Triring heterocycle

Abstract

The present invention relates to tricyclic heterocycles. These heterocyclic compounds are useful as TEAD binders and / or inhibitors of YAP-TEAD and TAZ-TEAD protein-protein interactions or binding, and are also useful in the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases, particularly cancer.

Description

[Technical Field]

[0001] Field of the present invention This invention relates to tricyclic heterocyclic compounds. These heterocyclic compounds are useful as TEAD binders and / or inhibitors of YAP-TEAD protein-protein interaction or binding, as well as for the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases, particularly cancer. [Background technology]

[0002] Background of the present invention In recent years, the Hippo pathway has become an interesting target for the treatment of hyperproliferative disorders and diseases, particularly cancer (SASmith et al., J.Med.Chem.2019, 62, 1291-1305; KCLin et al., Annu.Rev.Cancer Biol.2018, 2:59-79; C.-L.Kim et al., Cells(2019), 8, 468; KFHarvey et al., Nature Reviews Cancer, Vol.13, 246-257(2013)). The Hippo pathway regulates cell growth, proliferation, and migration. In mammals, the Hippo pathway is thought to act as a tumor suppressor, and dysfunction of Hippo signaling is frequently observed in human cancers.

[0003] Furthermore, while the Hippo pathway plays a role in several biological processes—including the self-renewal and differentiation of stem cells and progenitor cells, wound healing and tissue regeneration, and interactions with other signaling pathways such as Wnt—its dysfunction can 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 the pathway's activity and regulation still require further investigation, it is already established that in its "switched-on" state, the Hippo pathway involves a cascade of kinases (including Mst 1 / 2 and Lats 1 / 2) in the cytoplasm, leading to the phosphorylation of two transcriptional coactivators: YAP (Yes-related protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif). Phosphorylation of YAP / TAZ sequesters them in the cytoplasm, ultimately leading to their degradation. In contrast, when the Hippo pathway is "switched-off" or dysfunctional, the unphosphorylated activated YAP / TAZ coactivators are translocated into the cell nucleus. The main target transcription factors are four proteins from the Transcriptional Enhanced Associate Domain (TEAD) transcription factor family (TEAD1-4). The binding of YAP or TAZ to TEAD (or other transcription factors) and the activation of TEAD (or other transcription factors) have been shown to induce the expression of several genes (many of which mediate cell survival and proliferation). Therefore, activated non-phosphorylated YAP and TAZ can act as oncogenes, while the activated, switch-on Hippo pathway can act as a tumor suppressor by inactivating (i.e., phosphorylating) YAP and TAZ.

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

[0006] As a result, dysfunction or abnormal regulation of the Hippo pathway as a tumor suppressor is thought to be an important event in the development of a variety of cancer types and diseases.

[0007] Therefore, inhibition of the protein-protein interactions of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD by pharmacological intervention appears to be a rational and valuable strategy for preventing and / or treating cancers and other hyperproliferative disorders and diseases associated with Hippo pathway dysfunction.

Summary of the Invention

[0008] Description of the present invention The present invention provides compounds useful for the prevention and / or treatment of medical conditions, disorders and / or diseases, particularly hyperproliferative disorders or diseases, which compounds are TEAD binders and / or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interactions.

[0009] In one aspect, the present invention provides a compound of formula I-A

Chemical Formula

[0010] In another aspect or embodiment, the present invention relates to Formula I [ka] During the ceremony W 1 CR W1 or represent N; W 2 CR W2 or represent N; W 3 CR W3 or represent N; W 4 CR W4 or represent N; Here W 1 , W 2 , W 3 , and W 4W is either one of them does not represent N, or it represents N at the same time. 1 , W 2 , W 3 , and W 4 It is either one of the following; and R W1 H, C 1~6 - Represents aliphatic and halogen; R W2 H, C 1~6 -Aliphatic; represents halogens; R W3 H, C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W Represents; R W4 H, C 1~6 - Represents aliphatic and halogen; Here Z 1 is either CH or N; Z 2 CR Z2 or N; Here's Z 1 and Z 2 At least one of them is not N; R 1 Ar 1 Hetar 1 ,Cyc 1 Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Het cyc 1 , C 1~8 - Represents an aliphatic element (which is substituted with one, two, or three halogens, which may be the same or different); R 2 is -C(=O)-OR 2a -C(=O)-NR 2b R 2c ,-(CH2) x -NR2d -C(=O)-R 2e , -SR 2f -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i -S(=O)2-OH, -S(=O)(=NR 2j )-OH, -S(=O)(=NR 2j )-R 2g -S(=O)(=NR 2k )-NR 2l R 2m , -P(=O)(OR 2o )(OR 2p ), -(CH2) y -NR 2q R 2r ,-(CH2) z -NR 2d -S(=O)2-R 2g -N=S(=O)-R 2s R 2t -C(=O)-N=S(=O)-R 2s R 2t -C(=O)-N=S(=NR) 2u )-R 2s R 2t , or Hetcyc X Represents ; Ar W Even if they are non-substitutions, or independent of each other, R W11 and / or R W12 This represents phenyl which may be mono- or di-substituted; R Z2 is a character that represents H; or R 2 Together with it, it forms a divalent radical -S(=O)2-N(H)-C(=O)-; R 2a C is either H, unsubstituted, or substituted. 1~8 - Represents aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or Cat; Cat represents a monovalent cation; R 2b , R 2c , R 2q , R 2rThese are H, unsubstituted, or substituted C, independently of each other. 1~8 - Represents aliphatic; or R 2b is R 2c Together with, and / or R 2q is R 2r Together with the nitrogen atom to which these are attached, they form a heteroring having 3, 4, 5, 6, or 7 ring atoms, which are unsubstituted or substituted, saturated, partially unsaturated, or aromatic, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one of the further ring atoms is a heteroatom selected from N, O, or S and the rest are carbon atoms; where the heteroring is optionally Hetar Z It may be condensed with; or R 2b and R 2c One of them is -CN or -S(=O)2-R 2g The other side represents H, or a non-substitutive or substituted C. 1~8 - Represents aliphatic phaganism; R 2d , R 2j , R 2k , R 2o , R 2p These are H, unsubstituted, or substituted C, independently of each other. 1~8 - Represents aliphatic and heteroaryl particles; R 2e C is H, halogen, unsubstituted or substituted. 1~8 -Aliphatic, aryl, heteroaryl; representing saturated or partially unsaturated heterocyclyls; R 2f , R 2g These are independent of each other, and are non-substitutive or substituted C 1~8 - Represents aliphatic phaganism; R 2h , R 2i These are H, unsubstituted, or substituted C, independently of each other. 1~8- Represents aliphatic, aryl, heterocyclyl, or heteroaryl; or, together with the nitrogen atom to which they are attached, they form a heteroring having 3, 4, 5, 6, or 7 ring atoms, which are unsubstituted or substituted, saturated, partially unsaturated, or aromatic, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or where one of the further ring atoms is a heteroatom selected from N, O, or S, and the rest are carbon atoms; R 2l , R 2m These are H, unsubstituted, or substituted C, independently of each other. 1~8 - Represents an aliphatic; or, together with the nitrogen atom to which they are attached, they form a heteroring having 3, 4, 5, 6, or 7 ring atoms, which are unsubstituted or substituted, saturated, partially unsaturated, or aromatic, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or where one of the further ring atoms is a heteroatom selected from N, O, or S, and the rest are carbon atoms; R 2s , R 2t These are independent of each other, and are non-substitutive or substituted C 1~8 - Represents an aliphatic; or together, unsubstituted or substituted divalent C 3~6 - Forms alkylene radicals; R 2u is hydrogen, or unsubstituted or substituted C 1~6 - Represents aliphatic phaganism; Ar 1 This is a monocyclic, dicyclic, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, where the aryl may be unsubstituted or substituted R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and / or R B7 These may be replaced by (they may be the same or different); Hetar 1This is a monocyclic, dicyclic, or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, where 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and / or R B7 These may be replaced by (they may be the same or different); Cyc 1 This is a saturated or partially unsaturated mono-, di-, or tricyclic carbon ring having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, where the carbon ring may be unsubstituted or R B8 , R B9 , R B10 , R B11 , R B12 , and / or R B13 (These may be the same or different) and may be substituted with; and here the carbon ring may optionally be Ar X And, the Ar X The condensation may occur via two adjacent ring atoms, and the condensed carbon ring may be unsubstituted or R C1 , R C2 , R C3 , R C4 , R C5 , and / or R C6 These may be replaced by (they may be the same or different); Hetcyc 1This is a saturated or partially unsaturated mono-, di-, or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, where 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle is unsubstituted or R B8 , R B9 , R B10 , R B11 , R B12 , and / or R B13 These may be replaced by (they may be the same or different); L 1 C is -S(=O)2-, unsubstituted or substituted linear or branched C 1~6 - Alkylene or C 1~6 -A divalent radical selected from the group consisting of alkenylenes (in both cases, one of the carbon units of the alkylene chain or alkenylene chain may be replaced by -O-); L 2 C is a linear or branched C that is either unsubstituted or substituted. 1~6 - Alkylene or C 2~6 -A divalent radical selected from the group consisting of alkenylenes (in both cases, one of the carbon units of the alkylene chain or alkenylene chain may be replaced by -O-); R W11 , R W12 These are, independently of each other, halogens, or unsubstituted or substituted C 1~6 - Represents aliphatic phaganism; R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 These are independent of each other, and are non-substitutive or substituted C 1~6 -Aliphatic, C 1~6 -Aliphatic oxy, -SC 1~6 -Aliphatic; halogen, -CN, -S(=O)-R b1, S(=O)2-R b1 , -NR b2 R b3 Ar 2 -CH2-Ar 2 Hetar 2 ,Cyc 2 Hetcyc 2 Represents; and / or two adjacent R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and / or R B7 Together, divalent -C 2~4 -Alkylene radical (where one of the alkylene carbon units in the radical may be replaced by a carbonyl unit (-C(=O)-)), or divalent -OC 1~3 -Alkylene radical, or divalent -OC 1~3 -Forms alkylene-O-radicals; R b1 C is either non-substitutive or substituted. 1~8 - Represents aliphatic phaganism; R b2 , R b3 These are H, unsubstituted, or substituted C, independently of each other. 1~8 - Represents aliphatic; or Together with the attached nitrogen atom, these form a heteroring having 3, 4, 5, 6, or 7 ring atoms, which are unsubstituted or substituted, saturated, partially unsaturated, or aromatic, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or where one of the further ring atoms is a heteroatom selected from N, O, or S, and the rest are carbon atoms; R B8 , R B9 , R B10 , R B11 , R B12 , R B13 These are, independently of each other, halogen, unsubstituted, or substituted C 1~6 -Aliphatic, C 1~6 -Aliphatic oxy, Ar Y Represents; and / or R attached to the same carbon atom of the carbon ring or heteroring B8 , R B9 , R B10 , R B11 , R B12 , R B13 Two of them form a divalent oxo (=O) group; and / or R attached to the same sulfur atom of the heterocycle B8 , R B9 , R B10 , R B11 , R B12 , R B13 Two of them, or R B8 , R B9 , R B10 , R B11 , R B12 , R B13 Four of these groups form a divalent oxo (=O) group, thereby creating either an -S(=O)- moiety or an -S(=O)2- moiety; Ar 2 This is a monocyclic or bicyclic aryl having 5, 6, 7, 8, 9, or 10 ring carbon atoms, where the aryl may be unsubstituted or substituted R D1 , R D2 , R D3 , R D4 , and / or R D5 These may be replaced by (they may be the same or different); Hetar 2 This is a monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, or 10 ring atoms, where 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R D1 , R D2 , R D3 , R D4 , and / or R D5 These may be replaced by (they may be the same or different); Cyc 2This is a saturated or partially unsaturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbon ring may be unsubstituted or R D6 , R D7 , R D8 , R D9 , and / or R D10 (These may be the same or different) and may be substituted; where the carbon ring is optionally Ar Z or Hetar Z And, the Ar Z or Hetar Z The ring may be fused via two adjacent ring atoms, and the fused carbon ring may be unsubstituted, or further R C1 , R C2 , R C3 , R C4 , R C5 , and / or R C6 These may be replaced by (they may be the same or different); Hetcyc 2 This is a monocyclic heterocycle having 3, 4, 5, 6, or 7 ring atoms, where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle is unsubstituted or R D6 , R D7 , R D8 , R D9 , and / or R D10 (These may be the same or different) and may be substituted; where the heteroring is optionally Ar Z or Hetar Z And, the Ar Z or Hetar Z The ring may be condensed via two adjacent ring atoms, and the condensed heteroring may be unsubstituted, or further R C1 , R C2 , R C3 , R C4 , R C5 , and / or R C6These may be replaced by (they may be the same or different); Ar X Ar Z These are, independently of each other, unsubstituted or substituted benzo rings; Ar Y is an unsubstituted or mono- or di-substituted phenyl; Hetar Y1 This is a 5- or 6-membered monocyclic heteroaryl, where one, two, three, or four ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or halogen, C 1~4 -It may be substituted with alkyl (which may optionally be substituted with OH); Hetar Z This is an unsubstituted or substituted 5-membered or 6-membered heteroaryl ring selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran; Cyc Y1 This is a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbon ring may be unsubstituted or contain halogens, OH, C 1~4 - May be substituted with alkyl groups; Hetcyc X This is a monocyclic heterocycle having 3, 4, 5, 6, or 7 ring atoms, which are saturated, partially unsaturated, or aromatic, where 1, 2, 3, or 4 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , and / or R X8These may be the same or different, and may be substituted with, and here the heterocycle is optionally a biological equivalent of a carboxylic acid; Hetcyc Y A monocyclic heterocycle having 3, 4, 5, 6, or 7 ring atoms, which are saturated, partially unsaturated, or aromatic, where 1, 2, 3, or 4 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms; Hetcyc Y1 A monocyclic heterocycle having five or six ring atoms, which are saturated or partially unsaturated, where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms; R C1 , R C2 , R C3 , R C4 , R C5 , R C6 These are independent of each other, and are non-substitutive or substituted C 1~6 - Represents aliphatic phaganism; R D1 , R D2 , R D3 , R D4 , R D5 These are independent of each other, and are non-substitutive or substituted C 1~6 - Represents aliphatic phaganism; R D6 , R D7 , R D8 , R D9 , R D10 These are independent of each other, and are non-substitutive or substituted C 1~6 -Aliphatic, unsubstituted, or substituted C 1~6 -Aliphatic oxy, halogen, hydroxy; Hetar Y1 CH2-Hetar Y1 ,Cyc Y1 Hetcyc Y1 -CH2-Hetcyc Y1 Represents; and / or R attached to the same ring atom of the carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , RD9 , R D10 Two of them are divalent C 2~6 - An alkylene radical may be formed, where one or two non-adjacent carbon units of the alkylene radical may be, optionally, independently of each other, O, NH, or NC. 1~4 -It may be replaced by an alkyl group, where the alkylene radical is optionally OH, C 1~4 -alkyl, or -OC 1~4 - May be substituted with alkyl; and / or R attached to different ring atoms of the carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 1~6 - An alkylene radical may be formed, where one or two non-adjacent carbon units of the alkylene radical may be, optionally, independently of each other, O, NH, or NC. 1~4 -May be replaced by alkyl; R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 These are independent of each other, and are non-substitutive or substituted C 1~6 -Aliphatic, C 1~6 -Aliphatic oxy, -OH, -NR 2d -S(=O)2-R 2g Hetcyc Y O-Hetcyc Y Represents; and / or R attached to the same carbon atom of the heterocycle X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 Two of them form a divalent oxo (=O) group; and / or attached to the same sulfur atom of the heterocycle, R X1 , RX2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 Two of them, or R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 Four of these groups form a divalent oxo (=O) group, thereby creating either an -S(=O)- moiety or an -S(=O)2- moiety; Halogens are F, Cl, Br, and I; w is either 1 or 2; x is 0, 1, or 2; y is either 1 or 2; z is 0, 1, or 2; This refers to the compounds represented by , or any of their N-oxides, solvates, tautomers, or stereoisomers, and / or pharmaceutically acceptable salts of each of the above, as well as mixtures thereof in any proportion.

[0011] In general, all residues, radicals, substituents, groups, moieties, etc., appear more than once, but may be identical or different, i.e., they are independent of each other. Above and below, residues and parameters have the meanings indicated for formulas IA and I unless otherwise clearly indicated. Consequently, the present invention relates, in particular, to compounds represented by formulas IA and I, in which at least one of the residues, radicals, and substituents has one of the preferred meanings indicated below.

[0012] Any of the specific or preferred embodiments of the Invention as specified below and in the claims include not only the compounds represented by the specified formulas IA and I, but also their N-oxides, solvates, tautomers, or stereoisomers, as well as pharmaceutically acceptable salts thereof, and unless otherwise specified, mixtures thereof in any proportion.

[0013] In a specific embodiment PE0, the compounds of the present invention are tricyclic heterocycles represented by formula IA, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts of any of the above, as well as mixtures thereof in any proportion, wherein in the formula Z 1 CH is; Z 2 CR Z2 is; Z 3 is either CH or N; R Z2 is H; or R 2 Together with it, it forms a divalent radical -S(=O)2-N(H)-C(=O)-;R Z2 H is particularly important.

[0014] In another specific embodiment of PE0, PE0a, Z 3 It is N. In another specific embodiment of PE0, PE0b, Z 3 CR Z3 It is; R Z3 H is H.

[0015] It will be understood that this specific embodiment PE0b is identical to the specific embodiment PE1 described below. In other words, Z in equation IA 3 CR Z3 Show, R Z3 When is H, the compound represented by formula IA may also be described as the compound represented by formula I.

[0016] In a specific embodiment PE1, the compound of the present invention is a tricyclic heterocycle represented by formula I, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion, wherein in the formula Z 1 CH is; Z 2 CR Z2 is; R Z2 is H; or R 2 Together with it, it forms a divalent radical -S(=O)2-N(H)-C(=O)-, The remaining radicals and residues are defined for Formula I above, or for any of the further specific embodiments described below this specification.

[0017] In another specific embodiment of PE1, PE1a, both Z 1 and Z 2 Both are CH.

[0018] In a further specific embodiment PE2-0, the compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein R W1 , R W2 , R W3 , and R W4 At least one of them is not H at the same time (i.e., W 1 , W 2 , W 3 , and W 4 Even if one of them represents N, W 1 , W 2 , W 3 , and W 4 (At least one substituent present in the ring containing is other than hydrogen.)

[0019] In a further specific embodiment PE2, the compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein in the formula (a) W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 This represents H; R W2 This represents H; R W3 C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W Represents; R W4 This represents H; Ar W This is true even if it is not a substitution or R W11 Represents phenyl which may be monosubstituted; R W11 This represents a halogen; preferably F; or (b) W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 This represents H; R W2C 1~6 - Represents aliphatic phaganism; R W3 This represents H; R W4 This represents H; or (c) W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 This represents H; R W2 This represents H; R W3 This represents H; R W4 C 1~6 - Represents aliphatic phaganism; or (d) W 1 CR W1 Represents; W 2 This represents N; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 This represents H; R W3 C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W Represents; R W4 This represents H; Ar W This is true even if it is not a substitution or R W11 Represents phenyl which may be monosubstituted; R W11This represents a halogen; preferably F; or (e) W 1 CR W1 Represents; W 2 This represents N; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 This represents H; R W3 This represents H; R W4 C 1~6 - Represents aliphatic phaganism; or (f) W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 This represents N; W 4 CR W4 Represents; R W1 This represents H; R W2 C 1~6 - Represents aliphatic phaganism; R W4 This represents H; or (g) W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 This represents N; W 4 CR W4 Represents; R W1 This represents H; R W2 This represents H; R W4 C1~6 - represents aliphatic; or (h) W 1 represents C-R W1 ; W 2 represents C-R W2 ; W 3 represents C-R W3 ; W 4 represents N; R W1 represents H; R W2 represents H; R W3 represents C 1~6 - aliphatic, -O-C 1~6 - aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W ; Ar W represents phenyl which may be unsubstituted or monosubstituted by R W11 ; R W11 represents halogen; preferably F; and the remaining radicals and residues are as defined for formula I-A or I above, or for any of the further specific embodiments described above or below in this specification.

[0020] In another specific embodiment PE3, the compounds of the present invention are tricyclic heterocycles represented by formula I-A or I, or any of their N-oxides, solvates, tautomers, or stereoisomers, and / or any pharmaceutically acceptable salts of each of the above, and mixtures thereof in any ratio, wherein (a) W 1 represents C-R W1 ; W 2 represents C-R W2 ; W 3 represents C-R W3 ; W 4 CR W4 Represents; R W1 This represents H; R W2 This represents H; R W3 C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W Preferably, it represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), or -CH2-(4-fluorophenyl); R W4 This represents H; Ar W This is true even if it is not a substitution or R W11 Represents phenyl which may be monosubstituted; R W11 This represents a halogen; preferably F; or (d) W 1 CR W1 Represents; W 2 This represents N; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 This represents H; R W3 C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W ; Represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), and -CH2-(4-fluorophenyl); R W4 This represents H; Ar W This is true even if it is not a substitution or R W11 Represents phenyl which may be monosubstituted; R W11 This represents a halogen; preferably F; or (h) W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 CR W3 Represents; W 4 This represents N; R W1 This represents H; R W2 This represents H; R W3 C 1~6 -aliphatic, -OC 1~6 -Aliphatic, halogen, -CN, -CH2-Ar W , or -CH2-CH2-Ar W ; Represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), and -CH2-(4-fluorophenyl); Ar W This is true even if it is not a substitution or R W11 Represents phenyl which may be monosubstituted; R W11 This represents a halogen; preferably F; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0021] In a further specific embodiment PE4, the compound of the invention is a tricyclic heterocycle represented by formula I-A or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, and / or mixtures thereof in any ratio, wherein R 1 is Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 , a straight-chain or branched C 1~6 -alkyl (which is substituted with one, two, or three F); Ar 1 is a monocyclic or bicyclic aryl having 6 or 10 ring carbon atoms (wherein the aryl may be unsubstituted or substituted with substituents R B1 , R B2 , and / or R B3 (which may be the same or different)); preferably phenyl or naphthalenyl, especially phenyl, which may be unsubstituted or substituted with substituents R B1 and / or R B2 (which may be the same or different); Hetar 1 is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein one, two, or three of the ring atoms are heteroatoms (singular or plural) selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or substituted with substituents R B1 , R B2 , and / or R B3(These may be the same or different) and may be substituted; preferably the heteroaryl is unsubstituted or substituted with R B1 and / or R B2 These are replaced by (they may be the same or different); Cyc 1 This is a monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, where the carbon ring may be unsubstituted or R B8 and / or R B9 (These may be the same or different) and may be substituted with; and here the carbon ring may optionally be Ar X And, the Ar X The fused ring may be formed via two adjacent ring atoms, and the fused carbon ring may be unsubstituted or R C1 and / or R C2 These may be replaced by (they may be the same or different); Hetcyc 1 A monocyclic heterocycle having 5 or 6 ring atoms, saturated or partially unsaturated (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R B8 and / or R B9 (These may be the same or different) and may be substituted, and if one of the heteroatoms is S, then the heteroring is also R B8 , R B9 , R B10 , and R B11 (may be substituted with); preferably a saturated monocyclic heterocycle having 5 or 6 ring atoms (where one of the ring atoms is a heteroatom selected from O and S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R B8 and / or R B9(These may be the same or different) and may be substituted, and if one of the heteroatoms is S, then the heteroring is also R B8 , R B9 , R B10 , and R B11 (This may be replaced by) L 1 C is -S(=O)2-, unsubstituted or substituted, linear or branched. 1~6 - Alkylene or C 2~6 -Selected from the group consisting of alkenylenes (in both cases, one of the carbon units of the alkylene chain or alkenylene chain may be replaced by -O-); preferably, a divalent radical selected from the group consisting of -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, and -CH2-CH=CH-; L 2 This refers to unsubstituted or substituted, linear or branched C 1~6 - Alkylene or C 2~6 -Selected from the group consisting of alkenylenes (in both cases, one of the carbon units of the alkylene chain or alkenylene chain may be replaced by -O-); preferably, a divalent radical selected from the group consisting of -CH2-, -CH2-CH2-; R B1 , R B2 , R B3 However, they are independent of each other, linear or branched C 1~6 -alkyl(that C 1~6 -Alkyl (may be unsubstituted, or monosubstituted with -CN, or substituted with one, two, or three halogens), linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens, -O-CH2-C≡CH, and may be linear or branched -SC 1~4 -alkyl(that-SC) 1~4-Alkyl can be unsubstituted, or it can be one, two, or three halogens, F, Cl, Br, -CN, -S(=O)-C 1~3 -alkyl, S(=O)2-C 1~3 -alkyl, -N(C 1~3 -alkyl)2, Ar 2 -CH2-Ar 2 Hetar 2 ,Cyc 2 Hetcyc 2 (May be replaced by) represents; Alternatively, two adjacent R B1 , R B2 , and / or R B3 Together, divalent -C 3~4 -Alkylene radical (where one of the alkylene carbon units in the radical may be replaced by a carbonyl unit (-C(=O)-)), or divalent -OC 2~3 - Forms alkylene radicals; Ar 2 It is phenyl; Hetar 2 This is a monocyclic heteroaryl having five or six ring atoms (where one, two, three, four, or five of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms); preferably, a monocyclic heteroaryl having five ring atoms (where one of the ring atoms is N and the rest are carbon atoms, or where one of the ring atoms is N and one of the ring atoms is S and the rest are carbon atoms); Cyc 2 These are cyclopropyl, cyclobutyl, and cyclopentyl, but each of these may be unsubstituted or R D6 Even if they are single substitutions, or if they are R independently of each other D6 and R D7 It may be substituted twice; Hetcyc 2 These are pyrrolidinyl and piperidinyl, but each of these can be unsubstituted or R D6 Even if they are single substitutions, or if they are R independently of each other D6and R D7 It may be substituted twice; R B8 , R B9 F and C are independent of each other. 1~2 -alkyl(that C 1~2 -Alkyl may be unsubstituted or substituted with one, two, or three F atoms), C 1~2 -alkoxy, Ar Y Represents; or R B8 and R B9 The carbon ring Cyc 1 or the heterocyclic Hetcyc 1 It is attached to the same carbon atom and forms a divalent oxo (=O) group; or R B8 and R B9 and R B10 and R B11 This refers to a group attached to the same sulfur atom of the heterocycle, forming two divalent oxo (=O) groups, thereby creating a -S(=O)2- moiety; Ar X is an unsubstituted benzo ring; Ar Y It is phenyl; R C1 , R C2 These are linear or branched C atoms, which are independent of each other. 1~4 - Represents alkyl, which may be independently substituted with one, two, or three F atoms; R D6 , R D7 The C atoms may be independently substituted with one, two, or three F atoms or one hydroxyl group. 1~6 - Represents alkyl or hydroxyl; Halogens are F, Cl, and Br. The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0022] In another specific embodiment of PE4, PE4a, R 1 Ar 1 Hetar 1 ,Cyc 1 Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Het cyc 1 , a straight-chain or branched C atom substituted with three F atoms at the same carbon atom (thus forming a CF3 group) 1~6 - Represents alkyl; Ar 1 These are phenyl or naphthalenyl, particularly phenyl, whether unsubstituted or substituent R B1 and / or R B2 These may be replaced by (they may be the same or different); Hetar 1 This is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where one, two, or three of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R B1 and / or R B2 These may be replaced by (they may be the same or different); Cyc 1 This is a monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, where the carbon ring may be unsubstituted or R B8 and / or R B9 (These may be the same or different) and may be substituted with; and here the carbon ring may optionally be Ar X And, the Ar XThe fused ring may be formed via two adjacent ring atoms, and the fused carbon ring may be unsubstituted or R C1 and / or R C2 These may be replaced by (they may be the same or different); Hetcyc 1 This is a saturated monocyclic heterocycle having 5 or 6 ring atoms, where one of the ring atoms is a heteroatom selected from O and S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R B8 and / or R B9 (These may be the same or different) and may be substituted, and if one of the heteroatoms is S, then the heteroring is also R B8 , R B9 , R B10 , and R B11 It may be replaced with; L 1 This is a divalent radical selected from the group consisting of -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, and -CH2-CH=CH-; L 2 is a divalent radical selected from the group consisting of -CH2- and -CH2-CH2-; R B1 , R B2 These are linear or branched C atoms, which are independent of each other. 1~6 -alkyl(that C 1~6 -Alkyl may be unsubstituted, or monosubstituted with -CN, or substituted with one, two, or three halogens (for example, -CH2F, -CHF2, -CF3, or -CF2Cl), linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens (for example, -OCF3, -O-CH-C≡CH), linear or branched -SC 1~4 -alkyl(that-SC)1~4 -Alkyl (may be unsubstituted or substituted with one, two, or three halogens), F, Cl, Br, -CN, -S(=O)-C 1~3 -alkyl, S(=O)2-C 1~3 -alkyl, -N(C 1~3 -alkyl)2, Ar 2 -CH2-Ar 2 Hetar 2 ,Cyc 2 Hetcyc 2 Represents; Alternatively, two adjacent R B1 , R B2 Together, divalent -C 3~4 -Alkylene radical (where one of the alkylene carbon units in the radical may be replaced by a carbonyl unit (-C(=O)-)), or divalent -OC 2~3 - Forms alkylene radicals; Ar 2 It is phenyl; Hetar 2 This is a monocyclic heteroaryl having five ring atoms, where one of the ring atoms is N and the rest are carbon atoms, or where one of the ring atoms is N and one of the ring atoms is S and the rest are carbon atoms; Cyc 2 These are cyclopropyl and cyclopentyl; Hetcyc 2 It is pyrrolidinil; R B8 , R B9 F and C are independent of each other. 1~2 -alkyl(that C 1~2 -Alkyl may be unsubstituted or substituted with one, two, or three F atoms), C 1~2 -alkoxy, Ar Y Represents; or R B8 and R B9 The carbon ring Cyc 1 or the heterocyclic Hetcyc 1It is attached to the same carbon atom, forming a divalent oxo (=O) group; or R B8 and R B9 and R B10 and R B11 This refers to the attachment of two divalent oxo (=O) groups to the same sulfur atom of the heterocycle, thereby forming the -S(=O)2- moiety; Ar X is an unsubstituted benzo ring; Ar Y It is phenyl; Halogens are F, Cl, and Br; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0023] In another specific embodiment of PE4 or PE4a, PE4b, R 1 Ar 1 Hetar 1 ,Cyc 1 Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Het cyc 1 , represents 3,3-dimethyl-4,4,4-trifluorobutyl; Ar 1 This applies even if the substituent R is unsubstituted or B1 and / or R B2 These are phenyls, which may be substituted with (they may be the same or different); Hetar 1These include furanyl, especially furan-2-yl; thiophenyl, especially thiophen-2-yl, thiophen-3-yl; thiazolyl, especially 1,3-thiazole-2-yl or 1,3-thiazole-4-yl; pyrazolyl, especially pyrazol-5-yl (1H-pyrazole-5-yl); imidazolyl, especially imidazole-2-yl (1H-imidazole-2-yl), imidazole-5-yl (1H-imidazole-5-yl); oxazolyl, especially 1,3-oxazole-2-yl; pyridinyl, especially pyridine-2-yl, pyridine-4-yl; pyrimidinyl, especially pyrimidine-2-yl; indolyl, especially 1 H-indole-6-yl; quinolinyl, especially quinoline-2-yl and quinoline-4-yl; benzofuranyl, especially 1-benzofuran-3-yl; benzothiophenyl, especially 1-benzothiophen-3-yl; isoquinolinyl, especially isoquinoline-3-yl; furo[3,2-b]pyridinyl, especially quinazolin-2-yl; pyrrolo[1,2-b]pyrazolyl, especially 4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-yl; pyrazolo[1,5-a]pyridinyl, especially pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl-7-yl; imidazo[1,2-a]pyridinyl, especially A heteroaryl selected from the group consisting of imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl; imidazo[1,5-a]pyridinyl, particularly imidazo[1,5-a]pyridin-1-yl, imidazo[1,5-a]pyridin-3-yl, imidazo[1,5-a]pyridin-5-yl; pyrazolo[1,5-c]pyrimidinyl, particularly pyrazolo[1,5-c]pyrimidin-3-yl; quinazolinyl, particularly quinazolin-2-yl; naphthiridinyl, particularly 1,5-naphthiridin-2-yl; where the heteroaryl is unsubstituted or substituted R B1 and / or R B2 These may be replaced by (they may be the same or different); Cyc 1The carbon ring is selected from the group consisting of cyclobutyl, cyclohexyl, cycloheptyl, cyclopentenyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.1]heptenyl, and methylbicyclo[3.1.1]heptenyl, where the carbon ring may be unsubstituted or R B8 and / or R B9 (These may be the same or different) and may be substituted with; and here the carbon ring may optionally be Ar X And, the Ar X The fused ring may be formed via two adjacent ring atoms, and the fused carbon ring may be unsubstituted or R C1 and / or R C2 These may be replaced by (they may be the same or different); Hetcyc 1 The heterocycle is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl, and thianyl, where the heterocycle may be unsubstituted or R B8 and / or R B9 (These may be the same or different) and may be substituted, and if one of the heteroatoms is S, then the heteroring is also R B8 , R B9 , R B10 , and R B11 It may be replaced with; L 1 This is a divalent radical selected from the group consisting of -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, and -CH2-CH=CH-; L 2 is a divalent radical selected from the group consisting of -CH2- and -CH2-CH2-; R B1 , R B2These are, independently of each other, methyl, ethyl, n-propyl, 2-propyl, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, -O-CH2-C≡CH, linear or branched -S-methyl, -S-CF 3、 F represents Cl, Br, -CN, -S(=O)-methyl, S(=O)2-methyl, -N(CH3)2, phenyl, -CH2-phenyl(benzyl), pyrrolyl, cyclopropyl, cyclopentyl, and pyrrolidinyl; Alternatively, two adjacent R B1 , R B2 Together, they form a divalent radical selected from the group consisting of -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-CH2-, -O-CH2-CH2-CH2-, -C(=O)-CH2-CH2-, and -C(=O)-CH2-CH2-CH2-; R B8 , R B9 These independently represent F, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, and phenyl; or R B8 and R B9 The carbon ring Cyc 1 or the heterocyclic Hetcyc 1 By being attached to the same carbon atom, it forms a divalent oxo (=O) group; or R B8 and R B9 and R B10 and R B11 This refers to the attachment of two divalent oxo (=O) groups to the same sulfur atom of the heterocycle, thereby forming the -S(=O)2- moiety; Ar X is an unsubstituted benzo ring; Ar Y It is phenyl; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0024] In a further specific embodiment PE5, the compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein R 2 is -C(=O)-OR 2a or Hetcyc X Represents; R 2a H, linear or branched, unsubstituted or substituted C 1~4 - Represents alkyl or cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na), and potassium (K); Hetcyc XThese include 1H-1,2,3,4-tetrazol-5-yl, 2H-1,2,3,4-tetrazol-5-yl, 2-methyl-2H-1,2,3,4-tetrazol-5-yl, 5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl (2H-1,2,4-oxadiazole-5-on-3-yl), 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl (4H-1,2,4-oxadiazole-5-on-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3-chloro-4,5-dihydro-1,2-oxazol-5-yl, and 3-(1H-1,2,3-triazol-1-yl )-4,5-dihydro-1,2-oxazol-5-yl, 3-(2H-1,2,3-triazol-2-yl)-4,5-dihydro-1,2-oxazol-5-yl, 3-(pyrimidine-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3-hydroxy-oxetane-3-yl, 5-hydroxy-4H-pyran-4-on-2-yl, 3,3-difluoropyrrolidine-2-on-4-yl, 3,3-difluoropyrrolidine-2-on-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrole-2-on-4-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrole-2-on-5-yl; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0025] In another specific embodiment of PE5, PE5a, R 2 is -C(=O)-OR 2a Represents; R 2a 'H' represents H, methyl, ethyl, or Cat; Cat represents a monovalent sodium cation; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0026] Furthermore, in a more specific embodiment PE6, the compound of the present invention is a tricyclic heterocycle represented by formula IA or I, or an N-oxide, solvate, tautomer, or stereoisomer of either thereof, and / or a pharmaceutically acceptable salt of each thereof, as well as mixtures thereof in any proportion, in the formula R 2 is -C(=O)-NR 2b R 2c It represents.

[0027] In a specific embodiment of PE6, PE6a, R 2 is -C(=O)-NR 2b R 2c Represents; and R 2b This represents hydrogen, R 2c hydrogen; linear or branched carbon 1~8 -alkyl (this is whether unsubstituted or R) E1 , R E2 , R E3 , R E4 , and / or R E5 (These may be the same or different) and may be replaced by; Cyc 2 or Hetcyc 2 This represents, but here R E1 , R E2 , R E3 , R E4 , and / or R E5 These are, independently of each other, halogens, especially F;-NR Ea R Eb , -OH, OR Ec Ar E Hetar E ,Cyc E Hetcyc E Represents; Ar E This refers to monocyclic or bicyclic aryl compounds having 6 or 10 ring carbon atoms (where the aryl is unsubstituted or substituted R). F1 , R F2 , and / or RF3 (These may be the same or different) and may be substituted with; preferably phenyl or naphthalenyl, especially phenyl; Hetar E This refers to a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms (where 1, 2, 3, or 4 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R F1 , R F2 , and / or R F3 (These may be the same or different) and may be substituted; in particular, heteroaryls may be unsubstituted or substituent R F1 and / or R F2 A monocyclic heteroaryl having five or six ring atoms, which may be substituted with (these may be the same or different); preferably the heteroaryl is selected from the group consisting of imidazolyl, 1H-imidazole-1-yl, and 1H-imidazole-2-yl, each of which is unsubstituted or C 1~4 -Single-substituted with alkyl); pyridyl, pyrido-2-yl, pyrido-3-yl, pyrido-4-yl (each of these may be unsubstituted or single-substituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; pyrazinyl, pyrazine-2-yl; pyridazinyl, pyridazine-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Cyc E This refers to a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms (where the carbon ring may be unsubstituted or R G1 and / or R G2(These may be the same or different) and may be substituted); in particular, saturated monocyclic carbon rings having 3, 4, 5, or 6 ring carbon atoms (where the carbon ring is unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted with; preferably cyclopropyl, cyclobutyl, or cyclohexenyl; Hetcyc E A monocyclic heterocycle having 4, 5, or 6 ring atoms, saturated or partially unsaturated (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted); in particular, a saturated monocyclic heterocycle having 5 or 6 ring atoms (where one or two of the ring atoms are heteroatoms (one or more) selected from N and / or O, and the rest are carbon atoms, where the heterocycle may be unsubstituted or R G1 (May be monosubstituted with -OH); preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of these may be unsubstituted or monosubstituted with -OH); pyrrolidinyl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl (each of these may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl (each of these may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl (each of these may be unsubstituted or monosubstituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; R Ea , R EbH and C are independent of each other. 1~4 -alkyl, -C(=O)-OC 1~4 - Represents alkyl; in particular, both represent H, or one represents H and the other represents C(=O)-O-tert.-butyl; R Ec is H or C 1~4 - Represents alkyl, especially H or methyl; R F1 , R F2 , and / or R F3 These are linear or branched C atoms, which are independent of each other. 1~6 -alkyl(that C 1~6 -Alkyl can be unsubstituted, or -CN, OH, -OC 1~4 -Single-substituted with alkyl, or substituted with one, two, or three halogens, linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens), linear or branched -SC 1~4 -alkyl(that-SC) 1~4 -Alkyl (may be unsubstituted or substituted with one, two, or three halogens), F, Cl, Br, -CN, -S(=O)-C 1~3 -alkyl, S(=O)2-C 1~3 -alkyl, -NH2, -NH(C 1~3 -alkyl), -N(C 1~3 -alkyl)2,-OH; in particular, representing methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably, R F1 , R F2 , and R F3 Only one of these exists, and it represents either methyl or F; and / or R attached to two different ring atoms of an aryl or heteroaryl F1 , R F2 , R F3 Two of them are divalent C 1~6- Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular -(CH2)4-, -CH2-O-(CH2)2-; R G1 and / or R G2 These are, independently of each other, halogen, hydroxyl, unsubstituted or substituted C 1~6 -Aliphatic, in particular C, which is optionally substituted with OH. 1~4 -alkyl, C 1~6 -Aliphatic oxy, in particular, -OC 1~4 -alkyl, -C(=O)-OC 1~4 -alkyl, Hetar Y2 -CH2-Hetar Y2 Hetcyc Y2 , in particular, representing hydroxyl; preferably, R G1 and R G2 Only one exists, and it represents hydroxyl; and / or R attached to the same ring atom of that carbocyclic or heterocyclic ring G1 and R G2 is divalent C 2~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 - May be replaced by alkyl, where the alkylene radical is optionally OH, C 1~4 -alkyl or -OC 1~4 -May be substituted with alkyl, in particular -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-; and / or R attached to two different ring atoms of the carbon ring or heteroring G1 and R G2 is divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4-May be replaced by alkyl groups, in particular, forming -CH2-; Cyc 2 This is a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbon ring may be unsubstituted or independently of each other, R D6 , R D7 , R D8 , R D9 , and / or R D10 It may also be substituted with, where the carbon ring is optionally Ar Z or Hetar Z And they may be condensed via two adjacent ring atoms, and here the condensed carbon rings may be optionally independent of each other, R C1 , R C2 , and / or R C3 It may be further replaced by; Hetcyc 2 This is a saturated monocyclic heterocycle having 4, 5, or 6 ring atoms, where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or independently of each other, R D6 , R D7 , R D8 , R D9 , and / or R D10 It may also be substituted with, where the heteroring is arbitrarily Ar Z or Hetar Z They may be condensed, and here the condensed heterorings may be any, independently of each other, R C1 , R C2 , and / or R C3 It may be further replaced by; R C1 , R C2 , R C3 They are independent of each other, C 1~4 - Represents alkyl; R D6 , R D7 , R D8 , R D9 , R D10These are C, independently of each other, substituted with halogens, particularly F; hydroxyl; optionally -OH and / or halogens. 1~4 -Alkyl, in particular methyl, hydroxymethyl, 2-fluoroethyl;-OC 1~4 -alkyl, especially methoxy, ethoxy; Hetar Y1 -CH2-Hetar Y1 ,Cyc Y1 Hetcyc Y1 -CH2-Hetcyc Y1 Represents; and / or R attached to the same ring atom of a carbocyclic or heterocyclic ring D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -It may be replaced by an alkyl group, where the alkylene radical is optionally OH, C 1~4 -alkyl, or -OC 1~4 -May be substituted with alkyl groups), in particular, forming -(CH2)3-, -CH2-CH(OC2H5)-CH2-, -(CH2)2-O-(CH2)2-; and / or R attached to two different ring atoms of a carbocyclic or heterocyclic ring D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 - may be replaced by alkyl groups, in particular, forming -CH2-, -(CH2)3-, -O-(CH2)2-, -O-(CH2)3-; Ar Z It is a benzo; Hetar Y1This refers to a 5-membered or 6-membered monocyclic heteroaryl (where 1, 2, 3, or 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or F, C 1~4 -Alkyl (which may optionally be substituted with an OH group); in particular, pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl, and methylpyridinyl; Hetar Y2 A 5-membered or 6-membered monocyclic heteroaryl (where one, two, three, or four ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or a halogen, C) is a 5-membered or 6-membered monocyclic heteroaryl. 1~4 -Alternatively substituted with alkyl (which may optionally be substituted with OH); in particular, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, and hydroxymethyloxazolyl; Hetar Z These are pyrrole, N-methylpyrrole, pyrazole, imidazole, and triazole; Cyc Y1 This refers to a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms (where the carbon ring may be unsubstituted, or contain halogens, OH, C). 1~4 - May be substituted with alkyl, especially cyclopropyl; Hetcyc Y1 This refers to saturated or partially unsaturated monocyclic heterocycles having five or six ring atoms (where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms); in particular, tetrahydrofuranyl; Hetcyc Y2These are saturated or partially unsaturated monocyclic heterocycles having five or six ring atoms (where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms); in particular, tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0028] In another specific embodiment of PE6a, PE6aa, R 2b This represents hydrogen, R 2c hydrogen; linear or branched carbon 1~8 -alkyl (this is whether unsubstituted or R) E1 , R E2 , R E3 , R E4 , and / or R E5 (These may be the same or different) and may be replaced by; Cyc 2 or Hetcyc 2 This represents, but here R E1 , R E2 , R E3 , R E4 , and / or R E5 These are, independently of each other, halogens, especially F;-NR Ea R Eb , -OH, OR Ec Ar E Hetar E ,Cyc E Hetcyc E Represents; Ar E This refers to monocyclic or bicyclic aryl compounds having 6 or 10 ring carbon atoms (where the aryl is unsubstituted or substituted R). F1 , R F2 , and / or R F3(These may be the same or different) and may be substituted with; preferably phenyl or naphthalenyl, especially phenyl; Hetar E This is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R F1 , R F2 , and / or R F3 (These may be the same or different) and may be substituted; in particular, heteroaryls are monocyclic heteroaryls having five or six ring atoms, which may be unsubstituted or substituted with substituent R F1 and / or R F2 (These may be the same or different) and may be substituted; preferably the heteroaryl is imidazolyl, 1H-imidazole-1-yl, 1H-imidazole-2-yl (each of these may be unsubstituted or C 1~4 -Single-substituted with alkyl); pyridyl, pyrido-2-yl, pyrido-3-yl, pyrido-4-yl (each of these may be unsubstituted or single-substituted with -F); selected from the group consisting of pyrimidinyl, pyrimidine-2-yl, pyrimidine-3-yl, and pyrimidine-4-yl; Cyc E This refers to a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms (where the carbon ring may be unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted); in particular, saturated monocyclic carbon rings having 3, 4, 5, or 6 ring carbon atoms (where the carbon ring is unsubstituted or R G1 and / or R G2(These may be the same or different) and may be substituted with; preferably cyclobutyl; Hetcyc E A monocyclic heterocycle having 5 or 6 ring atoms, saturated or partially unsaturated (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1 and / or R G2 (These may be the same or different); in particular, saturated monocyclic heterocycles having 5 or 6 ring atoms (where one or two of the ring atoms are heteroatoms (one or more) selected from N and / or O and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1 (These may be monosubstituted); preferably, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of these may be unsubstituted or monosubstituted with -OH); pyrrolidinyl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl (each of these may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl (each of these may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl; R Ea , R Eb H and C are independent of each other. 1~4 -alkyl, -C(=O)-OC 1~4 - Represents alkyl; in particular, both represent H, or one represents H and the other represents C(=O)-O-tert.-butyl; R Ec is H or C 1~4 - Represents alkyl, especially H or methyl; R F1 , R F2 , and / or R F3These are linear or branched C atoms, which are independent of each other. 1~6 -alkyl(that C 1~6 -Alkyl (may be unsubstituted, or monosubstituted with -CN, or substituted with one, two, or three halogens), linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens), linear or branched -SC 1~4 -alkyl(that-SC) 1~4 -Alkyl (may be unsubstituted or substituted with one, two, or three halogens), F, Cl, Br, -CN, -S(=O)-C 1~3 -alkyl, -NH2, -NH(C 1~3 -alkyl), -N(C 1~3 -alkyl)2,-OH; especially methyl, representing F; preferably, R F1 , R F2 , and R F3 Only one of these exists, and it represents either methyl or F; R G1 and / or R G2 These are, independently of each other, halogen, hydroxyl, unsubstituted or substituted C 1~6 - Represents aliphatic, especially hydroxyl; preferably, R G1 and R G2 Only one of them exists, and it represents a hydroxyl group; Cyc 2 This is a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbon ring may be unsubstituted or R D6 It may also be a single substitution, and here R D6 C is either unsubstituted or simply substituted with -OH. 1~4 -alkyl, particularly -CH2OH; Especially Cyc 2 These are cyclopropyl, cyclobutyl, or 1-hydroxymethyl-cyclobutyl; Hetcyc 2This refers to a saturated monocyclic heterocycle having five or six ring atoms (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or monosubstituted with hydroxyl); in particular tetrahydrofuranyl or hydroxytetrahydrofuranyl; preferably 4-hydroxytetrahydrofuranyl; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0029] In yet another specific embodiment of PE6, PE6b, R 2b and R 2c These, together with the nitrogen atom to which they are attached, form saturated or partially unsaturated heterocycles having 3, 4, 5, 6, or 7 ring atoms, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one of the further ring atoms is a heteroatom selected from N, O, or S and the rest are carbon atoms, and the heterocycles are optionally independent of each other, R Y1 , R Y2 , R Y3 , R Y4 , and / or R Y5 It is substituted with; here the heteroring is optionally Hetar Z It may be condensed with; and here the heterocycle is preferably selected from the group consisting of: azetidine, pyrrolidine, piperidine, piperazine, and morpholine; R Y1 , R Y2 , R Y3 , R Y4 , R Y5 These are, independently of each other, halogens, particularly F;-NH2, -N(H)-C 1~4 -alkyl, -N(H)-C(=O)-OC 1~4 -alkyl, -N(C 1~4 -alkyl)2;-OH; optionally substituted with -OH C1~4 -alkyl, -OC 1~4 -alkyl, -OC 3~7 -Cycloalkyl, -O-CH2-C 3~7 -Cycloalkyl, especially methyl, -CH2OH, -(CH2)2OH, (CH2)3OH, -CH2OCH3, (CH2)2OCH3, cyclopropylmethoxy;-OC 1~4 -alkyl, especially methoxy; Hetar Y2 ;-CH2-Hetar Y2 ;Hetcyc Y2 Represents; and / or R attached to the same ring atom of that heterocycle Y1 , R Y2 , R Y3 , R Y4 , R Y5 Two of them are divalent C 2~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular -(CH2)4-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-; and / or R attached to two different ring atoms of that heterocycle Y1 , R Y2 , R Y3 , R Y4 , R Y5 Two of them are divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular, forming -(CH2)4-; Hetar Y2 A 5-membered or 6-membered monocyclic heteroaryl (where one, two, three, or four ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or a halogen, C) is a 5-membered or 6-membered monocyclic heteroaryl. 1~4-Alternatively substituted with alkyl (which may optionally be substituted with OH); in particular, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, and pyrimidinyl; Hetar Z These are pyrrole, N-methylpyrrole, pyrazole, imidazole, and triazole; Hetcyc Y2 These are saturated or partially unsaturated monocyclic heterocycles having five or six ring atoms (where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms); in particular, tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0030] In another specific embodiment of PE6b, PE6bb, R 2b and R 2c These, together with the nitrogen atom to which they are attached, form a pyrrolidinyl ring or piperidinyl ring, but each of these is either unsubstituted, or single-substituted with -OH, or independently of each other, C 1~4 - Disubstituted with alkyl and / or -OH; preferably, together with the nitrogen atom to which they are attached, they form a 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl, or 3-hydroxypiperidinyl ring.

[0031] In yet another specific embodiment of PE6, PE6c, R 2b This is a linear or branched C, optionally substituted with OH. 1~4 -alkyl; in particular methyl, 2-hydroxyethyl; and R 2c Cyc 2 Hetcyc 2, or linear or branched C 1~8 -alkyl (this is either unsubstituted or R independently of each other) E1 , R E2 , R E3 , R E4 , and / or R E5 (These may be the same or different) and may be replaced by; and here Cyc 2 Hetcyc 2 , R E1 , R E2 , R E3 , R E4 , and R E5 This is defined above for PE6a or PE6aa, The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0032] In a further specific embodiment PE7, the compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein R 2 is, -(CH2) x -NR 2d -C(=O)-R 2e , -SR 2f -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i -S(=O)2-OH, -S(=O)(=NR 2j )-OH, -S(=O)(=NR 2j )-R 2g -S(=O)(=NR 2k )-NR 2l R 2m ,-(CH2) z -NR 2d -S(=O)2-R 2g -N=S(=O)-R2s R 2t -C(=O)-N=S(=O)-R 2s R 2t -C(=O)-N=S(=NR) 2u )-R 2s R 2t In particular, -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i -S(=O)(=NR 2j )-R 2g -S(=O)(=NR 2k )-NR 2l R 2m ,-(CH2) z -NR 2d -S(=O)2-R 2g -C(=O)-N=S(=O)-R 2s R 2t -C(=O)-N=S(=NR) 2u )-R 2s R 2t Preferably, these represent -S-CH3, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-NHCH3, -S(=O)(=NH)-CH3, S(=O)(=NH)-N(CH3)2, -NH-S(=O)2-CH3, -N(CH3)-S(=O)2-CH3, -NH-S(=O)2-CH=CH2, and -CH2-NH-S(=O)2-CH=CH2. R 2e However, C is substituted with H and optionally -OH. 1~6 -alkyl, or monocyclic 5-membered or 6-membered heteroaryl; C 3~7 -Cycloalkyl, monocyclic 5-membered or 6-membered heteroaryl; in particular, representing H, methyl, hydroxymethyl, methylpyridine-2-yl, methylpyridine-3-yl, methylpyridine-4-yl, cyclopropyl, pyridine-2-yl, pyridine-3-yl, pyridine-4-yl; R 2f , R 2g However, C is independent of each other, either non-substitutive or substituted. 1~8 -Aliphatic; in particular, independently of each other, C 1~4 -alkyl or C2~4 -Alkenyl; preferably, independently representing methyl or -CH=CH2: R 2h , R 2i However, H, unsubstituted or substituted C, are independent of each other. 1~8 - Represents aliphatic, aryl, heterocyclyl, or heteroaryl; or, together with the nitrogen atom to which they are attached, they form a heteroring having 3, 4, 5, 6, or 7 ring atoms, which are unsubstituted or substituted, saturated, partially unsaturated, or aromatic, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one of the further ring atoms is a heteroatom selected from N, O, or S, and the rest are carbon atoms; in particular, C independently substituted with H, or optionally with -OH. 1~4 -Alkyl, pyridyl, pyrimidyl, pyrazinyl, or pyridazinyl, together with the nitrogen atom to which these are attached, form a pyrrolidinyl ring (this ring is optionally substituted with -OH and / or phenyl), pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-5-yl; R 2d , R 2j , R 2k However, H, unsubstituted or substituted C, are independent of each other. 1~8 -Aliphatic; especially represents H and methyl; R 2l , R 2m However, H, unsubstituted or substituted C, are independent of each other. 1~8 - Represents an aliphatic; or, together with the nitrogen atom to which they are attached, they form a heteroring having 3, 4, 5, 6, or 7 ring atoms, which are unsubstituted or substituted, saturated, partially unsaturated, or aromatic, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one of the further ring atoms is a heteroatom selected from N, O, or S, and the rest are carbon atoms; in particular C 1~4 -alkyl; preferably representing methyl; R 2s , R 2t However, C may be substituted with -OH independently of each other.1~6 -alkyl, OC 1~4 -alkyl, NH2, NHC 1~4 -alkyl, N(C 1~4 -alkyl)2, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl; in particular, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-(N,N-dimethylamino)propyl; or together, divalent C 3~4 -Alkylene radical (which may optionally be substituted with -NH2, -CN), or divalent C 2~5 - Alkylene radical (where C is optionally 2~5 - One of the carbon units of the alkylene radical is O, NH, or NC 1~4 -May be replaced by alkyl; in particular, -(CH2)3-, -CH2-C(NH2)H-CH2-, -CH2-C(CN)H-CH2-, -CH2-C(CH2-NH-CH2)-CH2-, -(CH2)4-; R 2u However, hydrogen or C 1~4 - Represents alkyl; x represents either 0 or 1; z represents 0 or 1. The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0033] Furthermore, in a more specific embodiment PE8, the compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, in the formula (a) W 1 CH represents CH; W 2 CH represents CH; W 3 CR W3 Represents; W4 CH represents CH; R W3 This represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), and -CH2-(4-fluorophenyl); or (d) W 1 CH represents CH; W 2 This represents N; W 3 CR W3 Represents; W 4 CH represents CH; R W3 This represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), and -CH2-(4-fluorophenyl); or (h) W 1 CH represents CH; W 2 CH represents CH; W 3 CR W3 Represents; W 4 This represents N; R W3 This represents methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), and -CH2-(4-fluorophenyl); Furthermore, here Z 1 CH is; Z 2 CH is Z 3 CH is (in the case of formula IA); R 1Phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4-cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl, 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 3-fluoro-4-(n-propyl)phenyl, 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphthal-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazole-4-yl, 3-fluoropyridine-2-yl, 6-methylpyridine-3-yl, 6-methoxypyridine-3-yl, 3-ethylpyridine-2-yl, 6-ethylpyridine-3-yl, 4-difluoromethylpyridine-2-yl, 4-trifluoromethylpyridine-2-yl, 4-trifluoromethoxypyridine-2-yl, 4-cyanopyridine-2-yl, 5-trifluoromethylpyridine-2-yl, 6-trifluoromethylpyridine-2-yl, 6-trifluoromethylpyridine-3-yl (2-trifluoromethylpyridine- 5-yl), 6-trifluoromethoxypyridine-3-yl (2-trifluoromethoxypyridine-5-yl), 5-cyanopyridine-2-yl, 5-cyanomethylpyridine-2-yl, 5-methanesulfonylpyridine-2-yl, 6-methoxypyridine-2-yl, 4-methylpyrimidine-2-yl, 4-ethylpyrimidine-2-yl, 4-methylsulfanylpyrimidine-2-yl, 5-cyclopropylpyrimidine-2-yl, 5-ethylpyrimidine-2-yl, 5-difluoromethylpyrimidine-2-yl, 5-trifluoromethylpyrimidine- 2-yl, 5-cyanopyrimidine-2-yl, 5-cyano-3-fluoropyridine-2-yl, 5-cyano-6-methylpyridine-2-yl, 3-fluoro-5-(trifluoromethyl)pyridine-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridine-2-yl, 5,6,7,8-tetrahydroquinoline-2-yl, 5-oxo-5,6,7,8-tetrahydroquinoline-2-yl, 5H,6H,7H-cyclopenta[b]pyridine-2-yl, quinoline-2-yl, isoquinoline-3-yl, 6-methylquinoline-2-yl, 8-Methoxyquinoline-4-yl, fluoro[3,2-b]pyridine-5-yl, quinazoline-2-yl, 6-fluoroquinazoline-2-yl, 1,5-naphthyridine-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-yl, cyclohexyl, 4-methylcyclohexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohexa-1-enyl, 2-oxocycloheptyl, 6,6-Difluorospiro[3.3]heptan-2-yl, 1H-inden-2-yl;4-benzenesulfonyl (Phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidin-1-yl)phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)phenylmethyl, 3-tert-butylphenylmethyl, 3-(difluoromethoxy)phenylmethyl, 2-(difluoromethyl)phenylmethyl, 3-(difluoromethyl)phenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenylmethyl, 2-(propa-2-in-1-yloxy)phenylmethyl, 3-(1,3-thiazole-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3-methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrole-1-yl)phenylmethyl, 2-methyl-3-methoxyphenylmethyl ,3-trifluoromethyl-5-methylphenylmethyl,2-methyl-3-(trifluoromethyl)phenylmethyl,3-trifluoromethyl-4-fluorophenylmethyl,2-fluoro-5-(trifluoromethoxy)phenylmethyl,2-methoxy-3-trifluoromethoxyphenylmethyl,2-fluoro-3-methoxyphenylmethyl,2-fluoro-3-(trifluoromethyl)phenyl]methyl,2-fluoro-3-fluoromethoxyphenylmethyl,2-trifluoromethoxy-5-fluorophenylmethyl,2-fluoro-5-chlorophenylmethyl,3-fluoro-5-methylphenyl)methyl,3,5-difluorophenylmethyl,5-fluoro-2-(trifluoromethyl)phenylmethyl,3-fluoro-5-(trifluoromethyl)phenylmethyl,2-chloro-3-(trifluoromethyl)phenylmethyl,naphthalen-1-ylmethyl,5,6,7,8-tetrahydronaphthalene-1-ylmethyl,2,3-dihydro-1-benzofuran-7-ylmethyl,3,4-Dihydro-2H-1-benzopyran-8-ylmethyl, 2-phenylethyl, 2-(2-methylphenyl)ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2-(2,4-difluorophenyl)ethyl, 2-(difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl- 3-Phenylbutyl, 2-(benzyloxy)ethyl; 5-ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazole-2-ylmethyl, 2-methyl-1,3-thiazole-4-ylmethyl, 2-trifluoromethyl-1,3-thiazole-4-ylmethyl, 1-ethylpyrazole-5-ylmethyl, 1-(2-propyl)pyrazole-5-ylmethyl, 1-ethylimidazole-5-ylmethyl, 1-ethylimidazole-2-ylmethyl, 1-propylimidazo-l-2-ylmethyl, 1-benzylimidazo-l-2-yl)methyl, 1-(2-methylpropyl)-1H-imidazo-l-5-ylmethyl, 5-tert-butyl-1,3-Oxazole-2-ylmethyl, 3-Fluoropyridine-2-ylmethyl, 2-Methylpyridine-4-ylmethyl, 4-Trifluoromethylpyridine-2-yl, 4-Trifluoromethylpyridine-2-ylmethyl, 6-(Fluoromethyl)pyridine-2-ylmethyl, 6-Trifluoromethylpyridine-2-yl, 2-(Trifluoromethyl)pyridine-4-ylmethyl, 4-Methylpyrimidine-2-ylmethyl, 4-Trifluoromethylpyridine-2-ylmethyl, 6-(Fluoromethyl)pyridine-2-ylmethyl, 6-Trifluoromethyl Lupyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-methylpyrimidine-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5-trifluoromethylthiophen-2-ylmethyl, 1-methyl-1H-indole-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H-pyrrolo[1,2-b]pyrazole-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imidazo[ 1,2-a]pyridine-3-ylmethyl, 6-methylimidazo[1,2-a]pyridine-3-ylmethyl, imidazo[1,2-a]pyridine-5-ylmethyl, imidazo[1,5-a]pyridine-1-ylmethyl, imidazo[1,5-a]pyridine-3-ylmethyl, imidazo[1,5-a]pyridine-5-ylmethyl, pyrazolo[1,5-c]pyrimidine-3-ylmethyl, 3-(furan-2-yl)propa-2-en-1-yl; 3-trifluoromethylcyclobutylmethyl, 3-fluoro-3-phenylcyclobutylmethyl, cyclohexylmethyl Tyl, 4-methylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4-methoxycyclohexylmethyl, 4,4-dimethylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 3-trifluoromethyl-bicyclo[1.1.1]pentan-1-ylmethyl, bicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.2]octane-2-ylmethyl, bicyclo[2.2.1]hepta-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hepta-2-en-2-yl]methyl; 3,Represents 3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothiane-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3-trifluoropropane-1-in-1-yl; and, R 2-C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH3, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH2CH2-OH, -C( =O)-N(H)-CH2CH2-OCH3, -C(=O)-N(H)-CH2CH(CF3)-OH, -C(=O)-N(H)-CH(CH3)CH2-OH, -C(=O)-N(H)-CH2 CH(CH3)-OH, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H)-C(H)(CH3)-CH2OH, -C(=O)-N(H)-CH(CH2CH3)CH 2-OH, -C(=O)-N(H)-CH(CH(CH3)2)CH2-OH, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H)-CH(OH)CH2-OH, -C (=O)-N(H)-C(H)(CH2OH)-CH2CH2-O-CH3, -C(=O)-N(H)-C(CH3)(CH2OH)-phenyl, -C(=O)-N(H)-CH(CH(CH3) -OH)-phenyl, -C(=O)-N(H)-CH2-1H-1-methylimidazole-2-yl, -C(=O)-N(H)-(CH2)2-1H-imidazole-1-yl, -C(=O)-N(H)-CH2-pyridine-2-yl, -C(=O)-N(H)-CH2-pyridine-3-yl, -C(=O)-N(H)-CH2-pyridine-4-yl, -C(=O)-N(H)-CH2-1,3-Pyrimidine-4-yl, -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-(4-hydroxytetrahydrofuran-3-yl), -C(=O)-3-hydroxy-pyrrolidine-1-yl, -C(=O)-3-hydroxy-piperidine-1-yl, -NH-C(=O)-CH=CH2, -NH-C(=O)-CH2Cl, -CH2-NH-C(=O)-CH=CH2, -CH2-NH-C(=O) -CH2Cl, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-OH, -S(=O)2-NH2, -S(=O)(=NH)-N(CH3)2, -S(=O)(=N-CH3)-N(CH3)2, -S(=O)(=N-CH3)-O H, -S(=O)(=NH)-CH3, -P(=O)(OH)2, F, -CN; especially -C(=O)-OH, -C(=O)-ONa, -C(=O)-NH2, -C(=O)-NH-CH3, -C(=O)-N(H)-CH2CH2-OH, -C(= O)-N(H)-CH2CH(CF3)-OH, -C(=O)-N(H)-CH(CH3)CH2-OH, -C(=O)-N(H)-CH2CH(CH3)-OH, -C(=O)-N(H)-CH(CH2CH3)CH2-OH, -C(=O)-N( H)-CH(CH(CH3)2)CH2-OH, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H)-CH(OH)CH2-OH, -C(=O)-N(H)-C(H)(CH2OH)-CH2CH2-O-CH3, -C(= O)-N(H)-C(CH3)(CH2OH)-phenyl, -C(=O)-N(H)-CH(CH(CH3)-OH)-phenyl, -C(=O)-N(H)-CH2-1H-1-methylimidazole-2-yl, -C(=O)-N(H)-(CH2)2-1H-imidazole-1-yl, -C(=O)-N(H)-CH2-pyridine-2-yl, -C(=O)-N(H)-CH2-pyridine-3-yl, -C(=O)-N(H)-CH2-pyridine-4-yl, -C(=O)-N(H)-CH2-1,3-pyrimidine-4-yl, -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-(4-hydroxy-tetrahydrofuran-3-yl), -C(=O)-3-hydroxy-pyrrolidine-1-yl, -C(=O)-3-hydroxy-piperidine-1-yl; preferably representing -C(=O)-OH, -C(=O)-ONa, -C(=O)-NH-CH3, -C(=O)-N(H)-cyclopropyl.

[0034] In yet another specific embodiment of PE8, PE8a, the compound of the present invention is a tricyclic heterocycle represented by formula I or IA, but in the formula R 1 It is 4-trifluoromethylphenyl; R 2 These are -C(=O)-OH, -C(=O)-ONa, -C(=O)-NH-CH3, or -C(=O)-N(H)-cyclopropyl; Z 1 , Z 2 , and Z 3 In equation IA, all three are CH; W 1 , W 2 , and W 4 All three are CH; W 3 CR W3 is; R W3 This represents methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH2-phenyl, -CH2-(2-fluorophenyl), -CH2-(3-fluorophenyl), and -CH2-(4-fluorophenyl).

[0035] In another specific embodiment of PE8, PE8b, the compound of the present invention is a tricyclic heterocycle represented by formula I or IA, where R 1 It is 4-trifluoromethylphenyl; R 2These are -C(=O)-OH, -C(=O)-ONa, -C(=O)-NH-CH3, or -C(=O)-N(H)-cyclopropyl; Z 1 , Z 2 , and Z 3 In equation IA, all three are CH; W 1 and W 2 Both are CH; W 3 CR W3 is; R W3 'F' represents methyl, trifluoromethyl, methoxy, and F; W 4 It is N.

[0036] Furthermore, in a more specific embodiment PE9, the compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, in the formula W 1 This represents CH or N; W 2 This represents CH or N; W 3 This represents CH or N; W 4 This represents CH or N; Here W 1 , W 2 , W 3 , and W 4 W is either one of them does not represent N, or it represents N at the same time. 1 , W 2 , W 3 , and W 4 It is either one of the following; R 1 Ar 1 Hetar 1 , or L 1 -Ar 1 Preferably Ar 1 Represents; Ar1 This is a monocyclic or bicyclic aryl compound having 6 or 10 ring carbon atoms (where the aryl is at least one substituent R). B1 And, optionally, further substituent R B2 and / or R B3 It carries; preferably, R B1 It is a phenyl compound that is monosubstituted with; Hetar 1 This is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where one, two, or three of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl has at least one substituent R B1 And, optionally, further substituent R B2 and / or R B3 It supports; preferably, the heteroaryl is pyridyl and R B1 It is a single substitution; L 1 It is -CH2- (methylene); R B1 C is a linear or branched C 1~6 -alkyl (which is independently substituted with one, two, or three halogens); preferably represents trifluoromethyl; R B2 , R B3 These are linear or branched C atoms, which are independent of each other. 1~6 -alkyl(that C 1~6 -Alkyl (may be unsubstituted, or monosubstituted with -CN, or substituted with one, two, or three halogens), linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens, -O-CH2-C≡CH, and may be linear or branched -SC 1~4 -alkyl(that-SC) 1~4-Alkyl (may be unsubstituted or substituted with one, two, or three halogens), F, Cl, Br, -CN, -N(C 1~3 - Represents alkyl)2; Furthermore, the remaining radicals and residues are defined as above for formula IA or I, or for any of the further specific embodiments described above or below in this specification.

[0037] In another specific embodiment of PE9, PE9a, R 2 is -C(=O)-OR 2a or Hetcyc X ; preferably -C(=O)-OR 2a Represents; R 2a H, linear or branched, unsubstituted or substituted C 1~4 -Alkyl or Cat; preferably representing H, methyl, ethyl, or Cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na), and potassium (K); preferably sodium. Hetcyc XThese include 1H-1,2,3,4-tetrazol-5-yl, 2H-1,2,3,4-tetrazol-5-yl, 2-methyl-2H-1,2,3,4-tetrazol-5-yl, 5-oxo-2,5-dihydro-1,2,4-oxadiazole-3-yl (2H-1,2,4-oxadiazole-5-on-3-yl), 5-oxo-4,5-dihydro-1,2,4-oxadiazole-3-yl (4H-1,2,4-oxadiazole-5-on-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3-chloro-4,5-dihydro-1,2-oxazol-5-yl, and 3-(1H-1,2,3-triazol-1-yl )-4,5-dihydro-1,2-oxazol-5-yl, 3-(2H-1,2,3-triazol-2-yl)-4,5-dihydro-1,2-oxazol-5-yl, 3-(pyrimidine-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3-hydroxy-oxetane-3-yl, 5-hydroxy-4H-pyran-4-on-2-yl, 3,3-difluoropyrrolidine-2-on-4-yl, 3,3-difluoropyrrolidine-2-on-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrole-2-on-4-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrole-2-on-5-yl.

[0038] In another specific embodiment of PE9, PE9b, R 2 is -C(=O)-NR 2b R 2c It represents.

[0039] In yet another specific embodiment of PE9b, PE9ba, R 2b This represents hydrogen, R 2c is hydrogen; even if unsubstituted, or R E1 , R E2 , R E3 , R E4 , and / or R E5 Linear or branched C (these may be the same or different) may be substituted. 1~8-alkyl; Cyc 2 or Hetcyc 2 This represents, but here R E1 , R E2 , R E3 , R E4 , and / or R E5 These are, independently of each other, halogens, especially F;-NR Ea R Eb , -OH, OR Ec Ar E Hetar E ,Cyc E Hetcyc E Represents; Ar E This refers to monocyclic or bicyclic aryl compounds having 6 or 10 ring carbon atoms (where the aryl is unsubstituted or substituted R). F1 , R F2 , and / or R F3 (These may be the same or different) and may be substituted with; preferably phenyl or naphthalenyl, especially phenyl; Hetar E This is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R F1 , R F2 , and / or R F3 (These may be the same or different) and may be substituted; in particular, the heteroaryl is a monocyclic heteroaryl having five or six ring atoms, which may be unsubstituted or substituted with substituent R F1 and / or R F2 (These may be the same or different) and may be substituted; preferably the heteroaryl is imidazolyl, 1H-imidazole-1-yl, 1H-imidazole-2-yl (each of these may be unsubstituted or C1~4 -Single-substituted with alkyl); pyridyl, pyrido-2-yl, pyrido-3-yl, pyrido-4-yl (each of these may be unsubstituted or single-substituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl; pyrazinyl, pyrazin-2-yl, pyrimidine-5-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazinyl, pyridazin-3-yl; furanil, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; selected from the group consisting of oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Cyc E This refers to a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms (where the carbon ring may be unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted); in particular, saturated monocyclic carbon rings having 3, 4, 5, or 6 ring carbon atoms (where the carbon ring is unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted with; preferably cyclopropyl, cyclobutyl, or cyclohexenyl; Hetcyc E A monocyclic heterocycle having 4, 5, or 6 ring atoms, saturated or partially unsaturated (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1 and / or R G2 (These may be the same or different); in particular, saturated monocyclic heterocycles having 5 or 6 ring atoms (where one or two of the ring atoms are heteroatoms (one or more) selected from N and / or O and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1(May be monosubstituted with -OH); preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of these may be unsubstituted or monosubstituted with -OH); pyrrolidinyl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl (each of these may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl (each of these may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl (each of these may be unsubstituted or monosubstituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; R Ea , R Eb H and C are independent of each other. 1~4 -alkyl, -C(=O)-OC 1~4 - Represents alkyl; in particular, both represent H, or one represents H and the other represents C(=O)-O-tert.-butyl; R Ec is H or C 1~4 - Represents alkyl, especially H or methyl; R F1 , R F2 , and / or R F3 These are linear or branched C atoms, which are independent of each other. 1~6 -alkyl(that C 1~6 -Alkyl can be unsubstituted, or -CN, OH, -OC 1~4 -Single-substituted with alkyl, or substituted with one, two, or three halogens, linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens), linear or branched -SC 1~4 -alkyl(that-SC) 1~4-Alkyl (may be unsubstituted or substituted with one, two, or three halogens), F, Cl, Br, -CN, -S(=O)-C 1~3 -alkyl, S(=O)2-C 1~3 -alkyl, -NH2, -NH(C 1~3 -alkyl), -N(C 1~3 -alkyl)2,-OH; in particular, representing methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably, R F1 , R F2 , and R F3 Only one of these exists, and it represents either methyl or F; and / or R attached to two different ring atoms of an aryl or heteroaryl F1 , R F2 , R F3 Two of them are divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular -(CH2)4-, -CH2-O-(CH2)2-; R G1 and / or R G2 These are, independently of each other, halogen, hydroxyl, unsubstituted or substituted C 1~6 -Aliphatic, especially C which is optionally substituted with OH 1~4 -alkyl, C 1~6 -Aliphatic oxy, especially -OC 1~4 -alkyl, -C(=O)-OC 1~4 -alkyl, Hetar Y2 -CH2-Hetar Y2 Hetcyc Y2 , in particular representing hydroxyl; preferably, R G1 and R G2 Only one of them exists, and it represents a hydroxyl group; and / or R attached to the same ring atom of a carbocyclic or heterocyclic ring G1 and R G2 is divalent C 2~6- Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -It may be replaced by an alkyl group, where the alkylene radical is optionally OH, C 1~4 -alkyl, or -OC 1~4 -May be substituted with alkyl, in particular -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-; and / or R attached to two different ring atoms of a carbocyclic or heterocyclic ring G1 and R G2 is divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular, forming -CH2-; Cyc 2 This is a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbon ring may be unsubstituted or independently of each other, R D6 , R D7 , R D8 , R D9 , and / or R D10 It may also be substituted with, where the carbon ring is optionally Ar Z or Hetar Z And they may be condensed via two adjacent ring atoms, and here the condensed carbon rings may be optionally independent of each other, R C1 , R C2 , and / or R C3 It may be further replaced by; Hetcyc 2 This is a saturated monocyclic heterocycle having 4, 5, or 6 ring atoms, where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or independently of each other, R D6 , RD7 , R D8 , R D9 , and / or R D10 It may also be substituted with, where the heteroring is arbitrarily Ar Z or Hetar Z They may be condensed, and here the condensed heterorings may be any, independently of each other, R C1 , R C2 , and / or R C3 It may be further replaced by; R C1 , R C2 , R C3 They are independent of each other, C 1~4 - Represents alkyl; R D6 , R D7 , R D8 , R D9 , R D10 These are C, independently of each other, substituted with halogens, particularly F; hydroxyl; optionally -OH and / or halogens. 1~4 -Alkyl, in particular methyl, hydroxymethyl, 2-fluoroethyl;-OC 1~4 -alkyl, especially methoxy, ethoxy; Hetar Y1 -CH2-Hetar Y1 ,Cyc Y1 Hetcyc Y1 -CH2-Hetcyc Y1 Represents; and / or R attached to the same ring atom of a carbocyclic or heterocyclic ring D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -It may be replaced by an alkyl group, where the alkylene radical is optionally OH, C 1~4 -alkyl, or -OC 1~4-May be substituted with alkyl groups, in particular -(CH2)3-, -CH2-CH(OC2H5)-CH2-, -(CH2)2-O-(CH2)2-; and / or R attached to two different ring atoms of a carbocyclic or heterocyclic ring D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular -CH2-, -(CH2)3-, -O-(CH2)2-, -O-(CH2)3-; Ar Z It is a benzo; Hetar Y1 This refers to a 5-membered or 6-membered monocyclic heteroaryl (where 1, 2, 3, or 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or F, C 1~4 -Alkyl (which may optionally be substituted with an OH group); in particular, pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl, and methylpyridinyl; Hetar Y2 A 5-membered or 6-membered monocyclic heteroaryl (where one, two, three, or four ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or a halogen, C) is a 5-membered or 6-membered monocyclic heteroaryl. 1~4 -Alternatively substituted with alkyl (which may optionally be substituted with OH); in particular, pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, and hydroxymethyloxazolyl; Hetar Z These are pyrrole, N-methylpyrrole, pyrazole, imidazole, and triazole; Cyc Y1 This refers to a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms (where the carbon ring may be unsubstituted, or contain halogens, OH, C). 1~4 - May be substituted with alkyl, especially cyclopropyl; Hetcyc Y1 This refers to saturated or partially unsaturated monocyclic heterocycles having five or six ring atoms (where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms); in particular, tetrahydrofuranyl; Hetcyc Y2 These are saturated or partially unsaturated monocyclic heterocycles having five or six ring atoms (where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms); in particular, tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl; Furthermore, the remaining radicals and residues are defined as above for formula IA or I, or for any of the further specific embodiments described above or below in this specification.

[0040] In a further specific embodiment of PE9ba, PE9baa, R 2b This represents hydrogen, R 2c is hydrogen; even if unsubstituted, or R E1 , R E2 , R E3 , R E4 , and / or R E5 Linear or branched C (these may be the same or different) may be substituted. 1~8 -alkyl; Cyc 2 or Hetcyc 2 This represents, but here RE1 , R E2 , R E3 , R E4 , and / or R E5 These are, independently of each other, halogens, especially F;-NR Ea R Eb , -OH, OR Ec Ar E Hetar E ,Cyc E Hetcyc E Represents; Ar E This refers to monocyclic or bicyclic aryl compounds having 6 or 10 ring carbon atoms (where the aryl is unsubstituted or substituted R). F1 , R F2 , and / or R F3 (These may be the same or different) and may be substituted with; preferably phenyl or naphthalenyl, especially phenyl; Hetar E This is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or substituted R F1 , R F2 , and / or R F3 (These may be the same or different) and may be substituted; in particular, the heteroaryl is a monocyclic heteroaryl having five or six ring atoms, which may be unsubstituted or substituted with substituent R F1 and / or R F2 (These may be the same or different) and may be substituted; preferably the heteroaryl is imidazolyl, 1H-imidazole-1-yl, 1H-imidazole-2-yl (each of these may be unsubstituted or C 1~4-Single-substituted with alkyl); pyridyl, pyrido-2-yl, pyrido-3-yl, pyrido-4-yl (each of these may be unsubstituted or single-substituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl; selected from the group consisting of pyrazinyl and pyrazin-2-yl; Cyc E This refers to a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms (where the carbon ring may be unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted); in particular, saturated monocyclic carbon rings having 3, 4, 5, or 6 ring carbon atoms (where the carbon ring is unsubstituted or R G1 and / or R G2 (These may be the same or different) and may be substituted with; preferably cyclobutyl; Hetcyc E A monocyclic heterocycle having 5 or 6 ring atoms, saturated or partially unsaturated (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1 and / or R G2 (These may be the same or different); in particular, saturated monocyclic heterocycles having 5 or 6 ring atoms (where one or two of the ring atoms are heteroatoms (one or more) selected from N and / or O and the rest are carbon atoms, where the heterocycle is unsubstituted or R G1(These may be monosubstituted); preferably, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of these may be unsubstituted or monosubstituted with -OH); pyrrolidinyl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-3-yl (each of these may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidine-1-yl, piperidine-2-yl, piperidine-3-yl, piperidine-4-yl (each of these may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl; R Ea , R Eb H and C are independent of each other. 1~4 -alkyl, -C(=O)-OC 1~4 - Represents alkyl; in particular, both represent H, or one represents H and the other represents C(=O)-O-tert.-butyl; R Ec is H or C 1~4 - Represents alkyl, especially H or methyl; R F1 , R F2 , and / or R F3 These are linear or branched C atoms, which are independent of each other. 1~6 -alkyl(that C 1~6 -Alkyl (may be unsubstituted, or monosubstituted with -CN, or substituted with one, two, or three halogens), linear or branched C 1~4 -alkoxy(that C) 1~4 -The alkoxy may be unsubstituted or substituted with one, two, or three halogens), linear or branched -SC 1~4 -alkyl(that-SC) 1~4 -Alkyl (may be unsubstituted or substituted with one, two, or three halogens), F, Cl, Br, -CN, -S(=O)-C 1~3 -alkyl, S(=O)2-C 1~3 -alkyl, -NH2, -NH(C 1~3 -alkyl), -N(C1~3 -alkyl)2,-OH; especially methyl, representing F; preferably, R F1 , R F2 , and R F3 Only one of these exists, and it represents either methyl or F; R G1 and / or R G2 These are, independently of each other, halogen, hydroxyl, unsubstituted or substituted C 1~6 -Aliphatic, C 1~6 - Represents an aliphatic oxy, especially hydroxyl; preferably, R G1 and R G2 Only one of them exists, and it represents a hydroxyl group; Cyc 2 This is a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbon ring may be unsubstituted or R D6 It may also be replaced with R D6 C is either unsubstituted or simply substituted with -OH. 1~4 -alkyl, particularly -CH2OH; Especially Cyc 2 These are cyclopropyl, cyclobutyl, or 1-hydroxymethyl-cyclobutyl; Hetcyc 2 This refers to a saturated monocyclic heterocycle having five or six ring atoms (where one or two of the ring atoms are heteroatoms (one or more) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or monosubstituted with hydroxyl); in particular tetrahydrofuranyl or hydroxytetrahydrofuranyl; preferably 4-hydroxytetrahydrofuranyl; Furthermore, the remaining radicals and residues are defined as above for formula IA or I, or for any of the further specific embodiments described above or below in this specification.

[0041] In another specific aspect of PE9b, PE9bb R 2band R 2c These, together with the nitrogen atom to which they are attached, form saturated or partially unsaturated heterocycles having 3, 4, 5, 6, or 7 ring atoms, where one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one of the further ring atoms is a heteroatom selected from N, O, or S and the rest are carbon atoms, and the heterocycles are optionally independent of each other, R Y1 , R Y2 , R Y3 , R Y4 , and / or R Y5 It is substituted with; here the heteroring is optionally Hetar Z It may be condensed with; and here the heterocycle is preferably selected from the group consisting of: azetidine, pyrrolidine, piperidine, piperazine, and morpholine; R Y1 , R Y2 , R Y3 , R Y4 , R Y5 These are, independently of each other, halogens, particularly F;-NH2, -N(H)-C 1~4 -alkyl, -N(H)-C(=O)-OC 1~4 -alkyl, -N(C 1~4 -alkyl)2; optionally -OH substituted with -OH;C 1~4 -alkyl, -OC 1~4 -alkyl, -OC 3~7 -Cycloalkyl, -O-CH2-C 3~7 -Cycloalkyl, especially methyl, -CH2OH, -(CH2)2OH, (CH2)3OH, -CH2OCH3, (CH2)2OCH3, cyclopropylmethoxy;-OC 1~4 -alkyl, especially methoxy; Hetar Y2 ;-CH2-Hetar Y2 ;Hetcyc Y2 Represents; and / or R attached to the same ring atom of that heterocycle Y1 , R Y2 , R Y3 , R Y4 , R Y5 Two of them are divalent C 2~6- Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular -(CH2)4-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-; and / or R attached to two different ring atoms of that heterocycle Y1 , R Y2 , R Y3 , R Y4 , R Y5 Two of them are divalent C 1~6 - Alkylene radical (where optionally, one or two non-adjacent carbon units of the alkylene radical are independently of each other: O, NH, NC) 1~4 -May be replaced by alkyl groups, in particular, forming -(CH2)4-; Hetar Y2 A 5-membered or 6-membered monocyclic heteroaryl (where one, two, three, or four ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or a halogen, C) is a 5-membered or 6-membered monocyclic heteroaryl. 1~4 -Alternatively substituted with alkyl (which may optionally be substituted with OH); in particular, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, and pyrimidinyl; Hetar Z These are pyrrole, N-methylpyrrole, pyrazole, imidazole, and triazole; Hetcyc Y2 These are saturated or partially unsaturated monocyclic heterocycles having five or six ring atoms (where one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the rest are carbon atoms); in particular, tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl; Furthermore, the remaining radicals and residues are defined as above for formula IA or I, or for any of the further specific embodiments described above or below in this specification.

[0042] In a further specific embodiment of PE9bba, R 2b and R 2c These, together with the nitrogen atom to which they are attached, form a 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl, or 3-hydroxypiperidinyl ring.

[0043] In yet another specific embodiment of PE9b, PE9bc, R 2b This is a linear or branched C, optionally substituted with OH. 1~4 -alkyl; in particular methyl, 2-hydroxyethyl; and R 2c Cyc 2 Hetcyc 2 , or linear or branched C 1~8 -alkyl (this is either unsubstituted or R independently of each other) E1 , R E2 , R E3 , R E4 , and / or R E5 (These may be the same or different) and may be replaced by; and here Cyc 2 Hetcyc 2 , R E1 , R E2 , R E3 , R E4 , and R E5 This is defined above for PE9ba or PE9baa.

[0044] In another specific embodiment of PE9b, PE9bd, R 2 This represents -C(=O)-NH-CH3 or -C(=O)-NH-cyclopropyl.

[0045] In yet another specific embodiment PE10 of the present invention, the compound of the present invention is a tricyclic heterocycle represented by formula IA or I, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion, wherein R 1 teeth, [ka]

[0046] [ka]

[0047] [ka] Selected from the group consisting of, The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0048] In a specific embodiment of PE10, PE10a, R 1 teeth, [ka] Selected from the group consisting of; Furthermore, the remaining radicals and residues are as defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification. In particular, R 1 teeth, [ka] (Specific example PE10aa).

[0049] In another specific embodiment of the present invention, PE11, the compound of the present invention is a tricyclic heterocycle represented by formula IA or I, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion, wherein R 2 teeth, [ka]

[0050] [ka]

[0051] [ka]

[0052] [ka]

[0053] [ka]

[0054] [ka]

[0055] [ka]

[0056] [ka]

[0057] [ka]

[0058] [ka]

[0059] [ka]

[0060] [ka]

[0061] [ka]

[0062] [ka]

[0063] [ka] (R Z2 Selected from the group consisting of (and); The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0064] In a specific embodiment of PE11, PE11a, The compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein in the formula R 2 teeth, [ka] (R Z2 Selected from the group consisting of (and); The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0065] In a specific embodiment of PE11a, PE11aa, R 2 It is selected from the group consisting of -COOH.

[0066] In a specific embodiment of PE11, PE11b, The compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein in the formula R 2 teeth, [ka]

[0067] [ka]

[0068] [ka]

[0069] [ka]

[0070] [ka]

[0071] [ka]

[0072] [ka]

[0073] [ka]

[0074] [ka]

[0075] [ka]

[0076] [ka]

[0077] [ka] Selected from the group consisting of; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0078] In a specific embodiment of PE11b, PE11bb, R 2 teeth, [ka]

[0079] [ka] It is selected from the group consisting of the following.

[0080] In another specific embodiment of PE11, PE11c, The compounds of the present invention are tricyclic heterocycles represented by formula IA or I, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion, wherein in the formula R 2 teeth, [ka]

[0081] [ka]

[0082] [ka] Selected from the group consisting of, The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0083] In the embodiments PE10, PE10a, PE10aa, PE11, PE11a, PE11aa, PE11b, PE11bb, and PE11c shown above, the dotted line [ka] However, individual radicals R 1 and R 2 It is understood that each is used to indicate the position attached to the remaining molecule, i.e., the compound represented by formula I or IA.

[0084] In yet another specific embodiment PE12 of the present invention, the compound of the present invention is a tricyclic heterocycle represented by formula IA or I, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion, wherein in the formula R 1 The base is selected from those described above for PE10; and R 2 The base is selected from those described above for PE11; The remaining radicals and residues are defined for formula IA or I above, or for any of the further specific embodiments described above or below in this specification.

[0085] A specific embodiment of PE12, PE12a, in the formula R 1 The groups are selected from those described above for PE10a, and especially for PE10aa; and R 2 The base is selected from those described above for PE11.

[0086] Another specific embodiment of PE12 is PE12b, in which R 1 The groups are selected from those described above for PE10a, and especially for PE10aa; and R 2 The group is selected from the groups described above for PE11a, and especially for PE11aa.

[0087] Another specific embodiment of PE12 is PE12c, in which R 1 The groups are selected from those described above for PE10a, and especially for PE10aa; and R 2 The base is selected from those described above for PE11b, and especially for PE11bb.

[0088] Another specific embodiment of PE12 is PE12d, in the formula R 1 The groups are selected from those described above for PE10a, and especially for PE10aa; and R 2 The base is selected from those described above for PE11c.

[0089] Another specific embodiment of the present invention, PE13, in the formula: W 1 , W 2 , W 3 , and W 4 The six-membered ring containing is defined in one of the specific embodiments PE2-0, PE2, PE2(a), PE2(b), PE2(c), PE2(d), PE2(e), PE2(f), PE2(g), PE2(h), PE3, PE3(a), PE3(d), PE3(h), and PE9; and R 1 and R 2 The selection is made as described for PE12.

[0090] In a specific embodiment of PE13, PE13a, R 1 and R 2 R is selected as described for PE12a. In another specific embodiment of PE13, PE13b, R 1 and R 2 R is selected as described for PE12b. In another specific embodiment of PE13, PE13c, R 1 and R 2 The selection is as described for PE12c. For a further specific embodiment of PE13, PE13d, R 1 and R 2 The selection is made as described for PE12d.

[0091] In yet another specific embodiment PE14, the compounds of the present invention are tricyclic heterocycles selected from the compounds shown in Table 1 below, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion. In yet another specific embodiment PE14a of PE14, the compounds are selected from Table 1 and represented by formula I or IA as described herein and in the claims. Each single compound depicted in Table 1, as well as any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or pharmaceutically acceptable salts thereof, are understood to represent specific embodiments of the present invention. [Modes for carrying out the invention]

[0092] When used herein, unless otherwise specifically indicated or defined in the description and / or anywhere in the claims, the following definitions shall apply to any particular substituent, radical, residue, group, or part.

[0093] The terms “aliphatic” or “aliphatic group,” as used herein, mean a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain, or a monocyclic, bicyclic, or tricyclic hydrocarbon, which 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 herein as “carbocyclic,” “cycloaliphatic,” or “cycloalkyl”), which generally, and unless otherwise defined herein or in the appended claims, have a single attachment site to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1 to 8 or 1 to 6 aliphatic carbon atoms (each being a “C”). 1~8 -Aliphatic" and "C 1~6-Aliphatic). In some embodiments, the aliphatic group contains 1 to 5 aliphatic carbon atoms ("C"). 1~5 -Aliphatic). In other embodiments, the aliphatic group contains 1 to 4 aliphatic carbon atoms ("C"). 1~4 -Aliphatic). In another embodiment, the aliphatic group contains 1 to 3 aliphatic carbon atoms ("C"). 1~3 -Aliphatic). In another embodiment, the aliphatic group contains 1-2 aliphatic carbon atoms ("C"). 1~2 -Aliphatic). In some embodiments, "cycloaliphatic" ("cycloalkyl") refers to monocyclic C3-C7 hydrocarbons (i.e., monocyclic hydrocarbons having 3, 4, 5, 6, or 7 ring carbon atoms) or bicyclic C3-C7 hydrocarbons. 5~8Hydrocarbons (i.e., bicyclic hydrocarbons having 5, 6, 7, or 8 ring carbon atoms) that are either fully saturated or contain one or more unsaturated units, which are not aromatic and have a single attachment site to the rest of the molecule. In another embodiment, the term “cycloaliphatic” or “carbocyclic” refers to a monocyclic or bicyclic cycloaliphatic ring system, which is fused with an aromatic, heteroaromatic, or heterocyclic ring or ring system via two adjacent ring atoms of that aromatic, heteroaromatic, or heterocyclic ring or ring system; in other words, such a carbocyclic shares two ring atoms with the ring or ring system it fused with, thereby having two attachment sites to the rest of the molecule. In another embodiment, the term “carbocyclic” refers to a bicyclic spirocyclic ring formed by the fusion of two monocyclic carbocyclic rings via the same single carbon atom. Generally, the term “aliphatic” encompasses linear, i.e., unbranched, and branched hydrocarbon chains to the extent chemically viable, unless otherwise defined in specific examples. Also generally, the term encompasses unsubstituted and substituted hydrocarbon moieties to the extent chemically viable, unless otherwise defined in specific examples. Typical substituents on aliphatic groups, but not limited to, include halogens, particularly fluorine (F), cyano, hydroxyl, alkoxy, unsubstituted or mono- or di-substituted amino and aryl groups, particularly unsubstituted or substituted phenyl and heteroaryl groups, particularly unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl groups, particularly unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl groups. Preferred aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0094] 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 with one or more C=C double bonds, and the term "alkynyl" generally refers to an aliphatic and acyclic moiety with one or more C≡C triple bonds. It is understood that the term "alkenyl" includes all forms of isomers, namely E-isomers, Z-isomers, and mixtures thereof (E / Z-isomers). The exemplary aliphatic groups are linear or branched, substituted or unsubstituted C 1~8 -alkyl group, C 1~6 -alkyl group, C 1~4 -alkyl group, C 1~3 -alkyl group, C 1~2 -alkyl group, C 2~8 -Alkenyl group, C 2~6 -Alkenyl group, C 2~8 -Alkynyl group, C 2~6 - Alkynyl groups, and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0095] In particular, the term "C 1~3 "-alkyl" refers to an alkyl group, i.e., a saturated acyclic aliphatic group having one, two, or three carbon atoms. Example C 1~3 - Alkyl alkyl groups are methyl, ethyl, propyl, and isopropyl. Term "C 1~4 "-alkyl" refers to an alkyl group having one, two, three, or four carbon atoms. Example C 1~4 -Alkyl alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. Term "C 1~6 "-alkyl" refers to an alkyl group having one, two, three, four, five, or six 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. Term "C 1~8"-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Example C 1~8 -Alkyl groups include 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. Each of these alkyl groups may be linear, or branched (except for C1-alkyl and C2-alkyl groups), and unsubstituted, or substituted with one, two, or three substituents, the substituents may be the same or different, and unless otherwise specified as different in this specification and / or any of the appended claims, halogens, in particular F, hydroxy, alkoxy, unsubstituted or mono- or di-substituted aminos, in particular unsubstituted or substituted phenyl, heteroaryl, in particular unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, in particular unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. Examples of substituted alkyl groups include difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, and 2-hydroxyethyl.

[0096] In some cases, C 1~3 -alkyl group, C 1~4 -alkyl group, C 1~6 -alkyl group, C 1~8-Alkyl alkyl groups may also include residues in which one or two non-terminal and non-adjacent -CH2-(methylene) groups are replaced by -O-, -S-, and / or one or two non-terminal and non-adjacent -CH2- or -CH- groups are replaced by -NH- or -N-. These substitutions produce (modified) alkyl groups such as, for example, -CH2-CH2-O-CH3, -CH2-CH2-CH2-S-CH3, CH2-CH2-NH-CH2-CH3, CH2-CH2-O-CH2-CH2-O-CH3, CH2-CH2-N(CH3)-CH2-CH3, etc. Further substitutions and / or different substitutions of -CH- and -CH2- groups may also be defined somewhere in the description and / or claims for specific alkyl substituents or radicals.

[0097] The term “C 3~7 "Cycloalkyl" refers to cycloaliphatic hydrocarbons having 3, 4, 5, 6, or 7 ring carbon atoms, as defined above. Similarly, the term "C 3~6 "Cycloalkyl" refers to cycloaliphatic hydrocarbons that have 3, 4, 5, or 6 ring carbon atoms. 3~7 - The cycloalkyl group may be unsubstituted, or - unless otherwise specified elsewhere herein - may be substituted with one, two, or three substituents, which may be the same or different, and the group - unless otherwise specified elsewhere herein - C 1~6 -alkyl, OC 1~6 -Selected from the group comprising alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, and in particular unsubstituted or substituted phenyl. If substituted, C 3~7 -Cycloalkyls include all possible stereoisomers. Example C 3~7-Cycloalkyl groups include cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl. Term "bicyclic C 5~8 "-Cycloalkyl" refers to a bicyclic cycloaliphatic hydrocarbon having 5, 6, 7, or 8 ring carbon atoms, as defined above; this is a spirocyclic ring system, i.e., a bicyclic C 5~8 - A cycloalkyl ring system in which two carbon rings are attached to each other via the same carbon atom. 5~8 - The cycloalkyl group may be unsubstituted, or - unless otherwise specified elsewhere herein - may be substituted with one, two, or three substituents, the substituents may be the same or different, and - unless otherwise specified elsewhere herein - C 1~6 -alkyl, OC 1~6 -Selected from the group comprising alkyl (alkoxy), halogen, hydroxy, and unsubstituted or mono- or di-substituted aminos. If substituted, a bicyclic C 5~8 -Cycloalkyls include all possible stereoisomers. The example bicyclic C 5~8 -Cycloalkyls include spiro[3.3]heptanyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[2.2.1]hepta-5-en-2-ylmethyl, and bicyclo[3.1.1]hepta-2-en-2-yl.

[0098] The term "aliphatoxy" refers to a saturated or unsaturated aliphatic group or substituent, as defined above, that is connected to another structural part via an oxygen atom (-O-). 1~6"-Aliphatic oxy" refers to an aliphatic oxy radical that has one, two, three, four, five, or six carbon atoms in its aliphatic group. The term "alkoxy" refers to a specific subgroup of saturated aliphatic oxy, namely alkyl substituents and residues connected to another structural part via an oxygen atom (-O-). Sometimes this is also "O-alkyl," or more specifically "OC." 1~2 -alkyl, OC 1~3 -alkyl, OC 1~4 -alkyl, OC 1~6 -alkyl, OC 1~8 It is also called "-alkyl". Like similar alkyl groups, it may be linear or -OC. 1~ Alkyl and -OC 2~ Except for alkyl groups, the group is selected from halogens, unsubstituted or mono- or di-substituted aminos, which may be branched and unsubstituted or substituted with one, two or three substituents, which may be the same or different, and which are not specified otherwise herein. Exemplary alkoxy groups are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, and n-pentoxy.

[0099] The term "alkylene" refers to a divalent aliphatic group, particularly a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) x -where x 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 one, two, and three -CH2- groups, respectively; however, the term "alkylene" includes not only linear alkylene groups, i.e., "alkylene chains," but also branched alkylene groups. 1~6-Alkylene refers to an alkylene portion that is either linear, i.e., an alkylene chain, or branched, and has one, two, three, four, five, or six carbon atoms. 2~6 -Alkylene refers to an alkylene moiety that has 2, 3, 4, 5, or 6 carbon atoms, while "C 3~4 -Alkylene refers to an alkylene portion that has 3 or 4 carbon atoms, and "C 2~3 "-Alkylene" refers to an alkylene moiety having two or three carbon atoms. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by substituents (or by substituents). Preferred substituents include those described herein for substituted alkyl groups. In some cases, one or two methylene groups of the alkylene chain are, for example, O, S, and / or NH, or NC. 1~4 -The alkylene groups may be replaced by alkyl groups. Examples of alkylene groups are -CH2-, -CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-CH2-CH2-, -CH2-O-CH2-CH2-, -O-CH2-O-, -O-CH2-CH2-O-, -O-CH2-CH2-CH2-O-, -CH2-NH-CH2-CH2-, and -CH2-N(CH3)-CH2-CH2-.

[0100] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by substituents. Preferred substituents include those described herein for substituted aliphatic groups. The term "alkenylene" refers not only to linear divalent alkenylene radicals, i.e., alkenylene chains, but also to branched alkenylene groups. 2~6 -Alkenylene refers to an alkenylene radical having 2, 3, 4, 5, or 6 carbon atoms.

[0101] The term "alkynylene" refers to a divalent alkynyl group. A substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms are replaced by substituents. Preferred substituents include those described herein for substituted aliphatic groups.

[0102] The term "halogen" refers to F, Cl, Br, or I.

[0103] The term "heteroatom" means one or more oxygen (O), sulfur (S), or nitrogen (N) atoms, including any oxidized form of nitrogen or sulfur, e.g., N-oxides, sulfoxides, and sulfones; and also includes quaternized forms of basic or substituteable nitrogen atoms in heterocyclic or heteroaromatic rings, e.g., N (as seen in 3,4-dihydro-2H-pyrrolyl), NH (as seen in pyrrolidinyl), or N-SUB (as seen in N-substituted pyrrolidinyl), where SUB is a preferred substituent.

[0104] The term “aryl,” used alone or as part of a larger term such as “aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to monocyclic, dicyclic, and tricyclic ring systems having a total of 5 to 14 ring members (the ring members being carbon atoms), where 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, and 3), and those electrons are delocalized across the system, and where each ring in the system contains 3 to 7 ring members. Preferably, all rings or the entire ring system in the aryl system are aromatic. The term “aryl” is used interchangeably with the term “aryl ring.” In some embodiments of the present invention, “aryl” refers to an “aromatic ring system.” More specifically, these aromatic ring systems may be monocyclic, dicyclic, or tricyclic, having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. Even more specifically, these aromatic ring systems may be monocyclic or bicyclic, having 6, 7, 8, 9, or 10 ring carbon atoms. Exemplary aryl groups include phenyl, biphenyl, naphthyl, anthrasyl, etc., which may be unsubstituted or substituted with one or more identical or different substituents. Also included within the scope of the terms “aryl” or “aromatic ring system” are aromatic ring groups condensed with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenantridinyl, or tetrahydronaphthyl, as used herein. In the latter case, the "aryl" group or substituent is attached to its pendant group via the aromatic moiety of the ring system.

[0105] The term "benzo" refers to a six-membered aromatic ring (containing a carbocyclic atom) fused to another ring via two adjacent carbon atoms, which may be a cycloaliphatic, aromatic, heteroaromatic, or heterocyclic (heteroaliphatic) ring; as a result, a ring system is formed with at least two rings, in which the benzo ring shares two common carbon atoms with the other ring to which it is fused. For example, when a benzo ring is fused with a phenyl ring, a naphthalene ring system is formed, while when a benzo ring is fused with pyridine, either quinoline or isoquinoline is provided; and when a benzo ring is fused with a cyclopentene ring, an indene ring is provided.

[0106] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger phrase, for example, "heteroaralkyl" or "heteroaralkoxy", refer to groups having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (the atoms being 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 in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, encompassing any oxidized form of nitrogen or sulfur, and any quaternized form of basic nitrogen. In other words, a "heteroaryl" ring or ring system may also be described as an aromatic heteroring. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, flazanyl, pyridyl (pyridinyl), pyridadinyl, pyrimidinyl, pyrazinyl, indolidinyl, prinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, particularly pyrrolopyridinyl. The terms “heteroaryl” and “heteroar-” also, as used herein, include groups in which a heteroaromatic ring is condensed with one or more aryl rings, cycloaliphatic rings, or heterocyclyl rings, where the radical or attachment site is preferably on the heteroaromatic ring, or on the aryl ring, if present. Non-limiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranil, dibenzofuranil, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, sinnolinyl, phthalazinyl, quinazolinil, quinoxalinyl, 4H-quinolidinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranil, and pyrido[2,3-b]-1,4-oxazine-3(4H)-one.For example, the indolyl ring may be attached via one ring atom of a six-membered aryl ring or via one ring atom of a five-membered heteroaryl ring. The heteroaryl group is optionally mono-, di-, or tricyclic. The term “heteroaryl” is used interchangeably with the terms “heteroaryl ring,” “heteroaryl group,” or “heteroaromatic,” all of which include an unsubstituted ring or a ring substituted with one or more identical or different substituents. The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl, where the alkyl and heteroaryl moieties may be optionally substituted independently.

[0107] A heteroaryl ring can be attached to its pendant group by either its heterocyclic or carbocyclic atoms, and this attachment results in a stable structure or molecule: either the ring atoms are unsubstituted or substituted.

[0108] A typical example structure of a "heteroaryl" substituent, when used in the present invention, is shown below: [ka]

[0109] [ka]

[0110] [ka]

[0111] [ka]

[0112] These heteroaryl substituents can attach to any of the pendant groups, but via one of the ring atoms that is suitable for such attachment.

[0113] As used herein, the terms “heterocyclic,” “heterocyclyl,” “heterocyclic radical,” and “heterocyclic ring” are used interchangeably and refer to a stable mono-, di-, or tricyclic heterocyclic portion having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, where 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms, and where the heterocyclic portion is either saturated or partially unsaturated; heterocyclic portions that are aromatic rings or cyclic systems are usually referred to as “heteroaryl” portions as described herein. Preferably, the heterocyclic portion is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic, or a 7-, 8-, 9-, 10-, or 11-membered bicyclic, or an 11-, 12-, 13-, or 14-membered tricyclic.

[0114] When used in reference to ring atoms of heterocycles, the term "nitrogen" includes substituted nitrogen. For example, in saturated or partially unsaturated rings having 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen can be N (as seen in 3,4-dihydro-2H-pyrrolyl), NH (as seen in pyrrolidinyl), or N-SUB (as seen in N-substituted pyrrolidinyl), where SUB is a preferred substituent.

[0115] In the context of the term "heterocyclic," the term "saturated" refers to fully saturated heterocyclic systems such as pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxothianyl. With respect to the term "heterocyclic," the term "partially unsaturated" refers to (i) heterocyclic systems that contain one or more unsaturated units (e.g., C=C or C=heteroatomic bonds) but are not aromatic (e.g., tetrahydropyridinyl); or (ii) heterocyclic systems in which a heterocyclic ring (either saturated or unsaturated but not aromatic) is fused with an aromatic ring system or a heteroaromatic ring system, where, however, the "partially unsaturated heterocyclic" is attached to the remaining molecule (its pendant group) via one of the ring atoms of the "heterocyclic" part of the system, but without the presence of either an aromatic or heteroaromatic part. This first class (i) of “partially unsaturated” heterocycles is also sometimes referred to as “non-aromatic partially unsaturated” heterocycles. This second class (ii) of “partially unsaturated” heterocycles is also sometimes referred to as “partially aromatic” heterocycles (bicyclic or tricyclic), meaning that at least one of the rings in the heterocycle is a saturated or unsaturated but non-aromatic heterocycle fused with at least one aromatic or heteroaromatic ring system. Typical examples of these “partially aromatic” heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.

[0116] The heterocyclic ring may be attached to its pendant group by any heteroatom or carbon atom that provides a stable structure, and any of the ring atoms may be unsubstituted or substituted. Examples of such heterocyclic radicals, saturated or partially unsaturated, include, but are not limited to, tetrahydrofuranil, tetrahydropyranil, thianil, dioxothianil, tetrahydrothiophenyl, pyrrolidinil, piperidinil, pyrrolinil, morpholinil, tetrahydroquinolinil, tetrahydroisoquinolinil, decahydroquinolinil, oxazolidinil, piperazinil, dioxanil, dioxolanil, diazepinyl, oxazepinyl, thiazepinyl, morpholinil, and quinuclidinyl. The terms “heterocyclic,” “heterocyclyl,” “heterocyclyl ring,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic radical” are used interchangeably herein and also include groups in which a heterocyclyl ring is fused with one or more aryl, heteroaryl, or cycloaliphatic rings (such as indolinyl, 3H-indolyl, chromanyl, phenantridinyl, or tetrahydroquinolinyl, where the radical or attachment site is on the heterocyclyl ring). The heterocyclyl group is optionally monocyclic, dicyclic, or tricyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, where the alkyl moiety and the heterocyclyl moiety are independently unsubstituted or substituted.

[0117] The term "biological equivalent," when used alone or in combination with other terms (e.g., "biological equivalent radical"), refers to a compound or group, radical, moiety, substituent, etc., that produces similar biological effects to another compound, group, radical, moiety, or substituent, but is structurally different from one another. More broadly, a "biological equivalent" can be understood as a compound or group that has nearly identical molecular shape and volume, approximately the same electron distribution, and exhibits similar physical properties. A typical example of a biological equivalent is a biological equivalent of a carboxylic acid that exhibits similar physicochemical properties to a carboxylic acid group ("biological equivalent of a carboxylic acid"). When the group or radical of such a carboxylic acid biological equivalent is used in place of the group or radical of the carboxylic acid, it provides similar properties to a carboxyl group, but may also exhibit some potentially different properties compared to the carboxylic acid group (e.g., reduced polarity, increased lipophilicity, or enhanced pharmacokinetic properties). Typical examples of biological equivalents of carboxylic acids, though not limited to these, include -CN, fluoro, amide, sulfonamide, sulfonimide, and several aromatic and non-aromatic heterocycles, such as hydroxylated isoxazoles, sulfonamide-substituted oxadiazoles and oxo-oxadiazoles, for example, 5-oxo-2,5-dihydro-1,2,4-oxadiazole, and especially tetrazoles, for example, 1H-1,2,3,4-tetrazole and 2-methyl-2H-1,2,3,4-tetrazole.

[0118] The term "unsaturated" as used herein means that a part, group, or substituent has one or more unsaturated units.

[0119] When used herein in reference to any ring, ring system, ring portion, etc., the term “partially unsaturated” refers to a ring portion containing at least one double or triple bond. The term “partially unsaturated” is intended to encompass rings having multiple unsaturated moieties. In particular, it encompasses (i) unsaturated (mono-, di-, or tricyclic) ring systems that have no aromatic or heteroaromatic moieties or portions; and (ii) di- or tricyclic ring systems (e.g., tetrahydronaphthyl or tetrahydroquinolinyl) in which one of the rings in the system is an aromatic or heteroaromatic ring fused with another ring that is neither an aromatic nor a heteroaromatic ring. The first class (i) is sometimes referred to as “partially unsaturated” rings, ring systems, or ring parts, while the second class (ii) is sometimes referred to as “partially aromatic” rings, ring systems, or ring parts.

[0120] As used herein, the terms “bicyclic,” “bicyclic ring,” or “bicyclic ring system” refer to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more unsaturated units (i.e., partially unsaturated or aromatic), and having one or more atoms common to the two rings of the ring system. Thus, the terms encompass any acceptable ring condensation, such as ortho condensation or spirocyclic. As used herein, the term “heterobicyclic” is a subset of “bicyclic,” requiring that one or more heteroatoms be present in one or both rings of the bicyclic structure. Such heteroatoms may be present in ring junctions, may be optionally substituted, and may be selected from nitrogen (including N-oxide), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and so on. In some embodiments, a bicyclic group has 7 to 12 ring members and, independently, 0 to 4 heteroatoms selected from nitrogen, oxygen, or sulfur. Similarly, the terms “tricyclic,” “tricyclic ring,” or “tricyclic ring system” refer to any tricyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more unsaturated units (i.e., partially unsaturated or aromatic), in which a bicyclic ring system (as defined above) is fused with another, third ring. Thus, the terms encompass any acceptable ring fusion. As used herein, the term “heterotricyclic” is a subset of “tricyclic,” requiring that one or more heteroatoms be present in one or both of the three rings. Such heteroatoms may be present at ring junctions, may be optionally substituted, and may be selected from nitrogen (including N-oxide), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and so on. In some embodiments, the tricyclic group has 10 to 14 ring members and, independently, 0 to 5 heteroatoms selected from nitrogen, oxygen, or sulfur.

[0121] As described herein, some compounds of the present invention contain a “substituted” moiety or an “optionally substituted” moiety. Generally, the term “substituted” means that one or more hydrogens of a given moiety are replaced by a preferred substituent, whether preceded by the term “optionally.” “Substituted” applies to one or more hydrogens from a structure, whether explicit or implicit. Unless otherwise indicated, a “substituted” group or an “optionally substituted” group has preferred substituents at each of its substituted positions, and when more than one position in any given structure is substituted by more than one substituent selected from a particular group, the substituents are either the same or different at each position. If a group, substituent, moiety, or radical is “single substituted,” it has one (1) substituent. If it is “disubstituted / is disubstituted,” it has two (2) substituents that are either the same or different; if it is “trisubstituted / is trisubstituted,” it has three (3) substituents, where all three are the same, two are the same and the third is different, or all three are different from each other. The substituent combinations envisioned by the present invention are preferably combinations of substituents that result in the formation of a stable or chemically feasible compound. The term “stable,” as used herein, means a compound that is substantially unchanged when subjected to conditions that enable their production, detection, and, in some embodiments, their recovery, purification, and use for one or more purposes of disclosure herein.

[0122] Unless otherwise specified herein or in any of the appended claims, each substitutionable substituent on the carbon is independently a halogen;-(CH2) 0~4 R o ;-(CH2) 0~4 Ure o ;-O(CH2) 0~4 R o -O-(CH2) 0~4 C(O)OR o;-(CH2) 0~4 CH(OR o )2;-(CH2) 0~4 SR o ;R greater than or equal to 1 o -(CH2) may be substituted with 0~4 Ph;R greater than 1 o -(CH2) may be substituted with 0~4 O(CH2) 0~1 Ph;R greater than 1 o -CH=CHPh;R greater than or equal to 1 may be substituted. o -(CH2) may be substituted with 0~4 O(CH2) 0~1 -Pyridyl;-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 o ;-(CH2) 0~4 SC(O)R o ;-(CH2) 0~4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ,-(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)2R o ;-(CH2) 0~4 S(O)2OR o ;-(CH2) 0~4 OS(O)2R o ;-S(O)2NR o 2;-S(O)(NR o )R o -S(O)2N=C(NR o 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 alkylenes)ON(R o )2; or -(C 1~4 Linear or branched alkylenes)C(O)ON(R oIt is understood that the substituent is a monovalent substituent selected from )2. "Ph" means phenyl; and "-(CH2) 0~4 It is understood that if the subscript is "0" (zero), it means there are no alkylene groups, or that there are alkylene groups with 1, 2, 3, or 4 CH2 units.

[0123] Each R o These are, independently, hydrogen, halogen, and C 1~6 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, -CH2- (a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur), or, notwithstanding the above definition, two independently existing R o These intercalated atoms (one or more) together form a 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring, but independently have 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur, which are R selected from =O and =S. o It may be substituted by a divalent substituent on the saturated carbon atom; or each R o These are, independently, halogen, -(CH2) 0~2 R ● ,-(HaroR ● ), -(CH2) 0~2 OH, -(CH2) 0~2 Ure ● ,-(CH2) 0~2 CH(OR ● )2;-O(HaroR ● ), -CN, -N3, -(CH2) 0~2 C(O)R ● ,-(CH2) 0~2 C(O)OH, -(CH2) 0~2 C(O)OR ● ,-(CH2) 0~2 SR ● ,-(CH2) 0~2 SH, -(CH2) 0~2 NH2, -(CH2) 0~2 NHR● ,-(CH2) 0~2 NR ● 2, -NO2, -SiR ● 3. -OSiR ● 3, -C(O)SR ● ,-(C 1~4 Linear or branched alkylenes)C(O)OR ● , or -SSR ● It may be optionally substituted with a monovalent substituent selected from: "Ph" means phenyl; "halo" means halogen; and "-(CH2) 0~2 It is understood that if the subscript is "0" (zero), it means that there are no alkylene groups, or that there are alkylene groups with one or two CH2 units.

[0124] Each R ● Independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or selected from saturated, partially unsaturated, or aryl rings of 5-6 members (independently selected from nitrogen, oxygen, or sulfur, having 0-4 heteroatoms), where each R l is either unsubstituted or substituted with only one or more halogens if preceded by a halo; or, where any substituent on the saturated carbon is independently =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 A divalent substituent selected from S-, or a divalent substituent bonded to a substituted carbon adjacent to a group that "may be optionally substituted", is -O(CR * 2) 2~3 O-, and each R that exists independently here * is hydrogen, C 1~6Selected from aliphatic or unsubstituted 5-6 member saturated, partially unsaturated, or aryl rings (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur).

[0125] R * C 1~6 If it is aliphatic, R * Halogen, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR l , -NR ● 2, or may be optionally substituted with -NO2, where each R l Independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or selected from saturated, partially unsaturated, or aryl rings of 5-6 members (independently selected from nitrogen, oxygen, or sulfur, having 0-4 heteroatoms), and where each R l It is either unsubstituted, or substituted with only one or more halogens if a halo precedes it.

[0126] Any substitutionable substituent on nitrogen is 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 † Here, each R † These are, independently, hydrogen and C 1~6Aliphatic, unsubstituted -OPh, or unsubstituted 5-6 member saturated, partially unsaturated, or aryl ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur), or two independently present R † These intervening atoms (one or more) together form an unsubstituted 3-12 member saturated, partially unsaturated, or aryl monocyclic or bicyclic ring (independently having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur); where R † C 1~6 When it is aliphatic, R † Halogen, -R ● ,-(HaroR ● ), -OH, -OR ● ,-O(HaroR ● ), -CN, -C(O)OH, -C(O)OR ● -NH2, -NHR ● , -NR ● 2, or may be optionally substituted with -NO2, where each R ● Independently, C 1~4 Aliphatic, -CH2Ph, -O(CH2) 0~1 Ph, or selected from a 5-6 member saturated, partially unsaturated, or aryl ring (independently selected from nitrogen, oxygen, or sulfur, having 0-4 heteroatoms), and where each R ● It is either unsubstituted or substituted with only one or more halogens if preceded by "halo". "Ph" is understood to mean phenyl; and "halo" is understood to mean halogen.

[0127] The term "solvate" refers to the addition form of the compound of the present invention with a solvent, preferably a pharmaceutically acceptable solvent containing either a stoichiometric or non-stoichiometric amount of the solvent. Some compounds tend to trap solvent molecules in a fixed molar ratio in a crystalline solid state, thereby forming solvates. When the solvent is water, the solvate formed is a hydrate, e.g., a semi-, mono-, or dihydrate. When the solvent is an alcohol, the solvate formed is an alcoholate, e.g., a methanolate or ethanolate. When the solvent is an ether, the solvate formed is an etherate, e.g., a diethyl etherate.

[0128] The term "N-oxide" refers to such compounds of the present invention that contain an amine oxide moiety, i.e., an oxide of a tertiary amine group.

[0129] Compounds represented by formulas IA and I may have one or more chirality centers, depending on the properties of the substituents they may support. These may consequently result in various enantiomers and diastereomers, and in some cases (as the case may be, and be) racemic or optically active forms. Therefore, the present invention also relates to optically active forms, enantiomers, racemic compounds, diastereomers, and mixtures thereof in any ratio, collectively referred to for the purposes of the present invention as "stereoisomers" of these compounds. Since the pharmaceutically active properties of racemic compounds or stereoisomers of compounds according to the present invention may differ, it may be desirable to use a specific stereoisomer, for example, one specific enantiomer or diastereomer. In these cases, the compounds according to the present invention obtained as racemic compounds—or even intermediates thereof—may be separated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical means known to those skilled in the art. Another approach that may be applied to obtain one or more specific stereoisomers of the compounds of the present invention in concentrated or pure forms is to use a stereoselective synthetic procedure, for example, by applying a starting material in a stereoisomerically concentrated or pure form (for example, by using a pure or concentrated (R)- or (S)-enantiomer of a specific starting material having a chiral center), or by utilizing a chiral reagent or catalyst, in particular an enzyme. In the context of the present invention, the term “pure enantiomer” usually refers to the relative purity of one enantiomer to the other enantiomer (its counterpart), which is equal to or greater than 95%, preferably ≥98%, more preferably ≥98.5%, and even more preferably ≥99%.

[0130] Therefore, for example, compounds of the present invention having one or more chiral centers and existing as racemic compounds or as mixtures of enantiomers or diastereoisomers can be fractionated or separated into their optically pure or concentrated isomers, i.e., enantiomers or diastereomers, by methods known to the present. Separation of the compounds of the present invention can be performed by chromatography, for example, by column separation on a chiral or non-chiral phase, by recrystallization from any optically active solvent, by the use of an optically active acid or base, or by derivatization with an optically active reagent (e.g., an optically active alcohol) followed by radical elimination.

[0131] In the context of the present invention, the term "tautomer" refers to a compound of the present invention that may exist in tautomer form and may exhibit tautomerism; for example, carbonyl compounds may exist in their keto form and / or their enol form and may exhibit keto-enol tautomerism. These tautomers may exist in their individual forms, e.g., in keto or enol form, or as mixtures thereof, and are claimed individually and together as mixtures of any proportion. The same applies to cis / trans isomers, E / Z isomers, conformer isomers, etc.

[0132] In one embodiment, the compounds of the present invention are in the form of a free base or acid—in some cases—that is, in their non-salted (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.

[0133] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid, including inorganic bases or acids and organic bases or acids. Where a compound of the present invention contains one or more acidic or basic groups, the present invention also includes the corresponding pharmaceutically acceptable salts thereof. Thus, compounds of the present invention containing acidic groups such as carboxyl groups may exist in the form of salts, which, according to the present invention, can be used, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with ammonia, or salts with organic amines such as ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids. These salts are readily available, for example, by reacting compounds having acidic groups with suitable bases, 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 the present invention include, but are not limited to, salts of copper(I), copper(II), iron(II), iron(III), manganese(II), and zinc. Compounds of the present invention containing one or more basic groups, such as protonable groups, may exist in the form of salts and, according to the present invention, may be used in the form of inorganic or organic acids of their addition salts. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfamic 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 include, among others, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), tosylate, carbonate, bicarbonate, formate, acetate, sulfoacetate, trifluate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutaric acid, stearate, aspartate, and glutamate. Furthermore, the stoichiometry of the salts formed from the compounds of the present invention may be an integer multiple of 1 or a non-integer multiple.

[0134] The compounds of the present invention containing a basic nitrogen-containing group include (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides; di(C1-C4) alkyl sulfates, such as dimethyl sulfate, diethyl sulfate, and diamyl sulfate; (C 10 ~C 18 Alkyl halides, such as decyl, dodecyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; as well as aryl (C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide, can be used to quaternize the compounds. Both water- and oil-soluble compounds according to the present invention can be prepared using such salts.

[0135] If the compounds of the present invention simultaneously contain acidic and basic groups in their molecules, the present invention also encompasses intramolecular salts or betaines (amphoteric ions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example, by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also encompasses all salts of the compounds of the present invention that, due to their low physiological compatibility, are not directly suitable for pharmaceutical use but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0136] Therefore, the following items also conform to the present invention: (a) all stereoisomers or tautomers of the compound (including mixtures thereof in any proportion); (b) pharmaceutically acceptable salts of the compounds, as well as pharmaceutically acceptable salts of the items mentioned under (a); (c) pharmaceutically acceptable solvates of compounds, as well as pharmaceutically acceptable solvates of items mentioned under (a) and (b); (d) N-oxides of compounds, as well as N-oxides of items mentioned under (a), (b), and (c).

[0137] It should be understood that all references to compounds above and below are intended to encompass these items, in particular, pharmaceutically acceptable solvates of compounds, or pharmaceutically acceptable solvates of their pharmaceutically acceptable salts.

[0138] Furthermore, the compounds of the present invention are intended to encompass their isotopically labeled forms. The isotopically labeled forms of the compounds represented by formula I or IA are identical to the compounds, apart from the fact that one or more atoms of the compound are replaced by one or more atoms having atomic masses or mass numbers different from those of most naturally occurring atoms. Examples of isotopes that are commercially readily available and 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, for example, 2 H(D), 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F, and 36Each of CI is included. Compounds represented by formula I or IA, or pharmaceutically acceptable salts thereof, containing one or more other isotopes of the aforementioned isotopes and / or other atoms, are intended to be part of the present invention. Isotopically labeled compounds represented by formula I or IA can be used in a number of useful ways. For example, 3 H or 14 The isotope-labeled compounds of the present invention, which incorporate radioactive isotopes such as 13C, are suitable for pharmaceutical and / or substrate tissue distribution assays. These radioactive isotopes, namely tritium ( 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes (e.g., deuterium) 2 The incorporation of H)) into compounds represented by formula IA or I has therapeutic benefits due to the higher metabolic stability of the isotope-labeled compound. Higher metabolic stability directly translates to an increased in vivo half-life or lower dosage, which would represent a preferred embodiment of the present invention in most circumstances. Isotope-labeled compounds represented by formula I or IA can usually be prepared by performing the procedures disclosed in the synthesis scheme and related descriptions in the main text, in the examples section, and in the preparation section, replacing unlabeled reactants with readily available isotope-labeled reactants.

[0139] deuterium( 2H;D) can also be incorporated into compounds represented by formula I or IA for the purpose of manipulating the oxidative metabolism of the compound by the primary kinetic isotope effect. The primary kinetic isotope effect is a change in the rate of a chemical reaction resulting from the exchange of isotopic nuclei, which follows the change in ground state energy required for covalent bond formation after this isotope exchange. The exchange of heavier isotopes usually results in a decrease in ground state energy for chemical bonding, and consequently a reduction in the rate of rate-determining bond breakdown. If bond breakdown occurs in or near the saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be substantially altered. For illustrative purposes: If deuterium is bonded to a carbon atom in an inexchangeable position, k M / k D A typical rate difference is between 2 and 7. If this rate difference is successfully applied to compounds represented by formula I or IA that are prone to oxidation, the in vivo profile of these compounds can be dramatically altered, resulting in improved pharmacokinetic properties.

[0140] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are prone to oxidative metabolism. Currently available in vitro liver microsome assays provide valuable information about the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds represented by formula I or IA with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profile of compounds represented by formula I or IA can be obtained thereby, including in vivo half-life (t1 / 2) and concentration at maximum therapeutic effect (C). max It can be expressed quantitatively in terms of the increase in area under the dose-response curve (AUC) and F, as well as in terms of reduced clearance, dose, and material costs.

[0141] The following is intended to illustrate what is described above: Compounds represented by formula I or IA, which have multiple potential attack sites against oxidative metabolism (e.g., benzyl hydrogen atoms and hydrogen atoms bonded to nitrogen atoms), are prepared as a series of analogues in which various combinations of hydrogen atoms are replaced by deuterium atoms (so that some, almost, or all of these hydrogen atoms can be replaced by deuterium atoms). Determining the half-life allows for a preferred and accurate determination of the extent to which the resistance to oxidative metabolism has been improved. Thus, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

[0142] Deuterium-hydrogen exchange in the compounds of the present invention can also be used to achieve a preferred modification of the metabolite range of the starting compound in order to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites arise through oxidative carbon-hydrogen (CH) bond cleavage, it can be reasonably inferred that a deuterated analog would significantly reduce or eliminate the generation of unwanted metabolites, even if specific oxidation is not the rate-limiting step. Further information on the state of technology regarding 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.

[0143] Furthermore, the present invention relates to a pharmaceutical composition comprising, as an active ingredient, at least one compound represented by formula I or IA, or its N-oxide, solvate, tautomer, or stereoisomer, and each of the above pharmaceutically acceptable salts (including mixtures thereof in any ratio), together with a pharmaceutically acceptable carrier.

[0144] For the purposes of the present invention, the term “pharmaceutical composition” (or “pharmaceutical preparation”) means a composition or product comprising one or more active ingredients, one or more inactive ingredients constituting a carrier, and any products that result directly or indirectly from any combination of two or more of the ingredients, complex formation, or aggregation, or from the dissociation of one or more of the ingredients, or from one or more other types of reactions or interactions of the ingredients. Consequently, the pharmaceutical compositions of the present invention encompass any composition prepared by mixing at least one compound of the present invention with a pharmaceutically acceptable carrier. This may further include pharmaceutically acceptable excipients, auxiliaries, adjuvants, diluents, and / or additional pharmaceutically active substances other than the compounds of the present invention.

[0145] Pharmaceutical compositions include compositions and pharmaceutical preparations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ophthalmic (eye drops), pulmonary (nasal inhalation or oral inhalation), or nasal administration, but in any of the specified cases, the most suitable route will depend on the nature and severity of the disease being treated and the nature of the active ingredient. These may be presented in unit dosage forms for convenience and may be prepared by any method well known in the pharmaceutical art.

[0146] The pharmaceutical compositions of the present invention may further contain one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In specific embodiments, the pharmaceutical compositions further contain a second active ingredient, or its derivatives, prodrugs, solvates, tautomers, or stereoisomers thereof, and pharmaceutically acceptable salts of each of the above (including mixtures thereof in any ratio), wherein the second active ingredient is a compound other than the compound represented by formula I or IA; preferably, the second active ingredient is a compound that is also useful for the treatment, prevention, suppression, and / or recovery from a disease or pathological condition listed anywhere above or below. Such combinations of two or more active ingredients or drugs may be safer or more effective than any drug or active ingredient alone, or the combination may be safer or more effective than what would be predicted based on the additivity of the individual drugs. Other such drugs (one or more) may be administered contemporaneously or sequentially to the compounds of the present invention by a commonly used route and in the same amount. When the compound of the present invention is used contemporaneously with one or more other drugs or active ingredients, a combination product containing such other drugs (one or more) and the compound of the present invention—also referred to as a “fixed-dose combination”—is preferred. However, combination therapy also includes therapies in which the compound of the present invention and one or more other drugs are administered on different, overlapping schedules. When used in combination with other active ingredients, it is intended that the compound of the present invention, or the other active ingredients, or both, may be effective at lower doses than when each is used alone. Consequently, pharmaceutical compositions of the present invention also include those containing one or more other active ingredients in addition to the compound of the present invention.

[0147] The compounds of the present invention—or their N-oxides, solvates, tautomers, or stereoisomers, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any ratio—may be used as pharmaceuticals. They have been found to exhibit pharmacological activity by binding to TEAD and / or interfering with and / or inhibiting YAP-TEAD and / or TAZ-TEAD protein-protein interactions. This activity suggests that the compounds of the present invention may prevent or restore dysfunction of the Hippo pathway. By preventing this dysfunction, the Hippo pathway may be able to fulfill its role as a tumor suppressor. Apart from the prevention or restoration of Hippo pathway dysfunction, and independently of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention may also be useful in other pathophysiological scenarios where TEAD binding and / or inhibition or disruption of abnormal YAP-TEAD and / or abnormal TAZ-TEAD signaling would be beneficial.

[0148] Therefore, the compounds of the present invention, which are TEAD binders and / or inhibitors of the interaction between YAP-TEAD and / or TAZ-TEAD, are particularly useful for the treatment, prevention, suppression, and / or recovery of hyperproliferative disorders and cancers, including solid tumors such as breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma. While we do not wish to agree with any particular theory or explanation, it can be assumed that the compounds can achieve this by having a direct effect on cancer cells and / or indirectly by modulating the immune system's response to the tumor. Furthermore, the compounds of the present invention may also be useful for the treatment, prevention, suppression, and / or recovery of non-cancerous disorders and diseases, such as cardiovascular diseases and fibrosis (such as hepatic fibrosis).

[0149] In specific embodiments, the compounds of the present invention are for use in the prevention and / or treatment of any of the disorders or diseases listed above, preferably cancers, particularly tumors including solid tumors, of certain types of cancers disclosed in the preceding paragraph; or in the treatment of any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0150] Another specific aspect of the present invention is a method for preventing and / or treating, preferably treating, any disorder or disease selected from the group consisting of hyperproliferative disorders and cancers, particularly solid tumors, or of any of the specific types of cancers disclosed in the preceding paragraphs; or any of the noncancerous disorders or diseases disclosed in the preceding paragraphs.

[0151] A further specific aspect of the present invention is the use of the compounds of the present invention—or their derivatives, N-oxides, prodrugs, solvates, tautomers, or stereoisomers, and / or pharmaceutically acceptable salts thereof, and mixtures thereof in any ratio—for the manufacture of pharmaceuticals, in particular, selected from the group consisting of hyperproliferative disorders and cancers, including solid tumors, or specific types of cancers disclosed in the preceding paragraph; or any non-cancerous disorders or diseases disclosed in the preceding paragraph, preferably for the manufacture of pharmaceuticals for the prevention and / or treatment of such disorders or diseases.

[0152] Preferably, the present invention relates to the compounds of the present invention for use in the prevention and / or treatment of diseases—or, alternatively, a method for preventing and / or treating diseases by administering an effective amount of the compounds of the present invention; or, in another alternative, the use of the compounds of the present invention for the manufacture of a medicament for the prevention and / or treatment of diseases—where the disease is cancer, in particular solid tumors of the specific types of cancer disclosed in the preceding paragraphs; more preferably, herein the administration of the compounds is concurrent, sequential, or alternating with the administration of at least one other active agent.

[0153] The compounds of the present invention disclosed herein, in particular those represented by formula I or IA, may 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 cancer patient for the purpose of treating cancer. The anticancer treatments defined above may be applied as monotherapy or in combination with conventional surgery, radiotherapy, or medicinal therapy in addition to the compounds of the present invention disclosed herein. Such medicinal therapy (e.g., chemotherapy or targeted therapy) may include one or more of the following antitumor agents, preferably one of them:

[0154] Alkylating agent Altretamine, Bendamustine, Busulfan, Carmustine, Chlorambucil, Chlormetine, Cyclophosphamide, Dacarbazine, Ifosfamide, Improsulfan, Tosilate, Lomustine, Melphalan, Mitobronitol, Mitractol, Nimustine, Ranimustine, Temozolomide, Thiotepa, Treosulfan, Mechloretamine, Carbocon; Apadicon, Fotemustine, Gluphosphamide, Paliphosphamide, Pipobroman, Trophosphamide, Uramustine, Evophosamide, VAL-083 [4] etc;

[0155] platinum compound Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin, etc. DNA modifier Amrubicin, Bisanthren, Decitabine, Mitoxantrone, Procarbazine, Trabectedin, Clofarabine; Amsacrin, Brostaricin, Pixantrone, Laromustine [1],[3] etc;

[0156] Topoisomerase inhibitor Etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; amonafide, berotecan, eriptinium acetate, boreroxine, etc. microtubule modifier Cabazitaxel, docetaxel, eribulin, ixabepirone, paclitaxel, vinplastin, vincristine, vinorelbine, vindesine, vinflunin; Phospretabrin, tesetaxel, etc.

[0157] anti-metabolite Asparaginase [3] Azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, phloxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; Doxifluridine, Elacitabine, Larcitrexed, Sepacitabine, Tegafur [2],[3] , trimethotrexate, etc.

[0158] Anti-cancer antibiotics Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, rebamisol, miltefosine, mitomycin C, romidepsin, stereptozosin, barurubicin, dinostatin, zolubicin, daunorubicin, plicamycin; Acralubicin, peplomycin, pirarubicin, etc.

[0159] Hormones / Antagonists Abarelix, abiraterone, bicalutamide, buserelin, carsterone, chlorotonianicene, degarelix, dexamethasone, estradiol, flutocortrone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestorol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alpha, toremifene, trilostane, triptorelin, diethylstilbestrol; acorbifen, danazol, deslorerin, epithiostanol, orteronel, enzalutamide [1],[3] etc;

[0160] Aromatase inhibitor Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestan, etc.

[0161] Small molecule kinase inhibitors Crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; Afatinib, Alicertib, Dabrafenib, Dacomitinib, Dinaciclib, Dovitinib, Enzastaurin, Nintedanib, Lenvatinib, Linifanib, Lincitinib, Masitinib, Midostaurin, Motesanib, Neratinib, Orantinib, Perifosin, Ponatinib, Radotinib, Rigosatib, Tepotinib, Tipifanib, Tivantinib, Cibozanib, Trametinib, Pimasertib, Brivanib, Alaninate, Cejilanib, Apatinib [4] Cabozantinib S-Marat [1],[3] ibrutinib [1],[3] , icotinib [4] , Buparlisib [2] , cipatinib [4] Cobimetinib [1],[3] , Ideralicib [1],[3] , Fedratinib [1], tesevatinib, etc.

[0162] Photosensitizer Methoxsalen [3] ;Polyphymer sodium, talaporfin, temoporfin, etc.; antibody Alemtuzumab, becilesomab, brentuximab, vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab [2],[3] Katsumakisomab, elotuzumab, epratuzumab, faretuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, okalatuzumab, olegobomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zaltumumab, zanorimumab, matsuzumab, dalotuzumab [1],[2],[3] Onartuzumab [1],[3] , racotumomab [1] Tabalmab [1],[3] EMD-525797 [4] Atezolizumab, durvalumab, pembrolizumab, nivolumab [1],[3] etc;

[0163] Cytokine Aldesleukin, Interferon Alpha 2, Interferon Alpha 2a [3] Interferon alpha-2b [2],[3] ; Selmoleukin, Tasonelmin, Teseloukin, Operelbekin [1],[3] Recombinant interferon beta-1a [4] etc; Drug conjugate Deniloquin difutitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, afrivercept; syntredequin besudotox, edtreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technitium (99mTc) alsitumomab [1],[3] , vintafolide [1],[3] etc;

[0164] vaccine Cyproisel [3] Vitespen [3] Emepepimto-S [3] OncoVAX [4] Lindpepim [3] troVax [4] MGN-1601 [4] MGN-1703 [4] etc; others Alitretinoin, Bexarotene, Bortezomib, Everolimus, Ibandronate, Imiquimod, Lenalidomide, Lentinan, Methylosine, Mifamlutide, Pamidronic Acid, Pegaspargase, Pentostatin, Ciproisel [4] Schizophyllan, Tamibarotene, Temsirolimus, Thalidomide, Tretinoin, Bismodegib, Zoledronic acid, Vorinostat; Celecoxib, Silenditide, Entinostat, Etanidazole, Ganetespib, Idronoxyl, Iniparib, Ixazomib, Ronidamine, Nimorazole, Parabinostat, Pelletinoin, Pritidepsin, Pomalidomide, Procodazole, Ridaforolimus, Tascinimod, Terotristat, Simalfasin, Tirapazamin, Tosedostat, Travedersen, Ubenimex, Valspodar, Gendicin [4] Picibanil [4] , Leolysine [4] Letaspimycin hydrochloride [1],[3] Trevananib [2],[3]bilirudin [4] carfilzomib [1],[3] Endostatin [4] immucothel [4] , Bellinostat [3] ;

[0165] PARP inhibitor Olaparib, veliparib. MCT1 inhibitor AZD3965 [4] BAY-8002 [4] .

[0166] [1] Prop.INN (Proposed International Common Name) [2] Rec.INN (Recommended International Common Name) [3] USAN (United States Common Name) [4] No INN.

[0167] In another aspect of the present invention, a set or kit is provided comprising a therapeutically effective amount of at least one compound of the present invention and / or at least one pharmaceutical composition as described herein, and a therapeutically effective amount of at least one further pharmacologically active substance other than the compound of the present invention. This set or kit is, a) an effective amount of any of the compounds represented by formula I or IA, or their N-oxides, solvates, tautomers, or stereoisomers, as well as physiologically acceptable salts of each of the above (including mixtures thereof in any proportion), and b) An effective amount of further active ingredients, which are neither compounds represented by formula I nor compounds represented by formula IA. It is preferable to include separate packs.

[0168] A further aspect of the present invention is a process for producing a pharmaceutical composition of the present invention, characterized in that one or more compounds according to the present invention and one or more compounds selected from the group consisting of solid, liquid, or semi-liquid excipients, auxiliary agents, adjuvants, diluents, carriers, and pharmaceutically active agents other than compounds according to the present invention are converted into a suitable dosage form.

[0169] The pharmaceutical compositions (formulations) of the present invention may be administered by any means necessary to achieve their intended purpose. For example, administration may be via oral, parenteral, topical, intestinal, intravenous, intramuscular, inhalation, nasal, intraarticular, intrathecal, transtracheal, transocular, subcutaneous, intraperitoneal, transdermal, or oral routes. Alternatively or in parallel, administration may be via an oral route. The dosage administered will depend on the recipient's age, health condition, and weight, the type of current treatment (if any), the frequency of treatment, and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred.

[0170] Preferred dosage forms, though not limited to these, include capsules, tablets, pellets, sugar-coated tablets, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be produced according to methods known in the art, such as those listed below:

[0171] Tablets: The active ingredients (one or more) and auxiliary agents are mixed, the mixture is compressed into tablets (direct compression), and optionally a portion of the mixture before compression is granulated.

[0172] Capsules: The active ingredients (one or more) and auxiliary agents are mixed to obtain a fluid powder, the powder is optionally granulated, the powder / particles are filled into open capsules, and the capsules are sealed.

[0173] Semi-solids (ointments, gels, creams): The active ingredient(s) are dissolved / dispersed in an aqueous or fatty carrier; the aqueous / fatty phase is then mixed with a complementary fatty / aqueous phase and homogenized (creams only).

[0174] Suppositories (rectal and vaginal): The active ingredient(s) is dissolved / dispersed in a carrier material (rectal: the carrier material is usually wax; vaginal: the carrier is usually a heated solution of a gelling agent) that has been liquefied by heating, the mixture is molded into a suppository form, and the suppository is annealed and withdrawn from the mold.

[0175] Aerosol: The active ingredients (one or more) are dissolved / dispersed in a spraying agent, and the mixture is packed into a sprayer.

[0176] Generally, non-chemical routes for the production of pharmaceutical compositions and / or pharmaceutical preparations include processing steps by preferred mechanical means known in the art to transform one or more compounds of the present invention into dosage forms suitable for administration to patients requiring such treatment. Typically, transforming one or more compounds of the present invention into such dosage forms involves the addition of one or more compounds selected from the group consisting of carriers, excipients, auxiliaries, and pharmaceutically active ingredients other than the compounds of the present invention. Preferred processing steps, but not limited to these, include combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, molding, and / or compressing the active and inactive ingredients, respectively. Mechanical means for carrying out such processing steps are known in the art, for example, from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this regard, the active ingredients are preferably at least one compound of the present invention and optionally one or more additional compounds other than the compounds of the present invention that exhibit valuable pharmaceutical properties, preferably those pharmaceutically active ingredients other than the compounds of the present invention as disclosed herein.

[0177] Specifically suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, fruit juices, or intravenous infusions; suitable for rectal use are suppositories; suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, and also suspensions, emulsions, or implants; and suitable for topical use are ointments, creams, or powders. The compounds of the present invention may also be lyophilized, and the resulting lyophilized product may be used, for example, in the preparation of injectable preparations. The indicated preparations may be sterilized and / or contain assistants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for modifying osmotic pressure, buffers, dyes, flavors, and / or a number of further active ingredients, such as one or more vitamins.

[0178] Suitable excipients are organic or inorganic substances suitable for intra-enteral administration (e.g., oral administration), parenteral administration, or topical administration, which do not react with the compounds of the present invention, and include, for example, water, vegetable oil, benzyl alcohol, alkylene glycol, polyethylene glycol, glycerol triacetate, 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 calcium triphosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or vaseline.

[0179] If desired, the disintegrant may be the starch described above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts (such as sodium alginate). Auxiliaries include, but are not limited to, flow-regulating agents 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 tablet is provided with a suitable coating, which, if desired, is resistant to gastric juice. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. To produce a coating resistant to gastric juice, or to provide a dosage form offering the advantage of sustained action, tablets, sugar-coated tablets, or pills may contain internal and external dose components, the latter in the form of an envelope covering the former. The two components may be separated by an enteric coating that acts to resist disintegration in the stomach and allows the internal component to pass through the duodenum intact or delays its release. Various materials may be used for such enteric coatings or coatings, including numerous polymer acids, and mixtures of polymer acids with materials such as shellac, acetyl alcohol, or solutions of suitable cellulose preparations (such as acetylcellulose phthalate, cellulose acetate, or hydroxypropylmethylcellulose phthalate). Dyes or pigments may be added to the tablet or sugar-coated tablet coating, for example, for identification or to characterize combinations of active compound doses.

[0180] Suitable carrier materials are organic or inorganic substances that are suitable for intraenteral administration (e.g., oral administration), parenteral administration, or topical application, and that do not react with the novel compounds, such as water, vegetable oil, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc, and yellow petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, infusions, or suppositories are used for intraenteral administration; solutions, preferably oily 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 may also be lyophilized, and the resulting lyophilized products can be used, for example, for the production of injectable preparations.

[0181] Other pharmaceutical preparations that may be used orally include push-type capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer (such as glycerol or sorbitol). Push-type capsules may contain, in granular form, an active compound, which may be mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and optionally a stabilizer. In the soft capsule, the active compound is preferably dissolved or suspended in a suitable liquid such as a fatty oil, or in liquid paraffin. In addition, a stabilizer may also be added.

[0182] Liquid forms into which the novel compositions of the present invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oily suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar medicinal vehicles. Suitable dispersants or suspending agents for aqueous suspensions include synthetic and natural rubbers, such as tragacanth, acacia, alginic acid, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0183] Formulations suitable for parenteral administration include aqueous solutions of the active compound in its water-soluble form, such as water-soluble salts and alkaline solutions. In addition, suspensions of the active compound as suitable oily injectable suspensions may also be administered. Suitable lipophilic solvents or vehicles include fatty oils (e.g., sesame oil) or synthetic fatty acid esters, such as ethyl oleate or triglycerides or polyethylene glycol-400 (this compound is soluble in PEG-400).

[0184] The aqueous injection suspension may contain a substance that increases the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and / or dextran, and optionally the suspension may also contain a stabilizer.

[0185] For administration as an inhalation spray, a spray can be used in which the active ingredient is either dissolved or suspended in a spray gas or a mixture of spray gases (e.g., CO2 or carbon chlorofluoride). The active ingredient is used here in a favorably pulverized form, in which case one or more additional physiologically acceptable solvents, such as ethanol, may be present. The inhalation solution can be administered using a conventional inhaler.

[0186] Feasible pharmaceutical preparations that can be used transrectally include, for example, suppositories consisting of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffinic hydrocarbons. In addition, it is also feasible to use gelatin transrectal capsules consisting of a combination of an active compound with a base. Feasible bases include, for example, liquid triglycerides, polyethylene glycol, or paraffinic hydrocarbons.

[0187] Pharmaceutical preparations may be employed as pharmaceutical and veterinary drugs in humans. As used herein, the term “effective dose” means the amount of a drug or pharmaceutical product that would elicit a biological or medical response in a tissue, system, animal, or human (as sought, for example, by researchers or clinicians). Furthermore, the term also encompasses, within its scope, “therapeutably effective dose,” meaning any amount that results in an improved treatment, cure, prevention, or recovery of a disease, disorder, or side effect, or a reduction in the rate of progression of a disease or disorder or symptoms associated with such disease or disorder, compared to a corresponding subject that has not received such dose; this may also mean preventing or providing a preventive measure for a disease or disorder in a subject that has or is at risk of developing the disease disclosed herein. The term also encompasses, within its scope, an amount that is effective in enhancing normal physiological function. One or more of the compounds of the present invention in such therapeutically effective doses are known to those skilled in the art or can be readily determined by standard methods known in the art.

[0188] When used herein, “to treat” or “treatment” means the alleviation of all or part of the symptoms associated with a disorder or disease, or the delay or cessation of the further progression or worsening of those symptoms, or the prevention or preventive measure of a disease or disorder in a person at risk of developing the disease or disorder.

[0189] The compounds of the present invention and any additional active substances are generally administered in a manner similar to commercial preparations. Typically, 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. Daily doses are preferably between approximately 0.001 mg / kg body weight and approximately 10 mg / kg body weight.

[0190] Those skilled in the art will readily understand that dose levels may vary depending on the specific compound, the severity of the symptoms, and the subject's sensitivity to side effects. Some compounds are more potent than others. The preferred dosage for a given compound can be easily determined by those skilled in the art by various means. A preferred means is to measure the physiological efficacy of the given compound.

[0191] However, the specific dose for an individual patient, and especially for an individual human patient, depends on numerous factors, such as the efficacy of the particular compound employed, age, weight, general state of health, sex, diet, time and route of administration, elimination rate, type and dosage form of administration, combination of drugs, and the severity of the specific disorder related to the treatment. The specific therapeutically effective dose for an individual patient can be readily determined by standard experimental methods, for example, by a physician or doctor advising or participating in the therapeutic procedure.

[0192] The compounds of the present invention may be prepared using appropriate materials according to the following scheme and example procedures, as further illustrated by the following specific examples. These may also be prepared by methods known on their own, or more precisely, by known and suitable reaction conditions, as described in the literature (e.g., in standard works such as Houben-Weyl, Methods of Organic Chemistry, Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York). Modifications known on their own but not described in more detail here may also be used.

[0193] Similarly, the starting materials for the preparation of the compounds of the present invention can be prepared as described in the examples or by methods known in themselves, as described in the literature of synthetic organic chemistry and known to those skilled in the art, or they can be commercially obtained. The starting materials for the claimed process and / or utilized process may also be formed in situ, if desired, not by isolating them from the reaction mixture, but instead by immediately converting them to further compounds or intermediate compounds of the present invention. On the other hand, the reaction can generally also be carried out stepwise.

[0194] Preferably, the reaction of the compound is carried out in the presence of a suitable solvent (which is preferably inert under the respective reaction conditions). Examples of suitable solvents, but not limited to these, include 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 or monoethyl ether, or ethylene glycol dimethyl ether (diglym); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (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 such solvents or mixtures with water.

[0195] The reaction temperature is between approximately -100°C and 300°C, depending on the steps and conditions of the reaction used.

[0196] Reaction times generally range from a few minutes to several days, depending on the reactivity of each compound and the respective reaction conditions. A suitable reaction time can be easily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperature given above, a suitable reaction time generally ranges from 10 minutes to 48 hours.

[0197] Furthermore, by using the procedures described herein in conjunction with the ordinary skills of the relevant technical literature, additional compounds of the present invention claimed herein can be readily prepared. However, the compounds described in the examples should not be construed as forming only the genus considered to be the present invention. The examples further illustrate the preparation of the compounds of the present invention in detail. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparation procedures can also be used to prepare these compounds.

[0198] The present invention also relates to a process for producing compounds represented by formula I or IA in their most common forms, as well as specific embodiments described herein: PE0, PE0a, PE0b, PE1, PE1a, PE2-0, PE2 (including PE2(a), PE2(b), PE2(c), PE2(d), PE2(e), PE2(f), PE2(h)), PE3 (including PE3(a), PE3(d), PE3(h)), PE4, PE4a, PE4b, PE5, PE5a, PE6, PE6a, PE6aa, PE6b, PE6bb, PE6c, PE7, PE8, PE8a, PE9, PE9a, PE9b, PE9ba, PE9baa, PE9bb, PE9bba, PE9bc, PE9bd, PE10, PE10a, PE10aa, PE11, PE11a, PE11aa. This also refers to the process for producing any of the following: PE11b, PE11bb, PE11c, PE12, PE12a, PE12b, PE12c, PE12d, PE13, PE13a, PE13b, PE13c, PE13d, PE14, and PE14a, or their N-oxides, solvates, tautomers, or stereoisomers, and any of the pharmaceutically acceptable salts thereof, the process is as follows: (a) Equations II-a, II-Aa [ka] (Z in the formula 1 , Z 2 , Z 3 , W 1 , W 2 , W 3 , W 4, and R 2 This is defined for compounds represented by the above formula IA or I and as defined in the claims, where R 2 (This is neither -C(=O)-OH nor -C(=O)-OCat) A compound represented by; (a)(1) is Equation III R 1 -Hal III (R in the formula 1 (This refers to the compound represented by formula I or IA above, and as defined in any of the claims, where Hal represents Cl, Br, or I.) The compound represented by [the symbol] can be reacted with a CN cross-coupling reaction under suitable reaction conditions; or (a)(2) Firstly, under suitable reaction conditions in a CN cross-coupling reaction, formula IV or IV-A [ka] It is converted into a tricyclic compound represented by; and Next, equation III R 1 -Hal III The compound represented by [the symbol] can be reacted with another CN cross-coupling reaction under suitable reaction conditions; If either of the following occurs, (a)(3) Compounds represented by formula I or IA as defined above or in any of the claims are provided; and optionally (a)(4) In a compound represented by formula I or IA, R 2 However, -C(=O)-OR 2a If so (R 2a C is either non-substitutive or substituted. 1~8 -Aliphatic) When this compound represented by formula I or IA is subjected to conditions suitable for saponification, formula I or IA (R 2 Compounds represented as -C(=O)-OH or -C(=O)-OCat are provided; or, (b) Equations II-b, II-Ab [ka] (Z in the formula 1 , Z 2 , Z 3 , W 1 , W 2 , W 3 , W 4 , and R 2 In any of the claims, for a compound represented by formula I or IA above, and as defined in any of the claims, where R 2 (This is neither -C(=O)-OH nor -C(=O)-OCat) A compound represented by; (b)(1) is equation V R 1 -NH2V (R in the formula 1 (This is defined for compounds represented by formula I or IA above and as defined in any of the claims.) A compound represented by formula I or IA is provided by reacting a compound represented by formula I with a compound represented by formula I under suitable reaction conditions in a CN cross-coupling reaction; and optionally (b)(2) In a compound represented by formula I or IA, R 2 However, -C(=O)-OR 2a If so (R 2a C is either non-substitutive or substituted. 1~8 -Aliphatic) When this compound represented by formula I or IA is subjected to conditions suitable for saponification, formula I or IA (R 2 Compounds represented as -C(=O)-OH or -C(=O)-OCat are provided. It is characterized by one of the following:

[0199] As will be understood by those skilled in the art of organic synthesis, the compounds of the present invention, in particular those represented by formula I or IA, are readily accessible through various synthetic routes, some of which are illustrated in the accompanying experimental section. Those skilled in the art will readily recognize what kinds of reagents and reaction conditions to use and how to apply and adapt them in any specific case to obtain the compounds of the present invention, wherever necessary or useful. 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 certain specific functional groups present in the compounds of the present invention, or suitable precursor molecules thereof, into others by applying standard synthetic methods (known to those skilled in the art), such as reduction, oxidation, addition, or substitution reactions. Similarly, those skilled in the art will know—wherever necessary or useful—how to apply synthetic protecting (or protective) groups; suitable protecting groups, and methods for introducing and removing them, which are described in more detail, for example, in PGMWuts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0200] The following general synthetic routes, which may be used to prepare the compounds of the present invention, are described in more detail in schemes A, AA, B, and BA below: [ka] Scheme A (Z 1 , Z 2 , R 1 , R 2 , W 1 , W 2 , W3 , and W 4 (This is defined for formula I above and in the claims.)

[0201] [ka] Scheme AA (Z 1 , Z 2 , Z 3 , R 1 , R 2 , W 1 , W 2 , W 3 , and W 4 (This is defined in the above formula IA and in the claims.)

[0202] It will also be understood that the following description of Scheme A applies similarly to Scheme AA; and that Scheme AA and its description refer to compounds BA, DA, EA, and IA instead of compounds B, D, E, and I. The synthetic procedures and methods used are the same in Scheme A and AA.

[0203] Scheme A above illustrates a general synthetic route for preparing the tetrazole compound represented by formula I. In the reaction step, compound D is produced by reacting boronic acid B—which is readily available and, for example, by first reacting a bromo-substituted aryl or heteroaryl with a suitable organometallic base such as n-butyllithium, followed by a suitable borate ester such as B(OCH3)3—with a 1-amino-2-bromo-substituted phenyl or heterocyclic C under typical CC cross-coupling conditions, for example, under conditions typical of the Suzuki cross-coupling reaction (for example, a solution of B and C in a suitable solvent such as 1,4-dioxane is reacted with cesium carbonate in the presence of a palladium catalyst such as Pd(dppf)2Cl2(1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride). Compound D may then be subjected to an intramolecular CN cross-coupling reaction (step b), for example, under typical conditions of a Hartwig-Buchwald reaction (for example, the reaction with cesium carbonate in a suitable solvent such as 1,4-dioxane and in the presence of a suitable palladium catalyst such as di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphan{2'-amino-[1,1'-biphenyl]-2-yl}palladiumylium methanesulfonate), to produce a tricyclic heterocycle E. Next, in another CN coupling reaction (step c), under similar conditions, for example, cesium carbonate and bromide R in the presence of a suitable palladium catalyst (e.g., chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), X-Phosaminobiphenylpalladium chloride, XPhosPd G2) 1 Further reaction with -Br may provide the compound represented by formula I of the present invention. Various substituents R 1 , R 2 Properties and W 1 , W2 , W 3 , and W 4 Depending on the properties of, the compound represented by formula I may be arbitrarily transformed into a further compound represented by formula I. For example, R 2 is a carboxyl ester (-C(=O)-OR 2a If so, then this ester can be subjected to a saponification reaction using a suitable acid or base, thereby yielding each carboxylic acid (R 2 =-C(=O)-OH) or its salt (for example, R 2 The formula may be one of the following: =-C(=O)-OCat, where Cat is Li, Na, K, or NH4.

[0204] In some cases, compound D (and DA in scheme AA) as shown in scheme A above may be reacted with a suitable compound R1-Br under CN coupling conditions (in the presence of a suitable base such as cesium carbonate or sodium hydride and a suitable palladium catalyst) instead of being subjected to the subsequent reaction steps b and c, i.e., two consecutive CN coupling reactions, to directly provide the compounds represented by formula I (or IA in scheme AA).

[0205] In some further cases, compound D (or compound DA in scheme AA) is converted to either compound E (or EA) or compound I (or IA) before - W 1 , W 2 , W 3 , or W 4 Compound D may be modified by introducing suitable substituents. For example, in compound D, W 3 CR W1 (R W1 If it represents Br, then this bromo-substituted compound is represented by another substituent R. W1 (For example, -CH2-Ar WCompound D (or compound DA in scheme AA) may be provided by subjecting the compound to a suitable CC coupling reaction that introduces the compound.

[0206] Furthermore, starting from compound E, the compound represented by formula I (or starting from compound EA, the compound represented by formula IA) is a bromo-substituted compound R 1 It is well understood that other suitable reaction partners besides -Br may be used under suitable reaction conditions to synthesize it. For example, R 1 Selected L 1 -Ar or L 1 -Hetar 1 (L here) 1 If (i) is -S(=O)2-, then compound E may be reacted with each thionyl chloride under suitable reaction conditions to produce each sulfonyl derivative represented by formula I (or IA). [ka] Scheme B (Z 1 , Z 2 , R 1 , R 2 , W 1 , W 2 , W 3 , and W 4 (This is defined for formula I above and in the claims.)

[0207] [ka] Scheme BA (Z 1 , Z 2 , Z 3 , R 1 , R 2 , W 1 , W 2 , W 3 , and W 4(This is defined in the above formula IA and in the claims.)

[0208] It will also be understood that the following description of Scheme B applies similarly to Scheme BA; and that Scheme BA and its description refer to compounds BA, GA, and IA instead of compounds B, G, and I. The synthetic procedures and methods used are the same in Scheme B and BA.

[0209] Scheme B above depicts an alternative synthetic route for producing the compounds of the present invention. Here, boronic acid B (or a preferred boronic acid ester) is reacted with a 1-chloro-2-iodo-substituted heterocycle F in a CC cross-coupling reaction under the same conditions as described for step a in scheme A (step d), which produces a dichloro-substituted compound G. Compound G is then converted into a primary amine R 1 In the CN coupling reaction with -NH2 (step e), the compound may be converted in the presence of a suitable base such as cesium carbonate and a suitable palladium catalyst (as described for scheme A) to a desired compound represented by formula I (or IA for scheme BA).

[0210] Unless specifically defined or the context provides a different meaning, it should be noted that, generally, the number of terms, i.e., their singular and plural forms, are interchangeable and can be read interchangeably. For example, the singular term “compound” may also include or refer to plural compounds, while the plural term “compound” may also include or refer to the singular compound.

[0211] Examples and Experiment Parts The compounds of the present invention can be prepared using appropriate materials according to the procedures and examples of the following scheme, which are further illustrated by the following specific examples. The compounds are shown in Table 1. The analytical data of compounds prepared according to the following examples are also shown in Table 1.

[0212] The present invention will be described by reference to, but is not limited to, the specific embodiments described in the following examples. Unless otherwise indicated in the scheme, the variable parts have the same meaning as described above and in the claims.

[0213] Unless otherwise specified, all starting materials are obtained from commercial suppliers and used without further purification. Unless otherwise specified, all temperatures are expressed in °C, and all reactions are carried out at room temperature (RT). Compounds are purified by either silica chromatography or preparative HPLC.

[0214] 1 1H NMR: 1 H-NMR data is provided in Table 1 below. 1 ¹H NMR spectra were generally acquired using a Bruker Avance DRX 500, Bruker Avance 400, or Bruker DPX 300 NMR spectrometer under standard conditions, with TMS (tetramethylsilane) as the internal standard and DMSO-d6 as the standard solvent, unless otherwise reported. NS (number of scans): 32, SF (spectrometer frequency): as indicated. TE (temperature): 297K. Chemical shifts (δ) are reported in ppm relative to the residual solvent signal. 1 1H NMR data are reported as follows: chemical shift (multiplicity, coupling constant, and number of hydrogen atoms). Multiplicity is abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quadruplet), m (multitlet), dd (doublet of doublet), tt (triplet of triplet), td (triplet of doublet), br (broad), and the coupling constant (J) is reported in Hz.

[0215] LC-MS: The LC-MS data provided in Table 1 are given in mass units of m / z. The results can be obtained by one of the methods described below.

[0216] synthesis Example 1: 6-[(3-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid Example 1-1: Synthesis of 2'-amino-5'-bromo-6-chloro-[1,1'-biphenyl]-3-carboxylate ethyl [ka] To a mixture of [2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (4.40 g; 19.26 mmol), 4-bromo-2-iodoaniline (6.60 g; 22.15 mmol), and K2CO3 (5.32 g; 38.49 mmol) in dioxane (40 ml) and H2O (4 ml), Pd(dppf)Cl2CH2Cl2 (2.36 g; 2.89 mmol) was added at 25 °C. The dark brown mixture was stirred at 90 °C for 16 hours under a 1 bar nitrogen balloon. The reaction mixture was poured into water (100 mL) and extracted three times with ethyl acetate (EA) (30 mL). The combined organic phase was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product. (4.70g; 12.19mmol; 63.3%; yellow-brown solid). 1 H NMR (400MHz, CDCl3) δ 8.02 - 7.99 (m, 2H), 7.58 (d, J=8.0 Hz, 1H), 7.31 (dd, J=8.4, 2.4 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.68 (d, J=8.4 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.39 (t, J=7.2 Hz, 3H)

[0217] Example 1-2: Synthesis of 2'-amino-6-chloro-5'-[(3-fluorophenyl)methyl]-[1,1'-biphenyl]-3-carboxylate ethyl [ka] Chlorotrimethylsilane (46 mg; 0.42 mmol) was added to zinc (415 mg; 6.35 mmol) in THF (10 ml) at 25°C and the mixture was stirred at 25°C for 30 minutes. Then, 1-(bromomethyl)-3-fluorobenzene (805 mg; 4.26 mmol) was added and the mixture was stirred at 25°C for 3 hours. Next, ethyl 2'-amino-5'-bromo-6-chloro-[1,1'-biphenyl]-3-carboxylate (500 mg; 1.30 mmol), Pd(amphos)2Cl2 (150 mg; 0.21 mmol), and 1-methyl-1H-imidazole (24 mg; 0.29 mmol) were added at 25°C. The yellowish-brown mixture was stirred at 25°C for 16 hours under a 1 bar nitrogen balloon. The residue was obtained by concentrating the reaction solution. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product. (526.00 mg; 1.12 mmol; 87 %; yellow-brown oil).

[0218] Examples 1-3: Synthesis of 6-[(3-fluorophenyl)methyl]-9H-carbazole-3-carboxylate ethyl [ka] A mixture of ethyl 2'-amino-6-chloro-5'-[(3-fluorophenyl)methyl]-[1,1'-biphenyl]-3-carboxylate (526 mg; 1.12 mmol), copper iodide (45 mg; 0.24 mmol), and (2S)-pyrrolidine-2-carboxylic acid (40 mg; 0.35 mmol) in DMSO (40 ml) was mixed with K2CO3 (320 mg; 2.32 mmol) at 25 °C. The bluish-brown mixture was stirred at 120 °C under a 1 bar nitrogen balloon. The reaction solution was poured into water (150 mL) and extracted three times with EA (40 mL). The combined organic layers were concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product. (140 mg; 0.37 mmol; 33%; off-white solid).

[0219] Examples 1-4: Synthesis of 6-[(3-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate ethyl [ka] To a mixture of 6-[(3-fluorophenyl)methyl]-9H-carbazole-3-carboxylate ethyl (140 mg; 0.37 mmol), 1-bromo-4-(trifluoromethyl)benzene (110 mg; 0.49 mmol), and copper iodide (23 mg; 0.12 mmol) in DMSO (5 ml), (2S)-pyrrolidine-2-carboxylic acid (14 mg; 0.12 mmol) and K2CO3 (140 mg; 1.01 mmol) were added at 25 °C. The bluish-brown mixture was stirred at 120 °C for 16 hours under a 1 bar nitrogen balloon. The reaction mixture was poured into water (20 mL) and extracted three times with EA (20 mL). The combined organic layer was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product. (118 mg; 0.24 mmol; 66%; off-white solid). 1 H NMR (400MHz, CDCl3) δ 8.83 - 8.82 (m, 1H), 8.12 (dd, J=8.8, 1.6 Hz, 1H), 8.02 - 8.01 (m, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.71 (d, J=8.0 Hz, 2H), 7.40 - 7.35 (m, 2H), 7.31 - 7.24 (m, 2H), 7.04 (d, J=7.6 Hz, 1H), 6.94 - 6.89 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 4.18 (s, 2H), 1.46 (t, J=7.6 Hz, 3H)

[0220] Examples 1-5: Synthesis of 6-[(3-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid [ka] To a solution of ethyl 6-[(3-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate (80 mg; 0.16 mmol) in EtOH (4 ml) and H2O (1 ml), NaOH (20 mg; 0.50 mmol) was added at 25 °C. The yellowish-brown mixture was stirred at 70 °C for 1 hr. The reaction mixture was poured into H2O (10 mL) and the pH was adjusted to ~5 with 1 N aqueous hydrochloric acid solution (5 drops). The mixture was extracted three times with EA (10 mL), and the combined organic layer was concentrated to obtain the residue. The residue was purified by C18 column (ACN / H2O = 10%~90%) to obtain the desired product. (55.00 mg; 0.12 mmol; 71%; off-white solid). 1 H NMR (400MHz, DMSO-d6) δ 12.77 (s, 1H), 8.86 (d, J=1.6 Hz, 1H), 8.34 (s, 1H), 8.06 - 8.03 (m, 3H), 7.93 - 7.91 (m, 2H), 7.50 (d, J=8.4 Hz, 1H), 7.44 - 7.39 (m, 2H), 7.36 - 7.31 (m, 1H), 7.19 - 7.15 (m, 2H), 7.03 - 6.98 (m, 1H), 4.16 (s, 2H)

[0221] Example 2: 9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid Example 2-1: Synthesis of ethyl 2'-amino-6-chloro-[1,1'-biphenyl]-3-carboxylate [ka] To a mixture of [2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (500 mg; 2.19 mmol), 2-iodoaniline (530 mg; 2.42 mmol), and K2CO3 (600 mg; 4.34 mmol) in dioxane (10 ml) and H2O (1 ml), Pd(dppf)Cl2 (240 mg; 0.33 mmol) was added at 25 °C. The dark brown mixture was stirred at 60 °C for 5 hours under a 1 bar nitrogen balloon. The reaction mixture was poured into water (20 ml) and extracted three times with EA (10 ml). The combined organic layer was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product. (470 mg; 1.7 mmol; 77%; yellowish-brown oil). 1 H NMR (400MHz, CDCl3) δ 8.03 - 7.98 (m, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.24 - 7.21 (m, 1H), 7.06 - 7.04 (m, 1H), 6.85 - 6.79 (m, 2H), 4.37 (q, J=7.2 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H)

[0222] Example 2-2: Synthesis of ethyl 9H-carbazole-3-carboxylate [ka] To a solution of ethyl 2'-amino-6-chloro-[1,1'-biphenyl]-3-carboxylate (470 mg; 1.7 mmol), copper iodide (100 mg; 0.53 mmol), and (2S)-pyrrolidine-2-carboxylic acid (60 mg; 0.52 mmol) in DMSO (56 ml), K2CO3 (710 mg; 5.14 mmol) was added at 25 °C. The bluish-brown mixture was stirred at 130 °C for 16 hours under a 1 bar nitrogen balloon. The reaction mixture was poured into water (150 mL) and extracted three times with EA (30 mL). The combined organic layer was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product. (192 mg; 0.73 mmol; 43%; off-white solid).

[0223] Example 2-3: Synthesis of ethyl 9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate [ka] To a mixture of ethyl 9H-carbazole-3-carboxylate (180 mg; 0.68 mmol), 1-bromo-4-(trifluoromethyl)benzene (270 mg; 1.20 mmol), and copper iodide (45 mg; 0.24 mmol) in DMSO (5 ml), (2S)-pyrrolidine-2-carboxylic acid (30 mg; 0.26 mmol) and K2CO3 (330 mg; 2.39 mmol) were added at 25 °C. The bluish-brown mixture was stirred at 120 °C for 16 hours under a 1 bar nitrogen balloon. The reaction mixture was poured into water (20 mL) and extracted three times with EA (10 mL). The organic layer was concentrated to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to obtain the desired product (220 mg; 0.57 mmol; 83%; grayish-white solid). 1 H NMR (400MHz, CDCl3) δ 8.88 (d, J=1.2 Hz, 1H), 8.22 (d, J=7.6 Hz, 1H), 8.14 (dd, J=8.4, 1.6 Hz, 1H), 7.92 - 7.90 (m, 2H), 7.74 - 7.72 (m, 2H), 7.49 - 7.36 (m, 4H), 4.46 (q, J=7.2 Hz, 2H), 1.47 (t, J=7.2 Hz, 3H

[0224] Example 2-4: Synthesis of 9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid [ka] NaOH (29 mg; 0.73 mmol) was added at 25°C to a mixture of ethyl 9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate (93 mg; 0.24 mmol) in EtOH (4 ml) and water (1 ml). The yellowish-brown mixture was stirred at 70°C for 1 hour. The reaction mixture was poured into water (10 mL) and the pH was adjusted to ~5 with 1 N aqueous hydrochloric acid solution (5 drops). The mixture was extracted three times with EA (10 mL), and the combined organic layer was concentrated to obtain the residue. The residue was purified by C18 column (ACN / H2O = 10%~90%) to obtain the desired product. (76 mg; 0.21 mmol; 88%; off-white solid). 1 H NMR (400MHz, DMSO-d6) δ 12.78 (s, 1H), 8.90 (d, J=1.2 Hz, 1H), 8.41 (d, J=7.6 Hz, 1H), 8.08 - 8.05 (m, 3H), 7.95 - 7.93 (m, 2H), 7.53 - 7.48 (m, 3H), 7.41 - 7.37 (m, 1H)

[0225] Example 3: 9-(4-trifluoromethylphenyl)-9H-b-carboline-6-carboxylic acid Example 3-1: Synthesis of ethyl 4-chloro-3-(3-chloropyridine-4-yl)benzoate [ka] To a solution of [2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (500 mg; 2.19 mmol) in dioxane (5 ml) and water (0.5 ml), 3-chloro-4-iodopyridine (576 mg; 2.41 mmol), Pd(dppf)Cl2 (0.22 mmol), and K2CO3 (605 mg; 4.38 mmol) were added, and N2 was passed through the reaction. The reaction mixture was then stirred at 60°C under an N2 atmosphere for 6 hours. The mixture was poured into water (10 ml) and then extracted with EA (8 ml * 3). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H2O = 5%~95%) to obtain the purified product. (570 mg; 1.83 mmol; 84%; white solid). 1 H NMR (400MHz, CDCl3) δ 8.07 (dd, J=8.4, 2.1 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.24 (d, J=4.9 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).

[0226] Example 3-2: Synthesis of 9-[4-(trifluoromethyl)phenyl]-9H-pyrido[3,4-b]indole-6-carboxylate ethyl [ka] Pd2(dba)3 (0.65g; 0.71mmol) was added at 25°C to a solution of ethyl 4-chloro-3-(3-chloropyridine-4-yl)benzoate (1.30g; 4.35mmol), 4-(trifluoromethyl)aniline (0.70g; 4.35mmol), tri-tert-butylphosphanium tetrafluoroboranoid (1.30g; 4.48mmol), and Cs2CO3 (4.25g; 13.04mmol) in dioxane (360mL). The mixture was stirred at 140°C for 16 hours under a 1 bar nitrogen balloon. The mixture was filtered. The mixture was poured into water (100mL) and extracted three times with EA (300ml). The combined organic layer was concentrated to obtain the residue. The residue was purified and concentrated using a C18 column (ACN / 0.1% TFA in H2O = 5%~95%). 5 mL of MeOH was added, and the suspension was filtered. Washing the filtration cake with 2 mL of MeOH yielded the desired product (0.11 g; 0.29 mmol; 6.6%; yellow solid). 1H NMR (400MHz, DMSO-d6) δ 9.24 (d, J=1.2 Hz, 1H), 9.20-9.08 (m, 1H), 8.88 (d, J=5.5 Hz, 1H), 8.79-8.62 (m, 1H), 8.30 (dd, J=8.8, 1.7 Hz, 1H), 8.14 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 7.72 (d, J=8.9 Hz, 1H), 4.42 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).

[0227] Example 3-3: Synthesis of 9-(4-trifluoromethylphenyl)-9H-b-carbolin-6-carboxylic acid [ka] To a solution of ethyl 9-[4-(trifluoromethyl)phenyl]-9H-pyrido[3,4-b]indole-6-carboxylate (110 mg; 0.29 mmol) in EtOH (6 ml), 1 ml of 1 M aqueous sodium hydroxide solution was added. The mixture was stirred at 60°C for 1.5 hours. The mixture was concentrated and the pH was adjusted to 1-2 with 1 N hydrochloric acid. The product was obtained by purifying the mixture by HPLC (1%-95% 0.1% TFA / H2O). 9-[4-(trifluoromethyl)phenyl]-9H-pyrido[3,4-b]indole-6-carboxylic acid (70 mg; 0.19 mmol; white solid). 1 H NMR (400MHz, DMSO) δ 13.12 (s, 1H), 9.24 (d, J=1.1 Hz, 1H), 9.16 (s, 1H), 8.87 (d, J=5.6 Hz, 1H), 8.72 (d, J=5.7 Hz, 1H), 8.30 (dd, J=8.8, 1.7 Hz, 1H), 8.13 (d, J=8.5 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.8 Hz, 1H).

[0228] Example 4: 6-(2-fluorobenzyl)-9-(4-trifluoromethylphenyl)-9H-carbazole-3-carboxylic acid Examples 4-1 to 4-4: Synthesis of 6-[(2-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate ethyl Ethyl 6-[(2-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate was prepared using 1-(bromomethyl)-2-fluorobenzene instead of 1-(bromomethyl)-3-fluorobenzene (Example 1-2) in the second reaction step (Example 4-2), similar to the procedure provided in Examples 1-1 to 1-4.

[0229] Example 4-5: Synthesis of 6-(2-fluorobenzyl)-9-(4-trifluoromethylphenyl)-9H-carbazole-3-carboxylic acid [ka] To a solution of ethyl 6-[(2-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid (100 mg; 0.19 mmol) in EtOH (4 ml) and water (1 ml), NaOH (25 mg; 0.63 mmol) was added at 25 °C. The yellowish-brown mixture was stirred at 70 °C for 1 hour. The reaction mixture was adjusted to pH ~5 with 5 drops of 1 N aqueous hydrochloric acid solution, and the residue was obtained by concentration. The residue was purified by C18 column (ACN / H2O = 10%~95%) to obtain the title compound 6-[(2-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid (50 mg; 0.11 mmol; 55%; grayish-white solid). 1 H NMR (400MHz, DMSO-d6) δ 12.76 (s, 1H), 8.83 (d, J=1.2 Hz, 1H), 8.28 (s, 1H), 8.06 - 8.03 (m, 3H), 7.93 - 7.91 (m, 2H), 7.50 (d, J=8.8 Hz, 1H), 7.44 - 7.37 (m, 3H), 7.28 - 7.25 (m, 1H), 7.19 - 7.13 (m, 2H), 4.17 (s, 2H).

[0230] Example 5: 6-(4-fluorobenzyl)-9-(4-trifluoromethylphenyl)-9H-carbazole-3-carboxylic acid Examples 5-1 to 5-4: Synthesis of 6-[(4-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate ethyl Ethyl 6-[(4-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate was prepared using 1-(bromomethyl)-4-fluorobenzene instead of 1-(bromomethyl)-3-fluorobenzene (Example 1-2) in the second reaction step (Example 5-2), similar to the procedure provided in Examples 1-1 to 1-4.

[0231] Example 5-5: Synthesis of 6-(4-fluorobenzyl)-9-(4-trifluoromethylphenyl)-9H-carbazole-3-carboxylic acid [ka] To a solution of ethyl 6-[(4-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid (95 mg; 0.17 mmol) in EtOH (4 ml) and water (1 ml), NaOH (25 mg; 0.63 mmol) was added at 25 °C. The yellowish-brown mixture was stirred at 70 °C for 1 hour. The reaction mixture was adjusted to pH ~5 with 5 drops of 1 N aqueous hydrochloric acid solution, and the residue was obtained by concentration. The residue was purified by C18 column (ACN / H2O = 10%~95%) to obtain the title compound 6-[(4-fluorophenyl)methyl]-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid (55 mg; 0.12 mmol; 69%; grayish-white solid). 1 H NMR (400MHz, DMSO-d6) δ 12.78 (s, 1H), 8.85 (d, J=1.6 Hz, 1H), 8.31 (s, 1H), 8.06 - 8.02 (m, 3H), 7.93 - 7.91 (m, 2H), 7.51 (d, J=8.8 Hz, 1H), 7.44 - 7.34 (m, 4H), 7.14 - 7.09 (m, 2H), 4.13 (s, 2H).

[0232] Example 6: 5-(4-trifluoromethylphenyl)-5H-pyrido[4,3-b]indole-8-carboxylic acid Example 6-1: Synthesis of ethyl 4-chloro-3-(4-chloropyridine-3-yl)benzoate [ka] To a mixture of [2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (500 mg; 2.19 mmol) in dioxane (5 ml) and water (0.5 ml), 4-chloro-3-iodopyridine (524 mg; 2.19 mmol), Pd(dppf)Cl2 (161 mg), and K2CO3 (605 mg; 4.38 mmol) were added, and the reaction was passed through with N2. The reaction mixture was then stirred at 60°C under an N2 atmosphere for 6 hours. The mixture was poured into water (10 ml) and then extracted with EA (8 ml * 3). The combined organic phase was collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H2O = 5%~95%) to obtain the purified product. (240 mg; 0.79 mmol; 36%; white solid). 1 H NMR (400MHz, CDCl3) δ 8.57 (d, J=5.3 Hz, 1H), 8.50 (s, 1H), 8.07 (dd, J=8.4, 2.1 Hz, 1H), 7.97 (d, J=2.1 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.47 (d, J=5.4 Hz, 1H), 4.39 (q, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).

[0233] Example 6-2: Synthesis of 5-[4-(trifluoromethyl)phenyl]-5H-pyrido[4,3-b]indole-8-carboxylate ethyl [ka] In a shielded tube, ethyl 4-chloro-3-(4-chloropyridine-3-yl)benzoate (200 mg; 0.68 mmol), 4-(trifluoromethyl)aniline (109 mg; 0.68 mmol), XPhosPd G2 (27 mg; 0.03 mmol), and Cs2CO3 (660 mg; 2 mmol) were placed in dioxane (14 ml). The mixture was stirred at 120°C under N2 for 16 hours. The crude product was obtained as black oil by filtering and concentrating the mixture. The product was obtained by refining the crude product with C18 (ACN / 0.1% TFA = 5%~95%). (62 mg; 0.13 mmol; 19%; pale yellow powder). 1 H NMR (400MHz, DMSO) δ 9.28 (d, J=1.2 Hz, 1H), 8.79 (d, J=6.7 Hz, 1H), 8.64 (d, J=5.4 Hz, 1H), 8.59 (s, 1H), 8.29 (dd, J=8.7, 1.7 Hz, 5H), 8.18 (d, J=8.5 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.74 (d, J=5.4 Hz, 1H), 7.69 (d, J=8.8 Hz, 1H), 4.43 (d, J=7.1 Hz, 2H), 1.40 (t, J=7.1 Hz, 3H).

[0234] Example 6-3: Synthesis of 5-(4-trifluoromethylphenyl)-5H-pyrido[4,3-b]indole-8-carboxylic acid [ka] To a solution of ethyl 5-[4-(trifluoromethyl)phenyl]-5H-pyrido[4,3-b]indole-8-carboxylate (60 mg; 0.12 mmol) in MeOH (3 ml), 0.5 ml of 1 M aqueous sodium hydroxide solution was added. The mixture was stirred at 60°C for 1 hour. The mixture was concentrated and the pH was adjusted to 1-2 with 1 N hydrochloric acid. The product was obtained by purifying the mixture with C18 (0.1% TFA / H2O = 5-95%). (36 mg; 0.1 mmol; 78%; white powder). 1 H NMR (400MHz, DMSO) δ 13.17 (s, 1H), 10.00 (s, 1H), 9.24 (d, J=1.2 Hz, 1H), 8.76 (d, J=6.7 Hz, 1H), 8.26 (dd, J=8.7, 1.6 Hz, 1H), 8.17 (d, J=8.5 Hz, 2H), 8.03 (d, J=8.3 Hz, 2H), 7.89 (d, J=6.5 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H).

[0235] Example 7: 5-methyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid Example 7-1: Synthesis of 2'-amino-6-chloro-6'-methyl-[1,1'-biphenyl)-3-carboxylate ethyl [ka] To a solution of [2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (1.00 g; 4.16 mmol), 2-bromo-3-methylaniline (0.82 g; 4.19 mmol), and K2CO3 (1.20 g; 8.25 mmol) in THF (10.00 ml) and water (2.00 ml), Pd(PPh3)4 (0.50 g; 0.41 mmol; 0.10 eq.) was added at 25°C. The mixture was stirred at 80°C for 16 hours under a 1 bar nitrogen balloon. The mixture was poured into water (50 mL) and extracted with DCM (4 x 30 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the residue was obtained by concentrating the filtrate. The residue was purified by silica gel column chromatography (petroleum ether / EA = 1:1) to obtain the desired product (0.15 g; 0.42 mmol; 10%; light brown solid).

[0236] Example 7-2: Synthesis of 5-methyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate ethyl [ka] A mixture of ethyl 2'-amino-6-chloro-6'-methyl-[1,1'-biphenyl]-3-carboxylate (100 mg; 0.28 mmol), 1-bromo-4-(trifluoromethyl)benzene (80 mg; 0.34 mmol), and cesium carbonate (150 mg; 0.44 mmol) in dioxane-1,4 (3 ml) was mixed with a second-generation XPhos Pre catalyst (20 mg; 0.02 mmol) under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 80°C under a nitrogen atmosphere for 16 hours.

[0237] Example 7-3: Synthesis of 5-methyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid [ka] To a solution of ethyl 5-methyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylate (80 mg; 0.19 mmol) in MeOH (2 ml) and water (0.2 ml), NaOH (20 mg; 0.48 mmol) was added under a nitrogen atmosphere at room temperature. The resulting mixture was stirred at 60°C under a nitrogen atmosphere for 16 hours. The mixture was acidified to pH 4 with 1N HCl. The resulting mixture was extracted three times with DCM (10 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC under the following conditions ((2#SHIMADZU(HPLC-01)): column, XBridge Prep OBD C18 column, 30*150 mm 5 μm; mobile phase, water (10 MMOL / L NH4HCO3 + 0.1% NH3.H2O) and ACN (28% phase B to 58% up to 8 min); detector, UV). The purified product was obtained (13 mg; 18% yield; white solid). 1 H NMR (400MHz, DMSO-d6) δ 8.83 (d, J=1.6 Hz, 1H), 8.11 - 8.04 (m, 3H), 7.91 (d, J=8.2 Hz, 2H), 7.49 (d, J=8.6 Hz, 1H), 7.45 - 7.37 (m, 1H), 7.31 (d, J=8.2 Hz, 1H), 7.20 (d, J=7.2 Hz, 1H), 2.91 (s, 3H).

[0238] Synthesis of 2-methoxy-N-methyl-5-[4-(trifluoromethyl)phenyl]-5H-pyrido[3,2-b]indole-8-carboxamide [ka] DIEA (126 mg; 0.93 mmol) was added at room temperature to a stirred mixture of 2-methoxy-5-[4-(trifluoromethyl)phenyl]-5H-pyrido[3,2-b]indole-8-carboxylic acid (180 mg; 0.46 mmol), CH3NH2-HCl (36 mg; 0.51 mmol), and HATU (370 mg; 0.92 mmol) in DMF (10 ml). After 1 hour, the reaction was quenched with water, and the resulting mixture was extracted with RINKAN (3 x 50 mL). The combined organic layer was washed with brine (1 x 10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude product (80 mg) was purified by preparative HPLC, and the product was given as a white solid (36 mg; 19%; yield).

[0239] Synthesis of N-cyclopropyl-6,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxamide [ka] To 6,7-dimethyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxylic acid (50 mg; 0.13 mmol) in DMF (3 ml), cyclopropylamine (14 μl; 0.19 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50 mg; 0.26 mmol), 1-hydroxybenzotriazole (20 mg; 0.13 mmol), and 4-methylmorpholine (72 μl; 0.65 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours, and then purified directly by preparative HPLC - the product was given as a white solid (23 mg; 37%).

[0240] Separation of N-(2,3-dihydroxypropyl)-6-methyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxamide [ka] 30 mg of N-(2,3-dihydroxypropyl)-6-methyl-9-[4-(trifluoromethyl)phenyl]-9H-carbazole-3-carboxamide was separated by SFC. Device: THAR SFC; Column: YMC Amylose-C; Eluent: CO2 / 2-propanol = 80:20; Wavelength: 270 nm; Flow rate: 5 ml / min. Enantiomers of 11 mg (RT: analytic: 16.52 min; prep: 18.92 min) and 13 mg (RT: analytic: 19.7 min; prep: 23.09 min) were obtained.

[0241] Table 1 Table 1 below shows exemplary compounds of the present invention. These were synthesized as described in or in the same manner as described in the examples above. [Table 1-1]

[0242] [Table 1-2]

[0243] [Table 1-3]

[0244] [Table 1-4]

[0245] [Table 1-5]

[0246] [Table 1-6]

[0247] [Table 1-7]

[0248] Table 1-8

[0249] Table 1-9

[0250] Table 1-10

[0251] Table 1-11

[0252] Table 1-12

[0253] Table 1-13

[0254] Table 1-14

[0255] Table 1-15

[0256] Table 1-16

[0257] Table 1-17

[0258] Table 1-18

[0259] Table 1-19

[0260] Table 1-20

[0261] Table 1-21

[0262] Table 1-22

[0263] Table 1-23

[0264] Table 1-24

[0265] Table 1-25

[0266] Table 1-26

[0267] Table 1-27

[0268] [Table 1-28]

[0269] LC-MS conditions: Method A: XBridge C18, 3.5 μm, 3.0 x 30 mm; Solvent A: Water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2 ml / min; Gradient: 0 min: 5% B, 8 min: 100% B, 8.1 min: 100% B, 8.5 min: 5% B, 10 min: 5% B. Method B: Column: Waters XBridge C18 3.5μm, 50*4.6mm; 40-70%; Flow rate: 1.5mL / min; Analysis time: 6.5min; MS scanning range: 100-1000; Mobile phase A: 0.02% NH4OAc in water; Mobile phase B: Acetonitrile; Gradient: 0.15min: 40%B, 4.5min: 70%B, 4.6min: 95%B, 6.0min: 95%B, 6.1min: 5%B, 6.5min: 5%B. Method C: Column: Titank C18 1.8um, 30*2.1 mm; Column Oven: 40℃; Mobile Phase A: Water / 5mM NH4HCO3; Mobile Phase B: Acetonitrile Method D: Column: HALO, 3.0*30mm, 2um; Column oven: 40℃; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.5 mL / min; Gradient: 5%B to 100%B by 1.2 min, hold for 0.5 min; 254 nm. Method E: Column: Kinetex EVO 2.6um, 3.0*50mm; Column oven: 40℃; Mobile phase A: Water / 5mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.2mL / min; Gradient: 10%B to 95%B by 2.1min, hold for 0.6min; 254nm Method F: Agilent 1200 series; Chromolith RP-18e 50-4.6mm; 3.3ml / min; Solvent A: Water + 0.05% HCOOH; Solvent B: Acetonitrile + 0.04% HCOOH; 220nm; 0-2.0 min: 0%B-100%B; 2.0-2.5 min: 100%B Method G: Column: Poroshell HPH C18, 3.0*50mm, 2.7um; Column oven: 40C; Mobile phase A: 6.5mM NH4HCO3+NH4OH (pH=10), Mobile phase B: Acetonitrile; Flow rate: 1.2mL / min; Gradient: 10%B to 95%B by 1.0min, hold for 0.7min; 254nm

[0270] The melting points of the selected compounds in Table 1 were determined using a Tianjin Analytical Instrument RY-1 melting point detector. These melting points are shown in Table 1a below: Table 1a [Table 2]

[0271] biological activity SK-HEP-1 Reporter Assay To identify inhibitors of the YAP-TEAD interaction, an 8xTEAD response element that promotes the NanoLuc® luciferase gene was stably incorporated into SK-HEP-1 cells (ECACC#:91091816).

[0272] For the assay, cells were treated in two ways with 10 doses of the test compound, starting at a concentration of 30 μM (final assay concentration). After incubation at 37°C for 24 hours, 95% rH, 5% CO2, and a luciferase substrate / lysis reagent mix (NanoGlo®, Promega) were added to the cells to enable quantification of the cells' luciferase activity.

[0273] Cell culture medium: Cells were cultured in the following medium: MEM, +10% FBS, +1x GlutaMAX, +1 mM sodium pyruvate, +100 μM essential amino acids, +0.1 mg / ml hygromycin. The medium used in the assay was: MEM (w / o phenol red), +10% FBS, +1x GlutaMAX, +1 mM sodium pyruvate, +100 μM essential amino acids, +0.5% Pen / Strep.

[0274] reagent: The reagents used are listed below: [Table 3]

[0275] Cell culture: The cells were examined using an inverted microscope to check their health and cell density. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3 ml of pre-warmed Accutase® was added to an F75 flask and dispersed evenly, and the flask was left to stand in an incubator for 4-5 minutes.

[0276] Once a single-cell suspension was obtained, 7 ml of pre-warmed growth medium was added and the cells were resuspended. The cell suspension was transferred to a sterile 15 ml conical centrifuge tube and spun at 300 x g for 5 minutes at RT. The supernatant was discarded, and the pellet was resuspended in 10 ml of pre-warmed growth medium. The total number of cells was determined, and 20 μl of the desired number of cells was added to each well of a 384-well plate using Multidrop Combi. The plate was then incubated at 37°C, 95% rH, and 5% CO2 for 24 hours.

[0277] Compound treatment: Cells were treated with the compound 24 hours after seeding. A 1:333 dilution of the compound was prepared by diluting it in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer the compound to assay plates, 120 nl was dropped (shot) from Labcyte low-dead-volume plates into cell plates containing 20 μl of medium / well using an ECHO 555 liquid handling system. After treatment, cells were injected with 20 μl of fresh, pre-warmed assay medium using a Multidrop combi (fed). The assay plate was then incubated for another 24 hours at 37°C, 95% rH, and 5% CO2.

[0278] Luciferase reading: 24 hours after the procedure, the plate was removed from the incubator and left to stand until it reached RT (recovery time). 30 μl of NanoGlo® reagent was added to the dark plate. The plate was shaken on a dark Teleshake (~1500 rpm) for 20 minutes. Luminescence was then measured using an EnVision microplate reader. IC50 values ​​were generated using a Geneda Screener®.

[0279] The experimental data from the SK-HEP-1 reporter assay for the compounds listed in Table 1 are shown in Table 2 below, and they are classified into the following groups: Group A IC 50 It is in the range of 1 nM to 10 nM. Group B IC 50 It is in the range of >10nM to 100nM. Gunma CIC 50 It is in the range of >100nM to 1000nM. Group D IC 50 is in the range of >1000nM

[0280] Table 2 [Table 4-1]

[0281] [Table 4-2]

[0282] [Table 4-3]

[0283] [Table 4-4]

[0284] Survival assay in NCI-H226 (Yap-dependent) cells and SW620 Yap KO (Yap-independent) cells The ability of the YAP-TEAD inhibitor to inhibit tumor cell growth was evaluated using two different cell lines: NCI-H226 cells (which are a YAP-dependent cell line) and SW620 cells (where YAP and TAZ were knocked out using CRISPR to generate a YAP-independent cell line).

[0285] For the assay, cells were treated in two ways with 10 doses of the test compound in a 1:3 dilution step, starting at a concentration of 30 μM (final assay concentration). After incubation at 37°C for 96 hours, cells were added to 95% rH, 5% CO2, and a cell-permeable DNA-binding dye that stains only healthy cells (CyQUANT®, Promega) to enable quantification of cell viability.

[0286] Cell culture medium: NCI-H226 cells were cultured in the following medium: RPMI 1640, +10% FBS, +1x GlutaMAX, +10mM HEPES, +0.5% Pen / Strep. SW620-KO cells were cultured in the following medium: DMEM / F-12, +10% FBS, +1x GlutaMAX, +10mM HEPES, +0.5% Pen / Strep.

[0287] reagent: The reagents used are listed below: [Table 5]

[0288] Cell culture: The cells were examined using an inverted microscope to check their health, cell density, etc. To dissociate adherent cells, the monolayer of cells was washed once with pre-warmed PBS. After removing the PBS, 3 ml of pre-warmed Accutase was added to an F75 flask and dispersed evenly, and the flask was left to stand in an incubator for 4-5 minutes.

[0289] Once a single-cell suspension was obtained, 7 ml of pre-warmed growth medium was added and the cells were resuspended. The cell suspension was transferred to a sterile 15 ml conical centrifuge tube and spun at 300 x g at RT for 5 minutes. The supernatant was discarded, and the pellet was resuspended in 10 ml of pre-warmed growth medium. The total number of cells was determined, and 20 μl of the desired number of cells was added to each well of a 384-well plate using Multidrop Combi. The plate was then incubated at 37°C, 95% rH, and 5% CO2 for 24 hours.

[0290] Compound treatment: The cells were treated with a compound 24 hours after sowing. A 1:333 dilution of the compound was prepared by diluting it with DMSO, yielding a final concentration of DMSO of 0.3% per well. To transfer the compound to assay plates, 120 nl was dispensed from a Labcyte low-dead-volume plate into a cell plate containing 20 μl of medium per well using an ECHO 555 liquid handling system. After the procedure, the cells were injected with 20 μl of fresh, pre-warmed assay medium using a Multidrop combi. The assay plates were then incubated at 37°C, 95% rH, and 5% CO2 for 96 hours.

[0291] CyQuant® measurement 96 hours after treatment, 30 μl of CyQuant® reagent was added to the assay plate in the dark using a Multidrop combi. The plate was then incubated at 37°C, 95% rH, and 5% CO2 for 1 hour. The assay plate was then removed from the incubator and left uncovered in the dark for 30 minutes until RT. Finally, these were measured using an EnVision microplate reader with the FITC bottom reading program.

[0292] The experimental data from the SK-HEP-1 reporter assay for the compounds listed in Table 1 are shown in Table 3 below, and they are classified into the following groups: Group A IC 50 It is in the range of 1 nM to 10 nM. Group B IC 50 It is in the range of >10nM to 100nM. Gunma CIC 50 It is in the range of >100nM to 10000nM. Group D IC 50 It is in the range of >10000nM

[0293] Table 3 [Table 6-1]

[0294] [Table 6-2]

[0295] [Table 6-3]

[0296] The following examples relate to medicine: Example A: Injection vial A solution of 100 g of the active ingredient represented by formula I or IA and 5 g of disodium hydrogen phosphate in 3 L of double-distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, filtered sterile, transferred to injection vials, lyophilized under sterile conditions, and sealed under sterile conditions. Each injection vial contains 5 mg of the active ingredient.

[0297] Example B: Suppository A mixture of 20 g of the active ingredient represented by formula I or IA, 100 g of soy lecithin, and 1400 g of cocoa butter is melted, poured into a mold, and allowed to cool. Each suppository contains 20 mg of the active ingredient.

[0298] Example C: Solution Prepare a solution from 940 mL of double-distilled water, 1 g of the active ingredient represented by formula I or IA, 9.38 g of NaH2PO4·2H2O, 28.48 g of Na2HPO4·12H2O, and 0.1 g of benzalkonium chloride. Adjust the pH to 6.8 and sterilize the solution by irradiation up to 1 L. This solution can be used in the form of eye drops.

[0299] Example D: Ointment Mix 500 mg of the active ingredient represented by formula I or IA with 99.5 g of petrolatum under sterile conditions.

[0300] Example: Tablet Tablets are given by compressing a mixture of 1 kg of the active ingredient represented by formula I or IA, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate in the conventional manner, with each tablet containing 10 mg of the active ingredient.

[0301] Example F: Sugar-coated tablets The tablets are compressed in a manner similar to Example E, and then coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth, and dye.

[0302] Example G: Capsule Two kilograms of the active ingredient represented by formula I or IA are introduced into hard gelatin capsules using conventional methods, but each capsule contains 20 mg of the active ingredient.

[0303] Example H: Ampoule A solution of 1 kg of the active ingredient represented by formula I or IA in 60 L of double-distilled water is sterile filtered and transferred to ampoules, freeze-dried under sterile conditions, and sealed under sterile conditions. Each ampoule contains 10 mg of the active ingredient.

Claims

1. Equation I 【Chemistry 1-1】 During the ceremony W 1 CR W1 Represents; W 2 CR W2 Represents; W 3 CR W3 Represents; W 4 CR W4 Represents; R W1 represents H, C 1～6 -aliphatic, halogen; R W2 H, C 1～6 -Aliphatic; represents halogens; R W3 H, C 1～6 -aliphatic, -OC 1～6 -Aliphatic, halogen, -CN, -CH 2 -Ar W or -CH 2 -CH 2 -Ar W Represents; R W4 H, C 1～6 - Represents aliphatic and halogen; Z 1 CH is; Z 2 CR Z2 is; R 1 teeth, [Chemistry 1-2] or [Chemistry 1-3] Represents; R 2 is -C(=O)-OR 2a Represents; Ar W Even if they are non-substitutive, or independent of each other, R W11 and / or R W12 This represents phenyl which may be mono- or di-substituted; R Z2 This represents H; R 2a C is either H, unsubstituted, or substituted. 1～8 - Represents aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or Cat; Cat represents a monovalent cation; R W11 , R W12 These are, independently of each other, halogens, or unsubstituted or substituted C 1～6 - Represents aliphatic phaganism; Halogens are F, Cl, Br, and I; Compounds represented by , or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion.

2. R in the formula W1 , R W2 , R W3 , and R W4 At least one of them is not H at the same time. A compound according to claim 1, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.

3. During the ceremony (a) W 1 However, CR W1 Represents; W 2 However, CR W2 Represents; W 3 However, CR W3 Represents; W 4 However, CR W4 Represents; R W1 However, it represents H; R W2 However, it represents H; R W3 However, C 1～6 -aliphatic, -OC 1～6 -Aliphatic, halogen, -CN, -CH 2 -Ar W , or -CH 2 -CH 2 -Ar W Represents; R W4 However, it represents H; Ar W However, even if it is not a substitution, or R W11 Represents phenyl which may be monosubstituted; R W11 However, it represents halogen; or (b) W 1 However, CR W1 Represents; W 2 However, CR W2 Represents; W 3 However, CR W3 Represents; W 4 However, CR W4 Represents; R W1 However, it represents H; R W2 However, C 1～6 - Represents aliphatic phaganism; R W3 However, it represents H; R W4 However, it represents H; or (c) W 1 However, CR W1 Represents; W 2 However, CR W2 Represents; W 3 However, CR W3 Represents; W 4 However, CR W4 Represents; R W1 However, it represents H; R W2 However, it represents H; R W3 However, it represents H; R W4 However, C 1～6 - Represents an aliphatic; or (i) W 1 represents C-R W1 ; W 2 However, CR W2 Represents; W 3 However, CR W3 Represents; W 4 represents C-R W4 ; R W1 However, it represents H; R W2 However, C 1～6 - Represents aliphatic phaganism; R W3 However, C 1～6 - Represents aliphatic phaganism; R W4 However, representing H, A compound according to any one of claims 1 to 2, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.

4. During the ceremony (a) W 1 However, CH represents; W 2 However, CH represents; W 3 However, CR W3 Represents; W 4 However, CH represents; R W3 However, methyl, ethyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH 2 -phenyl, -CH 2 -(2-fluorophenyl), -CH 2 -(3-fluorophenyl), -CH 2 -(4-fluorophenyl) represents A compound according to any one of claims 1 to 3, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.

5. During the ceremony R 2 However, -C(=O)-OR 2a Represents; R 2a However, H, linear or branched, unsubstituted or substituted C 1～4 - Represents alkyl or cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na), and potassium (K); A compound according to any one of claims 1 to 4, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.

6. During the ceremony R 2a However, this represents H, methyl, ethyl, or Cat; Cat represents a monovalent cation, which is sodium. The compounds described in claim 5, or any of them, including N-oxides, solvates, tautomers, or stereoisomers, and / or pharmaceutically acceptable salts thereof, as well as mixtures thereof in any proportion.

7. During the ceremony (a) W 1 However, CH represents; W 2 However, CH represents; W 3 However, CR W3 Represents; W 4 However, CH represents; R W3 However, methyl, 2-propyl, trifluoromethyl, methoxy, trifluoromethoxy, F, -CN, -CH 2 -phenyl, -CH 2 -(2-fluorophenyl), -CH 2 -(3-fluorophenyl), -CH 2 -(4-fluorophenyl) represents; Furthermore, here Z 1 However, it is CH; Z 2 However, it is CH. R 1 However, this represents 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl; and R 2 However, -C(=O)-OH, -C(=O)-ONa, or -C(=O)-OCH 3 Representing, A compound according to any one of claims 1 to 6, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, as well as mixtures thereof in any proportion.

8. Table 1 Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8-1 Table 1-8-2 Table 1-9 Table 1-10 Compounds selected from the group consisting of the compounds, or N-oxides, solvates, tautomers, or stereoisomers thereof, and / or pharmaceutically acceptable salts of each thereof, as well as mixtures thereof in any proportion.

9. A pharmaceutical composition comprising any one of the compounds described in claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, or a mixture thereof in any ratio.

10. A pharmaceutical composition comprising any of the compounds described in any one of claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, or a mixture thereof in any ratio, for use in the prevention and / or treatment of a medical condition or disease selected from the group consisting of cancer, cardiovascular disease, and fibrosis.

11. The pharmaceutical composition according to claim 10, wherein the medical condition or disease is selected from the group consisting of tumors (including solid tumors), breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, stomach cancer, medulloblastoma, colon cancer, pancreatic cancer, tumors, cardiovascular disease, fibrosis, and hepatic fibrosis.

12. A pharmaceutical composition comprising, together with a pharmaceutically acceptable carrier, an active ingredient, at least one compound described in any one of claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt thereof, or a mixture thereof in any ratio.

13. Further comprising a second active ingredient, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or pharmaceutically acceptable salts thereof, or mixtures thereof in any ratio, The pharmaceutical composition according to claim 12, wherein the second active ingredient is not a compound represented by formula I as defined in any one of claims 1 to 8.

14. A process for producing any of the compounds described in claims 1 to 8, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or each of the above pharmaceutically acceptable salts, and mixtures thereof in any ratio, wherein the process is (a) Equation II-a 【Chemistry 2】 (Z in the formula 1 , Z 2 , Z 3 , W 1 , W 2 , W 3 , W 4 , and R 2 In any one of claims 1 to 8, formula I (where R 2 However, this is as defined for compounds that are neither -C(=O)-OH nor -C(=O)-OCat. A compound represented by; (a)(1) is Equation III R 1 - Hall III (R in the formula 1 (wherein Hal represents Cl, Br, or I, as defined in any one of claims 1 to 8 for a compound represented by formula I, and Hal represents Cl, Br, or I) The compound represented by [the symbol] can be reacted with a CN cross-coupling reaction under suitable reaction conditions; or (a)(2) First, under suitable reaction conditions in the CN cross-coupling reaction, formula IV 【Transformation 3】 It is converted into a tricyclic compound represented by; and Next, equation III R 1 - Hall III The compound represented by [the symbol] can be reacted with another CN cross-coupling reaction under suitable reaction conditions; If either of the following occurs, (a)(3) A compound represented by formula I as defined in any one of claims 1 to 8 is provided; and optionally (a)(4) In the compound represented by formula I, R 2 However, -C(=O)-OR 2a If so (R 2a C is either non-substitutive or substituted. 1～8 -Aliphatic) When this compound represented by formula I is provided under conditions suitable for the saponification reaction, formula I (R 2 Compounds represented as -C(=O)-OH or -C(=O)-OCat are provided; or, (b) Equation II-b 【Chemistry 4】 (Z in the formula 1 , Z 2 , Z 3 , W 1 , W 2 , W 3 , W 4 , and R 2 In any one of claims 1 to 8, formula I (where R 2 However, this is as defined for compounds that are neither -C(=O)-OH nor -C(=O)-OCat. A compound represented by; (b)(1) is equation V R 1 -NH 2 V (R in the formula 1 (This is defined in any one of claims 1 to 8 for a compound represented by formula I.) A compound represented by formula I, as defined in any one of claims 1 to 8, is provided by reacting a compound represented by formula I with a compound represented by formula I under suitable reaction conditions in a CN cross-coupling reaction; and optionally (b)(2) In the compound represented by formula I, R 2 However, -C(=O)-OR 2a If so (R 2a C is either non-substitutive or substituted. 1～8 -Aliphatic) When this compound represented by formula I is provided under conditions suitable for the saponification reaction, formula I (R 2 Compounds represented as -C(=O)-OH or -C(=O)-OCat are provided. The process characterized by any of the following.

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