Tricyclic heterocycles

Abstract

The present invention relates to tricyclic heterocycles. These heterocycles 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 treatment of the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases, particularly cancer.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to tricyclic heterocycles. These heterocycles are useful as TEAD binders and / or inhibitors of YAP-TEAD protein-protein interaction or binding, and for the prevention and / or treatment of several medical conditions, including hyperproliferative disorders and diseases, especially cancer. [Background technology]

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

[0003] Furthermore, the Hippo pathway plays a role in several biological processes, such as stem and progenitor cell self-renewal and differentiation, wound healing and tissue regeneration, and interactions with other signaling pathways such as Wnt, and its dysfunction may also play a role in human diseases other than cancer (C.-L.Kim et al.,Cells(2019),8,468;Y.Xiao et al.,Genes & Development(2019)33:1491-1505;KFHarvey et al.,Nature Reviews Cancer,Vol.13,246-257(2013)).

[0004] Although some aspects of the pathway's activity and regulation remain to be further investigated, it is already established that the Hippo pathway in its "switched-on" state 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-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motifs), in the cytoplasm. Phosphorylation of YAP / TAZ leads to their sequestration in the cytoplasm and eventually to their degradation. In contrast, when the Hippo pathway is "switched-off" or dysfunctional, the non-phosphorylated, activated YAP / TAZ coactivators are translocated into the cell nucleus. Their main target transcription factors are four proteins of the Transcriptional enhanced associate domain (TEAD) transcription factor family (TEAD1-4). Binding of YAP or TAZ to and activation of TEAD (or other transcription factors) has been shown to induce the expression of several genes, many of which mediate cell survival and proliferation. Thus, activated, unphosphorylated YAP and TAZ can act as oncogenes, whereas activated, switched-on Hippo pathway can act as tumor suppressors by inactivating (i.e., phosphorylating) YAP and TAZ.

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

[0006] Consequently, dysfunction or aberrant regulation of the Hippo pathway as a tumor suppressor is believed to be a key event in the development of a wide variety of cancer types and diseases.

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

[0008] Description of the 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 are TEAD binders and / or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interactions. Some of the compounds of the present invention may be useful for making other compounds of the present invention.

[0009] The present invention relates in one aspect to a compound of formula I [ka] During the ceremony Ring A is the following ring moiety: [ka] [ka] [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: Ring B is the following ring moiety: [ka] wherein the formula represents a 5-membered heteroaromatic ring selected from the group consisting of Z 1 CR Z1 or N; Z 2 is O, S, or NR Z2 is; Z 3 is O, S, or NR Z3 is; Z 4 CR Z4 or N; R 1 H, Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc 1 or unsubstituted or substituted C 1~8 - represents aliphatic; R 2 is -C(=O)-OR 2a , -C(=O)-NR 2b R 2c , -(CH 2 ) w -C(=O)-NR 2b R 2c , -(CH 2 ) 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 R2m , F, Cl, Br, I, -CN, -(CH 2 ) v -CN, -P(=O)(OR 2o )(OR 2p ), -(CH 2 ) y -NR 2q R 2r , -(CH 2 ) 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 , -B(OH) 2 , or Hetcyc X Represents; R A1 Ar 3 , Hetar 3 , Cyc 3 , Hetcyc 3 , L 3 -Ar 3 , L 3 -Hetar 3 , L 4 -Cyc 3 , L 4 -Hetcyc 3 , unsubstituted or substituted C 1~8 - represents aliphatic; R A2 , R A3 are independently H, halogen, Ar 3 , Hetar 3 , Cyc 3 , Hetcyc 3 , L 3 -Ar 3 , L 3 -Hetar 3 , L 4 -Cyc 3 , L 4 -Hetcyc 3 , unsubstituted or substituted C 1~8 - represents aliphatic; R Z1 , H, C 1~6 - represents an aliphatic group or a halogen; or R 2 together with the divalent radical -S(=O) 2 It forms -N(H)-C(=O)-; R Z2 is H or C 1~6 - represents aliphatic; R Z3 is H or C 1~6 - represents aliphatic; R Z4 , H, C 1~6 - represents an aliphatic or halogen; Ar 1 , Ar 3 are, independently of each other, mono-, bi-, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, where the aryl is unsubstituted or has a substituent R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and / or R B7 (which may be the same or different); Ar 2 , Ar 2b , Ar 4 are, independently of each other, monocyclic or bicyclic aryl having 5, 6, 7, 8, 9, or 10 ring carbon atoms, where the aryl is unsubstituted or contains a substituent R D1 , R D2 , R D3 , R D4 , and / or R D5 (which may be the same or different); Ar X , Ar Z are, independently of each other, an unsubstituted or substituted benzo ring; Ar Y is unsubstituted or mono- or di-substituted phenyl; Hetar1 , Hetar 3 are, independently of each other, mono-, bi-, 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 heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or is substituted by a substituent R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and / or R B7 (which may be the same or different); Hetar 2a , Hetar 2b , Hetar 4 , Hetar Y1 are, independently of each other, monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, where 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or is substituted by a substituent R D1 , R D2 , R D3 , R D4 , and / or R D5 (which may be the same or different); Hetar Z are pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Cyc 1 , Cyc 3 are, independently of each other, saturated or partially unsaturated, mono-, bi-, or tricyclic carbocyclic rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, where the carbocyclic rings may be unsubstituted or may be substituted with R B8 , R B9 , RB10 , R B11 , R B12 , and / or R B13 (which may be the same or different); and wherein the carbocycle is optionally substituted with Ar X And the Ar X and wherein the fused carbocycle may be unsubstituted or may be fused through two adjacent ring atoms of R C1 , R C2 , R C3 , R C4 , R C5 , R C6 (which may be the same or different); Cyc 2a Cyc4 are each independently a monocyclic saturated or partially unsaturated carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbocyclic ring may be unsubstituted or may be substituted with R D6 , R D7 , R D8 , R D9 , and / or R D10 (which may be the same or different); Cyc 2b is a saturated or partially unsaturated monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, which carbocyclic ring may be unsubstituted or may be, independently of each other, R D6 , R D7 , R D8 , R D9 , and / or R D10 wherein the carbocycle is optionally substituted with Ar Z Or Hetar Z and, via two adjacent ring atoms, wherein the fused carbocycles are optionally, independently of each other, R C1 , R C2 , and / or R C3 may be further substituted with; Cyc Y1is a saturated or partially unsaturated, monocyclic carbocycle having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbocycle may be unsubstituted or may contain halogen, hydroxy, unsubstituted or substituted C 1~6 - optionally aliphatically substituted; Hetcyc 1 Hetero 3 are, independently of each other, saturated or partially unsaturated, mono-, bi-, or tricyclic heterocycles having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring atoms, where 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycles are unsubstituted or are represented by R B8 , R B9 , R B10 , R B11 , R B12 , and / or R B13 (which may be the same or different); Hetcyc 2a , Hetcyc 4 are, independently of each other, saturated or partially unsaturated, monocyclic heterocycles having 3, 4, 5, 6, 7 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycles can be unsubstituted or can be selected from R D6 , R D7 , R D8 , R D9 and / or R D10 (which may be the same or different); Hetcyc 2b is a saturated monocyclic heterocycle having 5 or 6 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or may be, independently of each other,D6 , R D7 , R D8 , R D9 , and / or R D10 wherein the heterocycle is optionally substituted with Ar Z Or Hetar Z and wherein the fused heterocycles are optionally fused to, independently of each other, R C1 , R C2 , and / or R C3 may be further substituted with; Hetcyc X is a saturated, partially unsaturated, or aromatic monocyclic heterocycle having 3, 4, 5, 6, or 7 ring atoms, where 1, 2, 3, or 4 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or may be represented by R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , and / or R X8 (which may be the same or different), and wherein the unsubstituted or substituted heterocycle is optionally a bioisostere of a carboxylic acid; Hetcyc Y is a saturated, partially unsaturated or aromatic monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, where 1, 2, 3, 4 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms; Hetcyc Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; L 1 , L 3are each independently -C(=O)-, unsubstituted or substituted, linear or branched C 1~6 -Alkylene or C 2~6 -alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L 2 , L 4 are, independently of each other, -S(=O) 2 -, -C(=O)-, unsubstituted or substituted, straight or branched chain C 1~6 -Alkylene or C 2~6 -alkenylene, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; R 2a is H, unsubstituted or substituted C 1~8 -Aliphatic, Ar 2a , Hetar 2a , Cyc 2a , Hetcyc 2a , or represents Cat; Cat represents a monovalent cation; R 2b , R 2c Both represent H; Or, R 2b and R 2c One of the groups is H or unsubstituted or substituted C 1~8 - represents aliphatic, whereas R 2b and R 2c The other is unsubstituted or substituted C 1~10 -aliphatic, -OH, -OC 1~6 -Alkyl, -CN, -S(=O) 2 -R 2g , Ar 2b , Hetar 2b , Cyc 2b , or Hetcyc 2b Represents; Or, R 2b and R 2ctogether with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 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 remainder are carbon atoms; R 2d , R 2j , R 2k , R 2o , R 2p are, independently of each other, H, unsubstituted or substituted C 1~8 - represents aliphatic; R 2e is H, halogen, unsubstituted or substituted C 1~8 - aliphatic, aryl, heteroaryl; represents saturated or partially unsaturated heterocyclyl; R 2f , R 2g are, independently of each other, unsubstituted or substituted C 1~8 - represents aliphatic; R 2h , R 2i are each independently H, unsubstituted or substituted C 1~8 -Aliphatic, Ar 2b , Hetar 2b , Cyc 2b , or Hetcyc 2b or together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 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 remainder are carbon atoms; R 2l , R 2m , R 2q , R 2r are, independently of each other, H, unsubstituted or substituted C 1~8 - represents aliphatic; or R 2l is R 2m Together with and / or R 2q is R2r together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated, or aromatic heterocycle 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 remainder are carbon atoms; R 2s , R 2t are, independently of each other, unsubstituted or substituted C 1~8 - aliphatic; or together, unsubstituted or substituted divalent C 3~6 - forming an alkylene radical; R 2u is hydrogen or unsubstituted or substituted C 1~6 - represents aliphatic; R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , R B7 are each independently an unsubstituted or substituted, linear or branched C 1~6 -Aliphatic, C 1~6 -aliphatic oxy, -SC 1~6 -Aliphatic; halogen, -CN, -SF 5 , -S(=O)-R b1 , S(=O) 2 -R b1 , -NR b2 NR b3 , Ar 4 , -CH 2 -Ar 4 , Hetar 4 , Cyc 4 , Hetcyc 4 Represents; Or, two adjacent R B1 , R B2 , R B3 , R B4 , R B5 , R B6 , and / or R B7 together, bivalent -C 2~4- an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or the divalent -OC 1~3 -Alkylene radical or divalent -OC 1~3 - forming an alkylene-O- radical; R B8 , R B9 , R B10 , R B11 , R B12 , R B13 are each independently a halogen, unsubstituted or substituted C 1~6 -Aliphatic, C 1~6 -Aliphatic oxy, Ar Y represents; or R attached to the same carbon atom of the carbocyclic or heterocyclic ring B8 , R B9 , R B10 , R B11 , R B12 , R B13 two of which form a divalent oxo (=O) group; or R are attached to the same sulfur atom of the heterocycle. B8 , R B9 , R B10 , R B11 , R B12 , R B13 Two of these, or R B8 , R B9 , R B10 , R B11 , R B12 , R B13 Four of these form a divalent oxo (=O) group, which results in a -S(=O)- moiety or -S(=O) 2 - Any of the parts are formed; R C1 , R C2 , R C3 , R C4 , R C5 , R C6 are, independently of each other, unsubstituted or substituted C 1~6 - represents aliphatic; R D1 , R D2 , R D3 , R D4, R D5 are each independently a halogen, unsubstituted or substituted C 1~6 - represents aliphatic; R D6 , R D7 , R D8 , R D9 , R D10 are each independently halogen, hydroxy, unsubstituted or substituted C 1~6 -Aliphatic, unsubstituted or substituted -OC 1~6 -Aliphatic, Hetar Y1 , C.H. 2 -Hetar Y1 , Cyc Y1 , Hetcyc Y1 , -CH 2 -Hetcyc Y1 Represents; and / or R attached to the same ring atom of the carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl, and wherein the alkylene radical is optionally replaced by OH, C 1~6 -Aliphatic, or -OC 1~6 - optionally aliphatically substituted; and / or R attached to two 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 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 - optionally replaced by alkyl; R X1 , R X2 , R X3, R X4 , R X5 , R X6 , R X7 , R X8 are, independently of each other, unsubstituted or substituted C 1~6 -Aliphatic, C 1~6 -Aliphatic oxy, halogen, -OH, -NR 2d -S(=O) 2 -R 2g , Hetcyc Y , -O-Hetcyc Y 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 R form a divalent oxo (=O) group; and / or are attached to the same sulfur atom of the heterocycle; X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 Two of these, or R X1 , R X2 , R X3 , R X4 , R X5 , R X6 , R X7 , R X8 Four of these form a divalent oxo (=O) group, which results in a -S(=O)- moiety or -S(=O) 2 - Any of the parts are formed; R b1 is unsubstituted or substituted C 1~8 - represents aliphatic; R b2 , R b3 are, independently of each other, H, unsubstituted or substituted C 1~8 - represents aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated, or aromatic heterocycle 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 remainder are carbon atoms; Halogen is F, Cl, Br, I; v is 1 or 2; w is 1 or 2; x is 0, 1, or 2; y is 0, 1, or 2; z is 0, 1, or 2; or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios.

[0010] Generally, all residues, radicals, substituents, groups, moieties, etc., which occur more than once, may be identical or different, i.e. are independent of each other. Above and below, residues and parameters have the meanings indicated for formula I, unless otherwise clearly indicated. Consequently, the present invention relates in particular to compounds represented by formula I, in which at least one of the residues, radicals, substituents has one of the preferred meanings indicated below.

[0011] Any of those specific or even preferred embodiments of the invention as specified below and in the claims refer not only to the compounds of the specified formula I, but also to their N-oxides, solvates, tautomers or stereoisomers, as well as to pharma- ceutically acceptable salts of each of the above, and, unless otherwise specified, also encompasses mixtures thereof in all proportions.

[0012] In a specific embodiment PE1, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein in ring B: Z 1 is CH or N; and Z 2 is S; or Z 3 is S; and Z 4 is CH or N; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below. In other words, in PE1, ring B is derived from either a thiophene or a thiazole ring.

[0013] In another specific embodiment of PE1, PE1a, the compounds of the invention are tricyclic heterocycles of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein ring B is derived from a thiophene ring, i.e. Ring B is [ka] is; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0014] In a specific embodiment PE1aa of PE1a, ring B is ring BA-1. In an alternative specific embodiment PE1ab of PE1a, ring B is ring BB-1.

[0015] In a further specific embodiment PE2 of the invention, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein Ring A is the following ring moiety: [ka] [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0016] In a specific embodiment of PE2, PE2a, R A1 Ar 3 , L 3 -Ar 3 , linear or branched C 1~4 -alkyl (which may be optionally substituted, independently of one, two or three halogens), linear or branched C 2~4 -alkenyl, or C 2~4 -represents alkynyl; R A2 represents H; R A3 represents H; Ar 3 represents phenyl, which may optionally be replaced, independently of each other, by R B1 , R B2 , and / or R B3 may be substituted with; L 3 -CH 2 - represents; R B1 , R B2 , R B3 are, independently of one another, halogen, in particular F, or -CN; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0017] In yet another specific embodiment of PE2, PE2b, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: Ring A is the following ring moiety: [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: R A1 Ar 3 , L 3 -Ar 3 , linear or branched C 1~4 -alkyl (which may be optionally substituted, independently of one, two or three halogens), linear or branched C 2~4 -alkenyl, or C 2~4 -represents alkynyl; R A2 represents H; Ar 3 represents phenyl, which may optionally be replaced, independently of each other, by R B1 , R B2 , and / or R B3 may be substituted with; L 3 -CH 2 - represents; R B1 , R B2 , R B3 are, independently of one another, halogen, in particular F, or -CN; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0018] In a specific embodiment PE2aa of PE2a, or in a specific embodiment PE2ba of PE2b, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R A1 -CH 2 -phenyl(benzyl); 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl; methyl, ethyl, n-propyl, prop-2-yn-1-yl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0019] In yet another embodiment of PE2baa, R A1 represents methyl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0020] In another specific embodiment of the invention, PE3, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 1 Ar 1 , Hetar 1 , Cyc 1 , Hetcyc 1 , L 1 -Ar 1 , L 1 -Hetar 1 , L 2 -Cyc 1 , L 2 -Hetcyc1 , C 1~6 -Alkyl, C 2~6 -alkenyl, or C 2~6 -alkynyl, wherein the C 1~6 -Alkyl, C 2~6 -alkenyl, or C 2~6 -alkynyl is linear or branched and is unsubstituted or substituted with 1, 2 or 3 halogens; Ar 1 is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, where the aryl is unsubstituted or contains the substituent R B1 , R B2 , and / or R B3 (which may be the same or different); preferably phenyl or naphthalenyl, in particular unsubstituted or substituted with the substituent R B1 and / or R B2 (which may be the same or different); Ar 4 is phenyl; Ar X is an unsubstituted benzo ring; Ar Y is phenyl; Hetar 1 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 a heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or can be represented by a substituent R B1 , R B2 , and / or R B3 (which may be the same or different); preferably, heteroaryl is unsubstituted or is substituted by the substituent R B1 and / or R B2(which may be the same or different); Hetar 4 is a monocyclic heteroaryl having 5 or 6 ring atoms, where 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms; preferably a monocyclic heteroaryl having 5 ring atoms, where one of the ring atoms is N and the remainder are carbon atoms, or one of the ring atoms is N, one of the ring atoms is S, and the remainder are carbon atoms; Cyc 1 is a saturated or partially unsaturated, mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, where the carbocyclic ring may be unsubstituted or may be substituted with R B8 and / or R B9 (which may be the same or different); and wherein the carbocycle is optionally substituted with Ar X And the Ar X and wherein the fused carbocycle may be unsubstituted or may be fused through two adjacent ring atoms of R C1 and / or R C2 (which may be the same or different); Cyc 4 is cyclopropyl, cyclobutyl, cyclopentyl, each of which may be unsubstituted or R D6 or independently of each other R D6 and R D7 optionally disubstituted with; Hetcyc 1 represents a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be substituted with R B8 and / or R B9(which may be the same or different), where if one of the heteroatoms is S then the heterocycle may also be substituted with R B8 , R B9 , R B10 , and R B11 or substituted; preferably a saturated monocyclic heterocycle having 5 or 6 ring atoms, in which one of the ring atoms is a heteroatom selected from O and S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be substituted with R B8 and / or R B9 (which may be the same or different), where if one of the heteroatoms is S then the heterocycle may also be substituted with R B8 , R B9 , R B10 , and R B11 or substituted); Hetcyc 4 is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or R D6 or independently of each other R D6 and R D7 optionally disubstituted with; L 1 is -S(=O) 2 -, unsubstituted or substituted, linear or branched C 1~6 -Alkylene or C 2~6 -alkenylene (in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); preferably -S(=O) 2 -, -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -C(CH 3 )H-, -CH 2 -CH 2 -C(CH 3 ) 2 -, -CH 2 -CH2 -O-CH 2 -, -CH 2 -CH=CH-; L 2 is an unsubstituted or substituted, linear or branched C 1~6 -Alkylene or C 2~6 -alkenylene (in both cases one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-); preferably -CH 2 -, -CH 2 -CH 2 - selected from the group consisting of; R B1 , R B2 , R B3 are, independently of each other, linear or branched C 1~6 -alkyl, but its C 1~6 -Alkyl may be unsubstituted or monosubstituted with -CN or may be substituted with 1, 2 or 3 halogens, linear or branched C 1~4 -alkoxy, wherein C 1~4 -Alkoxy may be unsubstituted or may contain 1, 2 or 3 halogens, -O-CH 2 -C≡CH, linear or branched -SC 1~4 -alkyl, and its -SC 1~4 -Alkyl may be unsubstituted or may contain 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 4 , -CH 2 -Ar 4 , Hetar 4 , Cyc 4 , Hetcyc 4 may be substituted with; Or, two adjacent R B1 , R B2 , and / or R B3together, bivalent -C 3~4 - an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or the divalent -OC 2~3 - forming an alkylene radical; R B8 , R B9 are, independently of each other, F, C 1~2 -alkyl, but its C 1~2 -Alkyl may be unsubstituted or contain 1, 2 or 3 F, C 1~2 -Alkoxy, Ar Y may be substituted with; Or, R B8 and R B9 is the carbocyclic ring Cyc 1 or the heterocycle Hetcyc 1 are attached to the same carbon atom of and form a divalent oxo (=O) group; Or, R B8 and R B9 and R B10 and R B11 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=O) groups, thereby forming -S(=O) 2 -Parts are formed; R C1 and R C2 are independent of each other, C 1~6 -represents alkyl, which may, independently of one another, be substituted by 1, 2 or 3 F atoms; R D6 , R D7 are each independently a C which may be substituted by 1, 2 or 3 F atoms or a hydroxyl group; 1~6 - alkyl; or hydroxy; Halogen is F, Cl, Br; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0021] In a specific embodiment PE3a of PE3, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 1 Ar 1 , Hetar 1 , Cyc 1 , L 1 -Ar 1 , L 2 -Cyc 1 , unsubstituted or substituted, linear or branched C 1~6 -alkyl, wherein the C 1~6 -alkyl is linear or branched and is unsubstituted or substituted with 1, 2 or 3 halogens; Ar 1 is R B1 is phenyl monosubstituted with; Hetar 1 is R B1 pyridyl, especially pyrid-2-yl, monosubstituted with Cyc 1 is a saturated monocyclic carbocyclic ring having 3, 4, 5, or 6 ring carbon atoms, where the carbocyclic ring is B8 In particular, Cyc 1 is a cyclobutane ring; L 1 , L 2 are, independently of each other, -CH 2 - is; R B1 , R B8 are independently one, two or three F atoms, in particular C substituted with three F atoms 1~2 -alkyl; C substituted with 1, 2 or 3 F atoms, in particular with 3 F atoms 1~2 -represents alkoxy; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0022] In yet another specific embodiment of PE3, PE3b, which is also a specific embodiment of PE3a, the compounds of the invention are tricyclic heterocycles represented by formula I, or any N-oxides, solvates, tautomers, or stereoisomers thereof, and / or any pharma- ceutically acceptable salts of each of the above, and mixtures thereof in all ratios, wherein: R 1 stands for trifluoromethylphenyl, especially 4-trifluoromethylphenyl; difluoromethylphenyl, especially 4-difluoromethylphenyl; difluoromethoxyphenyl, especially 4-difluoromethoxyphenyl; trifluoromethoxyphenyl, especially 4-trifluoromethoxyphenyl; trifluoromethylsulfanylphenyl, especially 4-trifluoromethylsulfanylphenyl; trifluoromethylpyridyl, especially 4-trifluoromethylpyridyl, 4-trifluoromethylpyrid-2-yl; trifluoromethoxypyridyl, especially 4-trifluoromethoxypyrid-2-yl, difluoromethoxypyridyl, especially 4-difluoromethoxypyrid-2-yl; trifluoromethylcyclobutylmethyl, especially 3-(trifluoromethyl)cyclobutylmethyl; 4,4,4-trifluoro-3,3-dimethylbutyl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0023] In another specific embodiment of PE3, PE3c, which is also a specific embodiment of PE3a or PE3b, the compounds of the invention are tricyclic heterocycles of formula I, or any N-oxides, solvates, tautomers, or stereoisomers thereof, and / or any pharma- ceutically acceptable salts of each of the above, and mixtures thereof in all ratios, wherein: R 1 stands for 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl; in particular for 4-trifluoromethylphenyl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0024] In another specific embodiment of the invention, PE4, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2 is -C(=O)-OR 2a or Hetcyc X Represents; and the remaining radicals and residues are as defined for formula I above, or for any of the further specific embodiments described herein above or below. In specific embodiment PE4, the substituent R 2 is a heterocyclic radical which may be a carboxylic acid radical, or a salt of a carboxylic acid radical, or an ester of a carboxylic acid radical, or optionally a bioisostere of a carboxylic acid.

[0025] In a specific embodiment of PE4, PE4a, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 is -C(=O)-OR 2a Represents; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0026] Specific Embodiments of PE4a In PE4aa, R 2a is H, linear or branched, unsubstituted or substituted C 1~4 -alkyl, in particular methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, tert.-butyl; or Cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na), and potassium (K); and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0027] In another specific embodiment of PE4, PE4b, which is also a specific embodiment of PE4a or PE4aa, the compounds of the invention are tricyclic heterocycles of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 is -C(=O)-OR 2a Represents; R 2a stands for H or Na: especially H. and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0028] In yet another specific embodiment of PE4, PE4c, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 Hetcyc X Represents. Hetcyc X are 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-oxadiazol-3-yl (2H-1,2,4-oxadiazol-5-one-3-yl), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl (4H-1,2,4-oxadiazol-5-one-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3-chloro-4,5-dihydro-1,2-oxazol-5-yl, 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-(pyrimidin-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3-hydroxy-oxetan-3-yl, 5-hydroxy-4H-pyran-4-one-2-yl, 3,3-difluoropyrrolidin-2-one-4-yl, 3,3-difluoropyrrolidin-2-one-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-one-4-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-one-5-yl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0029] In another specific embodiment of the invention, PE5, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2 is -C(=O)-NR 2b R 2c Represents; and the remaining radicals and residues are as defined for formula I above, or for any of the further specific embodiments described herein above or below. In specific embodiment PE5, the substituent R 2 is an amide.

[0030] In one specific embodiment of PE5, PE5a, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 is -C(=O)-NR 2b R 2c Represents; R 2b , R 2c Both represent H; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0031] In another specific embodiment of PE5, PE5b, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 is -C(=O)-NR 2b R 2c Represents; R2b and R 2c One of them represents H, while the other represents R 2b and R 2c The other is Cyc 2b , Hetcyc 2b , linear or branched C 1~10 -alkyl (which may be unsubstituted or R E1 , R E2 , R E3 , R E4 , and / or R E5 (which may be the same or different), wherein the C 1~10 In -alkyl, one or two non-adjacent and non-terminal methylene moieties are independently -O- and / or -S- and / or -NH- and / or -N(C 1~4 -alkyl)-; Cyc 2b is a saturated monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, which carbocyclic ring may be unsubstituted or may be, independently of each other, R D6 , R D7 , R D8 , R D9 , and / or R D10 wherein the carbocycle is optionally substituted with Ar Z Or Hetar Z and, via two adjacent ring atoms, wherein the fused carbocycles are optionally, independently of each other, R C1 , R C2 , and / or R C3 may be further substituted with; Hetcyc 2b is a saturated monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be, independently of each other, D6 , R D7 , R D8 , RD9 , and / or R D10 wherein the heterocycle is optionally substituted with Ar Z Or Hetar Z and wherein the fused heterocycles are optionally fused to, independently of each other, R C1 , R C2 , and / or R C3 may be further substituted with; R E1 , R E2 , R E3 , R E4 , and / or R E5 are, independently of one another, halogen, in particular F; -NR Ea R Eb , OR Ec , Ar E , Hetar E , Cyc E , Hetcyc E Represents; Ar E is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, where the aryl is unsubstituted or contains the substituent R F1 , R F2 , and / or R F3 (which may be the same or different); in particular phenyl or naphthalenyl; Ar Z is benzo; Hetar E 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 heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may be represented by a substituent R F1 , R F2 , and / or R F3(which may be the same or different); especially imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl (each of which may be unsubstituted or substituted with C 1~4 -alkyl); pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl (each of which may be unsubstituted or monosubstituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Hetar Y1 is a 5- or 6-membered monocyclic heteroaryl, where 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or is selected from F, C, 1~4 -alkyl (optionally substituted with OH); especially pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl, methylpyrimidinyl; Hetar Y2 is a 5- or 6-membered monocyclic heteroaryl, where 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or substituted with halogen, C 1~4 -alkyl (optionally substituted with OH); especially pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl; Hetar Z are pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Cyc E R represents a saturated or partially unsaturated mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, which may be unsubstituted or may be substituted with R G1 and / or R G2 (which may be the same or different): in particular saturated monocyclic carbocyclic rings having 3, 4, 5 or 6 ring carbon atoms, which carbocyclic rings may be unsubstituted or may be substituted with R G1 and / or R G2 (which may be the same or different); Cyc Y1 is a saturated or partially unsaturated, monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, which may be unsubstituted or may contain halogen, OH, C 1~4 -alkyl), especially cyclopropyl, cyclohexenyl; Hetcyc E represents a saturated or partially unsaturated, monocyclic heterocycle having 4, 5, or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be substituted with R G1 and / or R G2 (which may be the same or different); especially saturated monocyclic heterocycles having 5 or 6 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N and / or O, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or may be substituted with R G1 and / or R G2substituted with ); preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl (each of which may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl (each of which may be unsubstituted or monosubstituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; Hetcyc Y1 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl; Hetcyc Y2 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl, morpholinyl, tetrahydropyranyl; R C1 , R C2 , R C3 are independent of each other, C 1~4 - represents alkyl; R D6 , R D7 , R D8 , R D9 , R D10 are each independently a halogen, in particular F; hydroxy; C optionally substituted with -OH and / or halogen; 1~4 -Alkyl, especially methyl, hydroxymethyl, 2-fluoroethyl; -OC 1~4-Alkyl, especially methoxy, ethoxy; Hetar Y1 , -CH 2 -Hetar Y1 , Cyc Y1 , Hetcyc Y1 , -CH 2 -Hetcyc Y1 Represents; and / or R attached to the same ring atom of the carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl, and wherein the alkylene radical is optionally replaced by OH, C 1~4 -Alkyl, or -OC 1~4 -Alkyl, especially -(CH 2 ) 3 -, -CH 2 -CH(OC 2 H 5 )-CH 2 -, -(CH 2 ) 2 -O-(CH 2 ) 2 - optionally substituted; and / or R D6 , R D7 , R D8 , R D9 , R D10 (which are attached to two different ring atoms of the carbocyclic or heterocyclic ring) are two divalent C 1~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -Alkyl, especially -CH 2 -, -(CH 2 ) 3 -, -O-(CH 2 ) 2 -, -O-(CH2 ) 3 - may be replaced by; R Ea , R Eb are, independently of each other, H, C 1~4 -Alkyl, -C(=O)-C 1~4 -Alkyl, -C(=O)-OC 1~4 - represents alkyl; R Ec is H or C 1~4 - represents alkyl; R F1 , R F2 , R F3 are, independently of each other, linear or branched C 1~6 -Alkyl (its C 1~6 -Alkyl may be unsubstituted or may be -CN, -OH, -OC 1~4 - alkyl or substituted with 1, 2 or 3 halogens): straight or branched C 1~4 -Alkoxy (C 1~4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens); straight or branched -SC 1~4 -Alkyl (its -SC 1~4 -alkyl may be unsubstituted or substituted with 1, 2, or 3 halogens); halogen, OH, and / or C 1~4 -alkyl, C 3~7 -Cycloalkyl; F, Cl, Br, -CN, -S(=O)-C 1~3 -Alkyl, S(=O) 2 -C 1~3 -Alkyl, -NH 2 , -NH(C 1~3 -alkyl)-N(C 1~3 -alkyl) 2 , -OH; in particular methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably R F1 , R F2 , and R F3 is present and represents methyl or F; and / or R F1 , R F2 , R F3 (which are attached to two different ring atoms of the aryl or heteroaryl) are two divalent C 1~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -Alkyl, especially -(CH 2 ) 4 -, -CH 2 -O-(CH 2 ) 2 - may be replaced by; R G1 , R G2 are each independently a halogen; a hydroxyl; an unsubstituted or substituted C 1~6 - aliphatic, in particular C 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 ;-CH 2 -Hetar Y2 ;Hetcyc Y2 In particular, R G1 and R G2 is present and represents hydroxy; and / or R G1 and R G2 (which are attached to the same ring atom of the carbocyclic or heterocyclic ring) are divalent C 2~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl, and wherein the alkylene radical is optionally replaced by OH, C 1~4 -Alkyl, or -OC 1~4 -Alkyl, especially -(CH 2 ) 2 -O-CH 2 -, -(CH2 ) 2 -O-(CH 2 ) 2 - optionally substituted; and / or R G1 and R G2 (which are attached to two different ring atoms of the carbocyclic or heterocyclic ring) are divalent C 1~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -Alkyl, especially -CH 2 - may be replaced by; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0032] In a specific embodiment PE5ba of PE5b, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2b and R 2c One of them represents H, while the other represents R 2b and R 2c The other is Cyc 2b , Hetcyc 2b , or linear or branched C 1~8 -alkyl, which may be unsubstituted or R E1 , R E2 , R E3 , R E4 , and / or R E5 (which may be the same or different); Cyc 2b is cyclopropyl, cyclobutyl, or 1-hydroxymethyl-cyclobutyl; Hetcyc 2bis tetrahydrofuranyl or hydroxytetrahydrofuranyl; R E1 , R E2 , R E3 , R E4 , and / or R E5 are, independently of each other, F;-NR Ea R Eb , OR Ec , Ar E , Hetar E , Cyc E , Hetcyc E Represents; Ar E may be unsubstituted or may be substituted by R F1 , R F2 , and / or R F3 (which may be the same or different); Hetar E is imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl (each of which is unsubstituted or 1~4 -alkyl monosubstituted); pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl (each of which may be unsubstituted or monosubstituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrazin-4-yl-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Cyc E is cyclopropyl or cyclobutyl; Hetcyc Eis selected from the group consisting of tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or mono-substituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or mono-substituted with -OH); piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl (each of which may be unsubstituted or mono-substituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl (each of which may be unsubstituted or mono-substituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; R Ea , R Eb both represent H or one represents H and the other represents -C(=O)-methyl or -C(=O)-O-tert.-butyl; R Ec represents H or methyl; R F1 , R F2 , R F3 denote, independently of one another, methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; in particular R F1 , R F2 , and R F3 is present and represents methyl or F; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0033] In another specific embodiment of PE5, PE5baa, which is also a specific embodiment of PE5b or PE5ba, the compounds of the invention are tricyclic heterocycles of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 is -C(=O)-NR 2b R 2c Represents; R 2b and R 2c One of them represents H, while the other represents R 2b and R 2c The other is methyl; ethyl; 2-hydroxyethyl; 1-hydroxypropan-2-yl (-CH(CH 3 )-CH 2 OH), especially (2R)-1-hydroxypropan-2-yl, (2S)-1-hydroxypropan-2-yl; 2-hydroxypropanyl (2-hydroxypropyl; -CH 2 -C(CH 3 )-OH), especially (2S)-2-hydroxypropanyl, (2R)-2-hydroxypropanyl; 1-hydroxy-4-methoxybutan-2-yl (-CH(CH 2 OH)-(CH 2 ) 2 OCH 3 );1-Hydroxybutan-2-yl(-CH(CH 2 OH)-CH 2 CH 3 ), especially (2R)-1-hydroxybutan-2-yl, (2R)-1-hydroxybutan-2-yl; 1-(hydroxymethyl)cyclopropyl; 2,3-dihydroxypropanyl (-CH 2 -C(OH)CH 2OH); pyridinylmethyl, especially pyridin-2-ylmethyl, pyridin-3-ylmethyl, pyridin-4-ylmethyl; 2-hydroxy-1-pyridinylethyl, especially 2-hydroxy-1-(pyridin-2-yl)ethyl, especially (1R)-2-hydroxy-1-(pyridin-2-yl)ethyl, (1S)-2-hydroxy-1-(pyridin-2-yl)ethyl; 2-hydroxy-1-(1-methyl-1H-pyrazol-3-yl)ethyl.

[0034] In another specific embodiment of PE5, PE5c, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 is -C(=O)-NR 2b R 2c Represents; R 2b and R 2c one of which is a linear or branched alkyl group, optionally substituted with OH or halogen; 1~10 -alkyl, whereas R 2b and R 2c The other is Cyc 2b , Hetcyc 2b , linear or branched C 1~10 -alkyl (which may be unsubstituted or R E1 , R E2 , R E3 , R E4 , and / or R E5 (which may be the same or different), wherein the C 1~10 In -alkyl, one or two non-adjacent and non-terminal methylene moieties are independently -O- and / or -S- and / or -NH- and / or -N(C 1~4 -alkyl)-; Cyc 2bis a saturated monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, which carbocyclic ring may be unsubstituted or may be, independently of each other, R D6 , R D7 , R D8 , R D9 , and / or R D10 wherein the carbocycle is optionally substituted with Ar Z Or Hetar Z and, via two adjacent ring atoms, wherein the fused carbocycles are optionally, independently of each other, R C1 , R C2 , and / or R C3 may be further substituted with; Hetcyc 2b is a saturated monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be, independently of each other, D6 , R D7 , R D8 , R D9 , and / or R D10 wherein the heterocycle is optionally substituted with Ar Z Or Hetar Z and wherein the fused heterocycles are optionally fused to, independently of each other, R C1 , R C2 , and / or R C3 may be further substituted with; R E1 , R E2 , R E3 , R E4 , and / or R E5 are, independently of one another, halogen, in particular F; -NR Ea R Eb , OR Ec , Ar E , Hetar E , Cyc E , Hetcyc E Represents; ArE is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, which aryl may be unsubstituted or may contain the substituent R F1 , R F2 , and / or R F3 (which may be the same or different); especially phenyl or naphthalenyl; Ar Z is benzo; Hetar E 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 heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may be represented by a substituent R F1 , R F2 , and / or R F3 (which may be the same or different); especially imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl (each of which may be unsubstituted or substituted with C 1~4 -alkyl); pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl (each of which may be unsubstituted or monosubstituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Hetar Y1 is a 5- or 6-membered monocyclic heteroaryl, where 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or is selected from F, C, 1~4-alkyl (optionally substituted with OH); especially pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl, methylpyrimidinyl; Hetar Y2 is a 5- or 6-membered monocyclic heteroaryl, where 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or substituted with halogen, C 1~4 -alkyl (optionally substituted with OH); especially pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl; Hetar Z are pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Cyc E R represents a saturated or partially unsaturated mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, which may be unsubstituted or may be substituted with R G1 and / or R G2 (which may be the same or different): in particular saturated monocyclic carbocyclic rings having 3, 4, 5 or 6 ring carbon atoms, which carbocyclic rings may be unsubstituted or may be substituted with R G1 and / or R G2 (which may be the same or different); Cyc Y1 is a saturated or partially unsaturated, monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, which may be unsubstituted or may contain halogen, OH, C 1~4 -alkyl), especially cyclopropyl, cyclohexenyl; Hetcyc E represents a saturated or partially unsaturated, monocyclic heterocycle having 4, 5, or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be substituted with R G1 and / or R G2 (which may be the same or different); especially saturated monocyclic heterocycles having 5 or 6 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N and / or O, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or may be substituted with R G1 and / or R G2 substituted with ); preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl (each of which may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl (each of which may be unsubstituted or monosubstituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; Hetcyc Y1 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl; Hetcyc Y2is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl, morpholinyl, tetrahydropyranyl; R C1 , R C2 , R C3 are independent of each other, C 1~4 - represents alkyl; R D6 , R D7 , R D8 , R D9 , R D10 are each independently a halogen, in particular F; hydroxy; C optionally substituted with -OH and / or halogen; 1~4 -Alkyl, especially methyl, hydroxymethyl, 2-fluoroethyl; -OC 1~4 -Alkyl, especially methoxy, ethoxy; Hetar Y1 , -CH 2 -Hetar Y1 , Cyc Y1 , Hetcyc Y1 , -CH 2 -Hetcyc Y1 Represents; and / or R attached to the same ring atom of the carbocyclic or heterocyclic ring. D6 , R D7 , R D8 , R D9 , R D10 Two of them are divalent C 2~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl, and wherein the alkylene radical is optionally replaced by OH, C 1~4 -Alkyl, or -OC 1~4 -Alkyl, especially -(CH 2 ) 3 -, -CH 2 -CH(OC 2 H 5 )-CH2 -, -(CH 2 ) 2 -O-(CH 2 ) 2 - optionally substituted; and / or R D6 , R D7 , R D8 , R D9 , R D10 (which are attached to two different ring atoms of the carbocyclic or heterocyclic ring) are two divalent C 1~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -Alkyl, especially -CH 2 -, -(CH 2 ) 3 -, -O-(CH 2 ) 2 -, -O-(CH 2 ) 3 - may be replaced by; R Ea , R Eb are, independently of each other, H, C 1~4 -Alkyl, -C(=O)-C 1~4 -Alkyl, -C(=O)-OC 1~4 - represents alkyl; R Ec is H or C 1~4 - represents alkyl; R F1 , R F2 , R F3 are, independently of each other, linear or branched C 1~6 -Alkyl (its C 1~6 -Alkyl may be unsubstituted or may be -CN, -OH, -OC 1~4 - alkyl or substituted with 1, 2 or 3 halogens): straight or branched C 1~4 -Alkoxy (C 1~4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens); straight or branched -SC 1~4 -Alkyl (its -SC1~4 -alkyl may be unsubstituted or substituted with 1, 2, or 3 halogens); halogen, OH, and / or C 1~4 -alkyl, C 3~7 -Cycloalkyl; F, Cl, Br, -CN, -S(=O)-C 1~3 -Alkyl, S(=O) 2 -C 1~3 -Alkyl, -NH 2 , -NH(C 1~3 -alkyl)-N(C 1~3 -alkyl) 2 , -OH; in particular methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably R F1 , R F2 , and R F3 is present and represents methyl or F; and / or R F1 , R F2 , R F3 (which are attached to two different ring atoms of the aryl or heteroaryl) are two divalent C 1~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -Alkyl, especially -(CH 2 ) 4 -, -CH 2 -O-(CH 2 ) 2 - may be replaced by; R G1 , R G2 are each independently a halogen; a hydroxyl; an unsubstituted or substituted C 1~6 - aliphatic, in particular C 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 ;-CH 2 -Hetar Y2;Hetcyc Y2 In particular, R G1 and R G2 is present and represents hydroxy; and / or R G1 and R G2 (which are attached to the same ring atom of the carbocyclic or heterocyclic ring) are divalent C 2~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl, and wherein the alkylene radical is optionally replaced by OH, C 1~4 -Alkyl, or -OC 1~4 -Alkyl, especially -(CH 2 ) 2 -O-CH 2 -, -(CH 2 ) 2 -O-(CH 2 ) 2 - optionally substituted; and / or R G1 and R G2 (which are attached to two different ring atoms of the carbocyclic or heterocyclic ring) are divalent C 1~6 -alkylene radical, wherein optionally, one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -Alkyl, especially -CH 2 - may be replaced by; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0035] In a specific embodiment PE5ca of PE5c, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2b and R 2c One of the groups represents methyl, ethyl, or 2-hydroxyethyl, while the other represents methyl, ethyl, or 2-hydroxyethyl. 2b and R 2c The other is Cyc 2b , Hetcyc 2b , or linear or branched C 1~8 -alkyl, which may be unsubstituted or R E1 , R E2 , R E3 , R E4 , and / or R E5 (which may be the same or different); Cyc 2b is cyclopropyl, cyclobutyl, or 1-hydroxymethyl-cyclobutyl; Hetcyc 2b is tetrahydrofuranyl or hydroxytetrahydrofuranyl; R E1 , R E2 , R E3 , R E4 , and / or R E5 are, independently of each other, F;-NR Ea R Eb , OR Ec , Ar E , Hetar E , Cyc E , Hetcyc E Represents; Ar E may be unsubstituted or may be substituted by R F1 , R F2 , and / or R F3 (which may be the same or different); Hetar Eis imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl (each of which is unsubstituted or 1~4 -alkyl monosubstituted); pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl (each of which may be unsubstituted or monosubstituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrazin-4-yl-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Cyc E is cyclopropyl or cyclobutyl; Hetcyc E is selected from the group consisting of tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or mono-substituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or mono-substituted with -OH); piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl (each of which may be unsubstituted or mono-substituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl (each of which may be unsubstituted or mono-substituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; R Ea , R Eb both represent H or one represents H and the other represents -C(=O)-methyl or -C(=O)-O-tert.-butyl; R Ec represents H or methyl; R F1 , R F2 , R F3denote, independently of one another, methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; in particular R F1 , R F2 , and R F3 is present and represents methyl or F; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0036] In another specific embodiment of PE5, PE5d, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2 is -C(=O)-NR 2b R 2c Represents; R 2b and R 2c together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocycle, said rings being optionally, independently of each other, R Y1 , R Y2 , R Y3 , R Y4 , and / or R Y5 wherein the heterocycle is optionally substituted with Hetar Z and wherein the heterocycle is selected from the group consisting of: azetidine, pyrrolidine, piperidine, piperazine, morpholine; R Y1 , R Y2 , R Y3 , R Y4 , R Y5 are, independently of one another, halogen, in particular F; -NH 2 , -N(H)-C 1~4 -Alkyl, -N(H)-C(=O)-OC 1~4 -Alkyl, -N(C 1~4 -alkyl) 2;-OH;C optionally substituted with -OH 1~4 -Alkyl, -OC 1~4 -Alkyl, -OC 3~7 -Cycloalkyl, -O-CH 2 -C 3~7 -cycloalkyl, especially methyl, -CH 2 OH, -(CH 2 ) 2 OH, -(CH 2 ) 3 OH, -CH 2 OCH 3 , -(CH 2 ) 2 OCH 3 , cyclopropylmethoxy; -OC 1~4 -Alkyl, especially methoxy; Hetar Y2 ;-CH 2 -Hetar Y2 ;Hetcyc Y2 Represents; and / or R attached to the same ring atom of the heterocycle. Y1 , R Y2 , R Y3 , R Y4 , R Y5 Two of them are divalent C 2~6 - an alkylene radical, where optionally one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl), in particular -(CH 2 ) 4 -, -(CH 2 ) 2 -O-(CH 2 ) 2 -, -(CH 2 ) 2 -O-(CH 2 ) 3 - Forming; and / or R attached to two different ring atoms of the heterocycle. Y1 , R Y2 , R Y3 , R Y4 , R Y5 Two of them are divalent C 1~6- an alkylene radical, where optionally one or two non-adjacent carbon units of the alkylene radical are independently selected from O, NH, NC 1~4 -alkyl), in particular -(CH 2 ) 4 - Forming; Hetar Y2 is a 5- or 6-membered monocyclic heteroaryl, where 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl is unsubstituted or substituted with halogen, C 1~4 -alkyl (optionally substituted with OH); especially pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl; Hetar Z are pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Hetcyc Y2 is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl, morpholinyl, tetrahydropyranyl; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0037] In a specific embodiment of PE5d, PE5da, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2b and R 2ctogether with the nitrogen atom to which they are attached form a pyrrolidinyl or piperidinyl ring, each of which is unsubstituted or mono-substituted with -OH or, independently of each other, C 1~4 di-substituted with -alkyl and / or -OH; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0038] In the specific embodiment PE5daa of PE5da, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2b and R 2c together with the nitrogen atom to which they are attached form a pyrrolidin-3-ol ring, in particular a (3S)-pyrrolidin-3-ol ring.

[0039] In another specific embodiment of the invention, PE6, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2 is -(CH 2 ) 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 )-R2g , -S(=O)(=NR 2k )-NR 2l R 2m , -(CH 2 ) 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 In particular, -(CH 2 ) x -NR 2d -C(=O)-R 2e , -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 , -(CH 2 ) 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 ; preferably -NH-C(=O)-CH 3 , -S(=O)-CH 3 , -S(=O) 2 -CH 3 , -S(=O) 2 -NH 2 , -S(=O) 2 -NHCH 3 , -S(=O)(=NH)-CH 3 , S(=O)(=NH)-N(CH3 ) 2 , -NH-S(=O) 2 -CH 3 , -NH-S(=O) 2 -CH=CH 2 , -CH 2 -NH-S(=O) 2 -CH=CH 2 , -N=S(=O)(CH 3 ) 2 , C(=O)-N=S(=O)(CH 3 ) 2 Represents; R 2e is H, optionally substituted with -OH 1~6 -alkyl, or monocyclic 5- or 6-membered heteroaryl; C 3~7 -cycloalkyl, monocyclic 5- or 6-membered heteroaryl; especially H, methyl, hydroxymethyl, methylpyridin-2-yl, methylpyridin-3-yl, methylpyridin-4-yl, cyclopropyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; R 2f , R 2g are, independently of each other, unsubstituted or substituted C 1~8 - aliphatic; in particular, independently of each other, C 1~4 -Alkyl or C 2~4 -alkenyl; preferably, independently of each other, methyl or -CH=CH 2 Represents; R 2h , R 2i are, independently of each other, H, unsubstituted or substituted C 1~8 - aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached, form an unsubstituted or substituted, saturated, partially unsaturated or aromatic heterocycle with 3, 4, 5, 6, 7 ring atoms, in which 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 remainder are carbon atoms; in particular, independently of each other, H or C 1~4 - represents alkyl; R2d , R 2j , R 2k are, independently of each other, H, unsubstituted or substituted C 1~8 -Aliphatic; especially representing H; R 2l , R 2m are, independently of each other, H, unsubstituted or substituted C 1~8 - aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, in which 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 remainder are carbon atoms; especially C 1~4 - alkyl; preferably represents methyl; R 2s , R 2t are independent of each other, C 1~6 -alkyl (which may optionally be -OH, OC 1~4 -Alkyl, NH 2 , N.H.C. 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, the divalent C 3~4 -alkylene radical (which may optionally be -NH 2 , -CN) or divalent C 2~5 - an alkylene radical, where optionally, 2~5 -One of the carbon units of the alkylene radical is O, NH, or NC 1~4 -alkyl); in particular -(CH 2 ) 3 -, -CH 2 -C(NH 2 )H-CH 2 -, -CH 2 -C(CN)H-CH 2-, -CH 2 -C(CH 2 -NH-CH 2 )-CH 2 -, -(CH 2 ) 4 - Forming; R 2u is hydrogen or C 1~4 - represents alkyl; x represents 0 or 1; z represents 0 or 1; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0040] In a specific embodiment of PE6, PE6a, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2 is -C(=O)-N=S(=O)(CH 3 ) 2 Represents; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0041] In another specific embodiment of the invention, PE7, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein Ring A is the following ring moiety: [ka] [ka] [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: Ring B is the following ring moiety: [ka] represents a 5-membered heteroaromatic ring selected from the group consisting of: Z 1 is CH or N; and Z 2 is S; or Z 3 is S; and Z 4 is CH or N; R 1are phenyl, 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, bisphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl, 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl, 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-Thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2-yl, 4-difluoromethoxypyridin-2-yl, 4-cyanopyridin-2-yl, 5-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-2-yl, 6-trifluoromethylpyridin-2-yl, Pyridin-3-yl (2-trifluoromethylpyridin-5-yl), 6-trifluoromethoxypyridin-3-yl (2-trifluoromethoxypyridin-5-yl), 5-cyanopyridin-2-yl, 5-cyanomethylpyridin-2-yl, 5-methanesulfonylpyridin-2-yl, 6-methoxypyridin-2-yl, 4-methylpyrimidin-2-yl, 4-ethylpyrimidin-2-yl, 4-methylsulfanylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoropyridin-2-yl fluoromethylpyrimidin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano-6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2-yl, Quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazolin-2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-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, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-difluorospiro[3.3]hept-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-(propane- 2-yl)phenylmethyl, 3-tert-butylphenylmethyl, 3-(difluoromethoxy)phenylmethyl, 2-(difluoromethyl)phenylmethyl, 3-(difluoromethyl)phenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenyl]methyl, 2-(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3-methanesulfonylphenylmethyl, 3-(dimethylamino)phenyl nylmethyl, 3-(pyrrol-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-fluoromethox diphenylmethyl, 2-trifluoromethoxy-5-fluorophenylmethyl, 2-fluoro-5-chloro-phenylmethyl, 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-tetrahydronaphthalen-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-thiazol-2-ylmethyl, 2-methyl-1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2-propyl)pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-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-Oxazol-2-ylmethyl, 3-Fluoropyridin-2-ylmethyl, 2-Methylpyridin-4-ylmethyl, 4-Trifluoromethylpyridin-2-yl, 4-Trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)pyridin-2-ylmethyl, 6-trifluoromethylpyridin-2-yl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-Methylpyrimidin-2-ylmethyl, 4-Trifluoromethylpyridin-2-ylmethyl, 4-Trifluoromethylpyridin-2-ylmethyl, 4-Trifluoromethylpyridin-2-ylmethyl, 6-(fluoro methyl)pyridin-2-ylmethyl, 6-trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5-trifluoromethylthiophen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H-pyrrolo[1,2-b]pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl pyrazolo[1,5-a]pyridin-3-ylmethyl, imidazo[1,2-a]pyridin-3-ylmethyl, 6-methylimidazo[1,2-a]pyridin-3-ylmethyl, imidazo[1,2-a]pyridin-5-ylmethyl, imidazo[1,5-a]pyridin-1-ylmethyl, imidazo[1,5-a]pyridin-3-ylmethyl, imidazo[1,5-a]pyridin-5-ylmethyl, pyrazolo[1,5-c]pyrimidin-3-ylmethyl, 3-(furan-2-yl)prop-2-en-1-yl; 3-trifluoromethylcyclobutylmethyl ethyl, 3-fluoro-3-phenylcyclobutylmethyl, cyclohexylmethyl, 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]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thi-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 4,4,4-trifluoro-3,3-dimethylbutyl, 3,3,3-trifluoroprop-1-yn-1-yl; and R 2 -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH 3 , -C(=O)-NH 2 , -C(=O)-NHCH 3 , -C(=O)-NHCH 2 CH 3 , -C(=O)-NH(CH 2 ) 2 CH 3 , -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH 2 CH 2 -OH, -C(=O)-N(H)-CH 2 CH 2 -OCH 3 , N(H)-CH 2 CH(CF 3 )-OH, -C(=O)-N(H)-CH(CH 3 )CH 2 -OH, -C(=O)-N(H)-CH 2 CH(CH 3 )-OH, -C(=O)-N(H)-CH 2 -C(H)(OH)-CH 3 , -C(=O)-N(H)-CH 2 C(CH 3 ) 2 OH, -C(=O)-N(H)-C(H)(CH 3 )-CH 2 OH, -C(=O)-N(H)-CH(CH 2 CH 3 )CH 2 -OH, -C(=O)-N(H)-CH(CH(CH3 ) 2 )CH 2 -OH, -C(=O)-N(H)-CH 2 C(CH 3 ) 2 OH, -C(=O)-N(H)-CH(OH)CH 2 -OH, -C(=O)-N(H)-C(H)(CH 2 CH 3 )-CH 2 OH, -C(=O)-N(H)-C(H)(CH 2 OH)-CH 2 CH 2 -O-CH 3 , -C(=O)-N(H)-C(CH 3 ) 2 CH 2 CH 2 OH, -C(=O)-N(H)-C(H)(CH 2 OH)-phenyl, -C(=O)-N(H)-CH(CH(CH 3 )-OH)-phenyl, -C(=O)-N(H)-C(CH 3 )(CH 2 OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH 3 )-phenyl, -C(=O)-N(H)-CH(CH 2 CH 2 OH)-1,3-thiazol-5-yl, -C(=O)-N(H)-CH 2 -1H-1-methylimidazol-2-yl, -C(=O)-N(H)-(CH 2 ) 2 -1H-imidazol-1-yl, -C(=O)-N(H)-CH 2 -pyridin-2-yl, -C(=O)-N(H)-CH 2 -pyridin-3-yl, -C(=O)-N(H)-CH 2 -pyridin-4-yl, -C(=O)-N(H)-C(H)(CH 2 OH)-pyridin-2-yl, -C(=O)-N(H)-CH 2 -1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH 2 -1,3-pyrimidin-4-yl, -C(=O)-N(H)-CH 2-pyridazin-2-yl, -C(=O)-NH-C(CH 2 -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-NH-CH 2 -azetidin-3-yl, -C(=O)-N(H)-(4-hydroxy-tetrahydrofuran-3-yl), -(C=O)-NH-CH 2 CH 2 -morpholin-4-yl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -C(=O)-3-hydroxy-piperidin-1-yl, -NH-C(=O)-CH=CH 2 , -NH-C(=O)-CF=CH 2 , -NH-C(=O)-CH 2 Cl, -NH-C(=O)-C≡CH, -CH 2 -NH-C(=O)-CH=CH 2 , -CH 2 -NH-C(=O)-CH 2 Cl, -CH 2 -NH-C(=O)-C≡CH, -S(=O)-CH 3 , -S(=O) 2 -CH 3 , -S(=O) 2 -OH, -S(=O) 2 -NH 2 , -S(=O) 2 -NHCH 3 , -S(=O)(=NH)-N(CH 3 ) 2 , -S(=O)(=N-CH 3 )-N(CH 3 ) 2 , -S(=O)(=N-CH 3 )-OH, -S(=O)(=NH)-CH 3 , -C(=O)-N=S(=O)-(CH 3 ) 2 , -C(=O)-N=S(=O)-(CH 3 )(CH 2 CH 2 CH 2 OH), -P(=O)(OH) 2 , F, -CN.

[0042] In a specific embodiment of PE7, PE7a, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: Ring A is [ka] Represents; Ring B is [ka] represents either; R 1 represents 4-trifluoromethylphenyl; 4-difluoromethoxyphenyl; 4-trifluoromethoxyphenyl; 3-(trifluoromethyl)cyclobutylmethyl; 4,4,4-trifluoro-3,3-dimethylbutyl; R 2 -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH 3 , -C(=O)-NH 2 , -C(=O)-NH-CH 3 , -C(=O)-NHCH 2 CH 3 , -C(=O)-NH(CH 2 ) 2 CH 3 , -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH 2 CH 2 -OH, -C(=O)-N(H)-CH 2 CH 2 -OCH 3 , -C(=O)-N(H)-CH(CH 3 )CH 2 -OH, -C(=O)-N(H)-CH 2 CH(CH 3 )-OH, -C(=O)-N(H)-CH 2 -C(H)(OH)-CH3 , -C(=O)-N(H)-CH 2 C(CH 3 ) 2 OH, -C(=O)-N(H)-C(H)(CH 3 )-CH 2 OH, -C(=O)-N(H)-CH(CH 2 CH 3 )CH 2 -OH, -C(=O)-N(H)-CH(CH(CH 3 ) 2 )CH 2 -OH, -C(=O)-N(H)-CH 2 C(CH 3 ) 2 OH, -C(=O)-N(H)-CH(OH)CH 2 -OH, -C(=O)-N(H)-C(H)(CH 2 CH 3 )-CH 2 OH, -C(=O)-N(H)-C(H)(CH 2 OH)-CH 2 CH 2 -O-CH 3 , -C(=O)-N(H)-C(CH 3 ) 2 CH 2 CH 2 OH, -C(=O)-N(H)-C(H)(CH 2 OH)-phenyl, -C(=O)-N(H)-CH(CH(CH 3 )-OH)-phenyl, -C(=O)-N(H)-C(CH 3 )(CH 2 OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH 3 )-phenyl, -C(=O)-N(H)-CH(CH 2 CH 2 OH)-1,3-thiazol-5-yl, -C(=O)-N(H)-CH 2 -1H-1-methylimidazol-2-yl, -C(=O)-N(H)-(CH 2 ) 2 -1H-imidazol-1-yl, -C(=O)-N(H)-CH 2 -pyridin-2-yl, -C(=O)-N(H)-CH 2-pyridin-3-yl, -C(=O)-N(H)-CH 2 -pyridin-4-yl, -C(=O)-N(H)-C(H)(CH 2 OH)-pyridin-2-yl, -C(=O)-N(H)-CH 2 -1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH 2 -1,3-pyrimidin-4-yl, -C(=O)-N(H)-CH 2 -pyridazin-2-yl, -C(=O)-NH-C(CH 2 -C(=O)-N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-NH-CH 2 -azetidin-3-yl, -C(=O)-N(H)-(4-hydroxy-tetrahydrofuran-3-yl), -(C=O)-NH-CH 2 CH 2 -morpholin-4-yl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -C(=O)-3-hydroxy-piperidin-1-yl, -C(=O)-N=S(=O)-(CH 3 ) 2 , -C(=O)-N=S(=O)-(CH 3 )(CH 2 CH 2 CH 2 OH).

[0043] In a specific embodiment of PE7b of PE7, which is also a specific embodiment of PE7a, the compounds of the invention are tricyclic heterocycles of formula I, or any N-oxides, solvates, tautomers, or stereoisomers thereof, and / or any pharma- ceutically acceptable salts of each of the above, and mixtures thereof in all ratios, wherein: Ring A is [ka] Represents; Ring B is [ka] represents either; R 1 is 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl; and R 2 is C(=O)-OH or C(=O)-ONa.

[0044] In another specific embodiment of the invention, PE8, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 1 teeth, [ka] [ka] [ka] [ka] selected from the group consisting of; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0045] In a specific embodiment PE8a of PE8, R 1 teeth, [ka] [ka] selected from the group consisting of; and the remaining radicals and residues are as defined for formula I above, or for any of the further specific embodiments described herein above or below. In particular, R1 teeth, [ka] (Specific embodiment PE8aa) or [ka] (Specific embodiment PE8ab).

[0046] In another specific embodiment of the invention, PE9, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 2 teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] (R Z1 together with; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0047] In a specific embodiment PE9a of PE9, The compounds of the present invention are tricyclic heterocycles represented by formula I, or any N-oxides, solvates, tautomers, or stereoisomers thereof, and / or any pharma- ceutically acceptable salts of each of the above, and mixtures thereof in all ratios, wherein R 2 teeth, [ka] [ka] (R Z1 together with; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0048] In a specific embodiment of PE9a, R 2is selected from the group consisting of -COOH and -COONa; in particular, -COOH.

[0049] In a specific embodiment of PE9, PE9b, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 teeth, [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] selected from the group consisting of; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0050] In a specific embodiment PE9ba of PE9b, R 2 teeth, [ka] [ka] is selected from the group consisting of:

[0051] In another specific embodiment of PE9, PE9c, the compound of the invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein: R 2 teeth, [ka] [ka] [ka] selected from the group consisting of; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0052] In a specific embodiment of PE9c, PE9ca, R 2 teeth, [ka] is selected from the group consisting of:

[0053] In the embodiments PE8, PE8a, PE8aa, PE8ab, PE9, PE9a, PE9aa, PE9b, PE9ba, PE9c, and PE9ca shown above, the dotted line [ka] is the individual radical R 1 and R 2 It is understood that each is used to indicate the position of attachment to the remainder of the molecule, ie, the compound of Formula I.

[0054] In yet another specific embodiment of the invention, PE10, the compound of the invention is a tricyclic heterocycle represented by formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in all ratios, wherein R 1 is selected from the groups described for PE8 above; and R 2 is selected from the groups described for PE9 above; and the remaining radicals and residues are as defined for Formula I above, or for any of the further specific embodiments described herein above or below.

[0055] Specific embodiment of PE10, PE10a, wherein R 1 is selected from the groups described for PE8a above, in particular PE8aa or PE8ab; and R 2 is selected from the groups described for PE9 above.

[0056] Yet another specific embodiment of PE10, PE10b, wherein R 1 is selected from the groups described for PE8a above, in particular PE8aa or PE8ab; and R 2is selected from the groups described for PE9a above, in particular PE8aa or PE9aa.

[0057] Yet another specific embodiment of PE10, PE10c, wherein R 1 is selected from the groups described for PE8a above, in particular PE8aa or PE8ab; and R 2 is selected from the groups described for PE9b, and particularly PE9ba, above.

[0058] Yet another specific embodiment of PE10, PE10d, wherein R 1 is selected from the groups described for PE8a above, in particular PE8aa or PE8ab; and R 2 is selected from the groups described for PE9c above, and particularly PE9ca.

[0059] Yet another specific embodiment of the present invention, PE11, wherein Ring B is as defined in one of the specific embodiments PE1, PE1a, PE1aa, PE1ab, PE7, PE7a, PE7b; and R 1 and R 2 is selected as described for PE10.

[0060] In a specific embodiment of PE11, PE11a, R 1 and R 2 is selected as described for PE10a. In another specific embodiment of PE11, PE11b, R 1 and R 2 is selected as described for PE10b. In another specific embodiment of PE11, PE11c, R 1 and R 2 is selected as described for PE11c. In yet a further specific embodiment PE11d of PE11, R 1 and R 2are selected as described for PE10d.

[0061] Yet another specific embodiment of the present invention is PE12, wherein Ring A is as defined in one of the specific embodiments PE2, PE2a, PE2aa, PE2b, PE2ba, PE2baa, PE7, PE7a, PE7b; and R 1 and R 2 is selected as described for PE10.

[0062] In a specific embodiment of PE12, PE12a, R 1 and R 2 is selected as described for PE10a. In another specific embodiment of PE12, PE12b, R 1 and R 2 is selected as described for PE10b. In another specific embodiment of PE12, PE12c, R 1 and R 2 is selected as described for PE10c. In yet a further specific embodiment of PE12, PE12d, R 1 and R 2 are selected as described for PE10d.

[0063] Yet another specific embodiment of the present invention is PE13, wherein Ring B is as defined in one of the specific embodiments PE1, PE1a, PE1aa, PE1ab, PE7, PE7a, PE7b; Ring A is as defined in one of the specific embodiments PE2, PE2a, PE2aa, PE2b, PE2ba, PE2baa, PE7, PE7a, PE7b; and R 1 and R 2 is selected as described for PE10; PE10a; PE10b; PE10c; or PE10d.

[0064] In specific embodiment PE13a of PE13, R 1 and R 2 is selected as described for PE10a. In another specific embodiment of PE13, PE13b, R 1 and R 2 is selected as described for PE10b. In another specific embodiment of PE13, PE13c, R 1 and R 2 is selected as described for PE10c. In yet a further specific embodiment of PE13, PE13d, R 1 and R 2 are selected as described for PE10d.

[0065] In yet another specific embodiment PE14, the compound of the present invention is a tricyclic heterocycle selected from the compounds shown in Table 1 and Table 1a below, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of each of the above, and mixtures thereof in any ratio. In another specific embodiment PE14a of PE14, the compound is a compound selected from Table 1 and Table 1a and represented by formula I as described above and in the claims. It is understood that each single compound depicted in Table 1 and Table 1a, and any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharma- ceutically acceptable salt of such compound, represent specific embodiments of the present invention. In yet another specific embodiment PE14b of PE14 or PE14a, the compound is selected from Table 1 and Table 1a and is represented by formula I as described above and in the claims, and is within Group A in the SK-HEP1 reporter assay and / or within Group A in the NCI-H226 assay as provided in Table 2 below.

[0066] As used herein, the following definitions shall apply unless otherwise specifically indicated or defined anywhere in the description and / or claims for a particular substituent, radical, residue, group, or moiety.

[0067] The term "aliphatic" or "aliphatic group," as used herein, means a straight-chained (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 units of unsaturation, such as one or more C=C double bond(s) and / or C≡C triple bond(s), but is not aromatic (also referred to herein as "carbocyclic," "cycloaliphatic," or "cycloalkyl"), which - generally, and unless otherwise defined in this specification or the appended claims - has a single point of attachment to the remainder of the molecule. Unless otherwise specified, an aliphatic group contains 1-10 (i.e., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10), 1-8 (i.e., 1, 2, 3, 4, 5, 6, 7, or 8), or 1-6 (i.e., 1, 2, 3, 4, 5, or 6) aliphatic carbon atoms (respectively, "C 1~10 -Aliphatic”, “C 1~8 -Aliphatic", and "C 1~6 In some embodiments, an aliphatic group contains 1 to 5 (i.e., 1, 2, 3, 4, or 5) aliphatic carbon atoms ("C 1~5 In other embodiments, the aliphatic group contains 1 to 4 (i.e., 1, 2, 3, or 4) aliphatic carbon atoms ("C 1~4 In yet other embodiments, the aliphatic group contains 1 to 3 (i.e., 1, 2, or 3) aliphatic carbon atoms ("C 1~3 -aliphatic"), in another embodiment, the aliphatic group contains 1 to 2 aliphatic carbon atoms ("C 1~2In some embodiments, a "cycloaliphatic" ("cycloalkyl") is a monocyclic C 3 ~C 7 Hydrocarbons (i.e., monocyclic hydrocarbons having 3, 4, 5, 6, or 7 ring carbon atoms) or bicyclic C 5~8It refers to a hydrocarbon (i.e., a bicyclic hydrocarbon having 5, 6, 7, or 8 ring carbon atoms) that is fully saturated or contains one or more unsaturated units, but is not aromatic, and has a single point of attachment to the rest of the molecule. In another embodiment, the term "cycloaliphatic" or "carbocycle" refers to a monocyclic or bicyclic cycloaliphatic ring system that is fused to an aromatic, heteroaromatic, or heterocyclic ring or ring system through two adjacent ring atoms of the aromatic, heteroaromatic, or heterocyclic ring or ring system; in other words, such a carbocycle shares two ring atoms with the ring or ring system to which it is fused, thereby having two points of attachment to the rest of the molecule. In another embodiment, the term "carbocycle" refers to a bicyclic spirocycle in which two monocyclic carbocycles are fused to each other through the same single carbon atom. In general, the term "aliphatic" encompasses linear, i.e., unbranched, as well as branched hydrocarbon chains, to the extent that is chemically feasible, unless otherwise defined in a specific example. In general, the term also encompasses unsubstituted and substituted hydrocarbon moieties, to the extent that is chemically feasible, unless otherwise defined in a specific example. Exemplary substituents for aliphatic groups include, but are not limited to, halogen, especially F, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups, and hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0068] The term "alkyl" generally refers to saturated aliphatic and acyclic moieties, whereas the term "alkenyl" generally refers to unsaturated aliphatic and acyclic moieties with one or more C=C double bonds, and the term "alkynyl" generally refers to aliphatic and acyclic moieties with one or more C≡C triple bonds. It is understood that the term "alkenyl" includes all isomeric forms, i.e., E-isomers, Z-isomers, and mixtures thereof (E / Z-isomers). Exemplary aliphatic groups include linear or branched, substituted or unsubstituted C 1~10 -Alkyl group, 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 hybrids thereof, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0069] In particular, the term "C 1~3 "-alkyl" refers to an alkyl group, i.e., a saturated acyclic aliphatic group having 1, 2, or 3 carbon atoms. 1~3 The alkyl groups are methyl, ethyl, propyl, and isopropyl. 1~4 "-alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. 1~4 The alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. 1~6 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. 1~6 -Alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. 1~8"-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Exemplary C 1~8 The alkyl groups are 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. 1~10 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbon atoms. Exemplary C 1~10 - the alkyl groups are methyl, ethyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl, 2,2,4-trimethylpentyl, and n-decyl, each of which may be linear or 1 -Alkyl and C 2 - with the exception of alkyl - may be branched and unsubstituted or substituted with one, two or three substituents, which may be the same or different and, unless specified differently elsewhere in this specification and / or the appended claims, may be selected from the group comprising halogen, especially F, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Exemplary substituted alkyl groups are difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, hydroxymethyl, 2-hydroxyethyl.

[0070] In some cases, C 1~3 -Alkyl group, C 1~4 -Alkyl group, C 1~6 -Alkyl group, C 1~8 -Alkyl group, C 1~10The -alkyl group may also contain one or two non-terminal and non-adjacent -CH 2 -(methylene) groups are replaced by -O-, -S-, and / or one or two non-terminal and non-adjacent -CH 2 It may also include those residues in which the - or -CH- group is replaced by -NH- or -N-. These replacements are illustratively -CH 2 -CH 2 -O-CH 3 , -CH 2 -CH 2 -CH 2 -S-CH 3 , C.H. 2 -CH 2 -NH-CH 2 -CH 3 , C.H. 2 -CH 2 -O-CH 2 -CH 2 -O-CH 3 , C.H. 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 3 , C.H. 2 -CH 2 -N(CH 3 )-CH 2 -CH 3 etc. The -CH- and -CH 2Further and / or different replacements of - groups may be defined elsewhere in the description and / or claims for specific alkyl substituents or radicals. As described above for "unmodified" alkyl groups, these "modified" alkyl groups may be optionally substituted with one, two or three substituents, which may be the same or different and, unless otherwise specified elsewhere in the present specification and / or the appended claims, may be selected from the group including halogen, especially F, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Exemplary modified alkyl groups are CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -NH 2 , C.H. 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -NH-C(=O)-CH 3 , C.H. 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -NH-C(=O)-OC(CH 3 ) 3 CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -O-CH 2 -CH 2 -NH 2 , C.H. 2 -CH 2 -CH 2 -CH 2 -CH 2-O-CH 2 -CH 2 -NH-C(=O)-CH 3 , C.H. 2 -CH(OH)-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -NH 2 , CHR-CH(OH)-CH 2 -CH 2 -O-CH 2 -CH 2 -O-CH 2 -CH 2 -NH 2 where "R" represents another substituent.

[0071] The term “C 3~7 "-cycloalkyl" refers to a cycloaliphatic hydrocarbon, as defined above, having 3, 4, 5, 6, or 7 ring carbon atoms. 3~6 -Cycloalkyl" refers to a cycloaliphatic hydrocarbon having 3, 4, 5, or 6 ring carbon atoms. 3~7 -cycloalkyl", and "C 3~6 "-cycloalkylalkyl" as used herein includes saturated cyclic hydrocarbons or cyclic hydrocarbons containing one or more units of unsaturation, such as a C=C double bond; such cyclic hydrocarbons having at least one unit of unsaturation may also be referred to as "cycloalkenyl" groups. 3~7 - a cycloalkyl group may be unsubstituted or - unless otherwise specified elsewhere in this specification - substituted with 1, 2 or 3 substituents which may be the same or different, and said group - unless otherwise specified elsewhere in this specification - is a cycloalkyl group. 1~6 -Alkyl, OC 1~6- alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl. If substituted, C 3~7 -Cycloalkyl includes all possible stereoisomers. 3~7 -Cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl. 5~8 "-cycloalkyl" refers to a bicyclic cycloaliphatic hydrocarbon as defined above having 5, 6, 7, or 8 ring carbon atoms; it does not include spirocyclic ring systems, i.e., bicyclic C 5~8 -Cycloalkyl includes ring systems in which the two carbocyclic rings of the cycloalkyl are attached to each other through the same carbon atom. 5~8 -Cycloalkyl groups may be unsubstituted or - unless otherwise specified elsewhere in this specification - substituted with 1, 2 or 3 substituents, which may be the same or different, and - unless otherwise specified elsewhere in this specification - C 1~6 -Alkyl, OC 1~6 -alkyl(alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. When substituted, bicyclic C 5~8 -Cycloalkyl includes all possible stereoisomers. Exemplary bicyclic C 5~8 -Cycloalkyl is spiro[3.3]heptanyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, bicyclo[3.1.1]hept-2-en-2-yl.

[0072] The term "aliphatoxy" refers to a saturated or unsaturated aliphatic group or substituent, as defined above, that is connected to another structural moiety through an oxygen atom (-O-). 1~6 "-Aliphatic oxy" refers to an aliphatic oxy radical having 1, 2, 3, 4, 5, or 6 carbon atoms in the aliphatic group. The term "alkoxy" refers to a specific subgroup of saturated aliphatic oxy, i.e., alkyl substituents and residues that are connected to another structural moiety via an oxygen atom (-O-). Sometimes it is also referred to as "O-alkyl", more specifically "OC 1~2 -alkyl", "OC 1~3 -alkyl", "OC 1~4 -alkyl", "OC 1~6 -alkyl", "OC 1~8 Like similar alkyl groups, it may be straight chain or may be -O-C. 1~ Alkyl and -OC 2~ With the exception of alkyl - which may be branched and may be unsubstituted or substituted with 1, 2 or 3 substituents which may be the same or different, and unless otherwise specified elsewhere in this specification, is selected from the group including halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxy groups are methoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy.

[0073] The term "alkylene" refers to a divalent aliphatic group, especially a divalent alkyl group. An "alkylene chain" refers to a polymethylene group, i.e., -(CH 2 ) j -, where j is a positive integer, preferably 1, 2, 3, 4, 5, or 6. In the context of the present invention, "C 1~3 -alkylene" refers to one, two, and three -CH 2-group; 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 moiety, either linear, i.e., an alkylene chain, or branched, and having 1, 2, 3, 4, 5, or 6 carbon atoms. 2~6 -alkylene" refers to an alkylene moiety having 2, 3, 4, 5, or 6 carbon atoms, whereas "C 3~4 -alkylene" refers to an alkylene moiety having 3 or 4 carbon atoms, and "C 2~3 "-alkylene" refers to an alkylene moiety having two or three carbon atoms. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms have been replaced by (or with) a substituent. Suitable substituents include those described herein for substituted alkyl groups. In some cases, one or two methylene groups of the alkylene chain can be replaced by, illustratively, O, S, and / or NH, or NC. 1~4 An exemplary alkylene group is -CH 2 -, -CH 2 -CH 2 -, -CH 2 -CH 2 -CH 2 -CH 2 -, -O-CH 2 -CH 2 -, -O-CH 2 -CH 2 -CH 2 -, -CH 2 -O-CH 2 -CH 2 -, -O-CH 2 -O-, -O-CH 2 -CH 2 -O-, -O-CH 2 -CH 2 -CH 2 -O-, -CH 2 -NH-CH 2 -CH 2 -, -CH 2 -N(CH3 )-CH 2 -CH 2 -It is.

[0074] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced with a substituent. Suitable substituents include those described herein for substituted aliphatic groups. The term "alkenylene" refers not only to straight-chain divalent alkenylene radicals, i.e., alkenylene chains, but also to branched alkenylene groups. The term "C 2~6 "-alkenylene" refers to an alkenylene radical having 2, 3, 4, 5, or 6 carbon atoms.

[0075] 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 with a substituent. Suitable substituents include those described herein for substituted aliphatic groups.

[0076] The term "halogen" means F, Cl, Br, or I.

[0077] The term "heteroatom" means one or more of oxygen (O), sulfur (S), or nitrogen (N), and also includes any oxidized form of nitrogen or sulfur, such as N-oxide, sulfoxide, and sulfone; the quaternized form of any basic or substitutable nitrogen of a heterocyclic or heteroaromatic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB (as in N-substituted pyrrolidinyl), where SUB is a suitable substituent.

[0078] The term "aryl", used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic, bicyclic, and tricyclic ring systems having a total of 5 to 14 ring members (wherein the ring members are 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, 3), the electrons are delocalized throughout the system, and where each ring in the system contains 3 to 7 ring members. Preferably, all rings in an aryl system or the entire ring system are aromatic. The term "aryl" is used interchangeably with the term "aryl ring". In certain embodiments of the invention, "aryl" refers to an "aromatic ring system". More specifically, the aromatic ring systems may be mono-, bi-, or tricyclic, having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. Even more specifically, the aromatic ring systems may be monocyclic or bicyclic, having 6, 7, 8, 9, or 10 ring carbon atoms. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl, and the like, which may be unsubstituted or substituted with one or more of the same or different substituents. Also included within the scope of the term "aryl" or "aromatic ring system," as they are used herein, are groups of aromatic rings fused with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. In the latter case, the "aryl" group or substituent is attached to the pendant group via an aromatic portion of a ring system.

[0079] The term "benzo" refers to a six-membered aromatic ring (having carbon ring atoms) fused through two adjacent carbon atoms to another ring, which is a cycloaliphatic, aromatic, heteroaromatic, or heterocyclic (heteroaliphatic) ring; thus forming a ring system having 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, whereas when a benzo ring is fused with a pyridine, either a quinoline or an isoquinoline is provided; when a benzo ring is fused with a cyclopentene ring, an indene ring is provided.

[0080] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl" or "heteroaralkoxy", refer to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms (wherein the atoms are carbon atoms and heteroatoms), preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or 14 π (pi) electrons shared in a cyclic array; and having 1, 2, 3, 4, or 5 heteroatoms in addition to the carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. In other words, a "heteroaryl" ring or ring system (or a heteroaromatic ring or ring system) may also be described as an aromatic heterocycle. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazanyl, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, especially pyrrolo[2,3-b]pyridinyl. The terms "heteroaryl" and "heteroara-" as used herein also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is preferably on the heteroaromatic or, if present, aryl ring.Non-limiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazolyl, dibenzofuranyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. For example, an indolyl ring may be attached through one of the ring atoms of a 6-membered aryl ring or through one of the ring atoms of a 5-membered heteroaryl ring. Heteroaryl groups are optionally mono-, bi-, or tricyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," all of which terms include rings that are unsubstituted or substituted with one or more of the same or different substituents. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, where the alkyl and heteroaryl portions independently may be optionally substituted.

[0081] A heteroaryl ring can be attached to its pendant group at either a heterocyclic atom or a carbon ring atom, which attachment results in a stable structure or molecule; any of the ring atoms can be unsubstituted or substituted.

[0082] Exemplary structures of "heteroaryl" substituents as used herein are depicted below: [ka] [ka] [ka] [ka]

[0083] The heteroaryl substituents may be attached to any pendant group via any of the ring atoms thereof that are suitable for such attachment.

[0084] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable mono-, bi-, or tricyclic heterocyclic moiety 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 moiety is either saturated or partially unsaturated; heterocyclic moieties that are aromatic rings or ring systems are often referred to as "heteroaryl" moieties, as described herein above. Preferably, the heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic, or 7-, 8-, 9-, 10-, or 11-membered bicyclic, or 11-, 12-, 13-, or 14-membered tricyclic heterocyclic moiety.

[0085] When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1 to 3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen is N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or N-SUB (as in N-substituted pyrrolidinyl), where SUB is a suitable substituent.

[0086] In the context of the term "heterocycle", the term "saturated" refers to a fully saturated heterocyclic system, such as pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxotianyl. In relation to the term "heterocycle", the term "partially unsaturated" refers to (i) a heterocyclic system that contains one or more units of unsaturation (e.g., C=C or C=heteroatom bonds) but is not aromatic (e.g., tetrahydropyridinyl); or (ii) a heterocyclic system in which a (saturated or unsaturated, but not aromatic) heterocyclic ring is fused to an aromatic or heteroaromatic ring system, where the "partially unsaturated heterocycle" is attached to the rest of the molecule (its pendant group) through one of the ring atoms of the "heterocyclic" portion of the system, but not through the aromatic or heteroaromatic portion. This first class (i) of "partially unsaturated" heterocycles may also be referred to as "non-aromatic partially unsaturated" heterocycles. This second class (ii) of "partially unsaturated" heterocycles may also be referred to as (bicyclic or tricyclic) "partially aromatic" heterocycles, which indicates that at least one of the rings of the heterocycle is a saturated or unsaturated, but not aromatic, heterocycle fused to 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.

[0087] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms can be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydropyranyl, thianyl, dioxotianyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings (such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring). Heterocyclyl groups are optionally mono-, bi-, or tricyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, where the alkyl and heterocyclyl moieties are independently unsubstituted or substituted.

[0088] The term "bioisomer", when used alone or in combination with other terms (e.g., "bioisomer radical"), refers to a compound or group, radical, moiety, substituent, etc., which elicits the same biological effect as another compound, group, radical, moiety, or substituent, but which are structurally distinct from one another. In a broader sense, a "bioisomer" can be understood as a compound or group that possesses approximately the same molecular shape and molecular volume and approximately the same electron distribution, and exhibits similar physical properties. A typical example of a bioisoster is a carboxylic acid bioisoster that exhibits similar physicochemical properties as a carboxylic acid group ("carboxylic acid bioisoster"). When utilized in place of a carboxylic acid group or radical, such a carboxylic acid bioisoster group or radical thereby provides similar properties to a carboxyl group, but may potentially exhibit some different properties compared to the carboxylic acid group (e.g., reduced polarity, increased lipophilicity, or enhanced pharmacokinetic properties). Representative examples of carboxylic acid bioisosteres include, but are not limited to, -CN, fluoro, amide, sulfonamide, sulfonimide, and several aromatic and non-aromatic heterocycles such as hydroxy-substituted isoxazoles, sulfonamide-substituted oxadiazoles and oxo-oxadiazoles, e.g., 5-oxo-2,5-dihydro-1,2,4-oxadiazole, especially tetrazoles, e.g., 1H-1,2,3,4-tetrazole, 2-methyl-2H-1,2,3,4-tetrazole.

[0089] The term "unsaturated" as used herein means that a moiety or group or substituent has one or more units of unsaturation.

[0090] As used herein with reference to any ring, ring system, ring moiety, etc., the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to cover rings with multiple sites of unsaturation. In particular, it covers (i) unsaturated (mono-, bi-, or tricyclic) ring systems without any aromatic or heteroaromatic moieties or portions; and (ii) bi- or tricyclic ring systems in which one of the rings in the system is an aromatic or heteroaromatic ring fused to another ring that is neither aromatic nor heteroaromatic (e.g., tetrahydronaphthyl or tetrahydroquinolinyl). The first class (i) of "partially unsaturated" rings, ring systems and ring moieties are sometimes referred to as "non-aromatic partially unsaturated" rings, ring systems and ring moieties, whereas the second class (ii) is sometimes referred to as "partially aromatic" rings, ring systems and ring moieties.

[0091] As used herein, the term "bicyclic", "bicyclic ring", or "bicyclic ring system" refers to any bicyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation (i.e., partially unsaturated or aromatic), having one or more atoms in common between the two rings of the ring system. Thus, the term encompasses any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" which requires that one or more heteroatoms are present in one or both rings of the bicycle. Such heteroatoms may be present at ring junctions, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, and the like. In some embodiments, bicyclic groups have 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Similarly, the term "tricyclic", "tricyclic ring", or "tricyclic ring system" refers to any tricyclic ring system, i.e., carbocyclic or heterocyclic, saturated or having one or more units of unsaturation (i.e., partially unsaturated or aromatic), in which a bicyclic ring system (as defined above) is fused to another, third ring. Thus, the term encompasses any permissible ring fusions. As used herein, the term "heterotricyclic" is a subset of "tricyclic" requiring that one or more heteroatoms be present in one or both rings of the tricycle. Such heteroatoms may be present at ring junctions, may be optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In some embodiments, tricyclic groups have 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0092] As described herein, certain compounds of the invention contain "substituted" or "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the specified moiety are replaced with a suitable substituent. "Substituted" applies to one or more hydrogens from a structure, either explicitly or implicitly. Unless otherwise indicated, a "substituted" or "optionally substituted" group has a suitable substituent at each substitutable position of the group, and when more than one position in any given structure is substituted with more than one substituent selected from a particular group, the substituents are either the same or different at each position. When a group, a substituent, a moiety, or a radical is "monosubstituted", it has one (1) substituent. If it is "disubstituted", it has two (2) substituents that are either the same or different; if it is "trisubstituted", it has three (3) substituents, where all three are the same, or two are the same and the third is different, or all three are different from each other. The combinations of substituents envisioned by the present invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable", as used herein, refers to compounds that are substantially unchanged when subjected to conditions that allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0093] Unless otherwise specified anywhere in this specification or the appended claims, each optional substituent on a substitutable carbon is independently selected from halogen; -(CH 2 ) 0~4 R o ;-(CH 2 ) 0~4 OR o ;-O(CH 2 ) 0~4 R o , -O-(CH2 ) 0~4 C(O)OR o ;-(CH 2 ) 0~4 CH(OR o ) 2 ;-(CH 2 ) 0~4 S.R. o ;R 1 or more o Optionally substituted with -(CH 2 ) 0~4 Ph;1 or higher R o Optionally substituted with -(CH 2 ) 0~4 O(CH 2 ) 0~1 Ph;1 or higher R o -CH=CHPh, optionally substituted with one or more R o Optionally substituted with -(CH 2 ) 0~4 O(CH 2 ) 0~1 -Pyridyl; -NO 2 ;-CN;-N 3 ;-(CH 2 ) 0~4 N(R o ) 2 ;-(CH 2 ) 0~4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH 2 ) 0~4 N(R o )C(O)NR o 2 ;-N(R o )C(S)NR o 2 ;-(CH 2 ) 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(Ro )C(O)OR o ;-(CH 2 ) 0~4 C(O)R o ;-C(S)R o ;-(CH 2 ) 0~4 C(O)OR o ;-(CH 2 ) 0~4 C(O)SR o ;-(CH 2 ) 0~4 C(O)OSiR o 3 ;-(CH 2 ) 0~4 OC(O)R o ;-OC(O)(CH 2 ) 0~4 SR-、SC(S)SR o ;-(CH 2 ) 0~4 SC(O)R o ;-(CH 2 ) 0~4 C(O)NR o 2 ;-C(S)NR o 2 ;-C(S)SR o ;-SC(S)SR o 、-(CH 2 ) 0~4 OC(O)NR o 2 ;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH 2 C(O)R o ;-C(NOR o )R o ;-(CH 2 ) 0~4 SSR o ;-(CH 2 ) 0~4 S(O) 2 R o ;-(CH 2 ) 0~4 S(O) 2 OR o ;-(CH 2 ) 0~4 OS(O) 2 Ro ;-S(O) 2 NR o 2 ;-S(O)(NR o )R o ;-S(O) 2 N=C(NR o 2 ) 2 ;-(CH 2 ) 0~4 S(O)R o ;-N(R o )S(O) 2 NR o 2 ;-N(R o )S(O) 2 R o ;-N(OR o )R o ;-C(NH)NR o 2 ;-P(O) 2 R o ;-P(O)R o 2 ;-OP(O)R o 2 ;-OP(O)(OR o ) 2 ;SiR o 3 ;-(C 1~4 Linear or branched alkylene)ON(R o ) 2 ; or -(C 1~4 Linear or branched alkylene)C(O)ON(R o ) 2 "Ph" means phenyl; and "-(CH 2 ) 0~4 " means that there is no alkylene group when the subscript is "0" (zero), or that there are 1, 2, 3, or 4 CH 2 It is understood that this means an alkylene group having a unit.

[0094] Each R o are independently hydrogen, halogen, C 1~6 Aliphatic, -CH 2 Ph, -O(CH 2 )0~1 Ph, -CH 2 -(a 5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or, notwithstanding the above definition, independently occurring 2 R o R taken together with their intervening atom(s) form a 3-12 membered saturated, partially unsaturated, or aryl, monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, selected from =O and =S. o or each R o are independently halogen, -(CH 2 ) 0~2 R ● , -(Halo R ● ), -(CH 2 ) 0~2 OH, -(CH 2 ) 0~2 OR ● , -(CH 2 ) 0~2 CH(OR ● ) 2 ;-O(Halo R ● ), -CN, -N 3 , -(CH 2 ) 0~2 C(O)R ● , -(CH 2 ) 0~2 C(O)OH, -(CH 2 ) 0~2 C(O)OR ● , -(CH 2 ) 0~2 S.R. ● , -(CH 2 ) 0~2 SH, -(CH 2 ) 0~2 NH 2 , -(CH 2 ) 0~2 NHR ● , -(CH 2 ) 0~2 NR ● 2 , -NO2 , -SiR ● 3 , -OSiR ● 3 , -C(O)SR ● , -(C 1~4 Linear or branched alkylene)C(O)OR ● , or -SSR ● "Ph" means phenyl; "halo" means halogen; and "-(CH 2 ) 0~2 " means that there is no alkylene group when the subscript is "0" (zero), or there are one or two CH 2 It is understood that this means an alkylene group having a unit.

[0095] Each R ● is independently 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, where each R l is unsubstituted or, if preceded by halo, substituted only with one or more halogens; or, where any substituents on the saturated carbon are independently selected from =O, =S, =NNR * 2 , =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O) 2 R * , =NR * , =NOR * , -O(C(R * 2 )) 2~3 O- or -S(C(R * 2 )) 2~3 S- or a divalent substituent attached to an adjacent substitutable carbon of an "optionally substituted" group is -O(CR *2 ) 2~3 O-, wherein each R * is hydrogen, C 1~6 aliphatic, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur).

[0096] R * C 1~6 If aliphatic, R * is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR l , -NR ● 2 , or -NO 2 where each R ● is independently 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ● is unsubstituted or, if preceded by halo, substituted only with one or more halogens.

[0097] The optional substituents on a substitutable nitrogen are independently -R † , -NR † 2 , -C(O)R † , -C(O)OR † , -C(O)C(O)R † , -C(O)CH 2 C(O)R † , -S(O) 2 R † , -S(O) 2 NR † 2, -C(S)NR † 2 , -C(NH)NR † 2 , or -N(R † )S(O) 2 R † where each R † are independently hydrogen, C 1~6 an aliphatic, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated, partially unsaturated, or aryl ring (having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur), or two independently occurring R † together with their intervening atom(s) form an unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; † C 1~6 When it is aliphatic, R † is halogen, -R ● , -(Halo R ● ), -OH, -OR ● , -O(HaloR ● ), -CN, -C(O)OH, -C(O)OR ● , -NH 2 , -NHR ● , -NR ● 2 , or -NO 2 where each R ● is independently 1~4 Aliphatic, -CH 2 Ph, -O(CH 2 ) 0~1 or a 5-6 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, and wherein each R ● is unsubstituted or, when preceded by halo, is substituted only with one or more halogens. "Ph" means phenyl; and "halo" is understood to mean halogen.

[0098] The term "solvate" refers to the addition form of the compound of the present invention with a solvent, preferably with a pharma- ceutically acceptable solvent containing either stoichiometric or non-stoichiometric amount of the solvent. Some compounds have the tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. When the solvent is water, the solvate formed is a hydrate, for example a hemi-, mono-, or dihydrate. When the solvent is alcohol, the solvate formed is an alcoholate, for example a methanolate or an ethanolate. When the solvent is ether, the solvate formed is an etherate, for example a diethyl etherate.

[0099] The term "N-oxide" refers to those compounds of the invention that contain an amine oxide moiety, i.e., an oxide of a tertiary amine group.

[0100] The compounds of formula I may - depending also on the nature of the substituents they may carry - have one or more centers of chirality. They may consequently give rise to various enantiomeric and diastereomeric forms, as the case may be, and be, racemic or optically active forms. The invention therefore also relates to the optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in any ratio, collectively: for the purposes of the invention also referred to as "stereoisomers" of these compounds. While the pharmaceutical activity of the racemates or stereoisomers of the compounds according to the invention may differ, it may be desirable to use a particular stereoisomer, for example one particular enantiomer or diastereomer. In these cases, the compounds according to the invention obtained as racemates - or even intermediates thereof - may be separated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical means known to the skilled artisan. Another approach that may be applied to obtain one or more specific stereoisomers of the compounds of the invention in enriched or pure form is to use stereoselective synthetic procedures, for example by applying starting materials in stereoisomerically enriched or pure form (illustratively using pure or enriched (R)- or (S)-enantiomers of specific starting materials with chiral centers), or by utilizing chiral reagents or catalysts, especially enzymes. In the context of the present invention, the term "pure enantiomer" refers mostly to a relative purity of one enantiomer with respect to the other enantiomer (its antipode) equal to or greater than 95%, preferably ≧98%, more preferably ≧98.5%, even more preferably ≧99%.

[0101] Thus, for example, compounds of the invention which have one or more centers of chirality and which exist as racemates or as mixtures of enantiomers or diastereomers can be fractionated or resolved into their optically pure or enriched isomers, i.e. enantiomers or diastereomers, by methods known per se. The separation of the compounds of the invention can be carried out by chromatographic methods, for example by column separation on chiral or non-chiral phases, or by recrystallization from any optically active solvent, or by the use of optically active acids or bases, or by derivatization with an optically active reagent, such as, for example, an optically active alcohol, followed by elimination of the radical.

[0102] In the context of the present invention, the term "tautomer" refers to compounds of the present invention that may exist in tautomeric forms and may exhibit tautomerism; for example, carbonyl compounds may exist in their keto and / or their enol forms and may exhibit keto-enol tautomerism. These tautomers may exist in their individual forms, for example, in the keto or enol forms, or as mixtures thereof, and are claimed individually and together as mixtures in all ratios. The same applies to cis / trans isomers, E / Z isomers, conformers, etc.

[0103] In one embodiment, the compounds of the invention are in the form of a free base or acid - as the case may be - i.e. in their non-salt (or salt-free) form. In another embodiment, the compounds of the invention are in the form of a pharma- ceutically acceptable salt, a pharma-ceutically acceptable solvate, or a pharma-ceutically acceptable solvate of a pharma-ceutically acceptable salt.

[0104] The term "pharmaceutical acceptable salt" refers to a salt prepared from a pharmaceutical acceptable base or acid, including inorganic bases or acids and organic bases or acids. In the case where the compound of the present invention contains one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutical acceptable salts. Thus, the compound of the present invention containing an acidic group, such as a carboxyl group, can exist in the form of a salt and can be used according to the present invention, for example, as an alkali metal salt, an alkaline earth metal salt, an aluminum salt, or as an ammonium salt. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with ammonia, or with organic amines, such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids. These salts can be easily obtained by reacting the compound having an acidic group with a suitable base, for example, 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 invention include, but are not limited to, copper(I), copper(II), iron(II), iron(III), manganese(II), and zinc salts. Compounds of the invention that contain one or more basic groups, such as groups that can be protonated, can exist in the form of salts and can be used in accordance with the invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids include hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, 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 are, among others, hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), tosylate, carbonate, bicarbonate, formate, acetate, sulfoacetate, triflate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutaric acid, stearate, aspartate, and glutamate. Moreover, 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.

[0105] The compounds of the invention that contain a basic nitrogen-containing group are (C 1 ~C 4 ) alkyl halides, such as methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides; di(C 1 ~C 4 ) 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; and aryl (C 1 ~C 4 ) alkyl halides, for example, benzyl chloride and phenethyl bromide, and other such agents. Both water- and oil-soluble compounds according to the invention can be prepared using such salts.

[0106] In the case where the compounds of the invention contain acidic and basic groups simultaneously in the molecule, the invention also includes, in addition to the salt forms mentioned, internal salts or betaines (zwitterions). The respective salts can be obtained by conventional methods known to those skilled in the art, for example by contacting them in a solvent or dispersant with an organic or inorganic acid or base, or by anion or cation exchange with other salts. The invention also includes all salts of the compounds of the invention which are not directly suitable for use in medicines due to their low physiological compatibility, but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0107] Thus, the following items are also in accordance with the invention: (a) all stereoisomers or tautomers of the compound, including mixtures thereof in all proportions; (b) Pharmaceutically acceptable salts of compounds, as well as pharmaceutically acceptable salts of the items referred to under (a); (c) Pharmaceutically acceptable solvates of the compounds, and pharma- ceutically acceptable solvates of the items referred to under (a) and (b); (d) N-oxides of compounds and N-oxides of items referred to under (a), (b), and (c).

[0108] It should be understood that all references hereinbefore to compounds are intended to encompass those items, particularly pharma- ceutically acceptable solvates of the compounds, or pharma- ceutically acceptable salts thereof.

[0109] Furthermore, the compounds of the present invention are intended to include isotopically labeled forms thereof. Isotopically labeled forms of the compounds of formula I are identical to the compounds except for the fact that one or more atoms of the compounds are replaced by an atom or atoms having an atomic mass or mass number different from the atomic mass or mass number of most naturally occurring atoms. Examples of isotopes that are readily commercially 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, e.g., 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 36 CI, respectively. Compounds of Formula I, or pharma- ceutically acceptable salts thereof, that contain one or more of the above-mentioned isotopes and / or other isotopes of other atoms are intended to be part of the present invention. Isotopically labeled compounds of Formula I can be used in a number of beneficial ways. For example, 3 H or 14 Isotopically labeled compounds of the present invention incorporating radioactive isotopes such as C are suitable for drug and / or substrate tissue distribution assays. 3 H) and carbon-14 ( 14 C is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes (e.g., deuterium ( 2Incorporation of H) into compounds of formula I has therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability translates directly into increased in vivo half-life or lower dosage, which will represent a preferred embodiment of the present invention under most circumstances. Isotopically labeled compounds of formula I can be prepared by carrying out the procedures disclosed in the synthetic schemes and related descriptions herein, in the Examples section, and in the Preparation section, replacing non-isotopically labeled reactants with readily available isotopically labeled reactants.

[0110] deuterium( 2 H;D) can also be incorporated into compounds of formula I for the purpose of manipulating the oxidative metabolism of the compound through the primary kinetic isotope effect. The primary kinetic isotope effect is the change in the rate of a chemical reaction due to the exchange of an isotope nucleus, which is caused secondarily by the change in the ground state energy required for covalent bond formation after this isotope exchange. The exchange of a heavier isotope usually results in a lowering of the ground state energy for a chemical bond, which in turn causes a reduction in the rate at which the rate-limiting bond breakage occurs. If the bond breakage occurs in or near a saddle point region along the coordinate of a multi-product reaction, the product distribution ratio can be substantially altered. To illustrate: if deuterium is attached to a carbon atom at a position that cannot be exchanged, k M / k D A rate difference of 2-7 is typical. If this rate difference is successfully applied to an oxidation-prone compound of formula I, the in vivo profile of the compound can be dramatically altered, resulting in improved pharmacokinetic properties.

[0111] When discovering and developing therapeutic agents, those skilled in the art attempt to optimize pharmacokinetic parameters while retaining 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 microsomal assays provide valuable information about the course of this type of oxidative metabolism, which in turn allows for the rational design of deuterated compounds of formula I with improved stability through resistance to such oxidative metabolism. Significant improvements in the pharmacokinetic profile of compounds of formula I are thereby obtained, improving in vivo half-life (t1 / 2), concentration at maximum therapeutic effect (C max ), area under the dose-response curve (AUC), and F; and quantitatively in terms of reduced clearance, dose, and material cost.

[0112] The following is intended to illustrate what has been described above: A compound represented by formula I, which has multiple potential attack sites for oxidative metabolism (e.g., benzylic hydrogen atoms and hydrogen atoms attached to nitrogen atoms), is prepared as a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms (so that some, most, or all of these hydrogen atoms can be replaced by deuterium atoms). Determination of the half-life allows a good and accurate determination of the extent to which the resistance to oxidative metabolism has been improved. In this way, 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.

[0113] Deuterium-hydrogen exchange in the compounds of the invention can also be used to achieve favorable modification of the metabolic spectrum of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite arises through oxidative carbon-hydrogen (CH) bond cleavage, it can be reasonably assumed that a deuterated analog would greatly reduce or eliminate the production of the unwanted metabolite, even if the specific oxidation is not the rate-limiting step. Further state of the art information on deuterium-hydrogen exchange may be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al. Carcinogenesis 16(4), 683-688, 1995.

[0114] Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound of formula I, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable salt of each of the above, including mixtures thereof in any ratio, as an active ingredient, together with a pharma- ceutically acceptable carrier.

[0115] For the purposes of the present invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") refers to a composition or product that includes one or more active ingredients and one or more inactive ingredients that constitute the carrier, as well as any product that results directly or indirectly from the combination, complexation, or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from any other type of reaction or interaction of one or more of the ingredients. Consequently, the pharmaceutical composition of the present invention encompasses any composition made by mixing at least one compound of the present invention with a pharmaceutically acceptable carrier. It may further include pharmaceutically acceptable excipients, auxiliaries, adjuvants, diluents, and / or additional pharmaceutically active substances other than the compound of the present invention.

[0116] Pharmaceutical compositions include compositions and pharmaceutical formulations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (eye drops), pulmonary (inhalation through the nose or mouth), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the condition being treated and on the nature of the active ingredient. These may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the pharmaceutical art.

[0117] The pharmaceutical composition of the present invention may additionally contain one or more other compounds as active ingredients (drugs), such as one or more additional compounds of the present invention. In a specific embodiment, the pharmaceutical composition further comprises a second active ingredient, or its derivatives, prodrugs, solvates, tautomers, or stereoisomers, and pharma- ceutically acceptable salts of each of the above, including mixtures thereof in any ratio, where the second active ingredient is other than the compound represented by formula I; preferably, the second active ingredient is a compound for which the compounds of the present invention are also useful and which are useful for treating, preventing, inhibiting, and / or ameliorating a disease state 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 of the drugs or active ingredients alone, or the combination is safer or more effective than would be expected based on the additivity of the individual drugs. Such other drug(s) may be administered contemporaneously or sequentially with the compounds of the present invention by a commonly used route and in the amounts thereof. 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 drug(s) and the compound of the present invention, also referred to as a "fixed dose combination", is preferred. However, combination therapy also includes therapy in which the compound of the present invention and one or more other drugs are administered on different overlapping schedules. It is contemplated that when used in combination with other active ingredients, the compound of the present invention or the other active ingredient, or both, may be effectively used at lower doses than when each is used alone. Accordingly, the pharmaceutical composition of the present invention also includes those that contain one or more other active ingredients in addition to the compound of the present invention.

[0118] The compounds of the present invention - or their N-oxides, solvates, tautomers, or stereoisomers, and / or pharma- ceutically acceptable salts of each of the above, and mixtures thereof in any ratio - can be used as medicines. They have been found to exhibit pharmacological activity by binding to TEAD and / or by interfering with and / or inhibiting YAP-TEAD and / or TAZ-TEAD protein-protein interactions. It is assumed that, through this activity, the compounds of the present invention can prevent or reverse the dysfunction of the Hippo pathway. By preventing its dysfunction, the Hippo pathway may be able to play its role as a tumor suppressor. Apart from preventing or reversing the dysfunction of the Hippo pathway and independent of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention may also be useful in other pathophysiological scenarios in which inhibition or disruption of TEAD binding and / or aberrant YAP-TEAD and / or aberrant TAZ-TEAD signaling would be beneficial.

[0119] Thus, the compounds of the present invention that are TEAD binders and / or inhibitors of YAP-TEAD and / or TAZ-TEAD interactions are particularly useful for treating, preventing, suppressing, and / or ameliorating hyperproliferative disorders and cancers, particularly tumors including solid tumors of breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, basal cell carcinoma. Without wishing to subscribe to any particular theory or explanation, it can be assumed that the compounds can achieve this by direct effects on cancer cells and / or indirectly by modulating the immune system's response to tumors. Furthermore, the compounds of the present invention may also be useful for treating, preventing, suppressing, and / or ameliorating non-cancerous disorders and diseases, such as cardiovascular disease and fibrosis (such as liver fibrosis).

[0120] In a particular embodiment, the compounds of the invention are for use in the prevention and / or treatment, in particular of any of the disorders or diseases listed above, preferably of cancer, in particular of tumors including solid tumors, of the specific types of cancer disclosed in the preceding paragraph; or in the treatment of any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0121] Another specific embodiment of the present invention is a method for preventing and / or treating, preferably treating, a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, especially tumors including solid tumors, or of the specific types of cancer disclosed in the preceding paragraph; or of any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0122] Yet another specific embodiment of the present invention is the use of a compound of the present invention - or a derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof, and / or a pharma- ceutically acceptable salt of each of the above, as well as mixtures thereof in any ratio - for the manufacture of a medicament, especially for preventing and / or treating, preferably treating, a disorder or disease selected from the group consisting of hyperproliferative disorders and cancer, especially tumors including solid tumors, or of the specific types of cancer disclosed in the preceding paragraph; or of any of the non-cancerous disorders or diseases disclosed in the preceding paragraph.

[0123] Preferably, the present invention relates to a compound of the present invention for use in the prevention and / or treatment of a disease - or, alternatively, to a method for preventing and / or treating a disease by administering an effective amount of a compound of the present invention; or, in another alternative, to the use of a compound of the present invention for the manufacture of a medicament for the prevention and / or treatment of a disease, wherein the disease is cancer, in particular tumors including solid tumors of the specific types of cancer disclosed in the previous paragraph; more preferably, wherein the administration of the compound is simultaneous, sequential or alternating with the administration of at least one other active agent.

[0124] The disclosed compounds of the present invention, particularly those represented by formula I, may be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" refers to any agent administered to a cancer patient for the purpose of treating cancer. The anti-cancer treatment defined above may be applied as a single agent therapy, or may involve, in addition to the compounds of the present invention disclosed herein, conventional surgery or radiation therapy or medicinal therapy. Such medicinal therapy (e.g., chemotherapy or targeted therapy) may include one or more of the following anti-tumor agents, but preferably one of them:

[0125] Alkylating Agents Altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dacarbazine, ifosfamide, improsulfan, tosilate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, treosulfan, mechlorethamine, carboquone; apaziquone, fotemustine, glufosfamide, palifosfamide, pipobroman, trofosfamide, uramustine, evofosamide, VAL-083 [4] etc;

[0126] platinum compound Carboplatin, cisplatin, eptaplatin, miriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin, etc.; DNA modifying agents Amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine; Amsacrine, Brostallicin, Pixantrone, Laromustine [1],[3] etc;

[0127] Topoisomerase inhibitors etoposide, irinotecan, razoxane, sobuzoxane, teniposide, topotecan; Ammonafide, Belotecan, Elliptinium acetate, Boreloxin, etc.; microtubule modifier Cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinplastine, vincristine, vinorelbine, vindesine, vinflunine; fosbretabine, tesetaxel, etc.;

[0128] anti-metabolite Asparaginase [3] , azacitidine, levofolinate calcium, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mercaptopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacitabine, raltitrexed, cepacitabine, tegafur [2],[3] , trimethotrexate, etc.;

[0129] Anticancer antibiotics Bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosine, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunorubicin, plicamycin; aclarubicin, peplomycin, pirarubicin, etc.;

[0130] Hormones / antagonists Abarelix, abiraterone, bicalutamide, buserelin, calcineurone, chlorotonianisene, degarelix, dexamethasone, estradiol, flutocortolone, fluoxymesterone, flutamide, fulvestrant, goserelin, histrelin, leuprorelin, megestrol, mitotane, nafarelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane, triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide [1],[3] etc;

[0131] Aromatase inhibitors Aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane, etc.;

[0132] Small Molecule Kinase Inhibitors Crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib; afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzas Taurine, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midostaurin, motesanib, neratinib, orantinib, perifosine, ponatinib, radotinib, rigosertib, tepotinib, tipifanib, tivantinib, tivozanib, trametinib, pimasertib, brivanib alaninate, cediranib, apatinib [4] , Cabozantinib S-malate [1],[3] , ibrutinib [1],[3] , Icotinib [4] , buparlisib [2] , cipatinib [4] , cobimetinib [1],[3] , idelalisiv [1],[3] , fedratinib [1] , tesevatinib, etc.;

[0133] Photosensitizers Methoxsalen [3] ;Polyfimer sodium, talaporfin, temoporfin, etc.; antibody Alemtuzumab, besilesomab, brentuximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, bevacizumab, pertuzumab [2],[3] ; Catumaxomab, elotuzumab, epratuzumab, farletuzumab, mogamulizumab, necitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregovomab, ramucirumab, rilotumumab, siltuximab, tocilizumab, zalutumumab, zanolimumab, matuzumab, dalotuzumab [1],[2],[3] , Onartuzumab [1],[3] , racotumomab [1] , tabalumab [1],[3] , EMD-525797 [4] , atezolizumab, durvalumab, pembrolizumab, nivolumab [1],[3] etc;

[0134] Cytokines Aldesleukin, Interferon Alpha 2, Interferon Alpha 2a [3] , interferon alpha 2b [2],[3] ; Celmoleukin, tasonermin, teseleukin, operelvekin [1],[3] , recombinant interferon beta-1a [4] etc; Drug Conjugates Denileukin diftitox, ibritumomab tiuxetan, iobenguane I123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; syntredekin besudotox, edotreotide, inotuzumab ozogamicin, naptumomab estafenatox, oportuzumab monatox, technitium (99mTc) arcitumomab [1],[3] , Vintaforid [1],[3] etc;

[0135] vaccine Sipuleucel [3] ; Bitespen [3] , emepepimut-S [3] , OncoVAX [4] , Lindopepimut [3] , troVax [4] , MGN-1601 [4] , MGN-1703 [4] etc; others Alitretinoin, bexarotene, bortezomib, everolimus, ibandronate, imiquimod, lenalidomide, lentinan, metyrosine, mifamurtide, pamidronate, pegaspargase, pentostatin, sipuleucel [3] , sizofiran, tamibarotene, temsirolimus, thalidomide, tretinoin, vismodegib, zoledronic acid, vorinostat; celecoxib, cilengitide, entinostat, etanidazole, ganetespib, idronoxyl, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, peretinoin, plitidepsin, pomalidomide, procodazol, ridaforolimus, tasquinimod, telotristat, simalfasin, tirapazamine, tosedostat, travedersen, ubenimex, valspodar, and gendicine [4] , Picibanil [4] , Leolysin [4] , Retaspimycin hydrochloride [1],[3] , Trebananib [2],[3], bilirudin [4] , carfilzomib [1],[3] , endostatin [4] , Immucothel [4] , Belinostat [3] ;

[0136] PARP inhibitors Olaparib, veliparib. MCT1 inhibitors AZD3965 [4] , BAY-8002 [4] . [1] Prop. INN (Proposed International Nonproprietary Name) [2] Rec. INN (Recommended International Nonproprietary Names) [3] USAN (United States Adopted Name) [4] No INN.

[0137] In another aspect of the invention, there is provided a set or kit comprising a therapeutically effective amount of at least one compound of the invention and / or at least one pharmaceutical composition as described herein, and a therapeutically effective amount of at least one further pharmacologically active substance other than a compound of the invention. The set or kit comprises: a) an effective amount of a compound of formula I, or any of its N-oxides, solvates, tautomers, or stereoisomers, as well as physiologically acceptable salts of each of the foregoing, including mixtures thereof in all ratios; and b) an effective amount of a further active ingredient, which is not a compound of formula I; It is preferred that the package includes separate packs of:

[0138] A further aspect of the invention is a process for the preparation of a pharmaceutical composition according to the invention, characterized in that one or more compounds according to the invention and one or more compounds selected from the group consisting of solid, liquid or semi-liquid excipients, auxiliaries, adjuvants, diluents, carriers and pharma- ceutical active agents other than the compounds according to the invention are converted into a suitable dosage form.

[0139] The pharmaceutical compositions (formulations) of the present invention may be administered by any means that achieve their intended purpose. For example, administration may be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intraarticular, intrathecal, tracheal, ocular, subcutaneous, intraperitoneal, transdermal, or buccal routes. Alternatively, or in parallel, administration may be via oral route. The dosage administered will depend on the age, health, and weight of the recipient, the type of current treatment (if any), the frequency of treatment, and the nature of the effect desired. Parenteral administration is preferred. Oral administration is particularly preferred.

[0140] Suitable dosage forms include, but are not limited to, capsules, tablets, pellets, dragees, semisolids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injections, poultices, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, emulsions, which can be produced according to methods known in the art, for example, as described below: Tablets: The active ingredient(s) are mixed with the auxiliaries and the mixture is compressed into tablets (direct compression), optionally granulating a portion of the mixture before compression.

[0141] Capsules: Mix the active ingredient(s) with the auxiliaries to obtain a free-flowing powder, optionally granulate the powder, fill the powder / granules into open capsules and cap the capsules.

[0142] Semisolids (ointments, gels, creams): The active ingredient(s) is dissolved / dispersed in an aqueous or fatty carrier; this is followed by mixing the aqueous / fatty phase with a complementary fatty / aqueous phase and homogenization (creams only).

[0143] Suppositories (rectal and vaginal): The active ingredient(s) is dissolved / dispersed in a carrier material that has been liquefied by heating (rectal: the carrier material is usually a wax; vaginal: the carrier is usually a heated solution of a gelling agent), the mixture is molded into a suppository form, and the suppository is removed from the annealing mold.

[0144] Aerosol: The active ingredient(s) is dissolved / dispersed in a propellant and the mixture is loaded into an nebulizer.

[0145] In general, the non-chemical route for the production of pharmaceutical compositions and / or pharmaceutical preparations comprises a processing step by suitable mechanical means known in the art to convert one or more compounds of the present invention into a dosage form suitable for administration to a patient in need of such treatment. Usually, converting one or more compounds of the present invention into such a dosage form comprises the addition of one or more compounds selected from the group consisting of carriers, excipients, auxiliaries, and pharmacoactive ingredients other than the compounds of the present invention. Suitable processing steps include, but are not limited to, combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, molding, and / or compressing the active and non-active ingredients, respectively. Mechanical means for carrying out said processing steps are known in the art, for example from Ullmann's Encyclopedia of Industrial Chemistry, 5th Edition. In this respect, 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 pharmacoactive agents disclosed herein other than the compounds of the present invention.

[0146] Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, also suspensions, emulsions or implants, suitable for topical use are ointments, creams or powders. The compounds of the invention may also be lyophilised and the resulting lyophilisates are used, for example, for the preparation of injectable preparations. The indicated preparations may be sterilised and / or may contain lubricants, preservatives, stabilisers and / or wetting agents, emulsifiers, salts for modifying the osmotic pressure, buffer substances, dyes, flavours and / or several further active ingredients, for example assistants such as one or more vitamins.

[0147] Suitable excipients are organic or inorganic substances suitable for enteral (e.g. oral), parenteral or topical administration, which do not react with the compounds of the invention, such as water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol, or starches (corn starch, wheat starch, rice starch, potato starch), cellulose preparations, and / or calcium phosphates, such as calcium triphosphate or calcium hydrogen phosphate, magnesium stearate, talc, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or vaseline.

[0148] If desired, disintegrants may be added to the above-mentioned starches, such 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. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To produce a coating that is resistant to gastric juices or to provide a dosage form that offers the advantage of sustained action, tablets, dragees, or pills can contain an inner dosage and an outer dosage component, the latter in the form of an envelope covering the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids, and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, solutions of suitable cellulose preparations (such as acetyl-cellulose phthalate, cellulose acetate, or hydroxypropylmethyl-cellulose phthalate, etc.). Dyes or pigments can be added to the tablets or dragee coatings, for example, for identification or to characterize combinations of active compound doses.

[0149] Suitable carrier materials are organic or inorganic materials suitable for enteral administration (for example, oral administration) or parenteral administration or topical application and do not react with the new compounds, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (such as lactose or starch), magnesium stearate, talc, and petroleum jelly.In particular, tablets, coated tablets, capsules, syrups, suspensions, drops, or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, and also suspensions, emulsions, or implants are used for parenteral administration, and ointments, creams, or powders are used for topical application.The compounds of the present invention can also be lyophilized, and the resulting lyophilizates can be used, for example, for the production of injection preparations.

[0150] Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers (such as glycerol or sorbitol). Push-fit capsules may contain the active compound in the form of granules, which may be mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid, such as fatty oils, or liquid paraffin. In addition, stabilizers may also be added.

[0151] 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 oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums, such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone, or gelatin.

[0152] Suitable formulations for parenteral administration include aqueous solutions of active compounds in water-soluble form, such as water-soluble salts and alkaline solutions.In addition, suspensions of active compounds as suitable oily injection suspensions can also be administered.Suitable lipophilic solvents or vehicles include fatty oils (such as sesame oil), or synthetic fatty acid esters, such as ethyl oleate or triglycerides or polyethylene glycol-400 (this compound is soluble in PEG-400).

[0153] Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and / or dextran; optionally the suspension may also contain stabilizers.

[0154] For administration as an inhalation spray, the active ingredient is mixed with a propellant gas or propellant gas mixture (e.g., CO 2 Sprays in which the active ingredient is either dissolved or suspended in a fluorocarbon or chlorofluorocarbon can be used. The active ingredient is advantageously used here in finely divided form, in which case one or more additional physiologically acceptable solvents, for example ethanol, may be present. Inhalation solutions can be administered with the aid of conventional inhalers.

[0155] The practicable pharmaceutical preparations that can be used rectally include, for example, suppositories that are composed of one or more active compounds combined with suppository bases.Suitable suppository bases are, for example, natural or synthetic triglycerides or paraffin hydrocarbons.In addition, it is also practicable to use gelatin rectal capsules that are composed of active compounds combined with bases.Practicable bases include, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.

[0156] The pharmaceutical preparations may be employed as human medicines and veterinary medicines. As used herein, the term "effective amount" refers to an amount of a drug or pharmaceutical agent that will elicit a biological or medical response in a tissue, system, animal, or human (which is illustratively sought by a researcher or clinician). Furthermore, the term also includes within its scope a "therapeutically effective amount," which refers to any amount that results in improved treatment, cure, prevention, or amelioration 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 not receiving such amount; it may also refer to preventing or providing a prophylactic method for a disease or disorder in a subject having or at risk of developing a disease disclosed herein. The term also includes within its scope an amount effective to enhance normal physiological function. The therapeutically effective amount of one or more of the compounds of the present invention will be known to those skilled in the art or can be readily determined by standard methods known in the art.

[0157] "Treating" or "treatment" as used herein means alleviating all or part of the symptoms associated with a disorder or disease, or slowing or halting the further progression or worsening of those symptoms, or preventing or prophylactically preventing a disease or disorder in a subject at risk of developing the disease or disorder.

[0158] The compound of the present invention and any additional active substances are generally administered similarly to commercial preparations.The suitable dose that is usually therapeutically effective is between 0.0005mg and 1000mg, preferably between 0.005mg and 500mg, particularly between 0.5mg and 100mg per dosage unit.The daily dose is preferably between about 0.001mg / kg body weight and about 10mg / kg body weight.

[0159] Those skilled in the art will readily understand that dosage levels may vary depending on the specific compound, the severity of symptoms, and the subject's susceptibility to side effects. Some specific compounds are more potent than others. The preferred dosage for a given compound can be readily determined by those skilled in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

[0160] However, the specific dose for an individual patient, and in particular for an individual human patient, depends on numerous factors, such as the potency of the specific compound employed, age, body weight, general state of health, sex, type of diet, time and route of administration, excretion rate, type of administration and dosage form administered, pharmaceutical combination, and the severity of the specific disorder for which the treatment is concerned. The specific therapeutically effective dose for an individual patient can be readily determined by routine experimentation, for example by the physician or doctor advising or participating in the therapeutic treatment.

[0161] The compounds of the present invention can be prepared by using the appropriate materials according to the procedures of the following schemes and examples, as further illustrated by the following specific examples. They can also be prepared by methods known per se, or precisely under reaction conditions known and suitable for the reaction, as described in the literature (e.g., in standard works such as Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York). Variants known per se, but not mentioned here in more detail, can also be used.

[0162] Likewise, the starting materials for the preparation of the compounds of the invention can be prepared by methods as described in the examples or by methods known per se, as described in the literature of synthetic organic chemistry and known to those skilled in the art, or can be obtained commercially. The starting materials for the claimed and / or utilized processes can also be formed in situ, if desired, not by isolating them from the reaction mixture, but instead by immediately converting them to further compounds of the invention or intermediate compounds. On the other hand, in general, the reactions can also be carried out stepwise.

[0163] It will be recognized by those skilled in the art that some of the compounds of formula I may serve as starting materials for making other compounds of formula I. By way of illustration, compounds of formula I bearing a carboxyl functionality may be readily converted to related compounds of formula I bearing an amide functionality by utilizing appropriate synthetic methods.

[0164] Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether, or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethylsulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents or mixtures with water.

[0165] The reaction temperature is between about -100°C and 300°C, depending on the reaction steps and conditions used.

[0166] The reaction time generally ranges between a few minutes and several days, depending on the reactivity of each compound and the respective reaction conditions.Suitable reaction times can be easily determined by methods known in the art, such as reaction monitoring.Based on the reaction temperature given above, suitable reaction times generally range between 10 minutes and 48 hours.

[0167] Moreover, by utilizing the procedures described herein in conjunction with ordinary skill in the art, additional compounds of the present invention claimed herein can be easily prepared. However, the compounds described in the examples should not be construed as forming the only genus considered as the present invention. The examples further explain 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.

[0168] The present invention also relates to processes for the preparation of compounds of formula I in their most general form, as well as to the specific embodiments described herein, PE1, PE1a, PE1aa, PE1ab, PE2, PE2a, PE2aa, PE2b, PE2ba, PE2baa, PE3, PE3a, PE3b, PE3c, PE4, PE4a, PE4aa, PE4b, PE4c, PE5, PE5a, PE5b, PE5ba, PE5baa, PE5c, PE5ca, PE5d, PE5da, PE5daa, PE6, PE6a, PE7, PE7a, PE7b, PE8, PE8a, PE8aa, P

[0033] The present invention also refers to a process for making any of E8ab, PE9, PE9a, PE9aa, PE9b, PE9ba, PE9c, PE9ca, PE10, PE10a, PE10b, PE10c, PE10d, PE11, PE11a, PE11b, PE11c, PE11d, PE12, PE12a, PE12b, PE12c, PE12d, PE13, PE13a, PE13b, PE13c, PE13d, PE14, and PE14a, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and a pharma- ceutically acceptable salt of each of the above, the process being represented by Formula II [ka] wherein rings A and B are as defined for compounds of formula I hereinbefore or in the claims, (a) Formula III R 1 -Hal III, (R in the formula 1is as defined for compounds of formula I hereinbefore or in any of the claims, and Hal represents Cl, Br, or I) under suitable reaction conditions in a C-N cross-coupling reaction; thereby providing compounds of formula I as defined hereinbefore or in any of the claims; and Optional (b) In the compound of formula I, R 2 But R 2a is unsubstituted or substituted C 1~8 -Aliphatic -C(=O)-OR 2a If so, then this compound of formula I may be subjected to a saponification reaction under suitable conditions to give R 2 is -C(=O)-OH or -C(=O)-OCat; and Optional (c)R 2 The compound of formula I, in which is -C(=O)-OH or -C(=O)-OCat, is represented by formula IV H-NR 2b R 2c IV (R in the formula 2b and R 2c is reacted with a compound of formula I, either as defined above or in the claims, under suitable reaction conditions; whereby R 2 -C(=O)-NR 2a R 2b (where R 2b and R 2c is as defined for compounds of formula I hereinbefore or in the claims. It is characterized by:

[0169] As will be appreciated by those skilled in the art of organic synthesis, the compounds of the present invention, in particular those represented by formula I, are easily accessible by various synthetic routes, some of which are illustrated in the accompanying experimental part. Those skilled in the art will easily recognize what kind of reagents and reaction conditions should be used and how to apply and adapt them in any specific case - wherever necessary or useful - to obtain the compounds of the present invention. Furthermore, a compound of the present invention can be easily synthesized by reacting another compound of the present invention under suitable conditions, for example by converting a specific functional group present in the compound of the present invention, or a suitable precursor molecule thereof, into another by applying standard synthetic methods such as reduction, oxidation, addition or substitution reactions, which are well known to those skilled in the art. Likewise, the skilled artisan will be aware - wherever necessary or useful - of synthetic protecting (or protective) groups; the application of suitable protecting groups as well as methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in PGM Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

[0170] The following general synthetic routes that may be utilized to prepare compounds of the present invention are described in more detail in Schemes A and B below: [ka] Scheme A

[0171] Scheme A above depicts a general synthetic route for preparing compounds of formula I (depicted here as formula F). Unless expressly defined otherwise, rings A, B, R 1 , and R 2is as defined for compounds of formula I hereinbefore or in the claims. The 1-amino-2-bromo-substituted 5-membered heterocycle A is either available from commercial sources or is readily accessible by utilizing synthetic methods and procedures well known to those skilled in the art. Similarly, the bromo-substituted starting material B - where R 2 may be, inter alia, a carboxylic acid ester, e.g., -C(=O)O-methyl -, which is either commercially available or readily accessible by utilizing synthetic methods and procedures well known to those skilled in the art. In reaction step (a), compounds A and B are reacted in a CN cross-coupling reaction in the presence of a suitable palladium catalyst, illustratively Pd-PEPPSI-IPentCl ([1,3-bis-(2,6-di-3-pentylphenyl)-imidazol-2-ylidene] (3-chloropyridyl-dichloropalladium(II)), in a suitable solvent, e.g., 1,4-dioxane, utilizing e.g., cesium carbonate, or in the presence of a suitable palladium catalyst, e.g., ... BuXPhos (2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl) / t-BuXPhos Reaction under conditions typical of the Hartwig-Buchwald reaction utilizing palladium carbonate in the presence of G3 ([(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)-methanesulfonate) provides a compound of formula C. The compound of formula C may then be subjected to an intramolecular CC cross-coupling reaction utilizing a palladium catalyst (e.g., palladium-di-acetate / 1,4-bis-(diphenylphosphino)-butane (DPPB)) in a suitable solvent (e.g., dimethylformamide (DMF)) under suitable reaction conditions (heating), thereby producing compound D (a compound of formula II) (reaction step (b)). This tricyclic heterocycle D is then subsequently coupled to R in another CN coupling reaction. 1-Hal (compound E) (compound of formula III) may be reacted (reaction step (c)) to provide compound F (compound of formula I). ​​Exemplary reaction conditions are illustratively cesium carbonate 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-Phos aminobiphenylpalladium chloride, XPhosPd G2) when Hal is Br, or potassium carbonate in the presence of copper-(I)-iodide (CuI) and 1,2-dimethylethylenediamine (DMEDA) in a suitable solvent such as 1,4-dioxane when Hal is I (iodine). R in compound B may be reacted with -Hal (compound E) (compound of formula III) to provide compound F (compound of formula I). ​​Exemplary reaction conditions are illustratively cesium carbonate 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-Phos aminobiphenylpalladium chloride, XPhosPd G2) when Hal is I (iodine), or potassium carbonate in the presence of copper-(I)-iodide (CuI) and 1,2-dimethylethylenediamine (DMEDA) in a suitable solvent such as 1,4-dioxane when Hal is I (iodine). 2 When is chosen to be a carboxylate group, the synthesis proceeds as follows: R 2 This will provide compound F with its carboxylic acid ester group as R . Saponification of this ester group by reaction with a base, for example lithium hydroxide, will provide the respective carboxylic acid (R 2 = -COOH) or carboxylate (R 2 Such carboxylic acids of formula I (or F) may then be transformed to provide different functional groups R 2 Illustrative examples include compounds of formula I having the formula: 2 = -C(=O)-NR 2b R 2c ) are readily accessible by applying typical amidation reaction conditions. Alternatively, other substituents R 2 Compounds of formula I, having the formula: may also be prepared by utilizing a suitably substituted compound of formula B as a starting material.

[0172] [ka] Scheme B

[0173] Intermediate compound C having a symmetric ring A, illustratively triazole ring A-24, may be prepared by utilizing alternative synthetic approaches (see Scheme B). In reaction step (d), amino-substituted compound H and dibromo-substituted compound G are reacted in a CN cross-coupling reaction in the presence of a suitable palladium catalyst, illustratively Pd-PEPPSI-IPentCl ([1,3-bis-(2,6-di-3-pentylphenyl)-imidazol-2-ylidene] (3-chloropyridyl-dichloropalladium(II)), in a suitable solvent, such as 1,4-dioxane, illustratively utilizing cesium carbonate or BuXPhos (2-di-tert-butylphosphine-2',4',6'-triisopropylbiphenyl) / t-Bu ... Reaction under conditions typical of the Hartwig-Buchwald reaction utilizing palladium carbonate in the presence of G3 ([(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II)-methanesulfonate) provides compounds of formula C.

[0174] [ka] Scheme C

[0175] Scheme C above depicts a general synthetic route for preparing compounds of formula I (depicted here as formula F). Unless expressly defined otherwise, rings A, B, R 1 , and R 2 is defined in the same manner as in the compounds of formula I hereinbefore or in the claims. The 1-amino-2-bromo-substituted 5-membered heterocycle A is either available from commercial sources or is readily accessible by utilizing synthetic methods and procedures well known to those skilled in the art. Similarly, the bromo-substituted starting material B - where R 2may be, inter alia, a carboxylic acid ester, for example -C(=O)O-methyl -, either commercially available or readily accessible by utilizing synthetic methods and procedures well known to those skilled in the art. In reaction step (a), compounds A and B are reacted in a CN cross-coupling reaction in the presence of a suitable palladium catalyst, for example XantPhos Pd G3 ([(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate), in a suitable solvent, for example DMAc, under conditions typical of the Hartwig-Buchwald reaction, for example using cesium carbonate, to provide a compound of formula C. The compound of formula C is then brominated in a suitable solvent, such as acetonitrile, under typical conditions, such as NBS, to provide a compound of formula J (reaction step (e)). The dibrominated compound J may then be protected with a suitable protecting group, e.g. pivaloyl, using standard conditions such as reaction with pivaloyl chloride in the presence of a base, e.g. DIPEA, and a catalyst, e.g. DMAP, to give intermediate K. The compound of formula K may then be subjected to an intramolecular Stille-Kelly cross-coupling ring closure utilizing CuI, hexamethylditin, a palladium catalyst, e.g. bis(tri-tert-butylphosphine)palladium / tri-tert-butylphosphine, in a suitable solvent, e.g. dioxane, under suitable reaction conditions (heating), thereby producing compound L (reaction step (g)). This tricyclic heterocycle L is then deprotected under suitable conditions, e.g. LDA, in the presence of a suitable solvent, e.g. THF, to give the deprotected intermediate of formula D (reaction step (h)). The compound of formula D may then be coupled to R in another CN coupling reaction. 1-Hal (compound E) (compound of formula III) may be reacted (reaction step (c)) to provide compound F (compound of formula I). ​​Exemplary reaction conditions are illustratively cesium carbonate 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-Phos aminobiphenylpalladium chloride, XPhosPd G2) when Hal is Br, or potassium carbonate in the presence of copper-(I)-iodide (CuI) and 1,2-dimethylethylenediamine (DMEDA) in a suitable solvent such as 1,4-dioxane when Hal is I (iodine). R in compound B may be reacted with -Hal (compound E) (compound of formula III) to provide compound F (compound of formula I). ​​Exemplary reaction conditions are illustratively cesium carbonate 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-Phos aminobiphenylpalladium chloride, XPhosPd G2) when Hal is I (iodine), or potassium carbonate in the presence of copper-(I)-iodide (CuI) and 1,2-dimethylethylenediamine (DMEDA) in a suitable solvent such as 1,4-dioxane when Hal is I (iodine). 2 When is chosen to be a carboxylate group, the synthesis proceeds as follows: R 2 This will provide compound F with its carboxylic acid ester group as R . Saponification of this ester group by reaction with a base, for example lithium hydroxide, will provide the respective carboxylic acid (R 2 = -COOH) or carboxylate (R 2 Such carboxylic acids of formula I (or F) may then be transformed to provide different functional groups R 2 Illustrative examples include compounds of formula I having the formula: 2 = -C(=O)-NR 2b R 2c ) are readily accessible by applying typical amidation reaction conditions. Alternatively, other substituents R 2 Compounds of formula I, having the formula: may also be prepared by utilizing a suitably substituted compound of formula B as a starting material.

[0176] It should be noted that, in general, the terms, i.e., the singular and plural forms thereof, may be used and read interchangeably - unless specifically stated or the context provides a different meaning. For example, the singular term "compound" may also include or refer to a plurality of compounds, while the plural term "compound" may also include or refer to a singular compound.

[0177] Examples and Experiments The compounds of the present invention can be prepared according to the procedures of the following schemes and examples using appropriate materials, and are further illustrated by the following specific examples. The compounds are shown in Table 1 and Table 1a. Analytical data for the compounds made according to the following examples are also shown in Table 1 and 1a.

[0178] The present invention is illustrated, but not limited, by reference to the specific embodiments described in the following examples. Unless otherwise indicated in the schemes, the variables have the same meanings as described above and in the claims.

[0179] 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.

[0180] 1 H NMR: 1 H-NMR data is provided in Table 1 and Table 1a below. 1H NMR spectra were mostly acquired on a Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300, or Bruker Avance III 700MHz (equipped with a TXI cryoprobe) NMR spectrometer under standard conditions using TMS (tetramethylsilane) as internal standard and DMSO-d6 as 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 TMS signal. 1 H NMR data are reported as follows: chemical shifts (multiplicities, coupling constants, and hydrogen numbers). Multiplicities are abbreviated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets), td (triplet of doublets), br (broad), and coupling constants (J) are reported in Hz.

[0181] LC-MS: The LC-MS data provided in Table 1 and Table 1a are given in mass in m / z units. The results can be obtained by one of the methods described below.

[0182] The melting points (mp) of selected compounds were determined by using a Tianjin Analytical Instrument RY-1.

[0183] synthesis Example 1: N,10-Dimethyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxamide Example 1-1: Synthesis of methyl 4-[(4-bromo-1-methyl-1H-pyrazol-3-yl)amino]thiophene-2-carboxylate [ka] Methyl 4-bromothiophene-2-carboxylate (20.0 g, 67.9 mmol) and K in dioxane (400 mL) 2 CO 3(19.8 g, 136 mmol), t-BuXPhos (3.04 g, 6.79 mmol), 4-bromo-1-methyl-1H-pyrazol-3-amine (15.1 g, 81.5 mmol), and t-BuXPhos G3 ([(2-di-tert-butylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) (5.68 g, 6.79 mmol) were added to a solution of N 2 The mixture was stirred at 120° C. for 16 h. After cooling to room temperature, the reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3× 300 mL) and the combined organic phase was washed with brine (3× 900 mL) and diluted with Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and 100% by weight. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc=2:1) ​​to give the desired product (7.00 g, 22.1 mmol, 32%, light yellow solid).

[0184] Example 1-2: Methyl 10-methyl-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(11),2(6),4,8-tetraene-4-carboxylate [ka] Into a sealed tube, methyl 4-[(4-bromo-1-methyl-1H-pyrazol-3-yl)amino]thiophene-2-carboxylate (7.00 g, 22.1 mmol), Pd(OAc) 2 (1.05 g, 4.43 mmol), and 1,4-bis(diphenylphosphino)butane (1.99 g, 4.43 mmol) were added and dissolved in N,N-dimethylacetamide (210 mL). The reaction mixture was irradiated in a microwave at 150 °C for 70 min. After cooling to room temperature, the reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3x 300 mL) and the combined organic phase was washed with brine (3x 1000 mL) to remove Na. 2 SO 4The mixture was dried over 100 ml of ethyl acetate and filtered. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc=2:1) ​​to give the desired product (805 mg, 3.32 mmol, 15%, green solid).

[0185] Example 1-3: Methyl 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(11),2(6),4,8-tetraene-4-carboxylate [ka] Methyl 10-methyl-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylate (375 mg, 1.59 mmol), 4-iodobenzotrifluoride 97% (302 μl, 1.99 mmol), Cs 2 CO 3 A mixture of 1.05 g (3.19 mmol) and 1,2-dimethylethylenediamine (173 μl, 1.59 mmol) was suspended in 1,4-dioxane (7.50 ml). The reaction vial was crimped, placed under vacuum, sonicated for 2 min, and backfilled with argon. This procedure was repeated twice, followed by the addition of CuI (152 mg, 0.80 mmol). The vial was crimped and the procedure described above was repeated, followed by stirring at 110° C. for 17 hr. The reaction mixture was filtered through Celite, washing with EtOAc (45 ml) and deionized water (30 ml). The filtrate was concentrated in vacuo to give crude methyl 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]undeca-1(11),2(6),4,8-tetraene-4-carboxylate (605 mg, 1.20 mmol, 76%, beige solid) and 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6] to give a mixture of undeca-1(11),2(6),4,8-tetraene-4-carboxylic acids (582 mg, 0.39 mmol, 24%, beige solid), which was used as such in the next step without further purification.

[0186] Example 1-4: 10-Methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid [ka] H 2 Methyl 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 To a solution of ]undeca-1(11),2(6),4,8-tetraene-4-carboxylate (47.0 mg, 0.12 mmol) was added LiOH (8.00 mg, 0.32 mmol). The reaction was stirred at room temperature for 16 h and then acidified to pH 4 with aqueous HCl. The mixture was extracted with EtOAc (3 x 10 mL) and the combined organic phase was washed with Na 2 SO 4 The mixture was dried over silica gel and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / MeOH 10:1) to give 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ] to give undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid (29.1 mg, 0.08 mmol, 63%, off-white solid, mp 206-208 °C).

[0187] Example 1-5: N,10-Dimethyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(11),2(6),4,8-tetraene-4-carboxamide [ka] 10-Methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 To a solution of ]undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid (55.0 mg, 0.15 mmol) was added methylamine (2M in THF, 113 μl, 0.23 mmol), 4-methylmorpholine (83.6 μl, 0.75 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (58.9 mg, 0.30 mmol), and 1-hydroxybenzotriazole hydrate (23.8 mg, 0.15 mmol). The reaction was stirred at room temperature for 15 hr. The crude product was purified by RP (reverse phase) flash chromatography (SunFire C18 5.0 μm 150-30 mm; A: H 2 Purification by 30% B: 0 → 3.0 min; 30% → 68% B: 3.0 → 19.5 min; flow: 45 mL / min) afforded N,10-dimethyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0]. 2,6 ] to give undeca-1(11),2(6),4,8-tetraene-4-carboxamide (39.3 mg, 69%, white solid, mp 247-249°C).

[0188] Example 2: 7-[4-(difluoromethoxy)phenyl]-10-methyl-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid [ka] This product was synthesized following the same protocol as described for Examples 1-4: 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid.

[0189] Example 3: 10-Methyl-7-[4-(trifluoromethoxy)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid [ka] This product was synthesized following the same protocol described for Examples 1-4 utilizing 4-iodo-1-trifluoromethoxyphenyl: 10-methyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid.

[0190] Example 4: 10-Methyl-7-(4,4,4-trifluoro-3,3-dimethylbutyl)-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid [ka] Methyl 10-methyl-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 A solution of ]undeca-1(11),2(6),4,8-tetraene-4-carboxylate (37.5 mg, 0.16 mmol) was inertised with argon and cooled to 0-5 °C in an ice bath. After addition of NaH (60% suspension in paraffin oil, 18.6 mg, 0.46 mmol), the reaction mixture was stirred at 0 °C for 0.25 hr, followed by the addition of 4-bromo-1,1,1-trifluoro-2,2-dimethylbutane (42.8 mg, 0.19 mmol). The vial was inertised with fresh argon and allowed to warm up to rt and stirred for 17.5 hr. The reaction was quenched by the addition of water (approximately 1 ml) and the mixture was analyzed by RP flash chromatography (SunFire C18 5.0 μm 150-30 mm; A: H 2The mixture was purified by elution with 25% CO+0.1% TFA (A: MeCN+0.1% TFA; 25% B: 0→5.5 min; 25%→60% B: 5.5→27.5 min; flow: 45 mL / min). Pure fractions were combined and concentrated, and the residue was coevaporated with deionized water (2x 5 ml) and once with toluene to give 10-methyl-7-(4,4,4-trifluoro-3,3-dimethylbutyl)-3-thia-7,9,10-triazatricyclo[6.3.0]. 2,6 ] to give undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid (36.9 mg, 0.10 mmol, 66%; pale gray solid).

[0191] Example 5: N,10-Dimethyl-7-{[(1s,3s)-3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxamide Example 5-1: 10-Methyl-7-{[3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid [ka] This product was synthesized following the same protocol as described for Example 4: 10-methyl-7-(4,4,4-trifluoro-3,3-dimethylbutyl)-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid.

[0192] Example 5-2: 10-Methyl-7-{[(1r,3r)-3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 ]undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid and 10-methyl-7-{[(1s,3s)-3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid [ka] 10-Methyl-7-{[(1r,3r)-3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6]undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid and 10-methyl-7-{[(1s,3s)-3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 The isomeric mixture of undeca-1(11),2(6),4,8-tetraene-4-carboxylic acid was purified by second RP flash chromatography (SunFire C18 5.0 μm 150-30 mm; A: H 2 The mixture was separated by 25% B: 0→9.0 min; 25%→60% B: 9.0→29.5 min; flow: 45 mL / min).

[0193] Example 5-3: N,10-Dimethyl-7-{[(1s,3s)-3-(trifluoromethyl)cyclobutyl]methyl}-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(11),2(6),4,8-tetraene-4-carboxamide [ka] This product was synthesized following the same protocol as described for Example 1: N,10-dimethyl-7-[4-(trifluoromethyl)phenyl]-3-thia-7,9,10-triazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(11),2(6),4,8-tetraene-4-carboxamide

[0194] Example 6: N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2,5,9-tetraene-10-carboxamide Example 6-1: Synthesis of methyl 4-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)amino]thiophene-2-carboxylate [ka] To a solution of methyl 4-aminothiophene-2-carboxylate (1.00 g, 6.04 mmol) and 4,5-dibromo-2-methyl-2H-1,2,3-triazole (1.80 g, 7.25 mmol) in dioxane (10 mL) was added Pd-PEPPSI™-IPentCl 2-methylpyridine ([1,3-bis(2,6-di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)dichloropalladium(II)) (0.50 g, 0.60 mmol) and Cs 2 CO 3 (4.10 g, 12.0 mmol) was added. The reaction mixture was stirred at 100° C. for 2 h. After cooling to room temperature, the reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3× 200 mL) and the combined organic phase was washed with brine (3× 900 mL) to remove Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc=85:15) to give the desired product (0.90 g, 2.84 mmol, 43%, yellow solid).

[0195] Example 6-2: Methyl 4-methyl-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2,5,9-tetraene-10-carboxylate [ka] To a stirred mixture of methyl 4-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)amino]thiophene-2-carboxylate (5.88 g, 18.1 mmol) in DMF (100.00 mL) was added N,N-diisopropylethylamine (6.62 mL, 36.1 mmol) and bis(tri-tert-butylphosphine)palladium(0) (971 mg, 1.81 mmol) at room temperature. The reaction was stirred overnight at 100° C. under nitrogen atmosphere. After cooling to room temperature, the reaction mixture was diluted with water and the aqueous phase was extracted with EtOAc (3×200 mL). The combined organic layers were washed with saturated NaCl solution and anhydrous Na 2 SO 4The mixture was dried over 100 ml of ethyl acetate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 75:25) to give methyl 4-methyl-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2,5,9-tetraene-10-carboxylate (4.00 g, 8.65 mmol, 48%, light brown solid, 51% purity).

[0196] Example 6-3: Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2,5,9-tetraene-10-carboxylate [ka] Methyl 4-methyl-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0] in 1,4-dioxane (20.0 mL) 2,6 ]To a mixture of undeca-1(8),2,5,9-tetraene-10-carboxylate (2.90 g, 6.27 mmol) and 1-iodo-4-(trifluoromethyl)benzene (3.59 g, 12.5 mmol), CuI (623.0 mg, 3.11 mmol), N,N'-dimethylethylenediamine (291.0 mg, 3.14 mmol), and K 2 CO 3 (1.82 g, 12.5 mmol) was added at room temperature. The resulting mixture was stirred at 100° C. under nitrogen atmosphere overnight. After cooling to room temperature, the reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3× 300 mL) and the combined organic phase was washed with saturated NaCl solution to obtain Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 80:20) to give methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ] to provide undeca-1(8),2,5,9-tetraene-10-carboxylate (2.00 g, 5.14 mmol, 82%, off-white solid).

[0197] Example 6-4: 4-Methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2,5,9-tetraene-10-carboxylic acid [ka] Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ] to a solution of undeca-1(8),2,5,9-tetraene-10-carboxylate (90.0 mg, 0.23 mmol), 2 NaOH (28.0 mg, 0.67 mmol) in 20O (1 mL) was added. The reaction mixture was stirred at 60 °C for 3 h and then acidified with aqueous HCl to pH 3. The resulting mixture was extracted with EtOAc (3x 50 mL) and the combined organic phase was washed with Na 2 SO 4 The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Halo C18 4.6*100mm, Solvent A: water / 0.05%TFA, Solvent B: MeCN / 0.05%TFA, flow: 1.2mL / min, gradient: 5%B to 100%B by 8.0min) to give 4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0]. 2,6 ] to give undeca-1(8),2,5,9-tetraene-10-carboxylic acid (50.4 mg, 0.14 mmol, 61%, white solid, mp 265-267 °C).

[0198] Example 6-5: N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2,5,9-tetraene-10-carboxamide [ka] 4-Methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6To a solution of ]undeca-1(8),2,5,9-tetraene-10-carboxylic acid (130 mg, 0.35 mmol) and 2-amino-2-(pyridin-2-yl)ethan-1-ol (102 mg, 0.70 mmol) was added 1-[bis(dimethylamine)methylene]-1H-1,2,3-triazole[4,5-b]pyridinium 3-oxide-hexafluorophosphate (210 mg, 0.52 mmol) and DIPEA (238 mg, 1.74 mmol). The reaction was stirred at room temperature for 12 h after which the reaction was quenched by the addition of water. The resulting mixture was extracted with EtOAc (3x 50 mL) and the combined organic phase was washed with saturated NaCl solution (1x 20 mL) and diluted with MgSO. 4 The residue was purified by preparative HPLC (column: Halo C18 4.6*100mm, solvent A: water / 0.05%TFA, solvent B: MeCN / 0.05%TFA, flow: 1.2mL / min, gradient: 5%B to 95%B by 8min) to give N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-4-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,4,5,7-tetraazatricyclo[6.3.0.0]. 2,6 ] to give undeca-1(8),2,5,9-tetraene-10-carboxamide (54.2 mg, 0.11 mmol, 32%, white solid, mp 220-222 °C).

[0199] Example 7: N-[Dimethyl(oxo)-λ 6 -sulfanylidene]-4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2,5,10-tetraene-10-carboxamide Example 7-1: Synthesis of methyl 5-[(4-bromo-1-methyl-1H-pyrazol-3-yl)amino]thiophene-2-carboxylate [ka] Methyl 5-bromothiophene-2-carboxylate (1.00 g, 4.43 mmol), 4-bromo-1-methyl-1H-pyrazol-3-amine (903 mg, 4.88 mmol), and Cs in dioxane (20 mL). 2 CO 3To a suspension of (2.89 g, 8.87 mmol) was added XantPhos Pd G3 ([(4,5-bis(diphenylphosphino)-9,9-dimethylxanthene)-2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate) (221 mg, 0.22 mmol). The reaction mixture was stirred at 110 °C for 19 h. After cooling to room temperature, the reaction was diluted by the addition of water. The resulting mixture was extracted with EtOAc (3x 75 mL) and the combined organic phase was washed with brine (3x 20 mL) to remove Na. 2 SO 4 The mixture was dried over 100 ml of ethyl acetate and 1.23 g of 5-[(4-bromo-1-methyl-1H-pyrazol-3-yl)amino]thiophene-2-carboxylate (1.23 g, 2.93 mmol, 66%, dark yellow solid) was obtained. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc=1:1) to give methyl 5-[(4-bromo-1-methyl-1H-pyrazol-3-yl)amino]thiophene-2-carboxylate (1.23 g, 2.93 mmol, 66%, dark yellow solid).

[0200] Example 7-2: Methyl 4-methyl-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2,5,10-tetraene-10-carboxylate [ka] Into a sealed tube was added methyl 5-[(4-bromo-1-methyl-1H-pyrazol-3-yl)amino]thiophene-2-carboxylate (100 mg, 0.29 mmol), potassium 2,2-dimethylpropanoate (58.7 mg, 0.41 mmol), and bis(tri-tert-butylphosphane)palladium (30.3 mg, 0.06 mmol) dissolved in DMF (1.95 mL). The reaction mixture was irradiated at 160° C. for 2 h. After cooling to room temperature, the reaction was diluted by the addition of water. The resulting mixture was extracted with EtOAc (3× 30 mL) and the combined organic phase was washed with brine (3× 10 mL) and water (2× 5 ml) and diluted with Na 2 SO 4The mixture was dried over ice. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc=1:3) to give methyl 4-methyl-9-thia-4,5,7-triazatricyclo[6.3.0.0]. 2,6 ] to give undeca-1(8),2,5,10-tetraene-10-carboxylate (29.0 mg, 0.11 mmol, 18%, deep purple solid).

[0201] Example 7-3: Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(8),2,5,10-tetraene-10-carboxylate [ka] Methyl 4-methyl-9-thia-4,5,7-triazatricyclo[6.3.0.0] in 1,4-dioxane (434 μl) 2,6 ] to a solution of undeca-1(8),2,5,10-tetraene-10-carboxylate (21.7 mg, 0.08 mmol) and 4-iodobenzotrifluoride 97% (15.8 μl, 0.10 mmol), 2 CO 3 (54.9 mg, 0.17 mmol), N-N'-dimethylethylenediamine (9.06 μl, 0.08 mmol), and CuI (7.94 mg, 0.04 mmol) were added. The reaction mixture was stirred at 110 °C for 18 h. After cooling to room temperature, the reaction was diluted by the addition of water. The resulting mixture was extracted with EtOAc (3x 5 mL) and the combined organic phase was washed with brine (1x 2 mL) to remove Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2,5,10-tetraene-10-carboxylate (32.9 mg, 0.07 mmol, 83%, light brown solid).

[0202] Example 7-4: 4-Methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2,5,10-tetraene-10-carboxylic acid [ka] Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 To a solution of ]undeca-1(8),2,5,10-tetraene-10-carboxylate (32.9 mg, 0.07 mmol) was added LiOH (20.0 mg, 0.82 mmol). The reaction was stirred at rt for 14.5 h after which it was concentrated to dryness and purified by RP flash chromatography (C18 column, H 2 The compound was purified by 35% to 70% TFA / MeCN+0.1% TFA to obtain 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2,5,10-tetraene-10-carboxylic acid (13.5 mg, 0.04 mmol, 53%, pale beige solid).

[0203] Example 7-5: N-[dimethyl(oxo)-λ 6 -sulfanylidene]-4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(8),2,5,10-tetraene-10-carboxamide [ka] 4-Methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2,5,10-tetraene-10-carboxylic acid (19.1 mg, 0.05 mmol), iminodimethyl-λ 6To a solution of 10.2 mg, 0.10 mmol) and 4-methylmorpholine (34.8 μl, 0.31 mmol) was added N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (20.4 mg, 0.10 mmol) and 1-hydroxybenzotriazole hydrate (8.24 mg, 0.05 mmol). The reaction was stirred at rt for 112 hr, after which the crude product was purified by RP flash chromatography (SunFire C18, A:H 2 The pure fractions were combined and purified by elution with saturated NaCl. 2 CO 3 The mixture was basified with EtOAc (4 mL) and extraction was performed with EtOAc (2x 10 mL). The combined organic layers were washed with Na 2 SO 4 The solid was concentrated by filtration under suction and dried over CH 2 Cl 2 and EtOH (10 ml / 2 ml), filtered through a 4 g silica gel column, and then added to CH 2 Cl 2 The filtrate was concentrated to give N-[dimethyl(oxo)-λ 6 -sulfanylidene]-4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-4,5,7-triazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2,5,10-tetraene-10-carboxamide (14.7 mg, 0.03 mmol, 64%, white solid).

[0204] Example 8: N,3-Dimethyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),4,9-tetraene-10-carboxamide Example 8-1: 1-Methyl-5-(tributylstannyl)-1H-imidazole [ka] EtO 2To a mixture of 5-bromo-1-methyl-1H-imidazole (3.00 g, 17.7 mmol) in hexanes (30 mL) was added nBuLi in hexanes (7.79 mL, 19.5 mmol) dropwise at -78 °C. The reaction was stirred at -78 °C under nitrogen for 30 min, followed by the dropwise addition of tributyl(chloro)stannane (8.73 g, 26.6 mmol). The reaction was stirred at -78 °C for 1 h, then saturated NH 4 Cl solution was added at 0° C. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine and anhydrous Na 2 SO 4 After filtration, the filtrate was concentrated under reduced pressure to give 1-methyl-5-(tributylstannyl)-1H-imidazole (6.60 g, 17.5 mmol, 99%, yellow oil).

[0205] Example 8-2: Methyl 5-(1-methyl-1H-imidazol-5-yl)-4-nitrothiophene-2-carboxylate [ka] To a stirred mixture of 1-methyl-5-(tributylstannyl)-1H-imidazole (6.30 g, 11.6 mmol) and methyl 5-bromo-4-nitrothiophene-2-carboxylate (3.26 g, 11.6 mmol) in toluene (60 mL) was added tetrakis(triphenylphosphane)palladium (1.41 g, 1.16 mmol) and CsF (3.72 g, 23.3 mmol) in portions at room temperature. The reaction was stirred at 100° C. under nitrogen overnight after which it was allowed to cool down to room temperature. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine and purified by elution with anhydrous Na 2 SO 4 The mixture was dried over ice and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (CH 2 Cl 2 / EtOAc 53:47) to give methyl 5-(1-methyl-1H-imidazol-5-yl)-4-nitrothiophene-2-carboxylate (2.40 g, 8.65 mmol, 74%, yellow oil).

[0206] Example 8-3: Methyl 3-methyl-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),4,9-tetraene-10-carboxylate [ka] To a mixture of methyl 5-(1-methyl-1H-imidazol-5-yl)-4-nitrothiophene-2-carboxylate (600 mg, 2.23 mmol) in 12-dichlorobenzene (6.00 mL) was added [2-(diphenylphosphanyl)ethyl]diphenylphosphane (1.12 g, 2.68 mmol) in small portions at room temperature. The reaction was stirred at 160° C. under nitrogen atmosphere overnight after which it was allowed to cool to room temperature. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine and purified by elution with anhydrous NaCl. 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 45:55) to give methyl 3-methyl-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2(6),4,9-tetraene-10-carboxylate (350 mg, 1.43 mmol; 64%, brown-yellow solid).

[0207] Example 8-4: Methyl 3-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),4,9-tetraene-10-carboxylate [ka] Methyl 3-methyl-11-thia-3,5,7-triazatricyclo[6.3.0.0] in 1,4-dioxane (2.00 mL) 2,6 ]To a mixture of undeca-1(8),2(6),4,9-tetraene-10-carboxylate (70.0 mg, 0.26 mmol) and 1-iodo-4-(trifluoromethyl)benzene (88.0 mg, 0.31 mmol), CuI (26.0 mg, 0.13 mmol), N,N'-dimethylethylenediamine (12.0 mg, 0.13 mmol), and K 2 CO 3(75.0 mg, 0.52 mmol) was added at room temperature. The reaction was stirred at 100° C. under nitrogen atmosphere overnight, after which it was allowed to cool to room temperature. The mixture was extracted with EtOAc (3×20 mL) and the combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 50:50) to give methyl 3-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2(6),4,9-tetraene-10-carboxylate (40.0 mg, 0.10 mmol, 40%, yellow solid).

[0208] Example 8-5: 3-Methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),4,9-tetraene-10-carboxylic acid [ka] Methyl 3-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo 6.3.0.0 in methanol (2.00 mL) 2,6 To a mixture of ]undeca-1(8),2(6),4,9-tetraene-10-carboxylate (130 mg, 0.34 mmol) was added dropwise sodium hydroxide (42.0 mg, 1.00 mmol) dissolved in water (0.40 mL) at room temperature. The resulting mixture was stirred at 60 °C under nitrogen atmosphere for 3 h, after which it was allowed to cool to room temperature. The mixture was diluted with water and acidified to pH = 2-3 with aq. HCl. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate and concentrated under reduced pressure to give 3-methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ] to provide undeca-1(8),2(6),4,9-tetraene-10-carboxylic acid (120.0 mg, 0.32 mmol, 95%, yellow solid).

[0209] Example 8-6: N,3-Dimethyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),4,9-tetraene-10-carboxamide [ka] 3-Methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0] in DMF (1.00 mL) 2,6 ]To a solution of undeca-1(8),2(6),4,9-tetraene-10-carboxylic acid (110.00 mg, 0.29 mmol), HATU (176.0 mg, 0.44 mmol), N,N-diisopropylethylamine (0.16 mL, 0.88 mmol), and NH 4 Cl (33.0 mg, 0.44 mmol) was added at room temperature. The reaction was stirred at room temperature under nitrogen atmosphere overnight, after which it was diluted with water. The mixture was acidified with aq. HCl to pH=2-3 and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The crude product was purified by preparative HPLC (column: C18 4.6*100mm, mobile phase A: water / 0.05%TFA, mobile phase B: MeCN / 0.05%TFA, flow rate: 1.5mL / min, gradient: 5% to 100% by 8.0min) to give N,3-dimethyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0]. 2,6 ] to give undeca-1(8),2(6),4,9-tetraene-10-carboxamide (50.2 mg, 0.13 mmol, 45%; pink solid).

[0210] Example 9: Example 24: N,4-Dimethyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),3,9-tetraene-10-carboxamide Example 9-1: Synthesis of 2-methyl-4-(tributylstannyl)-1,3-thiazole [ka] To a mixture of 4-bromo-2-methyl-1,3-thiazole (2.00 g, 10.7 mmol) in ethyl ether (20 mL) was added n-BuLi in hexane (4.70 mL, 11.7 mmol) dropwise at -78 °C. The reaction was stirred at -78 °C under nitrogen atmosphere for 30 min, after which tributyl(chloro)stannane (7.02 g, 21.3 mmol) was added dropwise. The reaction was stirred at -78 °C for 1 h and then saturated Na 2 CO 3 This was followed by the addition of solution at 0° C. The mixture was extracted with EtOAc (3 x 200 mL) and the combined organic layers were washed with brine and anhydrous Na 2 SO 4 The mixture was dried over 100 ml and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 95:5) to give 2-methyl-4-(tributylstannyl)-1,3-thiazole (4.00 g, 9.72 mmol, 91%, light yellow oil).

[0211] Example 9-2: Synthesis of methyl 5-(2-methyl-1,3-thiazol-4-yl)-4-nitrothiophene-2-carboxylate [ka] To a mixture of 2-methyl-4-(tributylstannyl)-1,3-thiazole (4.00 g, 9.72 mmol) and methyl 5-bromo-4-nitrothiophene-2-carboxylate (2.72 g, 9.72 mmol) in toluene (40.00 mL) was added tetrakis(triphenylphosphane)palladium (1.18 g, 0.97 mmol) and CsF (3.11 g, 19.44 mmol) in small portions at room temperature. The reaction was stirred at 100° C. under nitrogen overnight, after which it was allowed to cool to room temperature. The mixture was diluted with water and extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine and extracted with anhydrous Na 2 SO 4The residue was purified by silica gel column chromatography (PE / EtOAc 85:15) followed by RP flash chromatography (column: C18; mobile phase A: water, mobile phase B: MeCN, gradient 70%-80% over 20 min) to give methyl 5-(2-methyl-1,3-thiazol-4-yl)-4-nitrothiophene-2-carboxylate (2.00 g, 6.78 mmol, 70%, yellow solid).

[0212] Example 9-3: Methyl 4-methyl-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2(6),3,9-tetraene-10-carboxylate [ka] To a mixture of methyl 5-(2-methyl-1,3-thiazol-4-yl)-4-nitrothiophene-2-carboxylate (340 mg, 1.14 mmol) in 1,2-dichlorobenzene (10 mL) was added [2-(diphenylphosphanyl)ethyl]diphenylphosphane (524 mg, 1.25 mmol) in small portions at room temperature. The reaction was stirred at 160° C. under nitrogen overnight, after which it was allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3×50 mL) and the combined organic layers were washed with brine and purified with anhydrous NaCl. 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 95:5) to give methyl 4-methyl-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2(6),3,9-tetraene-10-carboxylate (150 mg, 0.59 mmol, 52%, yellow-brown solid).

[0213] Example 9-4: Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2(6),3,9-tetraene-10-carboxylate [ka] Methyl 4-methyl-5,11-dithia-3,7-diazatricyclo[6.3.0.0] in dioxane (5.00 mL) 2,6 ]Undeca-1(8), 2(6),3,9-tetraene-10-carboxylate (110 mg, 0.43 mmol) and 1-iodo-4-(trifluoromethyl)benzene (185 mg, 0.65 mmol) were added to a mixture of EPhos Pd G4 (42.00 mg; 0.04 mmol) and Cs 2 CO 3 (295 mg, 0.86 mmol) was added in small portions at room temperature. The reaction was stirred at 100 °C under nitrogen atmosphere overnight, after which it was allowed to cool to room temperature and diluted with water. The mixture was extracted with EtOAc (3 x 100 mL) and the combined organic layers were washed with brine and diluted with anhydrous Na 2 SO 4 The mixture was dried over 1000 ml and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE / EtOAc 82:18) to give methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 ] to give undeca-1(8),2(6),3,9-tetraene-10-carboxylate (170 mg, 0.42 mmol, 98%, pale yellow solid).

[0214] Example 9-5: 3-Methyl-7-[4-(trifluoromethyl)phenyl]-11-thia-3,5,7-triazatricyclo[6.3.0.0 2,6 Synthesis of undeca-1(8),2(6),4,9-tetraene-10-carboxylic acid [ka] Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0] in MeOH (2.00 mL) 2,6To a mixture of ]undeca-1(8),2(6),3,9-tetraene-10-carboxylate (50.00 mg; 0.12 mmol) was added dropwise a solution of NaOH (15.00 mg; 0.36 mmol) in water (0.40 ml) at room temperature. The reaction was stirred overnight at 60 °C under nitrogen atmosphere after which it was allowed to cool to room temperature and diluted with water at 0 °C. The mixture was acidified to pH 2-3 with aq. HCl and extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine and anhydrous MgSO 4 The mixture was dried over 1000 ml of 4-methyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 ] to provide undeca-1(8),2(6),3,9-tetraene-10-carboxylic acid (50.0 mg, 0.08 mmol, 68%, yellow solid).

[0215] Example 9-6: N,4-Dimethyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(8),2(6),3,9-tetraene-10-carboxamide [ka] 4-Methyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 To a mixture of ]undeca-1(8),2(6),3,9-tetraene-10-carboxylic acid (70.0 mg, 0.16 mmol) and methylammonium chloride (24.0 mg, 0.32 mmol) was added HATU (98.0 mg, 0.24 mmol) and N,N-diisopropylethylamine (0.15 mL, 0.82 mmol) at room temperature. The reaction was stirred at room temperature overnight. The mixture was extracted with EtOAc (3 x 50 mL) and the combined organic layers were washed with brine and purified by anhydrous MgSO 4The residue was purified by preparative HPLC (column: Halo C18 4.6*100mm, phase A: water / 0.05%TFA, phase B: MeCN / 0.05%TFA, flow: 1.2mL / min, gradient: 5%-95% by 8min) to give N,4-dimethyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0]. 2,6 ] to provide undeca-1(8),2(6),3,9-tetraene-10-carboxamide (53.8 mg, 0.14 mmol, 83%, off-white solid).

[0216] Example 10: N,4-Dimethyl-7-[4-(trifluoromethoxy)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2(6),3,9-tetraene-10-carboxamide [ka] This product was synthesized following the same protocol as described for Example 9: N,4-dimethyl-7-[4-(trifluoromethyl)phenyl]-5,11-dithia-3,7-diazatricyclo[6.3.0.0 2,6 ]Synthesis of undeca-1(8),2(6),3,9-tetraene-10-carboxamide.

[0217] Example 11: 4-Methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2,5,10-tetraene-10-carboxylic acid Example 11-1: Synthesis of methyl 5-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)amino]thiophene-2-carboxylate [ka] Methyl 5-bromothiophene-2-carboxylate (5.7 g, 25.3 mmol), 5-bromo-2-methyl-2H-1,2,3-triazol-4-amine (5.0 g, 27.8 mmol), Xantphos (2.3 g, 3.8 mmol), and Cs 2 CO 3(12.4 g, 37.9 mmol) was suspended in N,N-dimethylacetamide (114 mL). The flask was placed under vacuum, sonicated for 2 min, and backfilled with argon three times. XantPhos Pd G3 (2.5 g, 2.5 mmol) was then added. The flask was closed, placed under vacuum, sonicated for 2 min, and backfilled with argon three additional times. The reaction mixture was stirred at 110° C. for 4 h. After cooling to room temperature, the reaction mixture was filtered through Celite and washed with DMF (approximately 50 mL). The filtered solution was poured into deionized water (approximately 1.75 L) and stirred with ice cooling for 0.5 h, forming a greenish precipitate, which was filtered off and washed twice with deionized water. The filtered solid was dried at 60° C. overnight to give 6.15 g of crude product, which was treated with a 3:1 mixture of n-heptane and MTB ether (approximately 40 mL) and stirred vigorously for 3 h. The solid was filtered to give the desired product (5.7 g, 17.2 mmol, 68% yield) as a brown-green solid.

[0218] Example 11-2: Synthesis of methyl 4-bromo-5-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)amino]thiophene-2-carboxylate [ka] To an ice-cold suspension of methyl 5-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)amino]thiophene-2-carboxylate (1.25 g, 13.76 mmol) in acetonitrile (25 mL) was added N-bromosuccinimide (697 mg, 3.88 mmol). The reaction mixture was stirred at 0-5 °C for 1.5 h. The reaction mixture was diluted with deionized water and ethyl acetate and the insoluble contents were filtered off. The filtered solid was washed with additional ethyl acetate and dichloromethane. The aqueous phase was combined with DCM and ethyl acetate and extracted three times with EtOAc. The combined organic phase was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (cyclohexane / EtOAc 7:3) to give the desired product (1.35 g, 3.40 mmol, 90% yield) as a blue solid.

[0219] Example 11-3: Synthesis of methyl 4-bromo-5-[N-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2,2-dimethylpropanamido]thiophene-2-carboxylate [ka] Methyl 4-bromo-5-[(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)amino]thiophene-2-carboxylate (849 mg, 2.14 mmol) and 4-(dimethylamino)pyridine (53 mg, 0.43 mmol) were dissolved in DCM (17.0 mL) and N-ethyldiisopropylamine (515 μL, 3.00 mmol) was added. The reaction mixture was cooled to 0-5 °C and trimethylacetyl chloride (373 μL, 3.00 mmol) was added. The reaction mixture was allowed to warm to room temperature and stirred for 15 h. The reaction mixture was neutralized with saturated ammonium chloride solution, diluted with deionized water and extracted twice with DCM. The combined organic phase was washed twice with a mixture of deionized water and saturated ammonium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting product was purified by flash column chromatography (cyclohexane / EtOAc, 7:3) to give the desired product (944 mg, 1.94 mmol, 90% yield) as a beige solid.

[0220] Example 11-4: Methyl 7-(2,2-dimethylpropanoyl)-4-methyl-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(8),2,5,10-tetraene-10-carboxylate [ka] Methyl 4-bromo-5-[N-(5-bromo-2-methyl-2H-1,2,3-triazol-4-yl)-2,2-dimethylpropanamido]thiophene-2-carboxylate (1.13 g, 2.35 mmol) was dissolved in toluene (22.5 mL). Hexamethylditin (516 μL, 2.46 mmol) and tri-tert-butylphosphine (917 μL, 3.71 mmol) were added under argon. The flask was closed, placed under vacuum, sonicated for 2 min, and backfilled with argon. This procedure was repeated twice, followed by the addition of copper(I) iodide (232 mg, 1.22 mmol) and bis(tri-tert-butylphosphane)palladium (648 mg, 1.24 mmol) in a glove box. The flask was then closed, placed under vacuum, sonicated for 2 min, and backfilled with argon. The reaction mixture was stirred at 125° C. for 8 h.

[0221] The reaction mixture was filtered over Celite, washed with EtOAc, and concentrated under vacuum. The resulting solid was triturated with a 4:1 mixture of n-heptane and MTB ether, stirred for 2 h, and then filtered. Both the cut-off and filtrate were purified by flash column chromatography (cyclohexane / EtOAc, 8:2) to give the desired product (730 mg, 2.21 mmol, 95% yield) as a beige solid.

[0222] Example 11-5: Methyl 4-methyl-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(8),2,5,10-tetraene-10-carboxylate [ka] THF (1.7 mL) was cooled to 0° C. and 1.0 mL LDA (1.0 M in THF / hexanes, 1.0 mL, 1.04 mmol) was added. Then, methyl 7-(2,2-dimethylpropanoyl)-4-methyl-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0] in THF (6.7 mL) was added. 2,6A solution of ]undeca-1(8),2,5,10-tetraene-10-carboxylate (167 mg, 0.52 mmol) was added dropwise. The reaction was heated to 45 °C and stirred for 2 h. The reaction mixture was quenched with saturated ammonium chloride solution, diluted with water and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash column chromatography (cyclohexane / EtOAc, 60:40 to 100% EtOAc) to give the desired product in pure form (105 mg, 0.44 mmol, 80% yield, beige solid).

[0223] Example 11-6: Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 Synthesis of ]undeca-1(8),2,5,10-tetraene-10-carboxylate [ka] Methyl 4-methyl-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ]undeca-1(8),2,5,10-tetraene-10-carboxylate (155 mg, 0.53 mmol), 4-iodobenzotrifluoride (101 μL, 0.67 mmol), Cs 2 CO 3 (350 mg, 1.06 mmol), and N,N'-dimethylethylenediamine (58 μL, 0.53 mmol) were suspended in 1,4-dioxane (3.1 mL). The vial was placed under vacuum, sonicated for 2 min, and backfilled with argon twice, copper(I) iodide (50.7 mg, 0.27 mmol) was added, and the vacuum / argon procedure was repeated. The reaction mixture was stirred at 110 °C for 15 h. The reaction mixture was cooled to room temperature, filtered over Celite, and washed with EtOAc. The filtrate was concentrated and purified by flash column chromatography (cyclohexane / EtOAc, 8:2 to 100% EtOAc) to give the desired product (131 mg, 0.34 mmol, 40% yield) as a pale red solid.

[0224] Example 11-7: Synthesis of 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0{2,6}]undeca-1(8),2,5,10-tetraene-10-carboxylic acid [ka] Methyl 4-methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0] in a mixture of THF (4.0 mL) and deionized water (1.0 mL). 2,6 To a suspension of ]undeca-1(8),2,5,10-tetraene-10-carboxylate (131 mg, 0.34 mmol) was added lithium hydroxide (33.6 mg, 1.4 mmol). The reaction mixture was stirred at 50° C. for 22 h and at room temperature for 42 h. The reaction mixture was concentrated, diluted with water, acidified to pH 2 with 1 M aq. HCl, and extracted three times with EtOAc. The combined organic phases were dried over sodium sulfate, filtered, concentrated and dried (60° C., 18 h, 0.4 mbar) to provide the desired product (112 mg, 0.30 mmol, 88% yield) as a pale red solid.

[0225] Example 12: N,4-Dimethyl-7-[4-(trifluoromethyl)phenyl]-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 ]Undeca-1(8),2,5,10-tetraene-10-carboxamide [ka] 4-Methyl-7-[4-(trifluoromethyl)phenyl]-9-thia-3,4,5,7-tetraazatricyclo[6.3.0.0 2,6 To a solution of ]undeca-1(8),2,5,10-tetraene-10-carboxylic acid (30.0 mg, 0.08 mmol), methylammonium chloride (11.0 mg, 0.16 mmol), and 4-methylmorpholine (53.5 μL, 0.48 mmol) was added EDC.HCl (31.4 mg, 0.16 mmol) and HOBt (12.7 mg, 0.08 mmol). The reaction mixture was stirred at 40° C. for 18 h. The crude product was purified by preparative HPLC (SunFire C18, A:H 2 The pure fractions were combined and purified by elution with saturated NaHCO 3The solution was basified with ethyl acetate and the acetonitrile was evaporated off. The aqueous phase was extracted twice with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated to give the desired product (24.0 mg, 0.06 mmol, 79% yield) as a white solid.

[0226] Table 1 and Table 1a Tables 1 and 1a below show exemplary compounds of the invention, which were synthesized as described in or analogously to the examples above. Table 1 [Table 1-1]

[0227] [Table 1-2]

[0228] [Table 1-3]

[0229] [Table 1-4]

[0230] [Table 1-5]

[0231] [Table 1-6]

[0232] [Table 1-7]

[0233]

Table 1-8

[0234]

Table 1-9

[0235]

Table 1-10

[0236]

Table 1-11

[0237]

Table 1-12

[0238]

Table 1-13

[0239]

Table 1-14

[0240]

Table 1-15

[0241]

Table 1-16

[0242]

Table 1-17

[0243]

Table 1-18

[0244]

Table 1-19

[0245]

Table 1-20

[0246]

Table 1-21

[0247]

Table 1-22

[0248]

Table 1-23

[0249]

Table 1-24

[0250]

Table 1-25

[0251]

Table 1-26

[0252]

Table 1-27

[0253]

Table 1-28

[0254]

Table 1-29

[0255]

Table 1-30

[0256]

Table 1-31

[0257]

Table 1-32

[0258]

Table 1-33

[0259]

Table 1-34

[0260]

Table 1-35

[0261]

Table 1-36

[0262]

Table 1-37

[0263]

Table 1-38

[0264]

Table 1-39

[0265]

Table 1-40

[0266] Table 1a

Table 1a-1

[0267]

Table 1a-2

[0268]

Table 1a-3

[0269]

Table 1a-4

[0270]

Table 1a-5

[0271]

Table 1a-6

[0272]

Table 1a-7

[0273]

Table 1a-8

[0274]

Table 1a-9

[0275]

Table 1a-10

[0276]

Table 1a-11

[0277]

Table 1a-12

[0278]

Table 1a-13

[0279]

Table 1a-14

[0280]

Table 1a-15

[0281]

Table 1a-16

[0282]

Table 1a-17

[0283]

Table 1a-18

[0284] [Table 1a-19]

[0285] Method A: Column: Kinetex EVO C18 2.6μm, 3.0*50mm, Column oven: 40℃, Mobile phase A: Water / 5mM NH 4 HCO 3 , Mobile phase B: MeCN, Flow rate: 1.2 mL / min, Gradient: 10% B to 95% B in 2.1 min, 254 nm

[0286] Method B: Column: HALO C18, 2μM, 3.0*30mm, Column oven: 40℃, Mobile phase A: Water / 0.05%TFA, Mobile phase B: MeCN / 0.05%TFA, Flow rate: 1.2mL / min, Gradient: 5%B~100%B in 1.2min, 254nm

[0287] Method C: Column: Kinetex EVO C18 5.0μm, 50*4.6mm, Mobile phase A: H 2 O+0.1%TFA B: MeCN+0.1%TFA, 1%→99% B: 0→1.8min, 99%B: 1.8→2.1min, T: 40℃, flow: 3.3mL / min, 254nM

[0288] Method D: Column: HALO C18, 2.0μM, 3.0*30mm, Column oven: 40℃, Mobile phase A: Water / 0.1%TFA, Mobile phase B: MeCN / 0.1%TFA, Flow rate: 1.5mL / min, Gradient: 5%~95% in 1.2min, 254nm

[0289] Method E: Column: HALO C18, 2.0μM, 3.0*30mm, Column oven: 40℃, Solvent A: Water+0.05%TFA, Solvent B: MeCN+0.05%TFA, Flow: 1.2mL / min, Gradient: 20%B~95%B in 2.5min, 254nM

[0290] Method F: Column: Kinetex EVO C18, 2.6μm, 3.0*50mm, Column oven: 40℃, Mobile phase A: 6.5mM NH 4 HCO 3+ NH 4 OH (pH=10), Mobile phase B: MeCN; Flow rate: 1.2 mL / min, Gradient: 10% to 95% in 1.9 min, 254 nm

[0291] Method G: Column: HALO C18, 2.0μM, 3.0*30mm, column oven: 40C, solvent A: water+0.05%TFA, solvent B: MeCN+0.05%TFA, flow: 1.2mL / min, gradient: 30%B~95%B by 1.2min, 254nm.

[0292] Method H: Column: Kinetex UPLC EVO C18, 1.7μm, 2.1*50mm, Column oven: 40℃, Mobile phase A: 6.5mM H 2 O + 0.05% HCO 2 H, mobile phase B: MeCN+0.04%HCO 2 H;Flow rate: 0.9mL / min, 1%→99% B: 0→1.0min, 99% B: 1.0→1.3min, 254nm

[0293] biological activity SK-HEP-1 reporter assay To identify inhibitors of the YAP-TEAD interaction, the 8xTEAD response element driving the NanoLuc® luciferase gene was stably engineered into SK-HEP-1 cells (ECACC#:91091816).

[0294] For the assay, cells were treated in duplicate with ten doses of test compound starting at 30 μM (final concentration in the assay). After 24 h incubation at 37° C., 95% rH2O, and 5% CO2, 2 A luciferase substrate / lysis reagent mix (NanoGlo™, Promega) was then added to the cells to allow quantification of cellular luciferase activity.

[0295] Cell Culture Media: 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.

[0296] reagent: The reagents used are listed below: [Table A]

[0297] Cell culture: Cells were examined using an inverted microscope to check for health and cell density. To dissociate attached cells, the monolayer was washed once with pre-warmed PBS. After removing the PBS, 3ml pre-warmed Accutase® was added to the F75 flask, evenly distributed, and the flask was placed in the incubator for ~4-5 minutes.

[0298] Once a single cell suspension was obtained, 7 ml of pre-warmed growth medium was added and resuspended with the cells. The cell suspension was transferred to a sterile 15 ml conical centrifuge tube and spun at 300xg for 5 min at RT. The supernatant was discarded and the pellet was resuspended in 10 ml of pre-warmed growth medium.

[0299] 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 a Multidrop Combi. The plate was then incubated at 37° C., 95% rH, and 5% CO 2 The mixture was incubated at RT for 24 hours.

[0300] Compound Treatment: 24 hours after seeding, cells were treated with compounds. Compounds were diluted 1:333 in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer compounds to the assay plate, 120 nl was dispensed with an ECHO 555 liquid handling system from a Labcyte low dead volume plate onto the cell plate containing 20 μl medium / well.

[0301] After treatment, cells were injected with fresh 20 μl pre-warmed assay medium using a Multidrop combi. The assay plate was then incubated at 37°C, 95% rH, and 5% CO 2 The mixture was incubated at RT for another 24 h.

[0302] Luciferase Readout: 24 h after treatment, plates were removed from the incubator and allowed to equilibrate to RT. 30 μl of NanoGlo® Reagent was added to the plate in the dark. Plates were shaken in the dark on a Teleshake (~1500 rpm) for 20 min. Luminescence was then measured using an EnVision microplate reader. IC50 values ​​were generated using Genedata Screener®.

[0303] Survival assay in NCI-H226 (Yap-dependent) and SW620 Yap KO (Yap-independent) cells The ability of YAP-TEAD inhibitors to inhibit tumor cell growth was evaluated using two different cell lines: NCI-H226, a YAP-dependent cell line, and SW620 cells, in which YAP and TAZ were knocked out using CRISPR to generate a YAP-dependent cell line.

[0304] For the assay, cells were treated in duplicate with ten doses of test compound in 1:3 dilution steps starting at 30 μM (final concentration in the assay). After 96 h incubation at 37° C., 95% rH2O, and 5% CO2, 2 A cell-permeable DNA-binding dye that only stains healthy cells (CyQUANT®, Promega) was added to the cells, allowing quantification of cell viability.

[0305] Cell Culture Media: 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.

[0306] reagent: The reagents used are listed below: [Table B]

[0307] Cell culture: Cells were examined using an inverted microscope to check for health, cell density, etc. To dissociate attached cells, the cell monolayer was washed once with pre-warmed PBS. After removing the PBS, 3ml pre-warmed Accutase was added to the F75 flask, evenly distributed, and the flask was placed in the incubator for approximately 4 minutes or 4-5 minutes.

[0308] Once a single cell suspension was obtained, 7 ml of pre-warmed Growth Medium was added and resuspended with the cells. The cell suspension was transferred to a sterile 15 ml conical centrifuge tube and spun at 300xg for 5 min at RT. The supernatant was discarded and the pellet was resuspended in 10 ml of pre-warmed Growth Medium.

[0309] 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 a Multidrop Combi. The plate was then incubated at 37° C., 95% rH, and 5% CO 2 The mixture was incubated at RT for 24 hours.

[0310] Compound Treatment: 24 hours after seeding, cells were treated with compounds. Compounds were diluted 1:333 in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer compounds to the assay plate, 120 nl was dispensed with an ECHO 555 liquid handling system from a Labcyte low dead volume plate onto the cell plate containing 20 μl medium / well.

[0311] After treatment, cells were injected with fresh 20 μl pre-warmed assay medium using a Multidrop combi. The assay plate was then incubated at 37°C, 95% rH, and 5% CO 2 The mixture was incubated at RT for 96 h.

[0312] CyQuant® Measurement 96 h 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% CO. 2 The plates were then incubated at RT for 1 h. Afterwards, the assay plates were removed from the incubator and allowed to warm to RT in the dark without the lid for 30 min. Finally, they were measured using an EnVision microplate reader with the FITC bottom reading program.

[0313] Experimental data in the SK-HEP-1 reporter assay for the compounds shown in Table 1 and Table 1a are shown in Table 2 below and are divided into the following groups: Group A IC 50 is in the range of 1nM to 10nM Group B IC 50is in the range of >10nM to 100nM Group C IC 50 is in the range of >100nM to 10,000nM Group D IC 50 is in the range of >10000nM nd Not detectable below the threshold given in brackets

[0314] Experimental data in the viability assay for the compounds shown in Table 1 and Table 1a are shown in Table 2 below and are divided into the following groups: NCI-H226 For cell viability assays: Group A IC 50 is in the range of 1nM to 100nM Group B IC 50 is in the range of >10nM to 100nM Group C IC 50 is in the range of >100nM to 10,000nM Group D IC 50 is in the range of >10000nM nd Not detectable below the threshold given in brackets

[0315] SW620 Yap KO cells For viability assays in: Group A IC 50 is in the range of 0.1μM to 1μM Group B IC 50 is in the range of >1μM to 10μM Group C IC 50 is in the range of >10μM to 30μM Group D IC 50 is in the range of >30 μM nd Not detectable below the threshold given in brackets

[0316] Table 2 [Table 2-1]

[0317] [Table 2-2]

[0318] [Table 2-3]

[0319] [Table 2-4]

[0320] [Table 2-5]

[0321] The following examples relate to pharmaceuticals: Example A: Injection vial A solution of 100 g of the active ingredient of formula I and 5 g of disodium hydrogen phosphate in 3 liters of double-distilled water is adjusted to pH 6.5 using 2N hydrochloric acid, sterile filtered, transferred into injection vials, lyophilized under sterile conditions and sealed under sterile conditions, each injection vial containing 5 mg of the active ingredient.

[0322] Example B: Suppositories A mixture of 20 g of an active ingredient of formula I, 100 g of soya lecithin and 1400 g of cocoa butter is melted and poured into moulds and allowed to cool. Each suppository contains 20 mg of the active ingredient.

[0323] Example C: Solution In 940 mL of double-distilled water, 1 g of the active ingredient of formula I, 9.38 g of NaH 2 PO 4 2H 2 O, 28.48g Na 2 HPO 4 12H 2A solution is prepared from 0.01 g of 1000 mM sodium chloride, 0.1 g of benzalkonium chloride, the pH is adjusted to 6.8, the solution is made up to 1 l and sterilized by irradiation. This solution can be used in the form of eye drops.

[0324] Example D: Ointment 500 mg of an active ingredient of formula I is mixed with 99.5 g of petrolatum under sterile conditions.

[0325] Example E: Tablets A mixture of 1 kg of active ingredient of formula I, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc, and 0.1 kg of magnesium stearate is compressed in a conventional manner to give tablets, each tablet containing 10 mg of active ingredient.

[0326] Example F: Dragees Tablets are compressed similarly to Example E and subsequently coated in a conventional manner with a coating of sucrose, potato starch, talc, tragacanth, and dye.

[0327] Example G: Capsule 2 kg of the active ingredient of formula I are conventionally introduced into hard gelatin capsules such that each capsule contains 20 mg of active ingredient.

[0328] Example H: Ampoule A solution of 1 kg of the active ingredient of formula I in 60 l of double-distilled water is sterile filtered into ampoules, lyophilized under sterile conditions and sealed under sterile conditions, each ampoule containing 10 mg of the active ingredient.

Claims

1. Formula I 【Chemistry 1】 During the ceremony Ring A is the following ring moiety: 【Chemistry 2】 represents a 5-membered heteroaromatic ring selected from the group consisting of: Ring B is 【Transformation 3】 During the ceremony R １ Ar 1, Hetar １ , Cyc １ , or Hetcyc 1 ; R ２ is -C(=O)-OR ２ａ , -C(=O)-NR ２ｂ R ２ｃ , -(CH ２ ) ｗ —C(═O)—NR ２ｂ R ２ｃ , -(CH ２ ) ｘ -NR ２ｄ -C(=O)-R 2e , Br, -CN, -(CH ２ ) ｙ -NR ２ｑ R ２ｒ , -(CH ２ ) ｚ -NR ２ｄ -S(=O) ２ -R ２ｇ , -N=S(=O)-R ２ｓ R ２ｔ , -C(=O)-N=S(=O)-R ２ｓ R 2t, or Hetcyc Ｘ Represents; R Ａ１ represents methyl; R A2 represents H; Ar 1, Ar ３ are, independently of each other, mono-, bi-, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, where the aryl is unsubstituted or has a substituent R Ｂ１ , R Ｂ２ , R Ｂ３ , R Ｂ４ , R Ｂ５ , R Ｂ６ , and / or R Ｂ７ (which may be the same or different); Ar ２ , Ar ２ｂ , Ar ４ are, independently of each other, monocyclic or bicyclic aryl having 5, 6, 7, 8, 9, or 10 ring carbon atoms, where the aryl is unsubstituted or contains a substituent R Ｄ１ , R Ｄ２ , R Ｄ３ , R Ｄ４ , and / or R Ｄ５ (which may be the same or different); Ar Ｘ , Ar Ｚ are, independently of each other, unsubstituted or substituted benzo rings; Ar Ｙ is unsubstituted or mono- or di-substituted phenyl; Hetar １ , Hetar ３ are, independently of each other, mono-, bi-, 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 heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may be substituted with a substituent R Ｂ１ , R Ｂ２ , R Ｂ３ , R Ｂ４ , R Ｂ５ , R Ｂ６ , and / or R Ｂ７ (which may be the same or different); Hetar ２ａ , Hetar ２ｂ , Hetar ４ , Hetar Ｙ１ are, independently of each other, monocyclic or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, where 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, where the heteroaryl may be unsubstituted or may contain a substituent R Ｄ１ , R Ｄ２ , R Ｄ３ , R Ｄ４ , and / or R Ｄ５ (which may be the same or different); Hetar Ｚ is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Cyc １ , Cyc ３ are, independently of each other, saturated or partially unsaturated, mono-, bi-, or tricyclic carbocyclic rings having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, where the carbocyclic rings may be unsubstituted or may be substituted with R Ｂ８ , R Ｂ９ , R Ｂ１０ , R Ｂ１１ , R Ｂ１２ , and / or R Ｂ１３ (which may be the same or different); and wherein the carbocycle is optionally substituted with Ar Ｘ and the Ar Ｘ and wherein the fused carbocycle may be unsubstituted or may be fused through two adjacent ring atoms of R Ｃ１ , R Ｃ２ , R Ｃ３ , R Ｃ４ , R Ｃ５ , R Ｃ６ (which may be the same or different); Cyc ２ａ , Cyc4 are, independently of each other, saturated or partially unsaturated mono-tricyclic carbocyclic rings having 3, 4, 5, 6, or 7 ring carbon atoms, where the carbocyclic rings may be unsubstituted or may be substituted with R Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , and / or R Ｄ１０ (which may be the same or different); Cyc ２ｂ is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or may be, independently of each other, R Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , and / or R Ｄ１０ wherein the carbocycle is optionally substituted with Ar Ｚ or Hetar Ｚ and R Ｃ１ , R Ｃ２ , and / or R Ｃ３ may be further substituted with; Cyc Ｙ１ is a saturated or partially unsaturated, monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbocyclic ring may be unsubstituted or may contain halogen, hydroxy, unsubstituted or substituted C １～６ - optionally aliphatically substituted; Hetcyc １ , Hetero ３ are, independently of each other, saturated or partially unsaturated, mono-, bi-, or tricyclic heterocycles having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, in which 1, 2, 3, 4, or 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycle may be unsubstituted or may be substituted with R Ｂ８ , R Ｂ９ , R Ｂ１０ , R Ｂ１１ , R Ｂ１２ , and / or R Ｂ１３ (which may be the same or different); Hetcyc ２ａ , Hetcyc ４ are, independently of each other, saturated or partially unsaturated, monocyclic heterocycles having 3, 4, 5, 6, 7 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, in which the heterocycles may be unsubstituted or may be substituted with R Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , and / or R Ｄ１０ (which may be the same or different); Hetcyc ２ｂ is a saturated monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and in which the heterocycle may be unsubstituted or may be, independently of each other, Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , and / or R Ｄ１０ wherein the heterocycle is optionally substituted with Ar Ｚ or Hetar Ｚ and wherein the fused heterocycles are optionally fused to, independently of each other, R Ｃ１ , R Ｃ２ , and / or R Ｃ３ may be further substituted with; Hetcyc Ｘ are 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-oxadiazol-3-yl (2H-1,2,4-oxadiazol-5-one-3-yl), 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl (4H-1,2,4-oxadiazol-5-one-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3-chloro-4,5-dihydro-1,2-oxazol-5-yl, 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-(pyrimidin-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3-hydroxy-oxetan-3-yl, 5-hydroxy-4H-pyran-4-one-2-yl, 3,3-difluoropyrrolidin-2-one-4-yl, 3,3-difluoropyrrolidin-2-one-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-one-4-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-one-5-yl; Hetcyc Ｙ is a saturated, partially unsaturated, or aromatic monocyclic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms; Hetcyc Ｙ１ is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; L3 is -S(=O) ２ -, -C(=O)-, unsubstituted or substituted, straight or branched C １～６ -Alkylene or C ２～６ -alkenylene, in which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; L4 is -C(=O)-, unsubstituted or substituted, linear or branched C １～６ -Alkylene or C ２～６ -alkenylene, in which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; R ２ａ is H, unsubstituted or substituted C １～８ - Aliphatic, Ar ２ａ , Hetar ２ａ , Cyc ２ａ , Hetcyc ２ａ , or represents Cat; Cat represents a monovalent cation; R ２ｂ , R ２ｃ Both represent H; Or, R ２ｂ and R ２ｃ one of which is H or unsubstituted or substituted C １～８ - represents aliphatic, whereas R ２ｂ and R ２ｃ The other is unsubstituted or substituted C １～１０ -Aliphatic, -OH, -OC １～６ -Alkyl, -CN, -S(=O) ２ -R ２ｇ , Ar ２ｂ , Hetar ２ｂ , Cyc ２ｂ , or Hetcyc ２ｂ Represents; Or, R ２ｂ and R ２ｃ together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one of the further ring atoms is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R 2d is H, unsubstituted or substituted C １～８ - represents aliphatic; R ２ｅ is H, halogen, unsubstituted or substituted C １～８ - aliphatic, aryl, heteroaryl; saturated or partially unsaturated heterocyclyl; R 2g are each independently unsubstituted or substituted C １～８ - represents aliphatic; R 2q, R ２ｒ are each independently H, unsubstituted or substituted C １～８ - represents an aliphatic group; or R ２ｌ is R ２ｍ together with and / or R ２ｑ is R ２ｒ together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there are no further ring atoms, or one further ring atom is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; R ２ｓ , R ２ｔ are each independently an unsubstituted or substituted C １～８ - aliphatic; or together, unsubstituted or substituted divalent C ３～６ - forming an alkylene radical; R B1, R Ｂ２ , R Ｂ３ , R Ｂ４ , R Ｂ５ , R Ｂ６ , R Ｂ７ are each independently an unsubstituted or substituted, straight-chain or branched C １～６ - Aliphatic, C １～６ -aliphatic oxy, -S-C １～６ -Aliphatic; halogen, -CN, -SF ５ , -S(=O)-R ｂ１ , S(=O) ２ -R ｂ１ , -NR ｂ２ NR ｂ３ , Ar ４ , -CH ２ -Ar ４ , Hetar ４ , Cyc ４ , Hetcyc ４ Represents; Alternatively, two adjacent R Ｂ１ , R Ｂ２ , R Ｂ３ , R Ｂ４ , R Ｂ５ , R Ｂ６ , and / or R Ｂ７ together, divalent -C ２～４ - an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C １～３ - alkylene radical or divalent -O-C １～３ -forming an alkylene-O- radical; R Ｂ８ , R Ｂ９ , R Ｂ１０ , R Ｂ１１ , R Ｂ１２ , R Ｂ１３ are each independently a halogen, an unsubstituted or substituted C １～６ - Aliphatic, C １～６ - aliphatic oxy, Ar Ｙ Represents; Alternatively, R are attached to the same carbon atom of the carbocyclic or heterocyclic ring. Ｂ８ , R Ｂ９ , R Ｂ１０ , R Ｂ１１ , R Ｂ１２ , R Ｂ１３ two of which form a divalent oxo (=O) group; Alternatively, R are attached to the same sulfur atom of the heterocycle. Ｂ８ , R Ｂ９ , R Ｂ１０ , R Ｂ１１ , R Ｂ１２ , R Ｂ１３ Two of these, or R Ｂ８ , R Ｂ９ , R Ｂ１０ , R Ｂ１１ , R Ｂ１２ , R Ｂ１３ Four of these form a divalent oxo (=O) group, thereby forming a -S(=O)- moiety or -S(=O) ２ - any of the parts is formed; R Ｃ１ , R Ｃ２ , R Ｃ３ , R Ｃ４ , R Ｃ５ , R Ｃ６ are, independently of one another, unsubstituted or substituted C １～６ - represents aliphatic; R Ｄ１ , R Ｄ２ , R Ｄ３ , R Ｄ４ , R Ｄ５ are each independently a halogen, an unsubstituted or substituted C １～６ - represents aliphatic; R Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , R Ｄ１０ are each independently halogen, hydroxy, unsubstituted or substituted C １～６ -aliphatic, unsubstituted or substituted -OC １～６ - Aliphatic, Hetar Ｙ１ , C.H. ２ -Hetar Ｙ１ , Cyc Ｙ１ , Hetcyc Ｙ１ , -CH ２ -Hetcyc Ｙ１ Represents; and / or R attached to the same ring atom of the carbocyclic or heterocyclic ring. Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , R Ｄ１０ Two of them are divalent C ２～６ - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ -alkyl, and wherein the alkylene radical is optionally substituted by OH, C １～６ -aliphatic, or -O-C １～６ - optionally aliphatically substituted; and / or R attached to two 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 - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ - optionally substituted by alkyl; R Ｘ１ , R Ｘ２ , R Ｘ３ , R Ｘ４ , R Ｘ５ , R Ｘ６ , R Ｘ７ , R Ｘ８ are each independently an unsubstituted or substituted C １～６ - Aliphatic, C １～６ -Aliphatic oxy, halogen, -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 R form a divalent oxo (=O) group; and / or are attached to the same sulfur atom of the heterocycle; Ｘ１ , R Ｘ２ , R Ｘ３ , R Ｘ４ , R Ｘ５ , R Ｘ６ , R Ｘ７ , R Ｘ８ Two of these, or R Ｘ１ , R Ｘ２ , R Ｘ３ , R Ｘ４ , R Ｘ５ , R Ｘ６ , R Ｘ７ , R Ｘ８ Four of these form a divalent oxo (=O) group, thereby forming a -S(=O)- moiety or -S(=O) ２ - any of the parts is formed; R ｂ１ is unsubstituted or substituted C １～８ - represents aliphatic; R ｂ２ , R ｂ３ are each independently H, unsubstituted or substituted C １～８ - represents aliphatic; or they together with the nitrogen atom to which they are attached form an unsubstituted or substituted, saturated, partially unsaturated, or aromatic heterocycle having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there are no additional ring atoms, or one additional ring atom is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; Halogen is F, Cl, Br, I; w is 1 or 2; x is 0, 1, or 2; y is 0, 1, or 2; z is 0, 1, or 2; or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in all ratios.

2. R １ But Ar １ , Hetar １ , Cyc １ , Hetcyc １ where optionally R 1 represents 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl; Ar １ is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryl is unsubstituted or contains a substituent R Ｂ１ , R Ｂ２ , and / or R Ｂ３ (which may be the same or different); preferably phenyl or naphthalenyl, especially unsubstituted or substituted with the substituent R Ｂ１ and / or R Ｂ２ (which may be the same or different); Ar ４ is phenyl; Ar Ｘ is an unsubstituted benzo ring; Ar Ｙ is phenyl; Hetar １ is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, where 1, 2, or 3 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and the heteroaryl may be unsubstituted or may contain a substituent R Ｂ１ , R Ｂ２ , and / or R Ｂ３ (which may be the same or different); preferably, heteroaryl is unsubstituted or is substituted with a substituent R Ｂ１ and / or R Ｂ２ (which may be the same or different); Hetar ４ is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms; preferably a monocyclic heteroaryl having 5 ring atoms, wherein one of the ring atoms is N and the remainder are carbon atoms, or one of the ring atoms is N, one of the ring atoms is S, and the remainder are carbon atoms; Cyc １ is a saturated or partially unsaturated, mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, wherein the carbocyclic ring may be unsubstituted or may be substituted with R Ｂ８ and / or R Ｂ９ (which may be the same or different); and wherein the carbocycle is optionally substituted with Ar Ｘ and the Ar Ｘ and wherein the fused carbocycle may be unsubstituted or may be fused through two adjacent ring atoms of R Ｃ１ and / or R Ｃ２ (which may be the same or different); Cyc ４ is cyclopropyl, cyclobutyl, cyclopentyl, each of which may be unsubstituted or R Ｄ６ or independently of each other, R Ｄ６ and R Ｄ７ optionally disubstituted with; Hetcyc １ is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, wherein one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and wherein the heterocycle may be unsubstituted or may be substituted with R Ｂ８ and / or R Ｂ９ (which may be the same or different), where if one of the heteroatoms is S, then the heterocycle may also be substituted with R Ｂ８ , R Ｂ９ , R Ｂ１０ , and R Ｂ１１ and preferably saturated monocyclic heterocycles having 5 or 6 ring atoms, where one of the ring atoms is a heteroatom selected from O and S, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or may be substituted with R Ｂ８ and / or R Ｂ９ (which may be the same or different), where if one of the heteroatoms is S, then the heterocycle may also be substituted with R Ｂ８ , R Ｂ９ , R Ｂ１０ , and R Ｂ１１ and optionally substituted; Hetcyc ４ is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or R Ｄ６ or independently of each other, R Ｄ６ and R Ｄ７ optionally disubstituted with; R B1, R Ｂ２ , R Ｂ３ are each independently a straight-chain or branched C １～６ - represents alkyl, but its C １～６ -Alkyl may be unsubstituted or monosubstituted with -CN or may be substituted with 1, 2 or 3 halogens, straight or branched C １～４ -alkoxy, and １～４ -alkoxy may be unsubstituted or may contain one, two or three halogens, -O-CH ２ -C≡CH, straight or branched -S-C １～４ -alkyl, and the -S-C １～４ -Alkyl may be unsubstituted or may contain 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 ４ , -CH ２ -Ar ４ , Hetar ４ , Cyc ４ , Hetcyc ４ optionally substituted with; Alternatively, two adjacent R Ｂ１ , R Ｂ２ , and / or R Ｂ３ together, divalent -C ３～４ - an alkylene radical, one of whose alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-), or a divalent -O-C ２～３ - forming an alkylene radical; R Ｂ８ , R Ｂ９ However, independently of each other, F, C １～２ - represents alkyl, but its C １～２ -Alkyl may be unsubstituted or contain 1, 2 or 3 F, C １～２ -alkoxy, Ar Ｙ optionally substituted with; Or, R Ｂ８ and R Ｂ９ wherein the carbocyclic ring Cyc １ or the heterocycle Hetcyc １ are attached to the same carbon atom of and form a divalent oxo (=O) group; Or, R Ｂ８ and R Ｂ９ and R Ｂ１０ and R Ｂ１１ are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=O) groups, thereby forming -S(=O) ２ - parts are formed; R Ｃ１ and R Ｃ２ However, independently of each other, C １～６ represents alkyl, which may be substituted, independently of one another, by 1, 2 or 3 F atoms; R Ｄ６ , R Ｄ７ are each independently substituted by 1, 2 or 3 F atoms or 1 hydroxy group; １～６ - alkyl; or hydroxy; The halogen is F, Cl, or Br; 10. A compound according to claim 1, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in all proportions.

3. R ２ is -C(=O)-OR ２ａ or Hetcyc Ｘ represents; and arbitrarily R 2a represents H, linear or branched, unsubstituted or substituted C 1-4 -alkyl or Cat; Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na), and potassium (K); Hetcyc X represents 5-oxo-2,5-dihydro-1,2,4-oxadiazol-3-yl (2H-1,2,4-oxadiazol-5-one-3-yl) or 5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl (4H-1,2,4-oxadiazol-5-one-3-yl), A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in any ratio.

4. R ２ is -C(=O)-OR ２ａ Represents; R ２ａ represents H or Na, A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in any ratio.

5. R ２ is -C(=O)-NR ２ｂ R ２ｃ Represents; And, moreover (a) R ２ｂ , R ２ｃ Both represent H; or (b) R ２ｂ and R ２ｃ One of them represents H, while R ２ｂ and R ２ｃ The other is Cyc ２ｂ , Hetcyc ２ｂ , linear or branched C １～１０ - alkyl (which may be unsubstituted or R Ｅ１ , R Ｅ２ , R Ｅ３ , R Ｅ４ , and / or R Ｅ５ (which may be the same or different), wherein the C １～１０ In -alkyl, one or two non-adjacent and non-terminal methylene moieties are independently -O- and / or -S- and / or -NH- and / or -N(C １～４ -alkyl)-; Cyc ２ｂ is a saturated monocyclic carbocycle having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or may be, independently of each other, Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , and / or R Ｄ１０ wherein the carbocycle is optionally substituted with Ar Ｚ or Hetar Ｚ and R Ｃ１ , R Ｃ２ , and / or R Ｃ３ may be further substituted with; Hetcyc ２ｂ is a saturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and wherein the heterocycle may be unsubstituted or may be, independently of each other, Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , and / or R Ｄ１０ wherein the heterocycle is optionally substituted with Ar Ｚ or Hetar Ｚ and wherein the fused heterocycles are optionally fused to, independently of each other, R Ｃ１ , R Ｃ２ , and / or R Ｃ３ may be further substituted with; R Ｅ１ , R Ｅ２ , R Ｅ３ , R Ｅ４ , and / or R Ｅ５ are, independently of one another, halogen, in particular F; -NR Ｅａ R Ｅｂ , OR Ｅｃ , Ar Ｅ , Hetar Ｅ , Cyc Ｅ , Hetcyc Ｅ Represents; Ar Ｅ is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryl is unsubstituted or contains a substituent R Ｆ１ , R Ｆ２ , and / or R Ｆ３ (which may be the same or different); especially phenyl or naphthalenyl; Ar Ｚ is a benzo; Hetar Ｅ is a monocyclic heteroaryl having 5 or 6 ring atoms, or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, 3, or 4 of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and wherein the heteroaryl is unsubstituted or contains a substituent R Ｆ１ , R Ｆ２ , and / or R Ｆ３ (which may be the same or different); especially imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl (each of which may be unsubstituted or substituted with C １～４ -alkyl); pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl (each of which may be unsubstituted or monosubstituted with -F); pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl; Hetar Ｙ１ is a 5- or 6-membered monocyclic heteroaryl (wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may be selected from F, C, １～４ -alkyl (optionally substituted by OH); especially pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl, methylpyrimidinyl; Hetar Ｙ２ is a 5- or 6-membered monocyclic heteroaryl (wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain halogen, C １～４ -alkyl (optionally substituted by OH); especially pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl; Hetar Ｚ is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Cyc Ｅ is a saturated or partially unsaturated mono- or bicyclic carbocyclic ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, which carbocyclic ring may be unsubstituted or may be substituted with R Ｇ１ and / or R Ｇ２ (which may be the same or different): saturated monocyclic carbocycles, especially those having 3, 4, 5, or 6 ring carbon atoms, where the carbocycle may be unsubstituted or may be substituted with R Ｇ１ and / or R Ｇ２ (which may be the same or different); Cyc Ｙ１ is a saturated or partially unsaturated, monocyclic carbocyclic ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbocyclic ring may be unsubstituted or may contain halogen, OH, C １～４ -alkyl), especially cyclopropyl, cyclohexenyl; Hetcyc Ｅ is a saturated or partially unsaturated, monocyclic heterocycle having 4, 5, or 6 ring atoms, wherein one or two of the ring atoms are heteroatom(s) selected from N, O, and / or S, and the remainder are carbon atoms, and wherein the heterocycle may be unsubstituted or may be substituted with R Ｇ１ and / or R Ｇ２ (which may be the same or different); especially saturated monocyclic heterocycles having 4, 5 or 6 ring atoms, where one or two of the ring atoms are heteroatom(s) selected from N and / or O, and the remainder are carbon atoms, where the heterocycle may be unsubstituted or may be substituted with R Ｇ１ and / or R Ｇ２ -substituted with); preferably azetidinyl, azetidin-3-yl, tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl (each of which may be unsubstituted or monosubstituted with -OH); morpholinyl, morpholin-1-yl, morpholin-2-yl, morpholin-4-yl (each of which may be unsubstituted or monosubstituted with methyl); 1,4-dioxanyl; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl; Hetcyc Ｙ１ is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl; Hetcyc Ｙ２ is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl, morpholinyl, tetrahydropyranyl; R Ｃ１ , R Ｃ２ , R Ｃ３ However, independently of each other, C １～４ represents alkyl; R Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , R Ｄ１０ are, independently of one another, halogen, in particular F; hydroxy; C optionally substituted with —OH and / or halogen; １～４ - alkyl, especially methyl, hydroxymethyl, 2-fluoroethyl; １～４ - alkyl, especially methoxy, ethoxy; Hetar Ｙ１ , -CH ２ -Hetar Ｙ１ , Cyc Ｙ１ , Hetcyc Ｙ１ , -CH ２ -Hetcyc Ｙ１ Represents; and / or R attached to the same ring atom of the carbocyclic or heterocyclic ring. Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , R Ｄ１０ Two of them are divalent C ２～６ - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ -alkyl, and wherein the alkylene radical is optionally substituted by OH, C １～４ -alkyl, or -O-C １～４ -alkyl, especially -(CH ２ ) ３ -, -CH ２ -CH(OC ２ H ５ )-CH ２ -, -(CH ２ ) ２ -O-(CH ２ ) ２ optionally substituted with -; and / or R Ｄ６ , R Ｄ７ , R Ｄ８ , R Ｄ９ , R Ｄ１０ (which are attached to two different ring atoms of the carbocyclic or heterocyclic ring) are divalent C １～６ - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ -alkyl, especially -CH ２ -, -(CH ２ ) ３ -, -O-(CH ２ ) ２ -, -O-(CH ２ ) ３ - may be replaced by; R Ｅａ , R Ｅｂ However, independently of each other, H, C １～４ -alkyl, -C(=O)-C １～４ -Alkyl, -C(=O)-OC １～４ represents alkyl; R Ｅｃ is H or C １～４ represents alkyl; R Ｆ１ , R Ｆ２ , R Ｆ３ are each independently a straight-chain or branched C １～６ -Alkyl (its C １～６ -Alkyl may be unsubstituted or may be substituted with -CN, OH, -O-C １～４ - alkyl or substituted with 1, 2 or 3 halogens): straight or branched C １～４ -alkoxy (the C １～４ -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens; straight or branched -SC １～４ -Alkyl (the -S-C １～４ - alkyl may be unsubstituted or substituted with 1, 2 or 3 halogens; halogen, OH, and / or C １～４ - optionally substituted with alkyl, C ３～７ -cycloalkyl; F, Cl, Br, -CN, -S(=O)-C １～３ -Alkyl, S(=O) ２ -C １～３ -Alkyl, -NH ２ , —NH(C １～３ -alkyl)-N(C １～３ -alkyl) ２ , —OH; especially methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably R Ｆ１ , R Ｆ２ , and R Ｆ３ is present and represents methyl or F; and / or R Ｆ１ , R Ｆ２ , R Ｆ３ (which are attached to two different ring atoms of the aryl or heteroaryl) are divalent C １～６ - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ -alkyl, especially -(CH ２ ) ４ -, -CH ２ -O-(CH ２ ) ２ - may be replaced by; R Ｇ１ , R Ｇ２ are each independently selected from halogen; hydroxy; unsubstituted or substituted C １～６ - aliphatic, in particular C optionally substituted with OH １～４ - alkyl; C １～６ - aliphatic oxy, especially -O-C １～４ -Alkyl; -C(=O)-O-C １～４ - alkyl; Hetar Ｙ２ ;-CH ２ -Hetar Ｙ２ ; Hetcyc Ｙ２ In particular, R Ｇ１ and R Ｇ２ is present and represents hydroxy; and / or R Ｇ１ and R Ｇ２ (which are attached to the same ring atom of the carbocyclic or heterocyclic ring) but a divalent C ２～６ - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ -alkyl, and wherein the alkylene radical is optionally substituted by OH, C １～４ -alkyl, or -O-C １～４ -alkyl, especially -(CH ２ ) ２ -O-CH ２ -, -(CH ２ ) ２ -O-(CH ２ ) ２ optionally substituted with -; and / or R Ｇ１ and R Ｇ２ (which are attached to two different ring atoms of the carbocyclic or heterocyclic ring) is a divalent C １～６ - alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N-C １～４ -alkyl, especially -CH ２ - may be replaced by; or (c) R ２ｂ and R ２ｃ one of which is optionally substituted with OH or halogen, １～１０ - alkyl, whereas R ２ｂ and R ２ｃ The other is Cyc ２ｂ , Hetcyc ２ｂ , linear or branched C １～１０ - alkyl (which may be unsubstituted or R Ｅ１ , R Ｅ２ , R Ｅ３ , R Ｅ４ , and / or R Ｅ５ (which may be the same or different), wherein Cyc ２ｂ , Hetcyc ２ｂ , R Ｅ１ , R Ｅ２ , R Ｅ３ , R Ｅ４ , and R Ｅ５ is as defined under (b) above, and wherein C １～１０ In -alkyl, one or two non-adjacent and non-terminal methylene moieties are independently -O- and / or -S- and / or -NH- and / or -N(C １～４ -alkyl)-; or (d) R ２ｂ and R ２ｃ together with the nitrogen atom to which they are attached form a saturated or partially unsaturated heterocycle, said rings optionally being independently Ｙ１ , R Ｙ２ , R Ｙ３ , R Ｙ４ , and / or R Ｙ５ wherein the heterocycle is optionally substituted with Hetar Ｚ and wherein the heterocycle is selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, morpholine; R Ｙ１ , R Ｙ２ , R Ｙ３ , R Ｙ４ , R Ｙ５ are, independently of one another, halogen, in particular F; ２ , —N(H)—C １～４ -Alkyl, -N(H)-C(=O)-O-C １～４ -alkyl, -N(C １～４ -alkyl) ２ -OH; C optionally substituted with -OH １～４ -alkyl, -O-C １～４ -alkyl, -O-C ３～７ -cycloalkyl, -O-CH ２ -C ３～７ -cycloalkyl, especially methyl, -CH ２ OH, -(CH ２ ) ２ OH, -(CH ２ ) ３ OH, -CH ２ OCH ３ , -(CH ２ ) ２ OCH ３ , cyclopropylmethoxy; —O—C １～４ - alkyl, especially methoxy; Hetar Ｙ２ ;-CH ２ -Hetar Ｙ２ ; Hetcyc Ｙ２ Represents; and / or R attached to the same ring atom of the heterocycle Ｙ１ , R Ｙ２ , R Ｙ３ , R Ｙ４ , R Ｙ５ Two of them are divalent C ２～６ an alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N—C １～４ -alkyl), especially -(CH ２ ) ４ -, -(CH ２ ) ２ -O-(CH ２ ) ２ -, -(CH ２ ) ２ -O-(CH ２ ) ３ - forming; and / or R attached to two different ring atoms of the heterocycle Ｙ１ , R Ｙ２ , R Ｙ３ , R Ｙ４ , R Ｙ５ Two of them are divalent C １～６ an alkylene radical, wherein optionally one or two non-adjacent carbon units of the alkylene radical are independently O, NH, N—C １～４ -alkyl), especially -(CH ２ ) ４ - forming; Hetar Ｙ２ is a 5- or 6-membered monocyclic heteroaryl (wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may contain halogen, C １～４ -alkyl (optionally substituted by OH); especially pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl; Hetar Ｚ is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole; Hetcyc Ｙ２ is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, in which one or two of the ring atoms are heteroatoms selected from N, O and / or S, and the remainder are carbon atoms; especially tetrahydrofuranyl, morpholinyl, tetrahydropyranyl, A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in any ratio.

6. R ２ But -(CH ２ ) ｘ -NR ２ｄ -C(=O)-R 2e , -(CH ２ ) ｚ -NR ２ｄ -S(=O) ２ -R ２ｇ , -N=S(=O)-R ２ｓ R ２ｔ , -C(=O)-N=S(=O)-R ２ｓ R 2t is preferably —NH—C(═O)—CH 3 or —NH—S(═O) ２ -CH ３ , -NH-S (=O) ２ -CH=CH ２ , -CH ２ —NH—S(═O) ２ -CH=CH ２ , -N=S(=O)(CH ３ ) ２ , C(=O)-N=S(=O)(CH ３ ) ２ Represents; R ２ｅ is optionally substituted with —OH, １～６ - alkyl, or monocyclic 5- or 6-membered heteroaryl; C ３～７ -cycloalkyl, monocyclic 5- or 6-membered heteroaryl; especially H, methyl, hydroxymethyl, methylpyridin-2-yl, methylpyridin-3-yl, methylpyridin-4-yl, cyclopropyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; R 2g is unsubstituted or substituted C １～８ aliphatic; in particular, independently of one another, C １～４ - alkyl or C ２～４ -alkenyl; preferably, independently of each other, methyl or -CH=CH ２ Represents; R 2d is H, unsubstituted or substituted C １～８ - aliphatic; especially representing H; R 2s, R ２ｔ However, independently of each other, C １～６ -alkyl (which may optionally be -OH, O-C １～４ -Alkyl, NH ２ , N.H.C. １～４ -Alkyl, N(C １～４ -alkyl) ２ , pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl); especially methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-(N,N-dimethylamino)propyl; or together, a divalent C ３～４ - an alkylene radical (which may optionally be -NH ２ , optionally substituted with —CN) or divalent C ２～５ - an alkylene radical (wherein optionally said C ２～５ - one of the carbon units of the alkylene radical is O, NH, or N—C １～４ -alkyl); especially -(CH ２ ) ３ -, -CH ２ -C(NH ２ ) H-CH ２ -, -CH ２ -C(CN)H-CH ２ -, -CH ２ -C(CH ２ -NH-CH ２ )-CH ２ -, -(CH ２ ) ４ -; x represents 0 or 1; z represents 0 or 1; A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in any ratio.

7. Ring A is 【Chemistry 4】 Represents; Ring B is 【Transformation 5】 represents one of the following; R １ is 4-trifluoromethylphenyl or 4-trifluoromethoxyphenyl; and R ２ is C(═O)—OH or C(═O)—ONa; A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of any of the above, and mixtures thereof in any ratio.

8. A compound selected from the table below, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio. Table 1 。

9. 3. A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer or stereoisomer thereof, and / or pharmaceutically acceptable salts of each of the above, and mixtures thereof in any ratio, for use as a pharmaceutical.

10. 3. A compound according to claim 1 or 2, or any N-oxide, solvate, tautomer or stereoisomer thereof, and / or a pharmaceutically acceptable salt of each of the above, and mixtures 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, especially breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, stomach cancer, medulloblastoma, colon cancer, pancreatic cancer, tumors (including solid tumors); cardiovascular disease and fibrosis, especially liver fibrosis.

11. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of each of the above, and mixtures thereof in any ratio, together with a pharmaceutically acceptable carrier.

12. 12. The pharmaceutical composition of claim 11, further comprising a second active ingredient, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of each of the foregoing, and mixtures thereof in any ratio, wherein the second active ingredient is other than a compound of formula I as defined in claim 1 or 2.

13. a) an effective amount of a compound of formula I according to claim 1 or 2, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of each of the foregoing, and mixtures thereof in any ratio; and b) an effective amount of a further active ingredient, wherein the further active ingredient is not a compound of formula I as defined in claim 1 or 2. A set (kit) containing separate packs of:

14. 10. A process for preparing a compound of claim 1 or 2, or an N-oxide, solvate, tautomer, or stereoisomer thereof, and / or a pharmaceutically acceptable salt of each of the foregoing, and mixtures thereof in any ratio, comprising reacting a compound of formula II 【Transformation 6】 wherein ring A and ring B are as defined for compounds of formula I in claim 1 or 2, (a) Formula III R １ ------ (In the formula R １ is as defined for compounds of formula I in claim 1 or 2, and Hal represents Cl, Br, or I, in a C-N cross-coupling reaction under suitable reaction conditions, thereby providing compounds of formula I as defined in claim 1 or 2; and arbitrarily (b) In the compound of formula I, R ２ But, R ２ａ is unsubstituted or substituted C １～８ -aliphatic -C(=O)-OR ２ａ If so, then this compound of formula I is subjected to a saponification reaction under suitable conditions to give R ２ is —C(═O)—OH or —C(═O)—OCat; and arbitrarily (c) R ２ is —C(═O)—OH or —C(═O)—OCat, the compound of formula I being H-NR ２ｂ R ２ｃ UV (In the formula R ２ｂ and R ２ｃ is reacted with a compound of formula I as defined for compounds of formula I in claim 1 or 2 under suitable reaction conditions; whereby R ２ is -C(=O)-NR ２ａ R ２ｂ (Here, R ２ｂ and R ２ｃ is as defined for compounds of formula I in claim 1 or 2. The process characterized in that

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