmaceutically acceptable carrier.

[0100] 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 of the said ingredients, or by other types of reactions or interactions of one or more of the said 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.

[0101] 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.

[0102] 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 certain embodiments, 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 a compound 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 overlap times. 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.

[0103] 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 signaling would be beneficial.

[0104] 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 tumors, including solid tumors such as breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colon 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).

[0105] 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.

[0106] 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.

[0107] 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.

[0108] Preferably, the present invention relates to compounds of the present invention suitable for the prevention and / or treatment of diseases; or alternatively, to methods for preventing and / or treating diseases by administering an effective amount of the compounds of the present invention; or in another alternative, to the use of the compounds of the present invention in the preparation of pharmaceutical agents for the prevention and / or treatment of diseases, wherein the disease is cancer, particularly tumors, 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.

[0109] 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 treatment defined above can be administered as a monotherapy or may involve conventional surgical or radiation therapy or medical therapy 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 agents Examples 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 inhibitors Examples 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 antibiotics Examples 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 inhibitors Examples include aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone, and formestane. Small molecule kinase inhibitors Examples 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; photosensitizer Examples 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 conjugates Examples include denileukin diftitox, ibritumomab tiuxetan, iobenguane I 123, prednimustine, trastuzumab bemtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; cintredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomabestafenatox, oportunumab monatox, technetium (99mTc) acipimomab, and vintafolide. PARP inhibitors Such as olaparib, veliparib, niraparib, rucaparib, talazoparib, pamiparib; KRAS inhibitors Such as sotorasib and adagrasib. Other medicines Examples include alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, metirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel, 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.

[0110] 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.

[0111] 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 individually packaged: a) An effective amount of a compound of formula I or any of its N-oxides, solvates, tautomers or stereoisomers, and pharmaceutically acceptable salts of the foregoing, including mixtures thereof in all proportions, and b) An effective amount of another active ingredient, which is not a compound of formula I.

[0112] 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.

[0113] 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.

[0114] 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.

[0115] 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 compounds of the invention into dosage forms suitable for administration to patients requiring such treatment. Typically, the transfer of one or more compounds of the invention into such dosage forms involves the addition of 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, dispersing, homogenizing, casting, and / or pressing the respective active and inactive ingredients. The mechanical tools used to perform 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 besides the compounds of the invention, exhibiting valuable pharmaceutical properties, preferably those pharmaceutically active agents besides the compounds of the invention, which are disclosed herein.

[0116] 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, to prepare injectable formulations. The indicated formulations may be sterilized and / or contain adjuvants such as lubricants, preservatives, stabilizers and / or humectants, emulsifiers, salts for adjusting osmotic pressure, buffering substances, dyes, flavoring agents, and / or several other active ingredients (e.g., one or more vitamins).

[0117] 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.

[0118] 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, if desired, is 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, lacquer solution, 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 a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, and solutions suitable for cellulose formulations, such as cellulose acetyl phthalate, cellulose acetate, or hydroxypropyl methyl phthalate. Dyes or pigments may be added to the coating of tablets or sugar-coated pills, for example, to identify or to characterize the dosage of the active compound.

[0119] 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 esters. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops, or suppositories are used for enteral administration; solutions (preferably oil solutions or aqueous solutions), as well as suspensions, emulsions, or implants are used for parenteral administration; 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 be used, for example, to produce injectable formulations.

[0120] Other orally administered pharmaceutical formulations include incorporation inserts made of gelatin and sealed soft capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Incorporation inserts may contain an active compound in particulate form, which may 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.

[0121] Novel compositions that can be incorporated into the present 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.

[0122] Suitable formulations for parenteral administration include aqueous solutions of the active compound in its water-soluble form (e.g., water-soluble salts) and alkaline solutions. Alternatively, suspensions of the active compound can be administered as suitable oily injectable suspensions. 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).

[0123] 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.

[0124] Possible pharmaceutical formulations that can be administered rectally include, for example, suppositories, which consist of a combination of one or more active compounds and a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons. Alternatively, gelatin-based rectal capsules, which consist of a combination of active compounds and a base, may also be used. Possible base materials include, for example, liquid triglycerides, polyethylene glycol, or paraffin hydrocarbons.

[0125] Pharmaceutical formulations may be used as human and veterinary medicines. As used herein, the term "effective amount" refers to 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, a researcher 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 individual who has not received this amount; it may also refer to prevention or provision of prevention of a disease or disorder in an individual who has or is at risk of developing a disease or disorder disclosed herein. The term also includes, within its scope, an amount that effectively enhances normal physiological function. Such therapeutically effective amount of one or more compounds of the present invention is known to those skilled in the art or can be readily determined by standard methods known in the art.

[0126] As used herein, “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 avoidance of a disease or disorder in an individual at risk of developing such a disorder or disease.

[0127] 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 between 0.005 mg and 500 mg, and particularly between 0.5 mg and 100 mg. The daily dose is preferably between about 0.001 mg / kg and 10 mg / kg body weight.

[0128] Those skilled in the art should readily understand that dosage levels 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 using various methods. A preferred method is to measure the physiological potency of the given compound.

[0129] 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 and dosage form of the drug, combination of drugs, 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.

[0130] The compounds of the present invention can be prepared using suitable materials according to the procedures of the following schemes 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.

[0131] Similarly, starting materials used in the preparation of the compounds of the present invention can be prepared by the methods 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. Starting materials for the claimed and / or employed methods, if desired, can also be formed in situ by immediately converting them further 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.

[0132] 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.

[0133] 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 said solvents or mixtures of said solvents with water.

[0134] The reaction temperature is between approximately -100°C and 300°C, depending on the reaction steps and conditions used.

[0135] Reaction times typically range from less than a minute to several days, depending on the reactivity of the compound and the reaction conditions. A suitable reaction time 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.

[0136] Furthermore, other 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 in this 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 in the following preparation procedures can be used to prepare these compounds.

[0137] This invention also relates to a method for preparing PE1, PE1a, PE1b, PE2, PE3, PE3a, PE3b, PE4, PE5, PE5a, PE5aa, PE5b, PE5ba, PE6, PE6a, PE6aa, PE6aaa, PE6aaaa, PE7, PE7a, PE7aa, PE8, PE9, PE10, PE10a, PE11, PE11a, PE11aa, PE11aaa, PE12, PE13, PE13a, PE13aa, PE14, PE14a, PE14aa, PE15, PE15a, PE16, PE16a. A method for processing compounds of formula I of any of PE16aa or their N-oxides, solvates, tautomers or stereoisomers, and pharmaceutically acceptable salts of the foregoing, characterized in that... (A) In the first reaction step, compound II is made II in R 1 R 3 and X 1 As defined above or as Formula I of any one of claims 1 to 25; Y 1 Indicates H or suitable protecting group PG 1 ; Hal 1 Indicates Cl, Br, or I; Reaction with compound of formula III under suitable C-C coupling reaction conditions Y 2 -AL 1 -B III in A, L 1 And B as defined above or as Formula I of any one of claims 1 to 25; Y 2 Indicates suitable borate ester functional groups; Compound of formula IV was obtained IV or (B) In the first reaction step, compound V is made... V in R1 R 3 and X 1 As defined above or as Formula I of any one of claims 1 to 25; Y 1 Indicates H or suitable protecting group PG 1 ; Y 3 Indicates suitable borate ester functional groups; Reaction with compound of formula VI under suitable CC coupling reaction conditions Hal 2 -AL 1 -B VI in A, L 1 And B as defined above or as Formula I of any one of claims 1 to 25; Hal 2 Indicates Cl, Br, or I; Compound of formula IV was obtained; And optionally, after step (A) or (B) (C) (1) If in equation 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 Compounds of formula I that are H; and / or (C) (2) If in the above equation IV, Y 1 If H represents the compound, then in another reaction step, compound IV reacts with compound VII under suitable reaction conditions. R 2 -LG 1 VII in R 2 As defined above or as claimed in any one of claims 1 to 25, but not H; and LG 1 Indicates a suitable leaving group; To obtain a compound of formula I as defined above or as claimed in any one of claims 1 to 25; or (D) In the first reaction step, compound VIII is made VIII in R 1 and R 3 As defined above or as Formula I of any one of claims 1 to 25; Y 1 Indicates H or suitable protecting group PG 1 ; Hal 1 Indicates Cl, Br, or I; Reaction with compound of formula III under suitable C-C coupling reaction conditions Y 2 -AL 1 -B III in A, L 1 And B as defined above or as Formula I of any one of claims 1 to 25; Y 2 Indicates suitable borate ester functional groups; Compound IX was obtained IX; or (E) In the first reaction step, compound X is made X in R 1 and R 3 As defined above or as Formula I of any one of claims 1 to 25; Y 1 Indicates H or suitable protecting group PG 1 ; Y 3 Indicates suitable borate ester functional groups; Reaction with compound of formula VI under suitable CC coupling reaction conditions Hal 2 -AL 1 -B VI in A, L 1 And B as defined above or as Formula I of any one of claims 1 to 25; Hal 2 Indicates Cl, Br, or I; Compound of formula IX is obtained; And optionally, after step (D) or (E) (F) (1) If in the above equation IX, Y 1 PG1 In the second reaction step, PG is removed under suitable reaction conditions. 1 , to obtain Y 1 Compounds of formula IX with H can also be described as having R. 2 Compounds of formula I that are H; and / or (F) (2) If in the above equation IX, Y 1 If H represents the compound, then in another reaction step, compound IX reacts with compound VII under suitable reaction conditions. R 2 -LG 1 VII in R 2 As defined in any one of claims 1 to 25, but not H; and LG 1 Indicates a suitable leaving group; To obtain a compound of formula I as defined above or as any one of claims 1 to 25.

[0138] As will be understood by those skilled in the art of organic synthesis, 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.

[0139] The general synthetic routes that can be used to prepare the compounds of the present invention are described in more detail in the following schemes A to E (unless otherwise stated, the various groups and substituents shown in the following schemes have the same meaning as in the specification and appended claims): Option A In reaction step a, the 1H-pyrrolo[3,2-b]pyridine derivative of formula A is treated with a suitable iodizing agent under appropriate reaction conditions (e.g., at room temperature with NIS (N-iodosuccinimide) in DMF) to give the corresponding iodine-substituted compound of formula B. In reaction b, the compound of formula B is subsequently reacted with a suitable iodizing agent under appropriate reaction conditions using a Y-containing reagent. 1 Suitable reagents are used to introduce suitable protecting groups Y. 1 This can be converted into a compound of formula C. For example, a compound of formula B can be reacted with p-toluenesulfonyl chloride (TsCl) in the presence of triethylamine and 4-dimethylaminopyridine (DMAP) to give a compound of formula C, wherein Y... 1 The protecting group is p-toluenesulfonyl. Other suitable protecting groups are, for example, tert-butylcarbamate (-C(=O)-O-tert-butyl) or triphenylmethyl (triphenylmethyl). In the next reaction step, step c, the ether moiety at the 2-position of the bicyclic ring is cleaved using a suitable reagent, such as hydrobromic acid in acetic acid, to convert the azaindole derivative of formula C into a lactam derivative of formula D. Next, the lactam nitrogen is deprotonated using a suitable base and alkylated using a suitable alkylating agent (step d) to give the alkylated bicyclic compound of formula E. A typical procedure uses a strong lithium organic base such as LiHMDS (lithium bis(trimethylsilyl)amino) / DMF and an alkyl iodide such as iodomethane or iodoethane. Then, the iodine substituent can be replaced with a suitable borate ester Y. 3 The alkylated lactam derivative of formula E is converted into a functionalized bicyclic compound of formula F (step e). The introduction of this borate ester allows for further conversion via CC or CN coupling reactions. For example, by adding a suitable boric acid reagent such as 4,4,5,5-tetramethyl-1,3,2-dioxaborane and a suitable organopalladium catalyst such as Pd(PPh3)4 to a solution of compound E in dioxane and triethylamine, the dioxaborane pentyl moiety is used as the functional group Y. 3 Introduced in compound F. Both compounds of formula E and formula F can be used as intermediates in the synthesis of compounds of formula I of this invention (see schemes D and E below).

[0140] Option B Compound E (as shown in Scheme A above) can also be synthesized according to the general reaction scheme B above: In the presence of a catalytic amount of DMAP, the 1H-pyrrolo[3,2-b]pyridine derivative of formula A is converted to a toluenesulfonated derivative of formula A-Ts (Ts = p-toluenesulfonyl group) by reaction with p-toluenesulfonyl chloride in triethylamine (reaction step f), and then the ether moiety at the 2-position is cleaved using a suitable reagent (e.g., hydrobromic acid in acetic acid) to convert it into a bicyclic compound of formula H (step g). Subsequently, alkylation is carried out using a suitable base and a suitable alkylating agent (step h) to give the alkylated bicyclic compound of formula J. A typical procedure is to use a strong lithium organic base such as LiHMDS (lithium bis(trimethylsilyl)amino) / DMF and an alkyl iodide such as iodomethane or iodoethane. The p-toluenesulfonyl protecting group can then be removed with a suitable base (step j), for example, by reacting compound J with sodium ethoxide in ethanol, to give a bicyclic compound of formula K. This compound can then be reacted with a suitable iodinating agent under suitable reaction conditions (step k), for example, iodine and potassium hydroxide. Then, under appropriate reaction conditions, compound K can be reacted with a protecting group Y... 1 The reaction proceeds with a suitable reagent to give compound E. For example, a compound of formula K can be reacted with p-toluenesulfonyl chloride (TsCl) in the presence of triethylamine and DMAP to give a compound of formula C, wherein Y... 1 It is p-toluenesulfonyl.

[0141] Option C Compounds of formulas S and T can serve as useful intermediates for the preparation of bicyclic compounds of formula I, wherein X 1 For N, it can be obtained via the synthetic route shown in scheme C above. The chlorinated bicyclic compound of formula M is converted to the toluenesulfonated compound of formula N under similar reaction conditions as described in schemes A and B above (reaction step m). For example, the substitution of the chlorine substituent with a hydroxyl group is achieved by using a suitable organopalladium catalyst, such as Pd₂dba₃. .The compound of formula N is reacted with K3PO4 in the presence of CHCl3 (tris(dibenzylacetone)dipalladium(O)) and tBuBrettPhos (2-di-tert-butylphosphine-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl) (step n) to give compound P. Alkylation with a suitable alkyl halide in the presence of a strong base such as iodomethane and LiHMDS (lithium bis(trimethylsilyl)amino) gives a lactam derivative of formula Q (step p). Removal of the p-toluenesulfonyl protecting group (step q) gives compound R, which is then reacted with an iodinizing agent (such as NIS) (step r) to give a bicyclic compound of formula S. The alkylated lactam derivative of formula S can then be reacted with a suitable protecting group Y under conditions similar to those described in step b of Scheme A. 1 This is converted into a functionalized bicyclic compound of formula T (step s). Compound T can then be converted using a suitable borate ester Y. 3 The iodine substituent is replaced to form a compound of formula U. The introduction of this borate ester allows for further conversion via CC or CN coupling reactions. The reagents and reaction conditions for step t are similar to those for reaction step e in scheme A.

[0142] Option D Scheme D describes a synthetic route for preparing certain compounds of Formula I of the present invention starting from intermediate F (see Scheme A). The compound contains a borate ester functional group Y. 3 Compound F reacts with compound W in reaction step u, wherein A and L 1 The definition of B is the same as that of Equation I, Hal 3 Representing Br or I, the reaction proceeds under typical C-C cross-coupling conditions (such as Suzuki coupling), for example in the presence of sodium carbonate and Pd(dppf)Cl2-CH2Cl2 ([1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride), whereby the compound of formula F reacts with the compound of formula W. The compound of formula W is readily available from commercial sources or through methods well known in the art. Reaction step u yields the compound of formula Z, with protecting group Y. 1 According to Y 1 The specific properties of the compound were determined by standard cleavage methods to yield a bicyclic compound of formula AA. For example, if Y... 1 If it is p-toluenesulfonyl, it can be removed using sodium ethoxide in ethanol. Finally, in reaction step w, compound AA is reacted with compound LG of formula BB. 1 -R 2 The reaction transforms it into compound CC, in which LG 1 It is a suitable leaving group, R 2As defined above for equation I. For example, if LG 1 If the halogen is selected from Cl, Br, or I, then reaction step w can be the reaction of compound AA with LG. 1 -R 2 Nucleophilic substitution reaction. According to LG 1 -R 2 The specific properties of the reaction can be determined by the following steps: deprotonation of the NH group using a suitable base (such as sodium hydride or cesium carbonate), followed by reaction of the intermediate with a suitable compound of formula BB (e.g., an alkyl iodide such as CH3-I, a bromide such as Br-CH2CN, or a chlorinating compound such as chloromethylimidazolium hydrochloride). The substituent R of the compound of formula CC... 2 Further modifications can be made to obtain other CC compounds. It should be noted that compounds of formula AA and formula CC represent certain embodiments of the compounds of formula I of this invention.

[0143] It should also be noted that compound U can be converted into compound I via a reaction route similar to that shown in scheme D, wherein ring D together with R 2 For D-1, X 1 For N, i.e., equation IB( ) compounds.

[0144] Alternatively, compound I can also be obtained by first reacting compound E with Y. 3 -AL 1 -B compound reaction, where A, L 1 The definition of B is the same as that of Equation I, and Y 3 The suitable boronic ester moiety is obtained by reacting under typical CC coupling reaction conditions (as described in step u of Scheme D) to give compound Z, which is then further converted to compound AA or CC, as shown in Scheme D above. Another method is to replace compound E with compound Y under similar reaction conditions using compound L (Scheme B). 3 -AL 1 The reaction of compound B directly yields compound AA. It can be understood that a similar reaction sequence can be applied to compounds of formula S or T (scheme C), ultimately yielding compound IB.

[0145] It should also be noted that in compounds of formula I, ring D is together with R 2 Compound D-2, i.e., of formula IC, can be obtained from compound S in scheme C above by carrying out reaction step s under suitable conditions, such that in addition to obtaining compound T, a corresponding regioisomer of the T-isomer is also obtained. The compound is then separated from its T-isomer by an appropriate method (e.g., column chromatography). The T-isomer can then be further converted to the U-isomer under reaction conditions similar to reaction step t in scheme C described above. The compound is then converted into a compound of formula IC using a reaction route similar to that shown in scheme D.

[0146] Option E Scheme E describes a synthetic procedure for preparing the compounds of the present invention, wherein (in Formula I) R 3 Halogens are compounds of the formula CC, where RC represents a halogen. 2 A suitable protecting group, such as toluenesulfonate, reacts with a suitable halogenating agent in reaction step x under suitable reaction conditions to give the corresponding halogenated compound of formula DD (where Hal is F, Cl, Br, or I). For example, such a suitable halogenating agent can be a fluorinating agent (Hal=F), such as 1-chloromethyl-4-fluoro-1,4-diazamonium bicyclo[2.2.2]octane-bis(tetrafluoroborate) (Selectfluor) in acetonitrile and water; or an iodinating agent (Hal=Br), such as N-iodosuccinimide (NIS), which is in dimethylformamide and in the presence of an organic acid such as trifluoroacetic acid. Compounds of formula CC react with similar chlorinating or brominizing agents (such as NCS or NBS) to give the corresponding compounds of formula DD, where Hal=Cl and Br, respectively. Halogenated compounds of formula I, where ring D is D-1, and X 1 For N (i.e., the compound of formula IB), and R 3 For halogens, it can be obtained in a similar manner from formula EE (where R 2 The preparation begins with a compound having a suitable protecting group (e.g., toluenesulfonate ester): Similarly, from formula FF( Compounds can be prepared using a similar method to those of formula IC, where R 3 It is a halogen.

[0147] It should be noted that, except where the specific statement or context provides a different meaning, terms are generally used in number, i.e., their singular and plural forms, and are read interchangeably. For example, the singular term "compound" may also include or refer to plural compounds, and the plural term "compound" may also include or refer to singular compounds.

[0148] Examples and Experiments The compounds of the present invention can be prepared using suitable materials according to the procedures of the following schemes and embodiments, 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.

[0149] 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 embodiments, variables have the same meaning as described above and in the claims.

[0150] 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 (no further characterization of intermediates was required).

[0151] 1 H 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. 1 1H 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 (doublet), tt (tripletuplet), td (triple-doublet), br (broad peak). Coupling constants (J) are reported in Hz.

[0152] LC-MS: The LC-MS data provided in Tables 1 and 1a are expressed in m / z. The results can be obtained by one of the methods described below.

[0153] synthesis Intermediate 1: 4-Methyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane) Cyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Intermediate 1.1: 3-Iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine A solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (10 g; 64.12 mmol) and NIS (18 g; 76 mmol) in DMF (100 mL) was stirred overnight at room temperature. The mixture was diluted with ethyl acetate (50 mL) and washed with brine. The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a crude product (12 g; 42%) as a yellow liquid, which was used without further purification.

[0154] Intermediate 1.2: 3-Iodo-5-methoxy-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine Et3N (45 mL) and DMAP (1.40 g; 10.89 mmol) were added to a stirred solution of 3-iodo-5-methoxy-1H-pyrrolo[3,2-b]pyridine (30 g; 102 mmol) in DCM (500 mL) at 0 °C. 3-(3-hydroxypropoxy)prop-1-ol (29 g; 205 mmol) was added to the resulting mixture at room temperature overnight. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (51 g; 56%) as a brown solid.

[0155] Intermediate 1.3: 3-Iodo-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one HBr / H₂O (30 mL) was added to a stirred solution of 26 g (58.61 mmol) of 3-iodo-5-methoxy-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine in AcOH (300 mL) at 25 °C. The resulting mixture was stirred at 80 °C for 4 hours. The mixture was neutralized to pH 8 with NaHCO₃ (aq). The precipitated solid was collected by filtration and washed with water. The product (23 g; 87%) was thus given as a yellow solid.

[0156] Intermediate 1.4: 3-Iodo-4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridine- 5-keto To a stirred solution of 12 g (26.67 mmol) of 3-iodo-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one in DMF (100 mL), LiHMDS (29 mL; 29.34 mmol) and CH3I (2.62 mL; 40 mmol) were added at 0 °C. The resulting mixture was stirred at 25 °C for 1 hour under a nitrogen atmosphere. After aqueous post-treatment, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (5.90 g; 43%) as a grayish-white solid.

[0157] Intermediate 1.5: 4-Methyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Pd(PPh3)4 (94.80 mg; 0.08 mmol) was added to a stirred mixture of 3-iodo-4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (400 mg; 0.78 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (210 mg; 1.56 mmol) in dioxane (10 mL) and TEA (3 mL) at 25 °C. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (500 mg; 87%) as a brown oil.

[0158] Intermediate 2: 4-Ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborane) Cyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Intermediate 2.1: 5-methoxy-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine TsCl (1.5 g; 76.94 mmol) and DMAP (2.5 g; 19.23 mmol) were added to a stirred solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (10 g; 64.12 mmol) and TEA (28.14 mL) in DCM (100 mL) at 25 °C and maintained for 5 hours. After concentration, the residue was purified by chromatography to give the product (18 g; 92%) as a brown semi-solid.

[0159] Intermediate 2.2: 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-ol HBr / AcOH (10 mL) was added to a stirred solution of 5-methoxy-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine (18 g; 58.95 mmol) in AcOH (100 mL) at 25 °C. The resulting mixture was stirred at 80 °C for 3 hours and then concentrated under vacuum. The residue was alkalized to pH 7 with NaHCO3(aq), the precipitate was filtered and washed with water to give the product (17 g; 98%) as a brown-orange solid.

[0160] Intermediate 2.3: 4-Ethyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-ol (17 g; 57.59 mmol) in DMF (150 mL) under N2 atmosphere at 0 °C, LiHMDS (53.16 mL; 69.11 mmol) and iodoethane (18.33 g; 115.18 mmol) were added. The resulting mixture was stirred at 25 °C for 2 hours, and after the addition of H2O (100 mL), the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (12.50 g; 68%) as a brown powder.

[0161] Intermediate 2.4: 4-Ethyl-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one EtONa / EtOH (w / w 21%; 25.28 g; 78.01 mmol) was added to a stirred solution of 4-ethyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (12.50 g; 39.01 mmol) in EtOH (150 mL) at 25 °C, and the mixture was maintained for 2 h. After adding water (100 mL), the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (6 g; 89%) as a grayish-white solid.

[0162] Intermediate 2.5: 4-Ethyl-3-iodo-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred mixture of 4-ethyl-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (6 g; 34.59 mmol) in DMF (100 mL), KOH (8.16 g; 138.34 mmol) and I₂ (9.24 g; 34.59 mmol) were added at 25 °C, and the mixture was maintained for 1 hour. H₂O (100 mL) was added, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. This yielded a crude product (6.40 g; 63%) as a yellow solid, which was used in the next step without further purification.

[0163] Intermediate 2.6: 4-Ethyl-3-iodo-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridine- 5-keto TsCl (5.27 g; 26.25 mmol) and DMAP (1.41 g; 10.94 mmol) were added to a stirred mixture of 4-ethyl-3-iodo-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (6.40 g; 21.88 mmol) and TEA (9.60 mL; 65.63 mmol) in DCM (100 mL) at 25 °C and maintained for 2 h. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (10.50 g; 97%) as a yellow solid.

[0164] Intermediate 2.7: 4-Ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred mixture of 4-ethyl-3-iodo-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (5 g; 10.12 mmol) and TEA (10 mL) in dioxane (100 mL), 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (2.64 g; 20.24 mmol) and Pd(PPh3)4 (1.23 g; 1.01 mmol) were added at 25 °C. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (3.80 g; 83%) as a brown oil.

[0165] Intermediate 3: 3-Iodo-2,4-dimethyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyrrole 5-Pyridoxine Intermediate 3.1: 5-methoxy-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine A solution of 5-methoxy-1H-pyrrolo[3,2-b]pyridine (2 g; 12.82 mmol), TsCl (4 g; 19.93 mmol), TEA (2.50 mL; 17.09 mmol), and DMAP (100 mg; 0.78 mmol) in DCM (50 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (800 mg; 20%) as a white solid.

[0166] Intermediate 3.2: 5-Methoxy-2-methyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine A solution of 5-methoxy-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine (150 mg; 0.47 mmol), TMEDA (0.16 mL; 1.05 mmol), and THF (2.50 mL) was added to n-BuLi / hexane (0.27 mL; 0.68 mmol) at -78 °C and maintained for 0.5 h. Then, CH3I (0.10 mL; 1.53 mmol) was added dropwise, and the mixture was heated to room temperature and maintained for 2 h. After quenching with NH4Cl (aq.), the mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (80 mg; 52%) as a white solid.

[0167] Intermediate 3.3: 3-Iodo-5-methoxy-2-methyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine A solution of 5-methoxy-2-methyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine (6.50 g; 19.93 mmol) and NIS (9.30 g; 39.27 mmol) in DMF (10 mL) was stirred overnight at 80 °C. The reaction was quenched at room temperature by the addition of water. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (6.20 g; 65%) as a yellow-brown solid.

[0168] Intermediate 3.4: 3-Iodo-2-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridine- 5-keto A solution of 3-iodo-5-methoxy-2-methyl-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine (2 g; 4.16 mmol) and HBr (1 mL) in AcOH (20 mL) was stirred at 100 °C for 1 hour under a nitrogen atmosphere. The reaction was quenched at room temperature by the addition of water. The resulting mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (440 mg; 24%) as a yellow-brown solid.

[0169] Intermediate 3.5: 3-Iodo-2,4-dimethyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b] Pyridin-5-one CH3I (378 µL) was added to a stirred mixture of 3-iodo-2-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (1.05 g; 2.33 mmol) and LiHMDS (1 M, in toluene, 3 mL) in DMF (5 mL) under N2 atmosphere at 0 °C. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched at 0 °C by the addition of water. The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (340 mg; 29%) as a brown solid.

[0170] Intermediate 4: 4-Methyl-3-(trimethylstanyl)-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4, [3-b]pyridin-5-one Intermediate 4.1: 5-chloro-1-(4-methylbenzenesulfonyl)-1H-pyrazolo[4,3-b]pyridine To a stirred solution of 5-chloro-1H-pyrazolo[4,3-b]pyridine (10 g; 61.86 mmol) in DCM (200 mL) under N2 atmosphere at room temperature, TsCl (14.90 g; 74.23 mmol), TEA (27.15 mL; 185.58 mmol) and DMAP (1.59 g; 12.37 mmol) were added, and the mixture was kept at room temperature for 4 hours. After evaporation, the residue was purified by chromatography to give the product (19.30 g; 97%) as a white solid.

[0171] Intermediate 4.2: 1-(4-methylbenzenesulfonyl)-1H-pyrazolo[4,3-b]pyridine-5-ol To a suspension of 5-chloro-1-(4-methylbenzenesulfonyl)-1H-pyrazolo[4,3-b]pyridine (19 g; 59.21 mmol) and K3PO4 (26 g; 116.37 mmol) in dioxane (400 mL), H2O (40 mL), Pd2dba3.CHCl3 (5.60 g; 5.36 mmol), and t-BuBrettPhos (6 g; 11.76 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was then stirred at 100 °C for 4 hours. After evaporation, the residue was purified by chromatography to give the product (16 g; 90%) as a yellow solid.

[0172] Intermediate 4.3: 4-Methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one CH3I (6.84 mL; 104.41 mmol) and LiHMDS (66 mL; 66 mmol) were added to a stirred solution of 1-(4-methylbenzenesulfonyl)-1H-pyrazolo[4,3-b]pyridine-5-ol (15.90 g; 52.76 mmol) in DMF (350 mL) at room temperature and maintained for 2 hours. After evaporation, the residue was purified by chromatography to give the product (10.80 g; 67%) as a yellow solid.

[0173] Intermediate 4.4: 4-Methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one TBAF / THF (1M, 16 mL; 16 mmol) was added to a stirred solution of 4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (4 g; 13.04 mmol) in THF (100 mL) at room temperature. The mixture was then stirred at 50 °C for 4 hours. The mixture was concentrated under reduced pressure to give a crude product (2.20 g; 97%) as a brown oil.

[0174] Intermediate 4.5: 3-Iodo-4-methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one NIS (3.28 g; 13.85 mmol) was added to a stirred solution of 4-methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (2.20 g; 12.60 mmol) in DMF (50 mL) at room temperature and maintained for 2 hours. After evaporation, the residue was purified by chromatography to give the product (3 g; 74%) as a yellow solid.

[0175] Intermediate 4.6: 3-Iodo-4-methyl-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one To a stirred solution of 3-iodo-4-methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (2 g; 6.18 mmol) in DMF (50 mL), NaH (370 mg; 9.25 mmol) was added at 0 °C. After 30 minutes, (chlorodiphenylmethyl)benzene (2.11 g; 7.42 mmol) was added. The resulting mixture was stirred at room temperature for 2 hours. After evaporation, the residue was purified by chromatography to give the product (2.30 g; 67%) as a yellow solid.

[0176] Intermediate 4.7: 4-Methyl-3-(trimethylstanyl)-1-(triphenylmethyl)-1H,4H,5H-pyrazolo [4,3-b]pyridin-5-one To a stirred solution of 3-iodo-4-methyl-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (2.30 g; 4.14 mmol) in dioxane (40 mL), hexamethyldistannane (2.06 g; 6.22 mmol) and PdCl2(PPh3)2 (320 mg; 0.41 mmol) were added at 100 °C under N2 atmosphere, and the mixture was maintained for 2 hours. After evaporation, the residue was purified by chromatography to give the product (1.10 g; 46%) as a yellow solid.

[0177] Intermediate 5: 4,4,5,5-Tetramethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1,3,2- dioxaborane heterocyclopentane Intermediate 5.1: 1-Bromo-3-methyl-5-[4-(trifluoromethyl)phenoxy]benzene To a stirred mixture of 3-bromo-5-methylphenol (2.40 g; 12.19 mmol) and 1-fluoro-4-(trifluoromethyl)benzene (2.11 g; 12.19 mmol) in DMA (40 mL), K₂CO₃ (5.32 g; 36.57 mmol) was added at 120 °C and allowed to stand overnight. The reaction was quenched at room temperature by the addition of water (120 mL). The resulting mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (1.20 g; 30%) as a colorless liquid.

[0178] Intermediate 5.2: 4,4,5,5-Tetramethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1,3, 2-Dioxaborane AcOK (90 mg; 0.91 mmol) and Pd(dppf)Cl2.CH2Cl2 (26 mg; 0.03 mmol) were added to a solution of 1-bromo-3-methyl-5-[4-(trifluoromethyl)phenoxy]benzene (100 mg; 0.30 mmol) and BPD (161 mg; 0.60 mmol) in dioxane (1 mL). After stirring overnight at 100 °C under nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The residue was purified by chromatography to give the product (30 mg; 26%) as a colorless oil.

[0179] Intermediate 6: 4-Chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine Intermediate 6.1: 4-Chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine To a stirred solution of 4,6-dichloro-2-methylpyrimidine (5 g; 29.75 mmol) and 4-(trifluoromethyl)phenol (4.90 g; 28.72 mmol) in DMSO (150 mL), K₂CO₃ (12.70 g; 87.30 mmol) was added at room temperature. The resulting mixture was then stirred at 50 °C for 2 hours under a nitrogen atmosphere. The reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to give a crude product (8.30 g; 79%) as a yellow oil, which was used without further purification.

[0180] Intermediate 7: 4,4,5,5-Tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-di Oxyborane Intermediate 7.1: 4,4,5,5-Tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2- dioxaborane heterocyclopentane A mixture of 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenol (2.20 g; 10 mmol) and 1-(chloromethyl)-4-(trifluoromethyl)benzene (2.93 g; 15.06 mmol) in DMF (50 mL) was added to K₂CO₃ (4.18 g; 30.24 mmol) at 80 °C under N₂ atmosphere and maintained for 16 h. The reaction mixture was washed with H₂O (100 mL) and extracted with ethyl acetate. The organic layer was dried over Na₂SO₄ and concentrated to give a crude product (3 g; 66%) as a yellow solid.

[0181] Intermediate 8: 2-Methyl-4-[4-(trifluoromethyl)phenoxy]-6-(trimethylsilyl)pyrimidine Intermediate 8.1: 2-Methyl-4-[4-(trifluoromethyl)phenoxy]-6-(trimethylmethylenetinyl)pyrimidine To a stirred solution of 4-chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (intermediate 6) (300 mg; 0.94 mmol) and Pd(PPh3)4 (99 mg; 0.08 mmol) in dioxane (6 mL), hexamethyldistinane (0.32 mL; 1.51 mmol) was added at 100 °C under N2 atmosphere and maintained for 1 hour. The resulting mixture was filtered, and the filter cake was washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the product (380 mg; 78%) as a brownish-black oil, which was used without further purification.

[0182] Intermediate 9: 4-Iodo-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine Intermediate 9.1: 4-Iodo-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine To a stirred solution of 4-chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (intermediate 6) (4 g; 11.38 mmol) in HI (57%, in H2O, 40 mL), NaI (400 mg; 2.54 mmol) was added and the mixture was kept in this state for 2 hours. The mixture was filtered, the filter cake was washed with DCM, and the filtrate was concentrated under reduced pressure. The crude product (3.50 g; 66%, brown oil) was used directly without further purification.

[0183] Intermediate 10: 5-Fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine Intermediate 10.1: 4-Chloro-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine KHMDS (6.20 mL; 6.20 mmol) 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 (0.90 g; 5.25 mmol) in THF (40 mL) under N2 atmosphere at 0 °C. The mixture was stirred at room temperature for 1 hour and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (750 mg; 34%) as a colorless oil.

[0184] Intermediate 10.2: 5-Fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine To a stirred solution of 4-chloro-5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (1.8 g; 5.16 mmol) in HI (57%, in H₂O, 20 mL), NaI (1 g; 6.34 mmol) was added at room temperature and allowed to stand overnight. The reaction mixture was extracted with ethyl acetate, 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 (1 g; 48%) as a brown oil.

[0185] Intermediate 11: 1-Bromo-3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}benzene Intermediate 11.1: 1-Bromo-3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}benzene To a stirred solution of (1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (1.61 g; 9.07 mmol) in DMA (40 mL), NaH (0.40 g; 9.98 mmol) was added at 0 °C under N2 atmosphere, and the mixture was maintained for 20 min. Then, 1-bromo-3-chloro-5-fluorobenzene (2 g; 9.07 mmol) was added, and the reaction mixture was stirred at 60 °C for another 3 h. For post-treatment, the resulting mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (2.60 g; 76%) as a clear, colorless oil.

[0186] Intermediate 12: 5-[(2-bromo-6-methylpyridin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine Intermediate 12.1: 5-[(2,6-dibromopyridin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine 2-(trifluoromethyl)pyrimidin-5-ol (1 g; 6.09 mmol) was added to DMF (30 mL) at 0 °C with NaH (0.49 g; 12.19 mmol) for 30 min. Then, 2,6-dibromo-4-nitropyridine (3.51 g; 12.19 mmol) was added dropwise to the DMF. The mixture was stirred at room temperature for another 5 h. The reaction was quenched at 0 °C by the addition of NH4Cl (aq.), and the mixture was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (0.99 g; 41%) as a white solid.

[0187] Intermediate 12.2: 5-[(2-bromo-6-methylpyridin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine To a solution of 5-[(2,6-dibromopyridin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine (intermediate 12.1) (2.99 mg; 7.46 mmol) and trimethyl-1,3,5,2,4,6-trioxaborane (1.98 g; 14.99 mmol) in dioxane (45 mL) and H₂O (9 mL), K₂CO₃ (2.72 g; 18.74 mmol) and Pd(PPh₃)₄ (912 mg; 0.75 mmol) were added at 100 °C under a nitrogen atmosphere and maintained for 16 hours. The mixture was then extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (800 mg; 32%) as a pale yellow solid.

[0188] Intermediate 13: 3-Iodo-4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyridine 5-keto Intermediate 13.1: 3-Iodo-4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyrazolium 5-Pyridoxine TsCl (744 mg; 3.71 mmol) and DMAP (44 mg; 0.34 mmol) were added to a stirred solution of 3-iodo-4-methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (intermediate 4.6) (1 g; 3.37 mmol) and TEA (1.48 mL; 10.12 mmol) in DCM (20 mL) under nitrogen atmosphere at 25 °C, and the mixture was maintained for 1 hour. The resulting mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (1.20 g; 68%) as a yellow solid.

[0189] Example 1: 4-Methyl-3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H,4H,5H-pyrrolo [3,2-b]pyridin-5-one (compound 2) Example 1.1: 4-Methyl-3-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1H,4H,5H-pyrrole [3,2-b]pyridin-5-one Pd(Amphos)Cl2 (41 mg; 0.06 mmol) was added to a mixture of 4,4,5,5-tetramethyl-2-(3-{[4-(trifluoromethyl)phenyl]methoxy}phenyl)-1,3,2-dioxaborhecyclopentane (intermediate 7) (400 mg; 0.88 mmol), 3-iodo-4-methyl-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtained via a procedure similar to that used for intermediates 2 and 2.5) (200 mg; 0.58 mmol), and K2CO3 (242 mg; 1.75 mmol) in dioxane (16 mL) and H2O (4 mL) under a nitrogen atmosphere at 50 °C, and maintained for 4 hours. The H2O was separated, evaporated, and the residue was purified by chromatography to give the product (127 mg; 54%) as a colorless solid.

[0190] Example 2: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo [3,2-b]pyridin-5-one (compound 1) Example 2.1: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrole [3,2-b]pyridin-5-one Pd(Amphos)2Cl2 (41.3 mg; 0.06 mmol) was added to a mixture of 3-iodo-4-methyl-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable via a procedure similar to that of intermediates 2 and 2.5) (200 mg; 0.58 mmol), 4,4,5,5-tetramethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1,3,2-dioxaborhecyclopentane (obtainable via a procedure similar to that of intermediate 7) (400 mg; 0.85 mmol), and K2CO3 (242 mg; 1.75 mmol) in dioxane (16 mL) and H2O (4 mL). The mixture was stirred at 50 °C for 4 hours under nitrogen. H2O was separated, evaporated, and the residue was purified by chromatography to obtain the desired product (145 mg; 61%), which was a white solid.

[0191] Example 3: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H- Pyrrolo[3,2-b]pyridin-5-one (compound 26) Example 3.1: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(4-methyl) (Benylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 36) Pd(PPh3)4 (33 mg; 0.03 mmol) and Na2CO3 (91 mg; 0.82 mmol) were added to a stirred solution of 4-chloro-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (intermediate 6) (96 mg; 0.27 mmol) and 4-methyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 1) (200 mg; 0.27 mmol) in dioxane (8 mL) and H2O (1 mL) at room temperature. The resulting mixture was then stirred at 60 °C for 3 hours under a nitrogen atmosphere. The crude product was purified by chromatography to give the product (38.30 mg; 25%) as a grayish-white solid.

[0192] Example 3.2: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H, 5H-pyrrolo[3,2-b]pyridin-5-one (Compound 26) Add EtONa / EtOH (w / w 21%) (114 mg; 0.35 mmol; 2.01 eq.) to EtOH (4 mL) containing 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3.1) (100 mg; 0.17 mmol) at room temperature for 30 minutes. Then, extract the reaction mixture with DCM, wash the combined organic layers with brine, and dry with sodium sulfate. After filtration, concentrate the filtrate under reduced pressure. The crude product was purified by chromatography to give the product (21.8 mg, 31%) as a white solid.

[0193] Example 4: 4-Methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridin-2-yl}-1H,4H,5H- Pyrrolo[3,2-b]pyridin-5-one (compound 28) Example 4.1: 4-Methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridin-2-yl}-1H,4H, 5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridin-2-yl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable by a procedure similar to that in Example 3) (220 mg; 0.33 mmol), EtONa / EtOH (w / w 21%) (0.14 mL; 0.65 mmol) was added dropwise at room temperature to the mixture in EtOH (4 mL) at room temperature for 1 hour. The resulting mixture was diluted with water (40 mL). The mixture was extracted with ethyl acetate, and the combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (46.50 mg; 36%) as a white solid.

[0194] Example 5: 4-Methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}pyridin-2-yl)- 1-(4-Methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 41) Example 5.1: 4-Methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}pyridin-2-yl)-1-(4-methyl) (benzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a solution of 4-methyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborphanecyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3) (170 mg; 0.36 mmol) and 5-[(2-bromo-6-methylpyridin-4-yl)oxy]-2-(trifluoromethyl)pyrimidine (intermediate 12.2) (183 mg; 0.55 mmol) in DME (3 mL) and H2O (0.60 mL), Na2CO3 (121.48 mg; 1.09 mmol) and Pd(PPh3)4 (44.15 mg; 0.04 mmol) were added. After stirring at 90 °C for 16 hours under N2 atmosphere, the resulting mixture was concentrated under reduced pressure.

[0195] The residue was absorbed into water and ethyl acetate, and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (35.50 mg; 18%) as a grayish-white solid.

[0196] Example 6: 4-Methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}pyridin-2-yl)- 1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 42) Example 5.1: 4-Methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}pyridine-2- )-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}pyridin-2-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 5, Example 5.1) (136 mg; 0.16 mmol) in EtOH (2 mL) at room temperature, EtONa / EtOH (w / w 21%) (0.07 mL; 0.33 mmol) was added dropwise. The resulting mixture was stirred for 1 hour and then diluted with water (40 mL). After extraction with ethyl acetate, the combined organic layers were dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (33.70 mg; 51%) as a white solid.

[0197] Example 7: 4-Methyl-3-(3-methyl-5-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)-1H,4H, 5H-pyrrolo[3,2-b]pyridin-5-one (compound 5) Example 7.1: 4-Methyl-3-(3-methyl-5-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)-1H, 4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-(3-methyl-5-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable by a procedure similar to that in Examples 3 and 3.1)) (55 mg; 0.10 mmol), EtONa / EtOH (w / w 21%) (0.04 mL; 0.20 mmol) was added to EtOH (6 mL) at room temperature and maintained for 1 hour. After removing all volatiles under vacuum, the residue was purified by chromatography to give the product (16.80 mg; 43%) as a grayish-white solid.

[0198] Example 8: 4-Methyl-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H,4H, 5H-pyrrolo[3,2-b]pyridin-5-one (compound 8) Example 8.1: 4-Methyl-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1H, 4H,5H-pyrrolo[3,2-b]pyridin-5-one EtONa (43 mg; 0.61 mmol) was added to a stirred solution of 4-methyl-3-(3-methyl-5-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}phenyl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable by a procedure similar to that in Examples 3 and 3.1) (100 mg; 0.16 mmol) in EtOH (10 mL) at room temperature and maintained for 1.5 h. After removing all volatiles under vacuum, the residue was purified by chromatography to give the product (13.10 mg; 21%) as a white solid.

[0199] Example 9: 4-Methyl-3-(3-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)-1H,4H, 5H-pyrrolo[3,2-b]pyridin-5-one (compound 9) Example 9.1: 4-Methyl-3-(3-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)-1H,4H,5H-pyrrolo [3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-(3-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable by a procedure similar to that in Synthetic Examples 3 and 3.1) (55 mg; 0.10 mmol), EtONa / EtOH (w / w 21%) (0.04 mL; 0.20 mmol) was added to EtOH (6 mL) at room temperature and maintained for 1 hour. After removing all volatile substances under vacuum, the residue was purified by chromatography to give the product (23.40 mg; 60%) as a light gray solid.

[0200] Example 10: 4-Methyl-3-(6-methyl-4-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}pyridin-2-yl)- 1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 31) Example 10.1: 4-Methyl-3-(6-methyl-4-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}pyridine-2- )-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-(6-methyl-4-{[5-(trifluoromethyl)pyrazin-2-yl]oxy}pyridin-2-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable by a procedure similar to that in Examples 3 and 3.1) (170 mg; 0.22 mmol), Cs₂CO₃ (75 mg; 0.22 mmol) was added at 25 °C under a nitrogen atmosphere in THF (5 mL) and EtOH (2.50 mL), and the mixture was maintained for 2 hours. After removing all volatile substances, the residue was purified by chromatography to give the product (6.50 mg; 7%) as a grayish-white solid.

[0201] Example 11: N-methyl-3-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine-4- 5-O-1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionamide (compound 53) Example 11.1: N-Methyl-3-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine-4- }-5-oxo-1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionamide N-methylprop-2-enamide (280 mg; 3.224 mmol) and KOH (80 mg; 1.28 mmol) were added to a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (80 mg; 0.19 mmol) in dioxane (5 mL) under N2 atmosphere at room temperature. The resulting mixture was stirred for 2 hours and then extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by chromatography to give the product (21.1 mg; 23%) as a white solid.

[0202] Example 12: 1-[2-(3-hydroxypyrrolidone-1-yl)ethyl]-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl) [Phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 55) Example 12.1: 1-(2-bromoethyl)-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine- 4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one K₂CO₃ (143 mg; 0.98 mmol) was added to a stirred mixture of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (200 mg; 0.49 mmol) and 1,2-dibromoethane (194 mg; 0.98 mmol) in DMF (8 mL) at 25 °C. The resulting mixture was stirred at 70 °C for 2 hours and then concentrated under vacuum. The residue was purified by chromatography to give the product (120 mg; 43%) as a pale yellow solid.

[0203] Example 12.2: 1-[2-(3-hydroxypyrrolidone-1-yl)ethyl]-4-methyl-3-{2-methyl-6-[4-(trifluoro [Methyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred mixture of 1-(2-bromoethyl)-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (100 mg; 0.17 mmol) and pyrrolidine-3-ol (24 mg; 0.26 mmol) in ACN (0.01 mL), K₂CO₃ (51 mg; 0.35 mmol) and NaI (14 mg; 0.09 mmol) were added at 25 °C. The resulting mixture was stirred at 70 °C for 2 hours. After removing all volatile substances, the crude product was purified by chromatography to give the product (15.5 mg; 17%) as a white solid.

[0204] Example 13: 1-{2-[imino(methyl)oxo-λ] 6 [-thio]ethyl}-4-methyl-3-{2-methyl-6-[4-] [(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 51) Example 13.1: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-[2- [(methylthio)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2 (150 mg; 0.32 mmol)) in DMF (5 mL), under N2 atmosphere, NaH (33 mg; 0.83 mmol) was added at 0 °C and maintained for 30 min. Then NaI (24 mg; 0.15 mmol) and 1-chloro-2-(methylthio)ethane (260 mg; 2.23 mmol) were added. Stirring was continued for 2 h at room temperature. After aqueous post-treatment, the mixture was extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (110 mg; 70%) as a purple solid.

[0205] Example 13.2: 1-{2-[imino(methyl)oxo-λ] 6 [-thio]ethyl}-4-methyl-3-{2-methyl-6- [4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-[2-(methylthio)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (90 mg; 0.18 mmol) in MeOH (5 mL), diacetic acid iodobenzene (169 mg; 0.50 mmol) and NH4OAc (25 mg; 0.31 mmol) were added at room temperature under a nitrogen atmosphere. The mixture was kept in this state for 1 hour. After removing all volatile substances, the crude product was purified by chromatography to give the product (48 mg; 49%) as a grayish-white solid.

[0206] Example 14: 1-(3-hydroxypropyl)-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine- 4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 50) Example 14.1: 1-(3-hydroxypropyl)-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine pyrrolo[3,2-b]pyridin-5-one A mixture of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (100 mg; 0.24 mmol) and K₂CO₃ (110 mg; 0.76 mmol) in DMF (10 mL) was stirred at 100 °C for 2 hours. The mixture was then extracted with ethyl acetate, the combined organic layers were washed with brine, dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (31.70 mg; 29%) as a white solid.

[0207] Example 15: 1-(2-hydroxyethyl)-4-methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidin-5-yl] ⇌ (oxy)pyridin-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 49) Example 15.1: 1-(2-hydroxyethyl)-4-methyl-3-(6-methyl-4-{[2-(trifluoromethyl)pyrimidine-5- [[3,2-b]pyridine-2-yl]-1H,4H,5H-pyrrolo[3,2-b]pyridine-5-one] To a stirred solution of 4-methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridin-2-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 6) (90 mg; 0.22 mmol) and DBU (106 mg; 0.66 mmol) in DMF (2 mL), 1,3-dioxane-2-one (59 mg; 0.66 mmol) was added at 70 °C and maintained for 12 hours. After removing all volatile substances, the crude product was purified by chromatography to give the product (34.20 mg; 34%) as a white solid.

[0208] Example 16: 6-Iodo-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methyl) (benzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 35) Example 16.1: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 3-iodo-4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 1.4) (4.5 g; 10.30 mmol) in dioxane (32 mL) and H₂O (8 mL) at room temperature, 4,4,5,5-tetramethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1,3,2-dioxaborhecyclopentane (intermediate 5.2) (7 g; 16.66 mmol), PdAMPHOS (0.5 g; 0.67 mmol), and K₂CO₃ (4.5 g; 31 mmol) were added under a nitrogen atmosphere. The mixture was irradiated with microwave at 110 °C for 1 hour. The resulting mixture was extracted with ethyl acetate, 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 obtain the product (1.3 g; 23%), which was a pink solid.

[0209] Example 16.2: 6-Iodo-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methyl) (pyrrolo[3,2-b]pyridin-5-one)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 16.1) (100 mg; 0.172 mmol) in DMF (5 mL), NIS (80 mg; 0.338 mmol) and TFA (30 mg; 0.250 mmol) were added at room temperature under a nitrogen atmosphere. The mixture was maintained for 2 hours. After post-treatment with sodium bicarbonate solution, the resulting mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over sodium sulfate. After evaporation, the residue was purified by chromatography to give the product (16 mg; 13%) as a pink solid.

[0210] Example 17: 6-Iodo-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H- Pyrrolo[3,2-b]pyridin-5-one (compound 48) Example 17.1: 6-Iodo-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H, 5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 6-iodo-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 16) (100 mg; 0.146 mmol) in EtOH (10 mL), EtONa / EtOH (w / w 21%) (0.067 mL; 0.309 mmol) was added at room temperature under a nitrogen atmosphere and maintained for 2 hours. After aqueous post-treatment, the resulting mixture was extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by chromatography to give the product (29.6 mg; 39%) as a white solid.

[0211] Example 18: 3-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionitrile (compound 46) Example 18.1: 3-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionitrile To a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (80 mg; 0.19 mmol) in dioxane (8 mL), propion-2-acrylonitrile (0.124 mL; 1.866 mmol) and KOH (30 mg; 0.481 mmol) were added at 0 °C under N2 atmosphere. The resulting mixture was stirred at 50 °C for 2 hours. After aqueous post-treatment, the mixture was extracted with ethyl acetate, the combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by chromatography to give the product (26.4 mg; 31%) as a white solid.

[0212] Example 19: 2-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetonitrile (compound 45) Example 19.1: 2-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetonitrile Cs₂CO₃ (238 mg; 0.72 mmol) was added to a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (100 mg; 0.24 mmol) and 2-bromoacetonitrile (152 mg; 1.20 mmol) in DMF (10 mL) at 100 °C and maintained for 4 hours. The reaction mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (43.40 mg; 40%) as a white solid.

[0213] Example 20: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-[2-(morpholine) [Lin-4-yl)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 44) Example 20.1: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-[2- [(morpholino-4-yl)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred mixture of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (100 mg; 0.24 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (71 mg; 0.36 mmol) in ACN (10 mL), K₂CO₃ (70 mg; 0.48 mmol) was added at 25 °C, and the reaction was stirred at 85 °C for 2 hours. After removing all volatile substances, the residue was purified by chromatography to give the product (53.50 mg; 43%) as a white solid.

[0214] Example 21: 3-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo (Compound 43) -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acrylamide Example 21.1: 3-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acrylamide To a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (80 mg; 0.17 mmol) in dioxane (8 mL), propenamide (200 mg; 2.76 mmol) and KOH (30 mg; 0.48 mmol) were added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at 50 °C for 2 hours. After aqueous posttreatment, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (26 mg; 32%) as a white solid.

[0215] Example 22: N-methyl-2-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine-4- β-5-oxo-1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide (compound 40) Example 22.1: N-methyl-2-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine-4- }-5-oxo-1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide A mixture of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (80 mg; 0.19 mmol) and K₂CO₃ (88 mg; 0.60 mmol) in DMF (5 mL) was stirred at 100 °C for 2 h. After aqueous posttreatment, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (54.10 mg; 60%) as a white solid.

[0216] Example 23: 2-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide (compound 39) Example 23.1: 2-(4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide To a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2.) (80 mg; 0.19 mmol) in DMF (8 mL), Cs₂CO₃ (160 mg; 0.47 mmol), NaI (32 mg; 0.20 mmol), and 2-chloroacetamide (90 mg; 0.91 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 2 hours. After aqueous post-treatment, the resulting mixture was concentrated under reduced pressure. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (20.9 mg; 25%) as a white solid.

[0217] Example 24: 1-(2-hydroxyethyl)-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine- 4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 37) Example 24.1: 1-(2-hydroxyethyl)-4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine pyrrolo[3,2-b]pyridin-5-one DBU (118 mg; 0.74 mmol) was added to a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (100 mg; 0.25 mmol) and 1,3-dioxane-2-one (110 mg; 1.24 mmol) in DMF (10 mL) at room temperature, and the resulting mixture was stirred at 90 °C for 4 hours. The mixture was concentrated under vacuum. The residue was purified by chromatography to give the product (20.80 mg; 19%) as a white solid.

[0218] Example 25: 1-[2-(3-hydroxypyrrolidone-1-yl)ethyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl) [3,2-b]pyridine-5-one (compound 33) Example 25.1: 1-[2-(3-hydroxypyrrolidone-1-yl)ethyl]-4-methyl-3-{3-methyl-5-[4-(trifluoro [Methyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 1-(2-bromoethyl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (which may be obtained similarly to Examples 12, 12.1, starting from Examples 2, 2.1 and 1,2-dibromoethane) (130 mg; 0.15 mmol) and pyrrolidine-3-ol (1.60 mg; 0.02 mmol) in ACN (5 mL), K₂CO₃ (64 mg; 0.44 mmol) and NaI (5 mg; 0.03 mmol) were added at room temperature. The resulting mixture was then stirred at 80 °C for 2 hours. After evaporation, the residue was purified by chromatography to give the product (21.20 mg; 28%) as a white solid.

[0219] Example 26: 1-(2-hydroxyethyl)-4-methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridine- 2-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 29) Example 26.1: 1-(2-hydroxyethyl)-4-methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridine }-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{6-methyl-4-[4-(trifluoromethyl)phenoxy]pyridin-2-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 4, Example 4.1) (90 mg; 0.22 mmol) and DBU (106 mg; 0.66 mmol) in DMF (2 mL), 1,3-dioxane-2-one (59 mg; 0.66 mmol) was added at 90 °C and maintained for 5 hours. After evaporation, the crude product was purified by chromatography to give the product (59.60 mg; 61%) as a white solid.

[0220] Example 27: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(3-methyl) Pyrazin-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 27) Example 27.1: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(3-methyl) pyrazin-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 3, Example 3.2) (100 mg; 0.25 mmol) and 2-bromo-3-methylpyrazine (43 mg; 0.24 mmol) in dioxane (10 mL), (1R,2R)-cyclohexane-1,2-diamine (6 mg; 0.05 mmol), K3PO4 (158 mg; 0.71 mmol), and CuI (10 mg; 0.05 mmol) were added at room temperature and maintained at 100°C for 2 hours under a nitrogen atmosphere. After evaporation, the residue was purified by chromatography to give the product (27.50 mg; 22%) as a white solid.

[0221] Example 28: 4-Methyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-3-{3-methyl-5-[4-(trifluoromethyl) [3,2-b]pyridine-5-one (compound 24) Example 28.1: 4-Methyl-1-[(1-methyl-1H-pyrazol-4-yl)methyl]-3-{3-methyl-5-[4-(trifluoro [Methyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (60 mg; 0.15 mmol), 4-(bromomethyl)-1-methyl-1H-pyrazole hydrobromide (76.32 mg; 0.30 mmol), and Cs₂CO₃ (256 mg; 0.75 mmol) in DMF (5 mL), under N₂ atmosphere at 100 °C, NaI (23.53 mg; 0.15 mmol) was added and maintained for 16 hours. The resulting mixture was diluted with water (20 mL) and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by chromatography to obtain the product (23.20 mg; 30%), which was a brown solid.

[0222] Example 29: N-methyl-3-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acrylamide (compound 23) Example 29.1: N-Methyl-3-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5- Oxo-1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionamide To 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1)KOH (24 mg; 0.39 mmol) and N-methylprop-2-enamide (120 mg; 1.38 mmol) were added to a stirred solution in dioxane (8 mL) at room temperature under a nitrogen atmosphere (N2). The resulting mixture was stirred at 50 °C for 2 hours and then concentrated under reduced pressure. The residue was absorbed into water and ethyl acetate and then extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (21.6 mg; 26%) as a pink solid.

[0223] Example 30: 1-[2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo- 1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)ethyl]pyrrolidine-2-one (compound 21) Example 30.1: 1-[2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo] -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)ethyl]pyrrolidin-2-one A mixture of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.24 mmol), 1-(2-bromoethyl)pyrrolidine-2-one (50 mg; 0.25 mmol), and NaH (20 mg; 0.50 mmol) in DMF (2 mL) was stirred at 80 °C for 4 hours. After aqueous posttreatment, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (14.50 mg; 11%) as a white semi-solid.

[0224] Example 31: 1-{2-[imino(methyl)oxo-λ] 6 [-thio]ethyl}-4-methyl-3-{3-methyl-5-[4-] (trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 20) Example 31.1: 1-{2-[imino(methyl)oxo-λ] 6 [-thio]ethyl}-4-methyl-3-{3-methyl-5- [4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-[2-(methylthio)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (which may be obtained similarly to Example 13, Example 13.1, starting from Example 2, Example 2.1 and 1-chloro-2-(methylthio)ethane) (200 mg; 0.41 mmol) in MeOH (5 mL), under a nitrogen atmosphere at room temperature, diacetic acid iodobenzene (340 mg; 1 mmol) and NH4OAc (49 mg; 0.60 mmol) were added, and the mixture was kept at room temperature for 2 hours. After evaporation, the crude product was purified by chromatography to give the product (69.40 mg; 34%) as a grayish-white solid.

[0225] Example 32: 1-[(3R,4S)-4-hydroxyoxacyclopentan-3-yl]-4-methyl-3-{3-methyl-5-[4-(tri- [Fluoromethyl]phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 19) and 1-[(3S,4R)-4-hydroxyoxacyclopentan-3-yl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)benzene} [Oxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 22) Example 32.1: A racemic mixture of the trans isomers of 1-(4-hydroxyoxacyclopentan-3-yl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred mixture of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (150 mg; 0.37 mmol) and K2CO3 (110 mg; 0.76 mmol) in DMF (10 mL), 3,6-dioxabicyclo[3.1.0]hexane (170 mg; 1.88 mmol) was added at 25 °C. The resulting mixture was stirred at 120 °C for 6 hours and then concentrated under vacuum. The residue was purified by chromatography to give the product (80 mg; 44%) as a white solid.

[0226] Example 32.2: 1-[(3R,4S)-4-hydroxyoxacyclopentan-3-yl]-4-methyl-3-{3-methyl-5-[4- [(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one and 1-[(3S,4R)-4-hydroxyoxacyclopentan-3-yl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)benzene} [Oxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A racemic mixture of the trans isomers of 1-(4-hydroxyoxacyclopentan-3-yl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 32.1) (80 mg; 0.16 mmol) was purified by chromatography: CHIRALPAK IG-3, 4.6 50 mm, 3 μm; Mobile phase A: Hex (0.1% DEA): EtOH = 75: 25; Flow rate: 1 mL / min; Gradient: 0% B to 0% B; Injection volume: 5 µL, yielding 1-[(3R,4S)-4-hydroxyoxacyclopentan-3-yl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (27.70 mg; 35 μm); %), as a white solid, and 1-[(3S,4R)-4-hydroxyoxacyclopentan-3-yl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (31.50 mg; 40%), as a white solid. Absolute configuration is assigned arbitrarily to fractions.

[0227] Example 33: 2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo-1H, 4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetonitrile (compound 18) Example 33.1: 2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo- 1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetonitrile To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (120 mg; 0.26 mmol) in DMF (10 mL), NaH (40 mg; 1 mmol) was added at 0 °C under N2 atmosphere. After 15 minutes, 2-chloroacetonitrile (120 mg; 1.6 mmol) was added, and the mixture was stirred at 100 °C for 3 hours. After aqueous post-treatment, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (68.4 mg; 61%) as a grayish-white color.

[0228] Example 34: 1-[(1H-imidazol-4-yl)methyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy] [3,2-b]pyridine-5-one (compound 17) Example 34.1: 1-[(1H-imidazol-4-yl)methyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)benzene} [Oxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.25 mmol) in DMF (3 mL), NaH (30 mg; 0.75 mmol) was added. The resulting mixture was stirred at 0°C for 10 minutes under N2 atmosphere, followed by the addition of 4-(chloromethyl)-1H-imidazolium hydrochloride (58 mg; 0.36 mmol) and TBAI (9 mg; 0.02 mmol) in portions. The resulting mixture was stirred overnight at 120°C, diluted with water, and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by chromatography to give the product (13.80 mg; 12%) as a white solid.

[0229] Example 35: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-[2-(morpholine-4- [[3,2-b]pyridin-5-one (compound 16)]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 35.1: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-[2-(morpholine- [4-yl)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A mixture of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (80 mg; 0.19 mmol), NaI (12 mg; 0.08 mmol), 4-(2-chloroethyl)morpholine (40 mg; 0.25 mmol), and K₂CO₃ (84 mg; 0.58 mmol) in DMF (1 mL) was stirred overnight at 100 °C. After aqueous posttreatment, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (18.30 mg; 19%) as a purple semi-solid.

[0230] Example 36: 1-(2-hydroxyethyl)-4-methyl-3-(3-methyl-5-{[2-(trifluoromethyl)pyrimidin-5-yl] (Oxyphenyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 15) Example 36.1: 1-(2-hydroxyethyl)-4-methyl-3-(3-methyl-5-{[2-(trifluoromethyl)pyrimidine-5- [3,2-b]pyridine-5-one DBU (96 mg; 0.60 mmol) was added to a stirred solution of 4-methyl-3-(3-methyl-5-{[2-(trifluoromethyl)pyrimidin-5-yl]oxy}phenyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 6, Example 6.1) (80 mg; 0.20 mmol) and 1,3-dioxane-2-one (90 mg; 1.01 mmol) in DMF (10 mL) under a nitrogen atmosphere at 100 °C and maintained for 3 hours. After evaporation, the residue was purified by chromatography to give the product (34.40 mg; 39%) as a white solid.

[0231] Example 37: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(3-methylpyrazine- 2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 14) Example 37.1: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(3-methylpyridine) (azin-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.25 mmol) and 2-bromo-3-methylpyrazine (45 mg; 0.25 mmol) in dioxane (5 mL), K3PO4 (167 mg; 0.75 mmol), CuI (10 mg; 0.05 mmol) and (1R,2R)-cyclohexane-1,2-diamine (6 mg; 0.05 mmol) were added at room temperature. The resulting mixture was then stirred at 100 °C for 1 hour under a N2 atmosphere. After evaporation, the residue was purified to give the product (69.90 mg; 57%) as a white solid.

[0232] Example 38: 3-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo-1H, 4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionitrile (compound 13) Example 38.1: 3-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo- 1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionitrile To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (80 mg; 0.19 mmol) in dioxane (8 mL), propion-2-acrylonitrile (0.12 mL; 1.87 mmol) and NaOH (16 mg; 0.38 mmol) were added at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hours. After aqueous post-treatment and extraction with ethyl acetate, the combined organic layers were washed with brine and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure after filtration. The crude product was purified by chromatography (13.8 mg; 15%) as a white solid.

[0233] Example 39: 3-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo-1H, 4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acrylamide (compound 12) Example 39.1: 3-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo- 1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)propionamide To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.21 mmol) in dioxane (10 mL), propenamide (140 mg; 1.93 mmol) and NaOH (20 mg; 0.48 mmol) were added at 0 °C under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 hours. After aqueous posttreatment, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (26 mg; 26%) as a grayish-white solid.

[0234] Example 40: 1-(2-hydroxyethyl)-4-methyl-3-(3-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl] (Oxyphenyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 11) Example 40.1: 1-(2-hydroxyethyl)-4-methyl-3-(3-methyl-5-{[6-(trifluoromethyl)pyridine-3- [3,2-b]pyridine-5-one DBU (80 mg; 0.50 mmol) was added to a stirred mixture of 4-methyl-3-(3-methyl-5-{[6-(trifluoromethyl)pyridin-3-yl]oxy}phenyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (obtainable by a procedure similar to that in Examples 3 and 3.2) (70 mg; 0.17 mmol) and 1,3-dioxane-2-one (75 mg; 0.84 mmol) in DMF (10 mL) at room temperature. The resulting mixture was stirred at 100 °C for 5 hours. After removing all volatile substances, the residue was purified by chromatography to give the product (33.20 mg; 44.4%) as a white solid.

[0235] Example 41: 1-(3-hydroxypropyl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]benzene 1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 10) Example 41.1: 1-(3-hydroxypropyl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]benzene }-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.249 mmol) in DMF (10 mL), Cs₂CO₃ (240 mg; 0.7 mmol), NaI (40 mg; 0.25 mmol), and 3-chloroprop-1-ol (120 mg; 1.24 mmol) were added at room temperature under N₂ atmosphere. The resulting mixture was stirred overnight at 100 °C. After aqueous posttreatment, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (17.2 mg; 15%) as a purple semi-solid.

[0236] Example 42: 1-[(dimethylphosphoryl)methyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy] [3,2-b]pyridine-5-one (compound 7) Example 42.1: 1-[(dimethylphosphoryl)methyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)benzene [Oxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.23 mmol) in DMF (10 mL), Cs₂CO₃ (240 mg; 0.7 mmol), NaI (40 mg; 0.25 mmol), and chloro(dimethylphosphoryl)methane (150 mg; 1.13 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 hours. After aqueous post-treatment, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography to give the product (22.6 mg; 20%) as a grayish-white solid.

[0237] Example 43: N-methyl-2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo -1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide (compound 6) Example 43.1: N-Methyl-2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5- Oxo-1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.23 mmol) in DMF (10 mL), K₂CO₃ (100 mg; 0.69 mmol), NaI (40 mg; 0.25 mmol), and 2-bromo-N-methylacetamide (200 mg; 1.29 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C. After removing all volatile substances, the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (35.4 mg; 32%) as a grayish-white solid.

[0238] Example 44: 2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo-1H, 4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide (compound 4) Example 44.1: 2-(4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-5-oxo- 1H,4H,5H-pyrrolo[3,2-b]pyridin-1-yl)acetamide To a stirred solution of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (100 mg; 0.23 mmol) in DMF (5 mL), Cs₂CO₃ (240 mg; 0.70 mmol), NaI (40 mg; 0.254 mmol), and 2-chloroacetamide (120 mg; 1.22 mmol) were added at room temperature under a nitrogen atmosphere. The resulting mixture was stirred at 100 °C for 4 hours under a nitrogen atmosphere. After aqueous posttreatment, the resulting mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (44.5 mg; 41%) as a white solid.

[0239] Example 45: 1-(2-hydroxyethyl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]benzene β-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 3) Example 45.1: 1-(2-hydroxyethyl)-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]benzene }-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one 1,3-dioxane-2-one (15 µL; 0.2 mmol) and NaOH (4.2 mg; 0.1 mmol) were added to 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 2, Example 2.1) (80 mg; 0.2 mmol) in DMF (3 mL). The reaction was stirred at 130 °C for 4 hours. After removing all volatile substances, the residue was purified by chromatography to give the product (56 mg; 82%) as a white solid.

[0240] Example 46: 4-Ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine- 4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 213) Example 46.1: 4-Ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Pd(PPh3)4 (670 mg; 6.05 mmol) was added to a stirred solution of 4-ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 2, intermediate 2.7) (2.50 g; 5.50 mmol) and 4-chloro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (which can be obtained by a procedure similar to that used in the synthesis of intermediate 10, intermediate 10.1, starting from 4,6-dichloro-2-methylpyrimidine and (1r,4r)-4-(trifluoromethyl)cyclohexane-1) (1.78 g; 6.05 mmol) in dioxane (50 mL) / H2O (5 mL). 0.55 mmol) and Na2CO3 (1.84 g; 16.50 mmol). The resulting mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. After removing the solvent, the residue was purified by chromatography to give the product (2.20 g; 54%) as a grayish-white solid.

[0241] Example 46.2: 4-Ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one EtONa / EtOH (w / w 21%; 1.25 mL; 5.50 mmol) was added to a stirred solution of 4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (2.04 g; 2.75 mmol) in EtOH (50 mL). The resulting mixture was stirred at room temperature for 1 hour. After removing the solvent, the residue was purified by chromatography to give the product (1.15 g; 93%) as a gray solid.

[0242] Example 47: 4-Ethyl-1-(2-hydroxyethyl)-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclo[]] [Hexyl]oxypyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 214) Example 47.1: 4-Ethyl-1-(2-hydroxyethyl)-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)} Cyclohexyl[oxy]pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 46, Example 46.2) (100 mg; 0.22 mmol) in DMF (8 mL), 1,3-dioxane-2-one (160 mg; 1.80 mmol) was added. The resulting mixture was stirred at 100 °C for 2 hours under a nitrogen atmosphere. After removing the solvent, the residue was purified by chromatography to give the product (61.40 mg; 59%) as a white solid.

[0243] Example 48: 1-(1,3-dihydroxypropyl-2-yl)-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoro [Methyl]cyclohexyl]oxy]pyrimidin-4-yl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Compound 282) Example 48.1: 1-(2,2-dimethyl-1,3-dioxane-5-yl)-4-ethyl-3-(2-methyl-6-yl) {[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 46, Example 46.2) (200 mg; 0.44 mmol) in toluene (10 mL), 2,2-dimethyl-1,3-dioxane-5-ol (90 mg; 0.66 mmol) and 2-(tributyl-5-phosphono)acetonitrile (340 mg; 1.34 mmol) were added. The reaction mixture was stirred at 110 °C for 4 hours under a nitrogen atmosphere. After evaporation, the residue was purified by chromatography to give the product (80 mg; 26%) as a brown oil.

[0244] Example 48.2: 1-(1,3-dihydroxypropyl-2-yl)-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(tri- [Fluoromethyl]cyclohexyl]oxy]pyrimidin-4-yl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 1-(2,2-dimethyl-1,3-dioxane-5-yl)-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 48.1) (70 mg; 0.10 mmol) in THF (5 mL), aq. HCl (2 mL; 6.00 mmol) was added at room temperature and maintained for 1 hour. After evaporation, the residue was purified by chromatography to give the product (21 mg; 42%) as a white solid.

[0245] Example 49: 2,4-Dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H, 4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 212) Example 49.1: 2,4-Dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1- (4-Methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A solution of 2-methyl-4-[4-(trifluoromethyl)phenoxy]-6-(trimethylmethylenetinyl)pyrimidine (intermediate 8) (380 mg; 0.73 mmol), Pd-PEPPSI-IPentCl 2-methylpyridine (30 mg; 0.03 mmol), 3-iodo-2,4-dimethyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 3, intermediate 3.5) (190 mg; 0.39 mmol), LiCl (45 mg; 1.78 mmol), and CuI (15 mg; 0.08 mmol) in dioxane (5 mL) was reacted at 100 °C under a nitrogen atmosphere for 12 hours. The resulting mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to obtain the product (150 mg; 25%), which was a white solid.

[0246] Example 49.2: 2,4-Dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H, 4H,5H-pyrrolo[3,2-b]pyridin-5-one 2,4-Dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 49.1) (100 mg; 0.14 mmol) was stirred at room temperature for 2 hours in EtONa / EtOH (w / w 21%) (0.08 mL; 0.35 mmol) and EtOH (3 mL). After removing all volatile substances, the residue was purified by chromatography to give the product (14.50 mg; 24%) as a white solid.

[0247] Example 50: 1-(2-hydroxyethyl)-2,4-dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy] Pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 233) Example 50.1: 1-(2-hydroxyethyl)-2,4-dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy [pyrimidin-4-yl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A mixture of 2,4-dimethyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 49, Example 49.2) (100 mg; 0.22 mmol), 1,3-dioxane-2-one (80 mg; 0.90 mmol), and DBU (80 mg; 0.50 mmol) in DMF (2.50 mL) was stirred at 100 °C for 2 hours. After vacuum concentration, the residue was purified by chromatography to give the product (12.30 mg; 12%) as a pale yellow solid.

[0248] Example 51: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H,5H- Pyrazolo[4,3-b]pyridin-5-one (compound 254) Example 51.1: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(triphenyl) )-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one Pd(PPh3)4 (270 mg; 0.22 mmol) and CuI (450 mg; 2.24 mmol) were added to a stirred solution of 4-methyl-3-(trimethylmtinyl)-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (intermediate 4, intermediate 4.7) (1.30 g; 2.23 mmol) and 4-iodo-2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidine (intermediate 9, intermediate 9.1) (1.24 g; 2.68 mmol) in DMF (20 mL) under nitrogen atmosphere at 100 °C, and the mixture was kept at this temperature for 2 hours. After evaporation, the residue was purified by chromatography to give the product (1.39 g; 94%) as a yellow solid.

[0249] Example 51.2: 4-Methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1H,4H, 5H-pyrazolo[4,3-b]pyridin-5-one TFA (0.20 mL; 2.09 mL) and Et3SiH (0.10 mL) were added to a stirred solution of 4-methyl-3-{2-methyl-6-[4-(trifluoromethyl)phenoxy]pyrimidin-4-yl}-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (Example 51.1) (120 mg; 0.18 mmol) in DCM (5 mL) at room temperature and maintained for 2 hours. After evaporation, the residue was purified by chromatography to give the product (23.70 mg; 33%) as a white solid.

[0250] Example 52: 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine-4- 4-Methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (compound 244) Example 52.1: 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine- 4-yl)-4-methyl-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one To a stirred solution of 5-fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (intermediate 10, intermediate 10.2) (1 g; 2.36 mmol) and 4-methyl-3-(trimethylmethylenetinyl)-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (intermediate 4, intermediate 4.7) (1 g; 1.75 mmol) in DMF (20 mL) at room temperature under a nitrogen atmosphere, Pd(PPh3)4 (285 mg; 0.23 mmol) and CuI (470 mg; 2.34 mmol) were added. The reaction mixture was then stirred at 100 °C for 2 hours. For post-treatment, the mixture was extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to obtain the product (1.04 g; 64%), which was a yellow solid.

[0251] Example 52.2: 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine- 4-yl)-4-methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one Et3SiH (2 mL) and TFA (5 mL) were added to a stirred solution of 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-4-methyl-1-(triphenylmethyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (Example 52.1) (900 mg; 1.31 mmol) in DCM (20 mL) at room temperature. The resulting mixture was then stirred overnight under a N2 atmosphere. After removing all volatile substances, the crude product was purified by chromatography to give the product (580 mg; 99%) as a white solid.

[0252] Example 53: 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-methyl- 1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 260) Example 53.1: 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-methyl- 1-(4-Methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Pd(PPh3)4 (99 mg; 0.08 mmol) and Na2CO3 (181 mg; 1.62 mmol) were added to a stirred mixture of 4-methyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexane-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 1, intermediate 1.5) (350 mg; 0.81 mmol) and 1-bromo-3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}benzene (intermediate 11, intermediate 11.1) (308 mg; 0.81 mmol) in dioxane (10 mL) and H2O (2 mL) at 25 °C. The resulting mixture was stirred at 60°C for 2 hours under a nitrogen atmosphere. For post-treatment, the mixture was concentrated under vacuum, and the residue was purified by chromatography to give the product (260 mg; 54%) as a yellow solid.

[0253] Example 53.2: 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-methyl- 1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 3-(3-chloro-5-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}phenyl)-4-methyl-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 53.1) (100 mg; 0.23 mmol) in DMF (10 mL), NaH (138 mg; 1.17 mmol) was added at 0 °C under a N2 atmosphere, and the mixture was maintained for 30 minutes. Then, 4-(chloromethyl)-1H-imidazolium hydrochloride (76 mg; 0.47 mmol) was added, and the reaction mixture was stirred at 25 °C for another 6 hours. For post-treatment, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by chromatography to give the product (16.3 mg; 14%) as a white solid.

[0254] Example 54: 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine-4- (1-methyl-1H-pyrazol-4-yl)methyl]-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (compound) Object 250) and 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-4-methyl- 2-[(1-methyl-1H-pyrazol-4-yl)methyl]-2H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (compound 252) To a stirred solution of 3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-4-methyl-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (Example 52, Example 52.2) (90 mg; 0.20 mmol) in DMF (8 mL), NaH (50 mg; 1.25 mmol) was added at 0 °C under N2 atmosphere. The resulting mixture was then stirred at room temperature for 30 minutes. 4-(bromomethyl)-1-methyl-1H-pyrazol hydrobromide (108 mg; 0.40 mmol) was added, and the mixture was maintained for 1 hour. The crude product was post-treated with an aqueous solution of ammonium chloride, extracted with ethyl acetate, dried with sodium sulfate, filtered, and evaporated. It was then purified by chromatography to give product 1 (compound 250) (24.80 mg; 24%) and product 2 (compound 252) (1.7 mg; 2%), both of which were white solids.

[0255] Example 55: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrazole [4,3-b]pyridin-5-one (compound 201) Example 55.1: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methylbenzene) sulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one To a stirred mixture of 3-iodo-4-methyl-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (intermediate 13, intermediate 13.1) (600 mg; 1.15 mmol) and 4,4,5,5-tetramethyl-2-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1,3,2-dioxaborhecyclopentane (intermediate 5, intermediate 5.2) (255 mg; 1.15 mmol) in dioxane (10 mL) and H2O (2 mL), Pd(dppf)Cl2 (88 mg; 0.11 mmol) and K2CO3 (334 mg; 2.30 mmol) were added at room temperature under a N2 atmosphere. The resulting mixture was stirred at 70 °C for 1 hour. The mixture was then concentrated under vacuum, and the residue was purified by chromatography to give the product (250 mg; 33%) as a yellow oil.

[0256] Example 55.2: 4-Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyridine Azo[4,3-b]pyridin-5-one EtONa / EtOH (w / w 21%) (0.20 mL; 0.91 mmol) was added to a stirred mixture of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (Example 55.1) (400 mg; 0.61 mmol) in EtOH (10 mL) at room temperature and maintained for 1 hour. The mixture was extracted with DCM, the combined organic layers were washed with brine and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (250 mg; 99%) as a yellow oil.

[0257] Example 56: 1-[(1H-imidazol-4-yl)methyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy] [4,3-b]pyridine-5-one (compound 211) and 2-[(1H-imidazol-4-yl)methyl]-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}- 2H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (compound 210) Towards 4- Methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1H,4H,5H-pyrazolo[4,3-b]pyridin-5-one (Example 55, Example 55.2) (80 mg; 0.19 mmol) was added to a stirred solution in DMF (1 mL) under N2 atmosphere at 0 °C with NaH (23 mg; 0.57 mmol). The mixture was stirred at room temperature for 30 minutes. TBAI (15 mg; 0.04 mmol) and 4-(chloromethyl)-1H-imidazolium hydrochloride (62 mg; 0.38 mmol) were added at 80 °C, and the mixture was maintained for 1 hour. The mixture was post-treated with aqueous ammonium chloride, extracted with ethyl acetate, dried over sodium sulfate, filtered, and evaporated. The crude product was purified by chromatography to give product 1 (5.70 mg; 6%) and product 2 (2 mg; 2%), both white solids.

[0258] Example 57: 6-Fluoro-4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methyl) (benzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (compound 63) A mixture of 4-methyl-3-{3-methyl-5-[4-(trifluoromethyl)phenoxy]phenyl}-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 16, Example 16.1) (1 g; 1.72 mmol) and selectfluor (2.50 g; 6.70 mmol) in ACN (20 mL) and H2O (4 mL) was stirred at room temperature for 1.5 hours. The mixture was then extracted with ethyl acetate, the combined organic layers were washed with brine, and dried over sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (32.9 mg; 3%) as a purple solid.

[0259] Example 58: rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy Pyrimidine-4-yl)-1-(2-hydroxyethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 58.1: 4-Ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy (Pyrimidin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a solution of 4-ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 2.7) (9.50 g; 20.40 mmol) and rel-5-fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (intermediate 10.2) (9.50 g; 22.33 mmol) in CPME (cyclopentyl methyl ether) (200 mL) / H2O (20 mL) at 60 °C under N2 atmosphere, SPhos Pd G3 (1.80 g; 2.06 mmol) and K3PO4 (13.70 g; 61.32 mmol) were added to the solution of 4-ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 2.7) (9.50 g; 20.40 mmol) and rel-5-fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (intermediate 10.2) (9.50 g; 22.33 mmol) in CPME (cyclopentyl methyl ether) (200 mL) / H2O (20 mL). The reaction mixture was then concentrated under reduced pressure for 2 hours, and the residue was purified by chromatography to give the product (6.40 g; 51%) as a light brown solid.

[0260] Example 58.2: rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] (Oxypyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 58.1) (500 mg; 0.84 mmol) in EtOH (20 mL), EtONa / EtOH (w / w 21%; 5 mL; 23.14 mmol) was added at 25 °C and maintained for 3 hours. The reaction was quenched with water at 0 °C. The mixture was diluted with DCM and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (340 mg; 76%) as a white solid.

[0261] Example 58.3: rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] oxypyrimidin-4-yl)-1-(2-hydroxyethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A solution of rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 58.2) (45 mg; 0.1 mmol) and 1,3-dioxane-2-one (120 mg; 1.35 mmol) in DMF (2 mL) was treated with DBU (50 mg; 0.31 mmol) at 80 °C for 2 hours. The mixture was then concentrated under reduced pressure, and the residue was purified by chromatography to give the product (31 mg; 63%) as a grayish-white solid.

[0262] Example 59: rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy (Pyrimidine-4-yl)-1-methyl-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of rel-4-ethyl-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 58, Example 58.2) (40 mg; 0.09 mmol) in THF (2 ml), NaH (5 mg; 0.13 mmol) was added at 0 °C under a nitrogen atmosphere and maintained for 10 minutes. Then CH3I (0.01 ml; 0.13 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the residue was purified by chromatography to give the product (24 mg; 60%) as a grayish-white solid.

[0263] Example 60: rel-4-ethyl-3-(6-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 60.1: rel-2-bromo-6-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine To a stirred mixture of rel-(1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (0.77 g; 4.38 mmol) in DMF (20 mL), NaH (193 mg; 4.83 mmol) was added at 0 °C under N2 atmosphere and maintained for 20 min. Then, 2-bromo-6-methyl-4-nitropyridine (1 g; 4.38 mmol) was added at 25 °C and maintained for 2 h. For post-treatment, the mixture was extracted with ethyl acetate, the organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified by chromatography to give the product (840 mg; 57%) as a pink solid.

[0264] Example 60.2: rel-4-ethyl-3-(6-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} Pyridin-2-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Pd(PPh3)4 (161 mg; 0.13 mmol) and Na2CO3 (296 mg; 2.65 mmol) were added to a stirred mixture of rel-2-bromo-6-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (Example 60.1) (450 mg; 1.33 mmol) and 4-ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 2.7) (630 mg; 1.28 mmol) in dioxane (10 mL) and H2O (2 mL) at 80 °C under N2 atmosphere, and the mixture was maintained for 2 hours. For post-treatment, the mixture was concentrated under vacuum. The residue was purified by chromatography to obtain the product (600 mg; 72%), which was a yellow solid.

[0265] Example 60.3: rel-4-ethyl-3-(6-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} pyridin-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one EtONa / EtOH (w / w 21%; 104 mg; 0.32 mmol) was added to a stirred solution of rel-4-ethyl-3-(6-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-2-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 60.2) (100 mg; 0.16 mmol) in EtOH (10 mL) at 25 °C and maintained for 2 h. For post-treatment, the reaction was quenched with H2O at 0 °C and diluted with DCM. After washing with brine, the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography to give the product (21 mg; 32%) as a white solid.

[0266] Example 61: rel-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 61.1: rel-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine To a stirred solution of rel-(1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (800 mg; 4.66 mmol) in DMF (20 mL), NaH (250 mg; 6.25 mmol) was added at 0 °C and maintained for 20 min. 2-Fluoro-4-iodo-6-methylpyridine (1 g; 4.13 mmol) was added at 80 °C under a nitrogen atmosphere and maintained for 2 h. The reaction was quenched by the addition of ice water, and the resulting mixture was diluted with ethyl acetate. After washing with brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (1.20 g; 63%) as a colorless oil.

[0267] Example 61.2: rel-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} Pyridin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A solution of 4-ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 2.7) (800 mg; 1.72 mmol) and rel-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (900 mg; 1.94 mmol) in CPME (20 mL) and H2O (4 mL) was added to SPhos Pd G3 (150 mg; 0.17 mmol) and K3PO4 (1.15 g; 5.15 mmol) at 60 °C under N2 atmosphere and maintained for 2 h. For post-treatment, the mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (550 mg; 54%) as a white solid.

[0268] Example 61.3: rel-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} pyridin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of rel-4-ethyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 61.2) (80 mg; 0.14 mmol) in EtOH (5 mL), EtONa / EtOH (w / w 21%; 0.06 mL; 0.28 mmol) was added at 25 °C and maintained for 2 hours. For post-treatment, the mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (39.90 mg; 70%) as a white solid.

[0269] Example 62: rel-4-ethyl-3-(3-fluoro-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy pyridine-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridine-5-one Example 62.1: rel-3-fluoro-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine To a stirred solution of rel-(1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (7.81 g; 44.15 mmol) in DMF (100 mL), NaH (2.21 g; 55.19 mmol) was added at 0 °C and maintained for 20 min. Then, under a nitrogen atmosphere, 2,3-difluoro-6-methylpyridine (5 g; 36.79 mmol) was added at 60 °C and maintained for 5 h. For post-treatment, the reaction was then quenched by adding ice water. The mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (9 g; 84%) as a colorless oil.

[0270] Example 62.2: rel-3-fluoro-4-iodo-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} Pyridine To a stirred solution of rel-3-fluoro-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (Example 62.1) (1 g; 3.44 mmol) in THF (20 mL), LDA / THF (5.20 mL; 10.40 mmol) was added dropwise at -65 °C under a N2 atmosphere, and the mixture was maintained for 30 minutes. Then, I2 (1.84 g; 6.89 mmol) / THF was added at this temperature, and the mixture was maintained for 1 hour. For post-treatment, an aqueous solution of ammonium chloride was added, and the mixture was diluted with ethyl acetate. After washing with brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (1.30 g; 90%) as a colorless oil.

[0271] Example 62.3: rel-4-ethyl-3-(3-fluoro-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] oxy}pyridin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A solution of 4-ethyl-1-(4-methylbenzenesulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (intermediate 2.7) (800 mg; 1.72 mmol) and rel-3-fluoro-4-iodo-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridine (Example 62.2) (900 mg; 2.13 mmol) in CPME (20 mL) and H2O (4 mL) was added to SPhos Pd G3 (150 mg; 0.17 mmol) and K3PO4 (1.15 g; 5.15 mmol) at 60 °C under N2 atmosphere and maintained for 2 hours. For post-processing, the mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (750 mg; 61%) as a grayish-white solid.

[0272] Example 62.4: rel-4-ethyl-3-(3-fluoro-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] oxy}pyridin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of rel-4-ethyl-3-(3-fluoro-6-methyl-2-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyridin-4-yl)-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 62.3) 100 mg; 0.14 mmol) in EtOH (5 mL), EtONa / EtOH (w / w 21%; 0.06 mL; 0.28 mmol) was added at 25 °C and maintained for 2 hours. Ethyl acetate was added, and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (37 mg; 60%) as a grayish-white solid.

[0273] Example 63: rel-6-fluoro-4-methyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy (pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 63.1: 6-Fluoro-3-iodo-1H-pyrrolo[3,2-b]pyridine 6-Fluoro-1H-pyrrolo[3,2-b]pyridine (2 g; 13.96 mmol) and NIS (4 g; 16.89 mmol) were reacted in THF (40 mL) at room temperature for 2 hours. H₂O was then added, and the mixture was diluted with ethyl acetate. After washing with brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude product (3.70 g; 99%) as a yellow oil, which was used for the next step without further purification.

[0274] Example 63.2: 6-Fluoro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3, 2-b]pyridine 6-Fluoro-3-iodo-1H-pyrrolo[3,2-b]pyridine (Example 63.1) (2 g; 7.47 mmol) was added to DMF (50 mL) at room temperature under a nitrogen atmosphere with NaH (600 mg; 15 mmol) and SEM-Cl (2 g; 11.40 mmol) for 4 hours. The mixture was then diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (2 g; 59%) as a yellow solid.

[0275] Example 63.3: 6-Fluoro-3-iodo-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyridine Trolo[3,2-b]pyridine-4-onium iodide MeI (0.20 ml; 3.05 mmol) was added to 6-fluoro-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine (Example 63.2) (200 mg; 0.50 mmol) in but-2-one (3 mL) at 40 °C and maintained for 16 hours. After filtration and washing with ethyl acetate, the product (175 mg; 65%) was given as a yellow solid and used in the next step without further purification.

[0276] Example 63.4: 6-Fluoro-3-iodo-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H, 4H,5H-pyrrolo[3,2-b]pyridin-5-one K3Fe(CN)6 (660 mg; 1.90 mmol) was added to a stirred solution of 6-fluoro-3-iodo-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[3,2-b]pyridine-4-onium iodide (Example 63.3) (150 mg; 0.25 mmol) in H2O (15 mL) at 0 °C and maintained for 10 minutes. Then KOH (235 mg; 3.77 mmol; aq.) was added dropwise, followed by toluene (25 mL). The resulting mixture was stirred at 55 °C for 5 hours. For post-treatment, Na2S2O3 (aq.) was added at 0 °C. The mixture was extracted with ethyl acetate, the organic layer was washed with brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by chromatography to give the product (110 mg; 96%) as a bright yellow solid.

[0277] Example 63.5: rel-6-fluoro-4-methyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] oxy}pyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyrrolo 5-Pyridoxine Pd(PPh3)4 (14 mg; 0.01 mmol) and CuI (22 mg; 0.11 mmol) were added to a solution of 6-fluoro-3-iodo-4-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 63.4) (100 mg; 0.17 mmol) and rel-2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-(trimethylsilyl)pyrimidine (which can be obtained by a procedure similar to that of Example 64.5) (250 mg; 0.26 mmol) in DMF (10 mL) under N2 atmosphere at 100 °C, and the mixture was maintained for 2 hours. For post-treatment, H2O was added and the resulting mixture was diluted with DCM. After washing with brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (60 mg; 65%) as a white solid.

[0278] Example 63.6: rel-6-fluoro-4-methyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] (Oxypyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one A solution of rel-6-fluoro-4-methyl-3-(2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 63.5) (60 mg; 0.09 mmol) and TBAF (1 M, in THF; 200 µL) in THF (5 mL) was stirred at 60 °C for 12 hours. Water was then added, and the resulting mixture was diluted with DCM. After washing with brine, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (14 mg; 37%) as a white solid.

[0279] Example 64: rel-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 64.1: 1-(4-methylbenzenesulfonyl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3, 2-b]pyridin-5-one To a stirred solution of 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-ol (intermediate 2.2) (2000 mg; 0.66 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.40 mL; 2.77 mmol) in dioxane (10 mL), K₂CO₃ (300 mg; 2.07 mmol) was added at room temperature and maintained for 1 hour, followed by microwave incubation at 120 °C for 2 hours. The mixture was then diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (160 mg; 65%) as a white solid.

[0280] Example 64.2: 4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one EtONa (55 mg; 0.78 mmol) was added to a stirred solution of 1-(4-methylbenzenesulfonyl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 64.1) (150 mg; 0.40 mmol) in EtOH (5 mL) at room temperature and maintained for 1 hour. The reaction was quenched with aqueous ammonium chloride solution, the mixture was diluted with ethyl acetate and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (80 mg; 89%) as a white solid.

[0281] Example 64.3: 3-Iodo-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of 4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 64.2) (70 mg; 0.31 mmol) and I2 (80 mg; 0.30 mmol) in DMF (4 mL), KOH (80 mg; 1.28 mmol) was added at 0 °C, and the mixture was kept at room temperature for 1 hour. Ethyl acetate was then added, and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (35 mg; 25%) as a white solid.

[0282] Example 64.4: 3-Iodo-1-(4-methylbenzenesulfonyl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrole [3,2-b]pyridin-5-one To a stirred solution of 3-iodo-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 64.3) (1.20 g; 2.69 mmol) and TsCl (650 mg; 3.24 mmol) in DCM (120 mL), Et3N (0.73 mL; 4.99 mmol) and DMAP (86 mg; 0.67 mmol) were added at room temperature and allowed to stand overnight. Ethyl acetate was then added, and the mixture was washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (1.20 g; 89%) as a white solid.

[0283] Example 64.5: rel-5-fluoro-2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6- (trimethyltinyl)pyrimidine To a stirred solution of rel-5-fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (intermediate 10.1) (500 mg; 0.98 mmol) in dioxane (10 mL), hexamethyldistinane (650 mg; 1.96 mmol) and Pd(PPh3)4 (120 mg; 0.10 mmol) were added at 100 °C under N2 atmosphere, and the mixture was maintained for 2 hours. The mixture was concentrated under reduced pressure to give a crude product (700 mg; 54%) as a black oil, which was used for the next step without further purification.

[0284] Example 64.6: rel-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-1-(4-methylbenzenesulfonyl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a stirred solution of rel-5-fluoro-2-methyl-4-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}-6-(trimethylmtinalkyl)pyrimidine (Example 64.5) (300 mg; 0.22 mmol), Pd(PPh3)4 (17.60 mg; 0.01 mmol), and CuI (32 mg; 0.15 mmol) in DMF (8 mL), 3-iodo-1-(4-methylbenzenesulfonyl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 64.4) (120 mg; 0.22 mmol) was added at 30 °C and maintained for 2 hours. The mixture was then diluted with ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to obtain the product (61 mg; 21%), which was a brownish-orange solid.

[0285] Example 64.7: rel-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (-4-yl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one To a solution of EtONa (9 mg; 0.13 mmol) in EtOH (2 mL), rel-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1-(4-methylbenzenesulfonyl)-4-(2,2,2-trifluoroethyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 64.6) (56 mg; 0.05 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 hour, diluted with ethyl acetate, and then washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography to give the product (14.10 mg; 55%) as a white solid.

[0286] Example 65: rel-4-ethyl-3-[2-(2H3)methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy [[Pyrimidin-4-yl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one] Example 65.1: rel-4-chloro-2-(2H3)methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy} Pyrimidine To a solution of rel-(1r,4r)-4-(trifluoromethyl)cyclohexane-1-ol (496 mg; 2.86 mmol) in THF (14 mL), NaH (60% suspension in paraffin oil; 137 mg; 3.43 mmol) was added under argon at 0 °C, and the mixture was maintained for 30 min. Then, 4,6-dichloro-2-(methyl-D3)pyrimidine (475 mg; 2.86 mmol) / THF (3 mL) was added, and the mixture was heated to room temperature. The reaction was quenched under cooling with a saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by chromatography to give the product (615 mg; 54%) as a colorless gel.

[0287] Example 65.2: rel-4-ethyl-3-[2-(2H3)methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] [[2-(trimethylsilyl)ethoxy]methyl]-1H,4H,5H-pyrrolo[3,2-b]pyrrolo 5-Pyridoxine 4-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (which can be obtained by a procedure similar to that in Example 66.4) (316 mg; 0.71 mmol) was added to dioxane (3 mL) / H2O (0.15 mL) at 100 °C with rel-4-chloro-2-(2H3)methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (200 mg; 0.50 mmol), Cs2CO3 (197 mg; 0.61 mmol) and tetrakis(triphenylphosphine)palladium (0) (58 mg; 0.05 mmol) (3 mL; 3 mL) and kept for 12 hours. After adding water, the mixture was extracted with ethyl acetate, the organic phase was washed with brine, dried with sodium sulfate, and filtered. After evaporation, the residue was purified by chromatography to give the product (276 mg; 24%) as a black oil.

[0288] Example 65.2: rel-4-ethyl-3-[2-(2H3)methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl] [Oxypyrimidin-4-yl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one TFA (2.2 mL) was added to rel-4-ethyl-3-[2-(2H3)methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 65.1) (276 mg; 0.12 mmol) at room temperature and maintained for 3 hours. The reaction was evaporated to dryness, and the residue was dissolved in dioxane (5.5 mL). Ammonia solution (32%; 5.5 mL) was added at room temperature and maintained for 12 hours. After evaporation, the residue was purified by chromatography to give the product (11 mg; 21%) as a white solid.

[0289] Example 66: rel-4-[(1,1,2,2,2-2H5)ethyl]-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one Example 66.1: 4-[(1,1,2,2,2-2H5)ethyl]-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrole [3,2-b]pyridin-5-one 1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine-5-ol intermediate 2.2) (5 g; 17 mmol) was dissolved in DMF (50 mL), and bis(trimethylsilyl)aminolithium (1N, in THF; 19 mL; 19 mmol) was slowly added at 0 °C, followed by the addition of iodoethane-D5 (3.1 g; 19 mmol) dissolved in DMF (25 mL). The mixture was stirred at 5 to 10 °C for 30 minutes and then stirred overnight at room temperature. The mixture was diluted with water and cooled in an ice bath. A precipitate formed. The suspension was filtered, and the filter cake was washed with water. The filtrate was extracted again with DCM, the organic layer was evaporated to dryness, and the residue was combined with the filter cake. The crude product was purified by chromatography to obtain the product (3.3 g; 60%) and 5-[(1,1,2,2,2-2H5)ethoxy]-1-(4-methylbenzenesulfonyl)-1H-pyrrolo[3,2-b]pyridine (0.9 g; 15%), both of which were colorless solids.

[0290] Example 66.2: 4-[(1,1,2,2,2-2H5)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one 4-[(1,1,2,2,2-2H5)ethyl]-1-(4-methylbenzenesulfonyl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 66.3) (3.3 g; 10 mmol) was suspended in EtOH (57 mL), and NaOEt (20%, in ethanol; 7.25 mL; 18.7 mmol) was added dropwise. The resulting mixture was stirred at 20 °C for 2 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The combined organic layers were evaporated to dryness, and the residue was purified by chromatography to give the product (1.73 g; 97%) as a yellow solid.

[0291] Example 66.3: 4-[(1,1,2,2,2-2H5)ethyl]-3-iodo-1H,4H,5H-pyrrolo[3,2-b]pyridine- 5-Ketone 4-[(1,1,2,2,2-2H5)ethyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 66.4) (1.73 g; 10 mmol) was suspended in DMF (26 mL), and KOH (2.26 g; 40 mmol) was added. The mixture was cooled to -20°C, and then I2 (2.69 g; 10 mmol) in a solution of DMF (9 mL) was slowly added over 30 minutes via a dropping funnel. The temperature was kept constant between -25 and -20°C during the addition. After the addition was complete, the mixture was stirred at -20°C for another 15 minutes. A light brown solution was formed. The mixture was treated with a saturated sodium thiosulfate solution and then warmed to room temperature. The mixture was poured into water, and the precipitate was filtered. A crude product (2 g; 63%) was given as a colorless solid, which was used for the next step without further purification.

[0292] Example 66.4: 4-[(1,1,2,2,2-2H5)ethyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy [methyl]-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one 4-[(1,1,2,2,2-2H5)ethyl]-3-iodo-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 66.5) (638 mg; 2.14 mmol) was suspended in DMF (30 mL) and cooled to 0 to 5 °C. NaH (60% suspension in paraffin oil; 332 mg; 8.31 mmol) was added in portions, and the mixture was stirred at 0 to 5 °C for 45 minutes. A turbid, pale yellow suspension was formed. Subsequently, 2-(trimethylsilyl)ethoxymethyl chloride (1.70 mL; 9.59 mmol) was added via syringe over a period of 5 minutes. The resulting mixture (pale brown dilute suspension) was stirred at 10 to 15 °C for 15 minutes. The mixture was poured into ice water and extracted with DCM. The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered, and evaporated to dryness. The residue was purified by chromatography to obtain the product (2.60 g; 95%), which was a light red oil.

[0293] Example 66.5: 4-[(1,1,2,2,2-2H5)ethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaboron) Heterocyclopentane-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridine- 5-keto 4-[(1,1,2,2,2-2H5)ethyl]-3-iodo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 66.6) (2.60 g; 6.05 mmol) and tetrakis(triphenylphosphine)palladium(0) (736 mg; 0.61 mmol) were dissolved in dioxane (40 mL). TEA (5 mL; 36 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentane (1.8 mL; 12 mmol) were added at 100 °C, and the mixture was kept for 1 hour. The mixture was cooled to room temperature, and a precipitate formed. This precipitate was filtered, and the filter cake was washed with ethyl acetate. The filtrate was evaporated to dryness, and the residue was suspended in ethyl acetate and filtered. The filtrate was purified by chromatography to obtain the product (2.51 g; 96%), which was an orange oil.

[0294] Example 66.6: rel-4-[(1,1,2,2,2-2H5)ethyl]-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H- Pyrrolo[3,2-b]pyridin-5-one To dioxane (50 mL) / H₂O (2.50 mL), rel-5-fluoro-4-iodo-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidine (Example 66.7) (1.17 g; 2.88 mmol) was added at 110 °C under an argon atmosphere to 4-[(1,1,2,2,2-2H₅)ethyl]-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (1.25 g; 2.88 mmol) and Cs₂CO₃ (Example 66.7) (1.88 g; 5.76 mmol) were added. 0.29 mmol) and tetra(triphenylphosphine)palladium (0) (333 mg; 0.29 mmol) were incubated overnight. The reaction mixture was diluted with water, extracted with ethyl acetate, the organic layer was washed with brine, dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography to give the product (1.31 g; 64%) as an orange oil.

[0295] Example 66.7: rel-4-[(1,1,2,2,2-2H5)ethyl]-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4- (trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one TFA (10 mL) was added to rel-4-[(1,1,2,2,2-2H5)ethyl]-3-(5-fluoro-2-methyl-6-{[(1r,4r)-4-(trifluoromethyl)cyclohexyl]oxy}pyrimidin-4-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H,4H,5H-pyrrolo[3,2-b]pyridin-5-one (Example 66.8) (1.31 g; 1.85 mmol) at room temperature and maintained for 5 hours. After evaporation to dryness, the residue was dissolved overnight in dioxane (30 mL) and ammonia solution (32%; 30 mL) at room temperature. The reaction mixture was filtered, the filter cake was washed with water, and dried under vacuum at 50 °C overnight to give the product (731 mg; 88%) as a colorless solid.

[0296] Tables 1 and 1a Tables 1 and 1a below show exemplary compounds of the present invention. They have been synthesized according to the methods described in or similar to those in the above embodiments.

[0297] Note: Unless otherwise specified for a particular compound and its structure (e.g., by designating the structure as “absolute”), the absolute configurations shown for the compound structures in Tables 1 and 1a below are arbitrarily designated.

[0298] Table 1 The LCMS methods mentioned in Table 1 Table 1a The LCMS methods mentioned in Table 1a Chiral separation methods mentioned in Table 1a Biological data SK-HEP-1 reporter assay To identify inhibitors of YAP-TEAD interaction, the 8xTEAD response element driving the NanoLuc® luciferase gene was stably integrated into SK-HEP-1 cells (ECACC #: 91091816).

[0299] For the analysis, cells were treated in duplicate with 10 doses of the test compound, with the highest concentration starting at 30 µM (the final concentration in the analysis). After culturing for 24 hours at 37°C, 95% rH, and 5% CO2, the luciferase substrate / lysis reagent mixture (NanoGlo) was used. TM Promega is added to cells, thereby allowing for the quantification of cytoluciferase activity.

[0300] 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.

[0301] Reagents:The reagents used are listed below: .

[0302] 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.

[0303] 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 x g for 5 min at room temperature. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[0304] 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.

[0305] Compound treatment: 24 hours after inoculation, the cells were treated with a compound.

[0306] 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, spray 120 nmol from a Labcyte low dead volume plate into a cell plate containing 20 µl of culture medium per well using an ECHO 555 liquid handling system.

[0307] After treatment, 20 µl of fresh, preheated analytical medium was added to the cells using a Multidrop combi.

[0308] The analytical plate was then incubated at 37°C, 95% rH and 5% CO2 for another 24 hours.

[0309] Luciferase reading: 24 h after treatment, the plate was removed from the incubator and equilibrated to room temperature. 30 µl of NanoGlo® reagent was added to the plate in the dark. The plate was then shaken on a Teleshake (approximately 1500 rpm) for 20 min in the dark. Efficacy was then measured using an EnVision microplate reader. ICs were generated using Genedata Screener®. 50 value.

[0310] Viability analysis in H226 (Yap-dependent) and SW620 Yap KO (non-Yap-dependent) cells The ability of YAP-TEAD inhibitors 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.

[0311] 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.

[0312] 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.

[0313] Reagents: The reagents used are listed below: .

[0314] 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.

[0315] 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 x g for 5 min at room temperature. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[0316] 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.

[0317] Compound treatment: 24 hours after inoculation, the cells were treated with a compound.

[0318] 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, spray 120 nmol from a Labcyte low dead volume plate into a cell plate containing 20 µl of culture medium per well using an ECHO 555 liquid handling system.

[0319] After treatment, 20 µl of fresh, preheated analytical medium was added to the cells using a Multidrop combi.

[0320] The analytical plate was then incubated at 37°C, 95% rH, and 5% CO2 for 96 h.

[0321] CyQuant® Measurement 96 h after treatment, 30 µl of CyQuant® reagent was added to the analytical 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 analytical plate was removed from the incubator and allowed to equilibrate to room temperature in the dark for 30 min uncovered. Finally, measurements were taken using an EnVision microplate reader with a FITC bottom readout procedure.

[0322] 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.

[0323] 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.

[0324] Reagents: The reagents used are listed below: .

[0325] 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.

[0326] 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 x g for 5 min at room temperature. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[0327] 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.

[0328] Compound treatment: Twenty-four hours after inoculation, the cells were treated with a compound.

[0329] 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, spray 120 nmol from a Labcyte low dead volume plate into a cell plate containing 20 µl of culture medium per well using an ECHO 555 liquid handling system.

[0330] After treatment, 20 µl of fresh, preheated analytical medium was added to the cells using a Multidrop combi.

[0331] The analytical plate was then incubated at 37°C, 95% rH and 5% CO2 for another 24 h.

[0332] CyQuant® Measurement: 96 h after treatment, 30 µl of a solution prepared at an inhibitor-to-stain ratio of 1:5 was added to the plate in the dark. 2x CyQuant ® staining solution. Incubate the plate at 37°C, 95% rH, and 5% CO2 for 1 h. Then equilibrate the plate to room temperature in the dark for 30 min. Fluorescence is then measured using an EnVision microplate reader with a FITC filter. Genedata Screener® generates IC50. 50 value.

[0333] The experimental data of the compounds shown in Tables 1 and 1a in the SK-HEP-1 reporter gene analysis are presented in Table 2 below (“Reporter Genes”) and are divided into the following groups: Group A IC 50In the range of 1 nM to 100 nM Group B IC 50 In the range of >100 nM to 1000 nM Group C IC 50 In the range of >1000 nM to 10000 nM Group D IC 50 In the range of >10000 to 30000 nM nd is below the threshold given in parentheses and was not detected.

[0334] The experimental data for the compounds shown in Tables 1 and 1a in the activity analysis (H226, H292; SW620 YapKO) are presented in Table 2 below and divided into the following groups: Group A IC 50 In the range of 1 nM to 100 nM Group B IC 50 In the range of >100 nM to 1000 nM Group C IC 50 In the range of >1000 nM to 10000 nM Group D IC 50 In the range of >10000 to 30000 nM nd is below the threshold given in parentheses and was not detected.

[0335] Table 2 Heat transfer analysis Micro-differential scanning fluorescence assay. NanoDSF was performed on a Prometheus NT.48 instrument (NanoTemper Technologies GmbH). Protein samples were briefly centrifuged before preparation. The final reaction mixture contained 11.8 μM hsTEAD1 (209-426), 7.3 μM hsTEAD2 (217-447)-His, 7.9 μM hsTEAD3 (216-435), or 11.7 μM hsTEAD4 (217-434)-Thrb-His diluted in 20 mM Tris pH 8.0, 150 mM NaCl, or 0.5 mM TCEP (for peptide 17, not included), with 1 μL of 100% DMSO (apo) or 100 μM of each compound added. This culture was performed at 4 °C for 2 h. 10 μL of sample was packed into a high-sensitivity capillary (NanoTemper Technologies) and placed on a Prometheus NT.48 sample holder. A temperature gradient of 1 °C / min was applied from 25 °C to 90 °C. Endogenous protein fluorescence and light scattering were recorded at 330 and 350 nm. Data on fluorescence (330 nm) and / or aggregation values ​​were analyzed. Melting temperature (Tm) was obtained by calculating the midpoint of each transformation using PR.ThermControl Software™ version 2.16 and Stability Analysis Software™ version 1.1. The thermal stability and aggregation of each compound were calculated by subtracting the Tm value obtained in the presence of DMSO from the Tm value obtained in the presence of the compound. A change in Tm was considered significant when |ΔTm| ≥ 2 °C. Samples were tested in duplicate or triplicate.

[0336] Table 3 .

Claims

1. Compounds of formula (I) I in Ring D and R 2 together or ; X 1 Indicates CR X1 Or N; R X1 Indicates H, halogen, straight-chain or branched C 1-4 -alkyl groups, which are unsubstituted or independently substituted with the following groups: 1, 2 or 3 halogens, and / or OH; R 1 This refers to straight-chain or branched C atoms that are not substituted or are independently substituted by one, two, or three halogens. 1-6 -alkyl; or C146 ... 3-7 -cycloalkyl, and the C 1-6 -alkyl or C 3-7 - In a cycloalkyl group, 1, 2, 3, 4, 5, 6 or 7 H atoms can be replaced by deuterium (D-atom); R 2 represents H or Alk 2 , Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 , -L 2 -Ar 2a ; R 3 Indicates H, halogen, or C 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6 -Alynyl groups, each of which may be unsubstituted or independently substituted by -OH or 1, 2 or 3 halogens; A represents a 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 a 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 or C 3-5 -Cycloalkyl mono- or di-substituted, the C 1-4 -The alkyl group is not substituted or is substituted with 1, 2 or 3 halogens, and the C 1-4 -alkyl or C 3-5 - In a cycloalkyl group, 1, 2, 3, 4, 5, 6 or 7 H atoms can be replaced by deuterium (D-atom); 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-, -NH-CH2-, -N(R 6 )-CH2-, -NH-C(=O)-, -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 This 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 unsubstituted or independently converted to 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 unsubstituted or independently converted to 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 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 not substituted or are independently substituted 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 Cyc 2a 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 connected to the same carbon atom of the carbon ring or the heterocycle B6 R B7 R B8 R B9 R B10 R B11 The two in the mixture form a divalent oxy group (=O); and / or R connected 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 a divalent oxo group or a divalent =NH or =NC group. 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 1, 2 or 3 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 1, 2 or 3 halogens -OC 1-4 -alkyl; Halogens are represented by F, Cl, Br, or I; 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.

2. Compounds of formula (I) I in Ring D and R 2 together or ; X 1 Indicates CR X1 Or N; R X1 Indicates H, halogen, straight-chain or branched C 1-4 -alkyl groups, which are unsubstituted or independently substituted with the following groups: 1, 2 or 3 halogens, and / or OH; R 1 This refers to straight-chain or branched C atoms that are not substituted or are independently substituted by one, two, or three halogens. 1-6 -alkyl; R 2 represents H or Alk 2 , Ar 2 , Hetar 2 , Cyc 2 , Hetcyc 2 , or -L 2 -Ar 2a ; R 3 Indicates H or halogen; A represents a 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 a 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 1, 2 or 3 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 This 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 unsubstituted or independently converted to 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 unsubstituted or independently converted to 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 not substituted or are independently substituted 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 connected to the same carbon atom of the carbon ring or the heterocycle B6 R B7 R B8 R B9 R B10 R B11 The two in the mixture form a divalent oxy group (=O); and / or R connected 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 a divalent oxo group or a divalent =NH or =NC group. 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 1, 2 or 3 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 1, 2 or 3 halogens -OC 1-4 -alkyl; Halogens are represented by F, Cl, Br, or I; 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.

3. The compound according to any one of claims 1 or 2, in Ring D and R 2 together ; X 1 Indicates CR X1 Or N; R X1 Represents H; and R 2 A, L 1 And B as defined in claim 1; 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 in X 1 Indicates CH; 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.

5. The compound according to any one of claims 1 or 2, in Ring D and R 2 together ;and R 2 A, L 1 And B as defined in claim 1; 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 in R 3 Indicates halogen; either F or I is optional; especially 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.

7. The compound according to any one of claims 1-5 in R 3 H 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.

8. The compound according to any one of the preceding claims in R 1 C represents the unreplaced straight or branched chain. 1-6 -alkyl, the C 1-6 The 1, 2, 3, 4, 5, 6, or 7 H atoms in the -alkyl group can be replaced by deuterium (D-atom); optionally -CH3, -CD3, -C2H5, or -C2D5; 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.

9. The compound according to any one of the preceding claims in R 2 Represents H, Alk 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a ; 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.

10. The compound according to any one of the preceding claims in R 2 Represents H, Alk 2 Hetar 2 Hetcyc 2 -L 2 -Ar 2a ; Alk 2 C represents a straight chain or a branch chain. 1-6 -alkyl 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; L 2 This 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 Each of the above 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 unsubstituted or independently converted to R B1 and / or R B2 replace; Cyc 2a This refers to a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon rings are not substituted or are 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 Common replacement; 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 -SR 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 ; 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 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 replacement; 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 connected to the same carbon atom of the heterocycle B8 and R B9 Forming divalent oxygen (=O) groups; and / or R attached to the same sulfur (S) atom of the heterocycle B6 R B7 R B8 R B9 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 The other two in it form a divalent oxo group or a divalent =NH or =NC group. 1-4 -alkyl groups, thereby forming -S(=O)2, -S(=O)(=NH) or -S(=O)(=NC 1-4 -alkyl) moiety; 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.

11. The compound according to any one of the preceding claims in R 2 Represents H, Alk 2 Hetar 2 Hetcyc 2 ; Alk 2 C represents a straight chain or a branch chain. 1-4 -alkyl groups, which may be unsubstituted or independently of each other, R 2a1 and / or R 2a2 replace; Hetar a 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, the C 1-4 -The alkyl group may be unsubstituted or substituted with one, two or three halogens; Cyc 2a This refers to a saturated monocyclic carbon ring having four ring carbon atoms, wherein the carbon ring is either unsubstituted or monosubstituted with -OH. Hetcyc 2 This refers to a saturated monocyclic heterocycle having 5 ring atoms, wherein one of the ring atoms is a heteroatom selected from O or S, and the remaining ring atoms are carbon atoms, wherein the heterocycle is unsubstituted or monosubstituted by OH. Hetcyc 2a This refers to a saturated monocyclic heterocycle having 4, 5, or 6 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 to OH, -OC 1-4 -alkyl or C 1-4 -alkyl monosubstituted, wherein the C 1-4 -Alkyl groups may be unsubstituted or replaced with -OH or -OC. 1-4 -Alkyl monosubstituted; R 2a1 R 2a2 F, -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)(=NR) g )R f -C(=O)NH2, -C(=O)NHR a C(=O)OR c -NH-C(=O)-R i Cyc 2a Hetar 2a Hetcyc 2a ; R a R b Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; 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 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 replacement; R c C represents a straight chain or a branch chain. 1-4 -alkyl; R d R e Each can be represented independently as a straight chain or a branch C. 1-6 -alkyl; R f C represents a straight chain or a branch chain. 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 B6 R B7 Each represents OH independently; R connected to the same carbon atom of the heterocycle B8 and R B9 Forming divalent oxygen (=O) groups; 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.

12. The compound according to any one of the preceding claims in R 2 Represents H; -CH3, -CH2-CN, -(CH2)2-CN, -(CH2)2-OH, -(CH2)3-OH, CH2-CH(CH3)-CH2-OH, -CH2-CHF-CH2-OH, -CH2-CH(O H)-CH2-OH, -CH(CH2OH)2, -CH2-CH(OH)-CH2-OCH3, -(CH2)3-S-CH3, -(CH2)2-S(=O)(=NH)CH3, -CH2-P(=O)(CH3)2 -CH2-C(=O)-NH2, -CH2-C(=O)-NHCH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-NH-C(=O)-H, -(CH2)2-NH-C(=O)-CH3, 2-(3-hydroxypyrrolidine-1-yl)ethyl, 2-(2-oxo-pyrrolidine-1-yl)ethyl, (2-morpholin-4-yl-ethyl); 1-methyl-1H-imidazol-4-yl, 1-methyl-1H-imidazolium -5-yl, 1,2-thiazolyl-2-yl, 1,3-thiazolyl-2-yl, 1,3-thiazolyl-4-yl, pyrazin-2-yl; (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (4-methyl-1H-imidazol-2-yl)methyl, 2-(1H-imidazol-4-yl)ethyl, (1H-pyrazol-4-yl)methyl, (1-methyl-1H-pyrazol-3-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 2-(1 -Methyl-1H-pyrazol-4-yl)-ethyl, 1-oxazol-2-ylmethyl, 1,3-thiazol-5-ylmethyl, 2-methyl-1,3-thiazol-4-ylmethyl, 2-methyl-1,3-thiazol-5-ylmethyl, 1H-1,2,3-triazol-4-ylmethyl, 1H-1,2,4-triazol-3-ylmethyl, pyrazin-2-ylmethyl, 3-methylpyrazin-2-ylmethyl, pyridazin-3-ylmethyl, pyrimidin-2-ylmethyl, pyrimidin-4-ylmethyl, 2-hydroxy-1-(pyrazin-2-yl)ethyl; 1-hydroxycyclobutylmethyl ( ), , , , [3-(hydroxymethyl)oxetane-3-yl]methyl( ), (3-hydroxyoxacyclopentan-3-yl)methyl ( ), (4-hydroxyoxacyclohexane-4-yl)methyl ( ); 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.

13. The compound according to any one of the preceding claims in R 2 Represents H; -CH3, -CH2-CN, -(CH2)2-CN, -(CH2)2-OH, -(CH2)3-OH, -CH(CH2OH)2, -(CH2)2-S(=O)(=NH)CH3, -CH2-P(=O)(C H3)2, -CH2-C(=O)-NH2, -CH2-C(=O)-NHCH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-NH-C(=O)-H, -( CH2)2-NH-C(=O)-CH3, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 1,3-thiazol-5-ylmethyl, 2-methyl-1,3-thiazol-5-ylmethyl, pyrazin-2-ylmethyl, 3-methylpyrazin-2-ylmethyl, pyrimidin-4-ylmethyl, 2-hydroxy-1-(pyrazin-2-yl)ethyl; -CH-(pyrazin-2-yl)-C(=O)OCH3; , , ; 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.

14. The compound according to any one of the preceding claims in A represents in This indicates that ring A and compound of formula I The connection point of the double-ring system, and L represents the compound of formula I. 1 -B group connection points; 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 in 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 in 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.

17. The compound according to any one of the preceding claims in B represents Ar 1 Hetar 1 Cyc 1 ; L 1 Represents -O-, -N(R) 4 -, -O-CH2-, -O-SO2-; R 4 Indicates H or 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 is divided by R C6 Single substitution or R C6 and R C7 Bisubstitution; R C1 Indicates F, Cl, CH3, CHF2, or CF3; R C2 It represents CH3 or C2H5; R C6 represents F, Cl; CH3, CHF2, CF3, -OCH3, -OCHF2, -OCF3; R C7 Indicate 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.

18. The compound according to any one of the preceding claims in L 1 It represents -O-, -NH-, or -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.

19. The compound according to any one of the preceding claims in 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 in 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 the preceding claims in L 1 Indicates -O-; 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 the preceding claims in L 1 Indicates -O-; 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 1-20 in L 1 It represents -O-CH2-; 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.

24. The compound according to any one of the preceding claims in 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.

25. The compound according to any one of the preceding claims in Ring D together with R 2 express ; X 1 Indicates CH or N; R 1 It represents CH3; R 2 Represents H; -CH3, -CH2-CN, -(CH2)2-CN, -(CH2)2-OH, -(CH2)3-OH, -CH(CH2OH)2, -(CH2)2-S(=O)(=NH)CH3, -CH2-P (=O)(CH3)2, -CH2-C(=O)-NH2, -CH2-C(=O)-NHCH3, -(CH2)2-C(=O)-NH2, -(CH2)2-C(=O)-NHCH3, -(CH2)2-NH -C(=O)-H, -(CH2)2-NH-C(=O)-CH3, (1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-4-yl)methyl, (1-methyl-1H-imidazol-5-yl)methyl, (1-methyl-1H-pyrazol-4-yl)methyl, 1,3-thiazol-5-ylmethyl, 2-methyl-1,3-thiazol-5-ylmethyl, pyrazin-2-ylmethyl, 2-methylpyrazin-3-ylmethyl, pyrimidin-4-ylmethyl, 2-hydroxy-1-(pyrazin-2-yl)ethyl; -CH-(pyrazin-2-yl)-C(=O)OCH3; , , ; R 3 H represents; 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 according to any one of claims 1 or 2, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, wherein the compound is selected from the compounds shown in Tables 1 and 1a.

27. 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.

28. The compound of any one of claims 1-26, 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 a medical condition or disease affected by the inhibition of the interaction between YAP-TEAD and / or TAZ-TEAD.

29. The compound according to any one of claims 1-26, 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 selected from: cancer, particularly tumors, including solid tumors such as breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer; cardiovascular diseases and fibrosis, particularly liver fibrosis.

30. A pharmaceutical composition comprising at least one compound as an active ingredient according to any one of claims 1-26, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, and a pharmaceutically acceptable carrier.

31. A pharmaceutical composition comprising (a) a compound of any one of claims 1-26, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all ratios, as a first active ingredient; and (b) a second active ingredient, wherein the second active ingredient is different from the compound of formula I of any one of claims 1-26.

32. A method for preparing a compound according to any one of claims 1-26, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, characterized in that: (A) In the first reaction step, compound II is made II in R 1 R 3 and X 1 As defined by Formula I of any one of claims 1 to 26; Y 1 Indicates H or suitable protecting group PG 1 ; Hal 1 Indicates Cl, Br, or I; Reaction with compound of formula III under suitable C-C coupling reaction conditions Y 2 -A-L 1 -B III in A, L 1 B is defined by Formula I as claimed in any one of claims 1 to 26; Y 2 Indicates suitable borate ester functional groups; Compound of formula IV was obtained IV or (B) In the first reaction step, compound V is made... V in R 1 R 3 and X 1 As defined by Formula I of any one of claims 1 to 26; Y 1 Indicates H or suitable protecting group PG 1 ; Y 3 Indicates suitable borate ester functional groups; Reaction with compound of formula VI under suitable CC coupling reaction conditions Hal 2 -AL 1 -B VI in A, L 1 B is defined by Formula I as claimed in any one of claims 1 to 26; Hal 2 Indicates Cl, Br, or I; Compound of formula IV was obtained; And optionally, after step (A) or (B) (C) (1) If in equation 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 Compounds of formula I that are H; and / or (C) (2) If in the above equation IV, Y 1 If H represents the compound, then in another reaction step, compound IV reacts with compound VII under suitable reaction conditions. R 2 -LG 1 VII in R 2 As defined in any one of claims 1 to 26, but not H; and LG 1 Indicates a suitable leaving group; To obtain a compound of formula I as defined in any one of claims 1 to 26; or (D) In the first reaction step, compound VIII is made VIII in R 1 and R 3 As defined by Formula I of any one of claims 1 to 26; Y 1 Indicates H or suitable protecting group PG 1 ; Hal 1 Indicates Cl, Br, or I; Reaction with compound of formula III under suitable C-C coupling reaction conditions Y 2 -A-L 1 -B III in A, L 1 B is defined by Formula I as claimed in any one of claims 1 to 26; Y 2 Indicates suitable borate ester functional groups; Compound of formula IX is obtained; IX; or (E) In the first reaction step, compound X is made X in R 1 and R 3 As defined by Formula I of any one of claims 1 to 26; Y 1 Indicates H or suitable protecting group PG 1 ; Y 3 Indicates suitable borate ester functional groups; Reaction with compound of formula VI under suitable CC coupling reaction conditions Hal 2 -AL 1 -B VI in A, L 1 B is defined by Formula I as claimed in any one of claims 1 to 26; Hal 2 Indicates Cl, Br, or I; Compound of formula IX is obtained; And optionally, after step (D) or (E) (F) (1) If in the above equation IX, Y 1 PG 1 In the second reaction step, PG is removed under suitable reaction conditions. 1 , to obtain Y 1 Compounds of formula IX with H can also be described as having R. 2 Compounds of formula I that are H; and / or (F) (2) If in the above equation IX, Y 1 If H represents the compound, then in another reaction step, compound IX reacts with compound VII under suitable reaction conditions. R 2 -LG 1 VII in R 2 As defined in any one of claims 1 to 26, but not H; and LG 1 Indicates a suitable leaving group; To obtain a compound of formula I as defined in any one of claims 1 to 26.

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