Tricyclic heterocycles as tead binding agents

Abstract

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

Description

Technical Field

[0001] This invention relates to tricyclic heterocyclic compounds. These heterocyclic compounds can be used as TEAD binding agents and / or inhibitors of YAP-TEAD protein-protein interactions or binding, and for the prevention and / or treatment of a variety of medical conditions, including hyperproliferative disorders and diseases, particularly cancer. Background Technology

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

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

[0004] While several aspects of pathway activity and regulation remain to be further investigated, it has been established that, in its "on" state, the Hippo pathway involves a series of kinases (including Mst 1 / 2 and Lats 1 / 2) in the cytoplasm, leading to phosphorylation of two transcriptional coactivators, YAP (Yes-associated protein) and TAZ (a transcriptional coactivator with a PDZ-binding motif). Phosphorylation of YAP / TAZ results in their sequestration in the cytoplasm and ultimately their degradation. Conversely, when the Hippo pathway is "off" or dysfunctional, the unphosphorylated, activated YAP / TAZ coactivators are translocated to the nucleus. Their primary target transcription factors are four proteins (TEAD1–4) of the transcription enhancement-associated domain (TEAD) family of transcription factors. The binding of YAP or TAZ to TEAD (or other transcription factors) and the activation of TEAD (or other transcription factors) have been shown to induce the expression of several genes, many of which mediate cell survival and proliferation. Therefore, activated, non-phosphorylated YAP and TAZ may act as oncogenes, while activated, turned-on Hippo pathways may act as tumor inhibitors by inactivating, i.e., phosphorylating YAP and TAZ.

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

[0006] Therefore, dysfunction or abnormal regulation of the Hippo pathway as a tumor inhibitor is considered an important event in the development of various cancer types and diseases.

[0007] Therefore, inhibiting YAP, TAZ, TEAD and YAP-TEAD or TAZ-TEAD protein-protein interactions through pharmacological intervention appears to be a rational and valuable strategy for the prevention and / or treatment of cancers and other hyperproliferative conditions and diseases associated with Hippo pathway dysfunction. Summary of the Invention

[0008] This invention provides compounds that can be used to prevent and / or treat medical conditions, symptoms and / or diseases, particularly hyperproliferative conditions or diseases, which are TEAD binding agents and / or inhibitors of YAP-TEAD or TAZ-TEAD protein-protein interactions.

[0009] In one embodiment, the present invention relates to compounds of formula IA.

[0010]

[0011] in

[0012] Ring A represents a five-membered heteroaryl ring selected from the following ring subsets:

[0013]

[0014]

[0015]

[0016] in

[0017] R A1 Representing H, D, C 1-6 -Aliphatic, -CH2-Ar A1 or -CH2-CH2-Ar A1 ;

[0018] R A2 Represents H, D, halogen, C 1-6 -Aliphatic, -CH2-Ar A2 or -CH2-CH2-Ar A2 ;

[0019] R A3 Representing H, D, C 1-6 -Aliphatic, -CH2-Ar A3 or -CH2-CH2-Ar A3 ;

[0020] Z 1 It is CR Z1 Or N;

[0021] Z 2 It is CR Z2 Or N;

[0022] Z 3 It is CR Z3 Or N;

[0023] Z 1 Z 2 and Z 3 At least two of them are not N;

[0024] R 1 Representing Ar 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 -Ar 1 L 1 -Hetar 1 L 2 -Cyc 1 L 2 -Hetcyc1 Unsubstituted or substituted, straight or branched C 1-8 -Aliphatic;

[0025] R 2 Represents -C(=O)-OR 2a -C(=O)-NR 2b R 2c -(CH2) w -C(=O)-NR 2b R 2c -(CH2) x -NR 2d -C(=O)-R 2e -SR 2f -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i , -S(=O)2-OH, -S(=O)(=NR 2j -OH, -S(=O)(=NR 2j )-R 2g -S(=O)(=NR) 2k )-NR 2l R 2m ,F,Cl,Br,I,-CN,-(CH2) v -CN、-P(=O)(OR 2o (OR) 2p -(CH2) y -NR 2q R 2r -(CH2) z -NR 2d -S(=O)2-R 2g -C(=O)-N=S(=O)-R 2s R 2t -C(=O)-N=S(=NR) 2u )-R 2s R 2t -B(OH)2 or Hetcyc X ;

[0026] Ar A1 Ar A2 Ar A3 Each of these can represent a phenyl group independently, and can be unsubstituted or independently converted to R. A11 and / or R A12 Mono- or di-substituted;

[0027] R Z1 Represents H or halogen;

[0028] R Z2 Represents H or halogen; or related to R 2 Together they form a divalent group -S(=O)2-N(H)-C(=O)-;

[0029] R Z3 Represents H or halogen;

[0030] R 2a Represents H, unsubstituted or substituted C 1-8 - Aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclic groups or carbohydrate-derived groups, or Cat;

[0031] Cat represents a monovalent cation;

[0032] R 2b R 2c R 2q R 2r Each of them independently represents H, unsubstituted or substituted C. 1-8 -Aliphatic, including C 3-7 - Alicyclic group; or

[0033] Together with the nitrogen atoms to which they are attached, they form unsubstituted or substituted saturated, partially unsaturated, or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O, or S and the remainder are carbon atoms; wherein the heterocycle may optionally be combined with Hetarium Z Condensation; or

[0034] R 2b and R 2c One of them represents -CN, -NH2, -OH, -OC 1-6 -alkyl, -S(=O)2-R 2g Ar 2 Hetar 2 Cyc 2 Or Hetcyc 2 The other represents H or unsubstituted or substituted C. 1-8 -Aliphatic;

[0035] R 2d R 2j R 2k R 2o R 2p Each of them independently represents H, unsubstituted or substituted C. 1-8 -Aliphatic;

[0036] R 2e Represents H, halogen, and unsubstituted or substituted C. 1-8 - Aliphatic, heteroaryl;

[0037] R 2f R 2g Each independently represents either unsubstituted or substituted C. 1-8 -Aliphatic;

[0038] R 2h R 2i Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic, aryl, heterocyclic, heteroaryl; or together with the nitrogen atom to which they are attached, forming 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 is no or one additional ring atom is a heteroatom selected from N, O, or S, and the remainder are carbon atoms.

[0039] R 2l R 2m Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic; or together with the nitrogen atoms to which they are attached, forming unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O or S, and the remainder are carbon atoms.

[0040] R 2s R 2t Each independently represents either unsubstituted or substituted C. 1-8 -Aliphatic; or together forming unsubstituted or substituted divalent C 3-6 -alkylene;

[0041] R 2u Represents hydrogen or unsubstituted or substituted C 1-6 -Aliphatic;

[0042] Ar 1 It is a monocyclic, bicyclic, or tricyclic aryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. B1 R B2 R B3 R B4 R B5 R B6 and / or R B7 replace;

[0043] Hetar 1It is a monocyclic, bicyclic, or tricyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl group may be unsubstituted or may be substituted with the same or different substituents R. B1 R B2 R B3 R B4 R B5 R B6 and / or R B7 replace;

[0044] Cyc 1 It is a monocyclic, bicyclic, or tricyclic carbon ring with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, which may be unsubstituted or may be replaced by the same or different R atoms. B8 R B9 R B10 R B11 R B12 and / or R B13 Substitution; and wherein the carbon ring may optionally be via Ar X The two adjacent ring atoms and the Ar X Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 R C2 R C3 R C4 R C5 R C6 replace;

[0045] Hetcyc 1 It is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. B8 R B9 R B10 R B11 R B12 and / or R B13 replace;

[0046] L 1 It is selected from -S(=O)2-, -C(=O)-, unsubstituted or substituted straight or branched C. 1-6 -alkylene or C 2-6- An alkylene divalent group, in which one of the carbon units of the alkylene or alkylene chain can be replaced by -O-;

[0047] L 2 It is selected from unsubstituted or substituted straight or branched C 1-6 -alkylene or C 2-6 - An alkylene divalent group, in which one of the carbon units of the alkylene or alkylene chain can be replaced by -O-;

[0048] R A11 R A12 Each of the following represents a halogen or an unsubstituted or substituted straight or branched C. 1-6 -Aliphatic;

[0049] R B1 R B2 R B3 R B4 R B5 R B6 R B7 Each of the following represents an unsubstituted or substituted straight or branched chain C. 1-6 -Aliphatic, C 1-6 -Aliphatic oxygen, -SC 1-6 - Aliphatic; Halogen, -CN, -S(=O)-R b1 S(=O)2-R b1 -NR b2 NR b3 Ar 2 -CH2-Ar 2 Hetar 2 Cyc 2 Hetcyc 2 ;

[0050] and / or two adjacent R B1 R B2 R B3 R B4 R B5 R B6 and / or R B7 Together they form divalent -C 2-4 -alkylene, where one of the alkylene carbon units can be replaced by a carbonyl unit (-C(=O)-), or a divalent -OC 1-3 -alkylene or divalent-OC 1-3 -alkylene-O-yl;

[0051] R b1 C represents unsubstituted or substituted C 1-8 -Aliphatic;

[0052] R b2 Rb3 Each independently represents H, unsubstituted or substituted C. 1-8 -Aliphatic; or

[0053] Together with the nitrogen atoms to which they are attached, they form unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycles having 3, 4, 5, 6 or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one other ring atom is a heteroatom selected from N, O or S and the remainder are carbon atoms.

[0054] R B8 R B9 R B10 R B11 R B12 R B13 Each of the following independently represents a halogen, an unsubstituted or substituted C. 1-6 -Aliphatic, C 1-6 -Aliphatic oxygen, Ar Y ; and / or

[0055] R connected to the same carbon atom of the carbon ring or the heterocycle B8 R B9 R B10 R B11 R B12 R B13 The two in form a divalent oxo (=O) group; and / or

[0056] R connected to the same sulfur atom of the heterocycle B8 R B9 R B10 R B11 R B12 R B13 The two or R in B8 R B9 R B10 R B11 R B12 R B13 The four in it form divalent oxo (=O) groups, thereby forming -S(=O)- or -S(=O)2- parts;

[0057] Ar 2 It is a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. D1 R D2 R D3 R D4 and / or R D5 replace;

[0058] Hetar 2It is a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl group may be unsubstituted or may be substituted with the same or different substituents R. D1 R D2 R D3 R D4 and / or R D5 replace;

[0059] Cyc 2 It is a saturated or partially unsaturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. D6 R D7 R D8 R D9 and / or R D10 Substitution; wherein the carbon ring may optionally be replaced by Ar Z or Hetar Z The two adjacent ring atoms and the Ar Z or Hetar Z Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 R C2 R C3 R C4 R C5 R C6 replace;

[0060] Hetcyc 2 It is a saturated or partially unsaturated monocyclic heterocycle having 3, 4, 5, 6, or 7 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, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. D6 R D7 R D8 R D9 and / or R D10 Substitution; wherein the heterocycle may optionally be replaced by Ar Z or Hetar Z The two adjacent ring atoms and the Ar Z or Hetar Z Fused, wherein the fused heterocycle may be further unsubstituted or replaced by R that may be the same or different. C1 R C2 R C3 R C4 R C5 R C6 replace;

[0061] Ar X Ar Z Each is an unsubstituted or substituted benzo[a] ring;

[0062] Ar Y It is an unsubstituted or mono- or disubstituted phenyl group;

[0063] Hetar Y1 It is a 5- or 6-membered monocyclic heteroaryl group, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms selected from N, O, and / or S, and the remaining atoms are carbon atoms. The heteroaryl group may be unsubstituted or halogenated, and the C atoms may be optionally substituted with OH. 1-4 -alkyl substitution;

[0064] Hetar Z It is an unsubstituted or substituted 5- or 6-membered heteroaromatic ring selected from pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, and pyran;

[0065] Cyc Y1 It is a saturated monocyclic carbon ring with 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or substituted with halogens, OH, C 1-4 -alkyl substitution;

[0066] Hetcyc X It 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 heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. X1 R X2 R X3 R X4 R X5 R X6 R X7 and / or R X8 Substitution, wherein the heterocycle is optionally a carboxylic acid bioisostere;

[0067] Hetcyc Y It 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 heteroatoms selected from N, O and / or S and the remainder are carbon atoms;

[0068] Hetcyc Y1 It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms;

[0069] RC1 R C2 R C3 R C4 R C5 R C6 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic;

[0070] R D1 R D2 R D3 R D4 R D5 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic;

[0071] R D6 R D7 R D8 R D9 R D10 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic, unsubstituted or substituted C 1-6 -Aliphatic oxygen, halogen, hydroxyl group; Hetar Y1 CH2-Hetar Y1 Cyc Y1 Hetcyc Y1 -CH2-Hetcyc Y1 ; and / or R connected to the same ring atom of the carbon ring or heterocycle D6 R D7 R D8 R D9 R D10 Two of them can form divalent C 2-6 -alkylene, wherein one or two non-adjacent carbon units of the alkylene may optionally be independently converted to O, NH or NC. 1-4 -Alkyl substitution, wherein the alkylene group may optionally be replaced by OH, C 1-4 -alkyl or -OC 1-4 -alkyl substitution; and / or R connected to different ring atoms of the carbide ring or heterocycle. D6 R D7 R D8 R D9 R D10 Two of them can form divalent C 1-6 -alkylene, wherein one or two non-adjacent carbon units of the alkylene may optionally be independently converted to O, NH or NC. 1-4 -Alkyl substitution;

[0072] R X1 R X2 RX3 R X4 R X5 R X6 R X7 R X8 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic, C 1-6 -Aliphatic oxygen groups, halogens, -OH, -NR 2d -S(=O)2-R 2g Hetcyc Y O-Hetcyc Y ; and / or

[0073] 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 The two groups in the ring form divalent oxo (=O) groups; and / or R groups 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 The two or R in X1 R X2 R X3 R X4 R X5 R X6 R X7 R X8 The four in it form divalent oxo (=O) groups, thereby forming -S(=O)- or -S(=O)2- parts;

[0074] Halogens are F, Cl, Br, and I;

[0075] v is 1 or 2;

[0076] w is 1 or 2;

[0077] x is 0, 1, or 2;

[0078] y is 0, 1, or 2;

[0079] z is 0, 1, or 2;

[0080] Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in all proportions.

[0081] In another embodiment of the invention, the invention relates to a compound of formula I.

[0082]

[0083] in

[0084] Ring A represents a five-membered heteroaryl ring selected from the following ring subsets:

[0085]

[0086]

[0087]

[0088] in

[0089] R A1 Representing H and C 1-6 -Aliphatic, -CH2-Ar A1 or -CH2-CH2-Ar A1 ;

[0090] R A2 Represents H, halogen, C 1-6 -Aliphatic, -CH2-Ar A2 or -CH2-CH2-Ar A2 ;

[0091] R A3 Representing H and C 1-6 -Aliphatic, -CH2-Ar A3 or -CH2-CH2-Ar A3 ;

[0092] Z 1 It is CR Z1 Or N;

[0093] Z 2 It is CR Z2 Or N;

[0094] Z 1 and Z 2 At least one of them is not N;

[0095] R 1 Representing Ar 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 -Ar 1 L 1 -Hetar 1 L2 -Cyc 1 L 2 -Hetcyc 1 Unsubstituted or substituted straight or branched C 1-8 -Aliphatic;

[0096] R 2 Represents -C(=O)-OR 2a -C(=O)-NR 2b R 2c -(CH2) w -C(=O)-NR 2b R 2c -(CH2) x -NR 2d -C(=O)-R 2e -SR 2f -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i , -S(=O)2-OH, -S(=O)(=NR 2j -OH, -S(=O)(=NR 2j )-R 2g -S(=O)(=NR) 2k )-NR 2l R 2m ,F,Cl,Br,I,-CN,-(CH2) v -CN、-P(=O)(OR 2o (OR) 2p -(CH2) y -NR 2q R 2r -(CH2) z -NR 2d -S(=O)2-R 2g -C(=O)-N=S(=O)-R 2s R 2t -C(=O)-N=S(=NR) 2u )-R 2s R 2t -B(OH)2 or Hetcyc X ;

[0097] Ar A1 Ar A2 Ar A3 Each of these can represent a phenyl group independently, and can be unsubstituted or independently converted to R. A11 and / or R A12 Mono- or di-substituted;

[0098] R Z1 Represents H or halogen;

[0099] R Z2 Represents H or halogen; or related to R 2 Together they form a divalent group -S(=O)2-N(H)-C(=O)-;

[0100] R 2a Represents H, unsubstituted or substituted C 1-8 - Aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclic groups or carbohydrate-derived groups, or Cat;

[0101] Cat represents a monovalent cation;

[0102] R 2b R 2c R 2q R 2r Each of them independently represents H, unsubstituted or substituted C. 1-8 -Aliphatic, including C 3-7 - Alicyclic group; or

[0103] Together with the nitrogen atoms to which they are attached, they form unsubstituted or substituted saturated, partially unsaturated, or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O, or S and the remainder are carbon atoms; wherein the heterocycle may optionally be combined with Hetarium Z Condensation; or

[0104] R 2b and R 2c One of them represents -CN, -NH2, -OH, -OC 1-6 -alkyl, -S(=O)2-R 2g Ar 2 Hetar 2 Cyc 2 Or Hetcyc 2 , and R 2b and R 2c Another representation in the formula is H or unsubstituted or substituted C. 1-8 -Aliphatic;

[0105] R 2d R 2j R 2k R 2o R 2p Each of them independently represents H, unsubstituted or substituted C. 1-8 -Aliphatic;

[0106] R2e Represents H, halogen, and unsubstituted or substituted C. 1-8 - Aliphatic, heteroaryl;

[0107] R 2f R 2g Each independently represents either unsubstituted or substituted C. 1-8 -Aliphatic;

[0108] R 2h R 2i Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic, aryl, heterocyclic, heteroaryl; or together with the nitrogen atom to which they are attached, forming 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 is no or one additional ring atom is a heteroatom selected from N, O, or S, and the remainder are carbon atoms.

[0109] R 2l R 2m Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic; or together with the nitrogen atoms to which they are attached, forming unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O or S, and the remainder are carbon atoms.

[0110] R 2s R 2t Each independently represents either unsubstituted or substituted C. 1-8 -Aliphatic; or together forming unsubstituted or substituted divalent C 3-6 -alkylene;

[0111] R 2u Represents hydrogen or unsubstituted or substituted C 1-6 -Aliphatic;

[0112] Ar 1 It is a monocyclic, bicyclic, or tricyclic aryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. B1 R B2 R B3 R B4 R B5 R B6 and / or R B7 replace;

[0113] Hetar 1It is a monocyclic, bicyclic, or tricyclic heteroaryl group having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl group may be unsubstituted or may be substituted with the same or different substituents R. B1 R B2 R B3 R B4 R B5 R B6 and / or R B7 replace;

[0114] Cyc 1 It is a monocyclic, bicyclic, or tricyclic carbon ring with 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring carbon atoms, which may be unsubstituted or may be replaced by the same or different R atoms. B8 R B9 R B10 R B11 R B12 and / or R B13 Substitution; and wherein the carbon ring may optionally be via Ar X The two adjacent ring atoms and the Ar X Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 R C2 R C3 R C4 R C5 R C6 replace;

[0115] Hetcyc 1 It is a saturated or partially unsaturated monocyclic, bicyclic, or tricyclic heterocycle having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. B8 R B9 R B10 R B11 R B12 and / or R B13 replace;

[0116] L 1 It is selected from -S(=O)2-, -C(=O)-, unsubstituted or substituted straight or branched C. 1-6 -alkylene or C 2-6- An alkylene divalent group, in which one of the carbon units of the alkylene or alkylene chain can be replaced by -O-;

[0117] L 2 It is selected from unsubstituted or substituted straight or branched C 1-6 -alkylene or C 2-6 - An alkylene divalent group, in which one of the carbon units of the alkylene or alkylene chain can be replaced by -O-;

[0118] R A11 R A12 Each of the following represents a halogen or an unsubstituted or substituted straight or branched C. 1-6 -Aliphatic;

[0119] R B1 R B2 R B3 R B4 R B5 R B6 R B7 Each of the following represents an unsubstituted or substituted straight or branched chain C. 1-6 -Aliphatic, C 1-6 -Aliphatic oxygen, -SC 1-6 - Aliphatic; Halogen, -CN, -S(=O)-R b1 S(=O)2-R b1 -NR b2 NR b3 Ar 2 -CH2-Ar 2 Hetar 2 Cyc 2 Hetcyc 2 ;

[0120] and / or two adjacent R B1 R B2 R B3 R B4 R B5 R B6 and / or R B7 Together they form divalent -C 2-4 -alkylene, where one of the alkylene carbon units can be replaced by a carbonyl unit (-C(=O)-), or a divalent -OC 1-3 -alkylene or divalent-OC 1-3 -alkylene-O-yl;

[0121] R b1 C represents unsubstituted or substituted C 1-8 -Aliphatic;

[0122] R b2 Rb3 Each independently represents H, unsubstituted or substituted C. 1-8 -Aliphatic; or

[0123] Together with the nitrogen atoms to which they are attached, they form unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycles having 3, 4, 5, 6 or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one other ring atom is a heteroatom selected from N, O or S and the remainder are carbon atoms.

[0124] R B8 R B9 R B10 R B11 R B12 R B13 Each of the following independently represents a halogen, an unsubstituted or substituted C. 1-6 -Aliphatic, C 1-6 -Aliphatic oxygen, Ar Y ; and / or

[0125] R connected to the same carbon atom of the carbon ring or the heterocycle B8 R B9 R B10 R B11 R B12 R B13 The two in form a divalent oxo (=O) group; and / or

[0126] R connected to the same sulfur atom of the heterocycle B8 R B9 R B10 R B11 R B12 R B13 The two or R in B8 R B9 R B10 R B11 R B12 R B13 The four in it form divalent oxo (=O) groups, thereby forming -S(=O)- or -S(=O)2- parts;

[0127] Ar 2 It is a monocyclic or bicyclic aryl group having 5, 6, 7, 8, 9, or 10 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. D1 R D2 R D3 R D4 and / or R D5 replace;

[0128] Hetar 2It is a monocyclic or bicyclic heteroaryl group having 5, 6, 7, 8, 9, or 10 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl group may be unsubstituted or may be substituted with the same or different substituents R. D1 R D2 R D3 R D4 and / or R D5 replace;

[0129] Cyc 2 It is a saturated or partially unsaturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. D6 R D7 R D8 R D9 and / or R D10 Substitution; wherein the carbon ring may optionally be replaced by Ar Z or Hetar Z The two adjacent ring atoms and the Ar Z or Hetar Z Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 R C2 R C3 R C4 R C5 R C6 replace;

[0130] Hetcyc 2 It is a saturated or partially unsaturated monocyclic heterocycle having 3, 4, 5, 6, or 7 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, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. D6 R D7 R D8 R D9 and / or R D10 Substitution; wherein the heterocycle may optionally be replaced by Ar Z or Hetar Z The two adjacent ring atoms and the Ar Z or Hetar Z Fused, wherein the fused heterocycle may be further unsubstituted or replaced by R that may be the same or different. C1 R C2 R C3 R C4 R C5 R C6 replace;

[0131] Ar X Ar Z Each is an unsubstituted or substituted benzo[a] ring;

[0132] Ar Y It is an unsubstituted or mono- or disubstituted phenyl group;

[0133] Hetar Y1 It is a 5- or 6-membered monocyclic heteroaryl group, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms selected from N, O, and / or S, and the remaining atoms are carbon atoms. The heteroaryl group may be unsubstituted or halogenated, and the C atoms may be optionally substituted with OH. 1-4 -alkyl substitution;

[0134] Hetar Z It is an unsubstituted or substituted 5- or 6-membered heteroaromatic ring selected from pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetraazole, pyridine, pyrimidine, pyrazine, and pyran;

[0135] Cyc Y1 It is a saturated monocyclic carbon ring with 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or substituted with halogens, OH, C 1-4 -alkyl substitution;

[0136] Hetcyc X It 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 heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. X1 R X2 R X3 R X4 R X5 R X6 R X7 and / or R X8 Substitution, wherein the heterocycle is optionally a carboxylic acid bioisostere;

[0137] Hetcyc Y It 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 heteroatoms selected from N, O and / or S and the remainder are carbon atoms;

[0138] Hetcyc Y1 It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms;

[0139] RC1 R C2 R C3 R C4 R C5 R C6 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic;

[0140] R D1 R D2 R D3 R D4 R D5 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic;

[0141] R D6 R D7 R D8 R D9 R D10 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic, unsubstituted or substituted C 1-6 -Aliphatic oxygen, halogen, hydroxyl group; Hetar Y1 CH2-Hetar Y1 Cyc Y1 Hetcyc Y1 -CH2-Hetcyc Y1 ; and / or R connected to the same ring atom of the carbon ring or heterocycle D6 R D7 R D8 R D9 R D10 Two of them can form divalent C 2-6 -alkylene, wherein one or two non-adjacent carbon units of the alkylene may optionally be independently converted to O, NH or NC. 1-4 -Alkyl substitution, wherein the alkylene group may optionally be replaced by OH, C 1-4 -alkyl or -OC 1-4 -alkyl substitution; and / or R connected to different ring atoms of the carbide ring or heterocycle. D6 R D7 R D8 R D9 R D10 Two of them can form divalent C 1-6 -alkylene, wherein one or two non-adjacent carbon units of the alkylene may optionally be independently converted to O, NH or NC. 1-4 -Alkyl substitution;

[0142] R X1 R X2 RX3 R X4 R X5 R X6 R X7 R X8 Each independently represents either unsubstituted or substituted C. 1-6 -Aliphatic, C 1-6 -Aliphatic oxygen groups, halogens, -OH, -NR 2d -S(=O)2-R 2g Hetcyc Y O-Hetcyc Y ; and / or

[0143] 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 The two groups in the ring form divalent oxo (=O) groups; and / or R groups 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 The two or R in X1 R X2 R X3 R X4 R X5 R X6 R X7 R X8 The four in it form divalent oxo (=O) groups, thereby forming -S(=O)- or -S(=O)2- parts;

[0144] Halogens are F, Cl, Br, and I;

[0145] v is 1 or 2;

[0146] w is 1 or 2;

[0147] x is 0, 1, or 2;

[0148] y is 0, 1, or 2;

[0149] z is 0, 1, or 2;

[0150] Or any of its N-oxides, solvates, tautomers or stereoisomers and / or any pharmaceutically acceptable salt of each of the above, including mixtures thereof in all proportions.

[0151] Generally, all residues, groups, substituents, bases, parts, variables, etc., appearing more than once may be the same or different, i.e., independent of each other. In the foregoing and hereinafter, unless otherwise expressly stated, residues and parameters have the meanings shown in formulas IA and I. Therefore, the present invention particularly relates to compounds of formulas IA and I, wherein at least one of said residues, groups, substituents, variables has one of the preferred meanings indicated below.

[0152] Any of the specific or even preferred embodiments of the invention specified below and in the claims relates not only to compounds of the specified formulas IA and I, but also to their N-oxides, solvates, tautomers or stereoisomers, and pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all proportions, unless otherwise stated.

[0153] In one specific embodiment PE0, the compound of the present invention is a tricyclic heterocycle of formula IA, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0154] Z 1 It is CR Z1 ;

[0155] Z 2 It is CR Z2 ;

[0156] Z 3 It is CR Z3 Or N;

[0157] R Z1 It is H or F; H is preferred;

[0158] R Z2 It is H or F; or with R 2 Together they form a divalent group -S(=O)2-N(H)-C(=O)-; preferably H;

[0159] R Z3 It is H or F; H is preferred.

[0160] In another specific implementation scheme of PE0, PE0a,

[0161] Z 3 It is N.

[0162] In another specific implementation scheme of PE0, PE0b,

[0163] Z 3 It is CR Z3 ;

[0164] R Z3 It is H.

[0165] It should be understood that this specific implementation scheme PE0b is the same as the specific implementation scheme PE1 described below. In other words, if Z in formula IA 3 Represents CR Z3 And R Z3 If H is present, then compound IA can also be described as compound I.

[0166] In a specific embodiment PE1, the compound of the present invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0167] Z 1 It is CR Z1 ;

[0168] Z 2 It is CR Z2 ;

[0169] R Z1 It is H or F;

[0170] R Z2 It is H or F; or with R 2 Together they form a divalent group -S(=O)2-N(H)-C(=O)-;

[0171] Furthermore, the remaining groups and residues are as defined in Formula I above or in any further specific embodiments described below.

[0172] In another specific implementation scheme of PE1, PE1a, R Z1 and R Z2 At least one of them is H. In another specific implementation scheme of PE1a, PE1b, R Z1 and R Z2 Both are H.

[0173] In another specific embodiment PE2, the compound of the present invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0174] Ring A represents a five-membered heteroaryl ring selected from the following ring subsets:

[0175]

[0176]

[0177] R A1 Representing C 1-6 -Aliphatic, -CH2-Ar A1 ;

[0178] R A2 Representing H, C 1-6 -Aliphatic;

[0179] R A3 Representing H, C 1-6 -Aliphatic;

[0180] Ar A1 The representative may not be replaced or may be R A11 Monosubstituted phenyl;

[0181] R A11 Represents halogens;

[0182] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0183] In another specific implementation scheme of PE2, PE2a,

[0184] R A1 The symbol can be arbitrarily assigned to 1, 2, or 3 F atoms or CN, C atoms. 2-4 -Alynyl groups (especially -CH2-C≡CH), -CH2-Ar A1 Replacement C 1-3 -alkyl;

[0185] R A2 Representing H and C 1-6 - Aliphatic, especially H and C 1-3 -alkyl group, optionally substituted with 1, 2 or 3 F atoms;

[0186] R A3 Represents H;

[0187] Ar A1 The representative may not be replaced or may be R A11 Monosubstituted phenyl;

[0188] R A11 Represents F;

[0189] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0190] In another specific embodiment PE2b of PE2 or PE2a, ring A is selected from rings A-1, A-4, A-7, A-9, A-10, A-12, A-13, A-15, A-17, A-23, and A-24. In another specific embodiment PE2c of PE2 or PE2a, ring A is ring A-4, wherein R is preferred. A1 It is methyl, ethyl, n-propyl or -CH2-C≡CH, more preferably methyl, and R A2 It is H.

[0191] In another specific embodiment, PE3, the compound of the present invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0192] R 1 Representing Ar 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 -Ar 1 L 1 -Hetar 1 L 2 -Cyc 1 L 2 -Hetcyc 1 Unsubstituted or substituted straight or branched C 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6- alkynyl group; among which

[0193] Ar 1 It is a monocyclic or bicyclic aryl group having 6 or 10 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. B1 R B2 and / or R B3 replace;

[0194] Hetar 1 It is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, or 3 of the 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 substituted with the same or different substituents R. B1 R B2 and / or R B3 Substitution; preferably, the heteroaryl group is unsubstituted or substituted with the same or different substituents R. B1 and / or R B2 replace;

[0195] Cyc 1 It is a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. B8 and / or R B9 Substitution; and wherein the carbon ring may optionally be via Ar X The two adjacent ring atoms and the Ar X Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 and / or R C2 replace;

[0196] Hetcyc 1 It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. B8 and / or R B9 Substitution, wherein if one of the heteroatoms is S, then the heterocycle can also be replaced by R. B8 R B9 R B10 and R B11 replace;

[0197] L 1 It is selected from -S(=O)2-, unsubstituted or substituted straight or branched C 1-6 -alkylene or C 2-6 - An alkylene divalent group, in which one of the carbon units of the alkylene or alkylene chain can be replaced by -O-;

[0198] L 2 It is selected from unsubstituted or substituted straight or branched C 1-6 -alkylene or C 2-6 - An alkylene divalent group, in which one of the carbon units of the alkylene or alkylene chain can be replaced by -O-;

[0199] R B1 R B2 R B3 Each can independently represent a straight chain or a branch chain C. 1-6 -alkyl, the C 1-6 -alkyl groups may be unsubstituted or monosubstituted with -CN or substituted with 1, 2 or 3 halogens; straight-chain or branched C 1-4 -alkoxy, the C 1-4 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 halogens; -O-CH-C≡CH, straight-chain or branched-SC 1-4-alkyl, the -SC 1-4 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 halogens; F, Cl, Br, -CN, -S(=O)-C 1-3 -alkyl, S(=O)2-C 1-3 -alkyl, -N(C) 1-3 -alkyl)2, Ar 2 -CH2-Ar 2 Hetar 2 Cyc 2 Hetcyc 2 ;

[0200] Or two adjacent R B1 R B2 and / or R B3 Together they form divalent -C 3-4 -alkylene, wherein one of the alkylene carbon units can be replaced by a carbonyl unit (-C(=O)-), or divalent -OC 2-3 -alkylene;

[0201] Ar 2 It is phenyl;

[0202] Hetar 2 It is a monocyclic heteroaryl group having 5 or 6 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms;

[0203] Cyc 2 It consists of cyclopropyl, cyclobutyl, and cyclopentyl groups, each of which can be unsubstituted or modified by R. D6 Single substitution or independent substitution by R D6 and R D7 Disubstituted; especially unsubstituted or R-substituted D6 Monosubstitution;

[0204] Hetcyc 2 It is pyrrolidinyl or piperidinyl, each of which may be unsubstituted or converted to R D6 Single substitution or independent substitution by R D6 and R D7 Disubstituted; especially unsubstituted or R-substituted D6 Monosubstitution;

[0205] R B8 R B9 Each represents F and C independently. 1-2 -alkyl, the C 1-2 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 F groups; C 1-2 -alkoxy group, Ar Y ;or

[0206] R B8 and R B9 Connected to the carbon ring Cyc 1 or the heterocyclic Hetcyc 1 The same carbon atoms form a divalent oxo (=O) group; or

[0207] R B8 and R B9 and R B10 and R B11 The same sulfur atom is attached to the heterocycle and forms two divalent oxo (=O) groups, thereby forming the -S(=O)2- moiety;

[0208] Ar X It is an unsubstituted benzo[a] ring;

[0209] Ar Y It is phenyl;

[0210] R C1 and R C2 Each represents C independently 1-6 -alkyl groups, which can be substituted by 1, 2 or 3 F atoms independently;

[0211] R D6 R D7 Each represents C independently 1-6 -alkyl group, which may be substituted by 1, 2 or 3 F atoms or 1 hydroxyl group; or hydroxyl group;

[0212] Halogens are F, Cl, and Br;

[0213] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0214] In another specific implementation scheme of PE3, PE3a,

[0215] R 1 Representing Ar 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 -Ar 1 L 1 -Hetar 1 L 2 -Cyc 1 L 2 -Hetcyc 1 Straight or branched C 1-6 -alkyl, C 2-6 -Alkenyl or C 2-6- alkynyl group, wherein the C1-6 -alkyl, C 2-6 -Alkenyl or C 2-6- The alkynyl group is either unsubstituted or substituted by one, two, or three halogens; among which

[0216] Ar 1 It is phenyl or naphthyl, especially phenyl, which may be unsubstituted or substituented by the same or different R groups. B1 and or R B2 replace;

[0217] Hetar 1 It is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, or 3 of the ring atoms are heteroatoms selected from N, O, and / or S and the remainder is a carbon atom, wherein the heteroaryl may be unsubstituted or may be substituted with the same or different substituents R. B1 and / or R B2 replace;

[0218] Cyc 1 It is a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. B8 and / or R B9 Replacement; and wherein the carbon ring may optionally be via the Ar X The two adjacent ring atoms and Ar X Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 and / or R C2 replace;

[0219] Hetcyc 1 It is a saturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one of the ring atoms is a heteroatom selected from O and S and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. B8 and / or R B9 Substitution, wherein if one of the heteroatoms is S, then the heterocycle can also be replaced by R. B8 R B9 R B10 and R B11 replace;

[0220] L 1 It is a divalent group selected from -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, and -CH2-CH=CH-;

[0221] L2 It is a divalent group selected from -CH2- and -CH2-CH2-;

[0222] R B1 R B2 Each can independently represent a straight chain or a branch chain C. 1-6 -alkyl, the C 1-6 -alkyl groups may be unsubstituted or monosubstituted with -CN or substituted with 1, 2 or 3 halogens, such as -CF3; straight-chain or branched C 1-4 -alkoxy, the C 1-4 -Alkoxy groups can be unsubstituted or substituted with one, two, or three halogens, such as -OCF3, -O-CH-C≡CH, straight-chain or branched-chain -SC. 1-4 -alkyl, the -SC 1-4 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 halogens; F, Cl, Br, -CN, -S(=O)-C 1-3 -alkyl, S(=O)2-C 1-3 -alkyl, -N(C) 1-3 -alkyl)2, Ar 2 -CH2-Ar 2 Hetar 2 Cyc 2 Hetcyc 2 ;

[0223] Or two adjacent R B1 R B2 Together they form divalent -C 3-4 -alkylene, wherein one of the alkylene carbon units can be replaced by a carbonyl unit (-C(=O)-), or divalent -OC 2-3 -alkylene;

[0224] Ar 2 It is phenyl;

[0225] Hetar 2 It is a monocyclic heteroaryl group having 5 ring atoms, wherein one of the ring atoms is N and the rest are carbon atoms, or one of the ring atoms is N and one of the ring atoms is S and the rest are carbon atoms;

[0226] Cyc 2 It is cyclopropyl, 1-trifluoromethylcyclopropyl, cyclopentyl;

[0227] Hetcyc 2 It is a pyrroleyl group;

[0228] R B8 R B9 Each represents F and C independently. 1-2 -alkyl, the C1-2 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 F groups; C 1-2 -alkoxy group, Ar Y ;or

[0229] R B8 and R B9 Connected to the carbon ring Cyc 1 or the heterocyclic Hetcyc 1 The same carbon atoms form a divalent oxo (=O) group; or

[0230] R B8 and R B9 and R B10 and R B11 The same sulfur atom is attached to the heterocycle and forms two divalent oxo (=O) groups, thereby forming the -S(=O)2- moiety;

[0231] Ar X It is an unsubstituted benzo[a] ring;

[0232] Ar Y It is phenyl;

[0233] R C1 and R C2 Each represents C independently 1-2 -alkyl groups, which can be substituted by 1, 2 or 3 F atoms independently;

[0234] Halogens are F, Cl, and Br;

[0235] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0236] In PE3b, another specific implementation scheme of PE3 or PE3a

[0237] R 1 Representing Ar 1 Hetar 1 Cyc 1 Hetcyc 1 L 1 -Ar 1 L 1 -Hetar 1 L 2 -Cyc 1 L 2 -Hetcyc 12,2-Dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, or 3,3,3-trifluoroprop-1-yn-1-yl; wherein

[0238] Ar 1 It is a phenyl group, which may be unsubstituted or substituted with the same or different substituents R. B1 and or R B2 replace.

[0239] Hetar 1 It is a heteroaryl group selected from furanyl, especially furan-2-yl; thienyl, especially thien-2-yl and thien-3-yl; thiazolyl, especially 1,3-thiazolyl-2-yl or 1,3-thiazolyl-4-yl; pyrazolyl, especially pyrazol-5-yl (1H-pyrazol-5-yl); imidazoleyl, especially imidazole-2-yl (1H-imidazole-2-yl) and imidazole-5-yl (1H-imidazole-5-yl); oxazolyl, especially 1,3-oxazol-2-yl; pyridyl, especially pyridyl-2-yl and pyridyl-3-yl. 5-O-cyclopentadien[b]pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopentadien[b]pyridin-2-yl; pyrimidinyl, especially pyrimidin-2-yl; indoleyl, especially 1H-indole-6-yl; quinolinyl, especially quinolin-2-yl and quinolin-4-yl; 5,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl; isoquinolinyl, especially isoquinolin-3-yl; benzofuranyl, especially 1-benzofuran-3-yl -yl; benzothiophene, especially 1-benzothiophene-3-yl; isoquinolinyl, especially isoquinolin-3-yl; furano[3,2-b]pyridinyl, especially quinazolin-2-yl; pyrrolo[1,2-b]pyrazolyl, especially 4H,5H,6H-pyrrolo[1,2-b]pyrazol-3-yl; pyrazolo[1,5-a]pyridinyl, especially pyrazolo[1,5-a]pyridin-3-yl and pyrazolo[1,5-a]pyridin-7-yl; imidazo[1,2-a]pyridinyl, especially imidazo[1,2-a]pyridinyl 3-pyridyl, imidazo[1,2-a]pyridin-5-yl; imidazo[1,5-a]pyridyl, particularly imidazo[1,5-a]pyridin-1-yl, imidazo[1,5-a]pyridin-3-yl, imidazo[1,5-a]pyridin-5-yl; pyrazolo[1,5-c]pyrimidinyl, particularly pyrazolo[1,5-c]pyrimidin-3-yl; quinazolinyl, particularly quinazolin-2-yl; naphridinyl, particularly 1,5-naphridin-2-yl; wherein the heteroaryl group may be unsubstituted or may be substituted with the same or different substituents R. B1 and / or R B2replace;

[0240] Cyc 1 Selected from cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, spiro[3.3]heptyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[2.2.1]heptenyl, methylbicyclo[3.1.1]heptenyl, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R B8 and / or R B9 Substitution; and wherein the carbon ring may optionally be via Ar X The two adjacent ring atoms and the Ar X Fusing, wherein the fused carbon ring may be further unsubstituted or may be replaced by the same or different R C1 and / or R C2 replace;

[0241] Hetcyc 1 Selected from pyrrolidinyl, tetrahydrofuranyl, and thiaalkyl, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R. B8 and / or R B9 Substitution, wherein if one of the heteroatoms is S, then the heterocycle can also be replaced by R. B8 R B9 R B10 and R B11 replace;

[0242] L 1 It is a divalent group selected from -S(=O)2-, -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-CH2-C(CH3)H-, -CH2-CH2-C(CH3)2-, -CH2-CH2-O-CH2-, and -CH2-CH=CH-;

[0243] L 2 It is a divalent group selected from -CH2- and -CH2-CH2-;

[0244] R B1 R B2 Each of these terms independently represents methyl, ethyl, n-propyl, 2-propyl, tert-butyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, -O-CH2-C≡CH, straight-chain or branched -S-methyl, -S-CF3, F, Cl, Br, -CN, -S(=O)-methyl, S(=O)2-methyl, -N(CH3)2, phenyl, -CH2-phenyl(benzyl), -O-CH2-phenyl(benzyloxy), pyrrolyl, thiazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl;

[0245] Or two adjacent R B1 R B2 Together they form divalent groups selected from -CH2-CH2-CH2-, -CH2-CH2-CH2-CH2-, -O-CH2-CH2-, -O-CH2-CH2-CH2-, -C(=O)-CH2-CH2-, and -C(=O)-CH2-CH2-CH2-.

[0246] R B8 R B9 Each can independently represent F, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or phenyl; or

[0247] R B8 and R B9 Connected to the carbon ring Cyc 1 or the heterocyclic Hetcyc 1 The same carbon atoms can form a divalent oxo (=O) group; or

[0248] R B8 and R B9 and R B10 and R B11 The same sulfur atom is attached to the heterocycle and forms two divalent oxo (=O) groups, thereby forming the -S(=O)2- moiety;

[0249] Ar X It is an unsubstituted benzo[a] ring;

[0250] Ar Y It is phenyl;

[0251] R C1 and R C2 Each represents CF3 independently;

[0252] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0253] In another specific embodiment, PE4, the compound of the present invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0254] R 2 Represents -C(=O)-OR 2a Or Hetcyc X ;

[0255] R 2aRepresents H, and unsubstituted or substituted C, whether it is a straight or branched chain. 1-4 -alkyl or Cat;

[0256] Cat represents a monovalent cation selected from lithium (Li), sodium (Na), and potassium (K);

[0257] Hetcyc X Represented by 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) -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-oxetane-3-yl, 5-hydroxy-4H-pyran-4-one-2-yl, 3,3-difluoropyrrolidine-2-one-4-yl, 3,3-difluoropyrrolidine-2-one-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrolo-2-one-4-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrolo-2-one-5-yl;

[0258] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0259] In another specific implementation scheme of PE4, PE4a,

[0260] R 2 Represents -C(=O)-OR 2a ;

[0261] R 2a Represents H, methyl, ethyl, or Cat;

[0262] Cat represents a monovalent sodium cation;

[0263] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0264] In another specific implementation scheme of PE4, PE4b,

[0265] R 2Represents -C(=O)-OR 2a ;

[0266] R 2a Represented by -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i , -S(=O)2-OH, -S(=O)(=NR 2j -OH, -S(=O)(=NR 2j )-R 2g -S(=O)(=NR) 2k )-NR 2l R 2m Replacement C 1-4 -alkyl, wherein R 2f R 2g R 2h R 2i R 2j R 2k R 2l and R 2m As defined above and below in the specification for formula IA or I;

[0267] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0268] In another specific embodiment PE5, the compound of the present invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0269] R 2 Represents -C(=O)-NR 2b R 2c ;

[0270] R 2b and R 2c Each can independently represent H or a straight chain or a branched chain C. 1-8 -Aliphatic, which may be unsubstituted or substituted by 1, 2, 3, 4 or 5 substituents that may be the same or different;

[0271] Or together with the nitrogen atoms to which they are attached, they form unsubstituted or substituted saturated, partially unsaturated, or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O, or S, and the remainder are carbon atoms; wherein the heterocycle may optionally be combined with Hetar as defined in any of the preceding claims.Z Fusing; particularly pyrrolidinyl rings or piperidinyl rings, each unsubstituted or monosubstituted with -OH or independently C 1-4 -alkyl and / or -OH disubstituted;

[0272] Or R 2b and R 2c One of them represents H, and the other represents Cyc. 2 Or Hetcyc 2 Specifically, it represents cyclopropyl or cyclobutyl, which are either unsubstituted or substituted with -CH2OH, or tetrahydrofuran, which are either unsubstituted or monosubstituted with -OH.

[0273] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0274] In another specific implementation scheme of PE5, PE5a,

[0275] R 2b Represents hydrogen,

[0276] R 2c Represents hydrogen; straight-chain or branched C 1-8 -alkyl group, which may be unsubstituted or may be the same or different R group. E1 R E2 R E3 R E4 and / or R E5 Replace; Cyc 2 Or Hetcyc 2 ,in

[0277] R E1 R E2 R E3 R E4 and / or R E5 They represent halogens independently of each other, especially F; -NR Ea R Eb -OH, OR Ec Ar E Hetar E Cyc E Hetcyc E ;

[0278] Ar E It is a monocyclic or bicyclic aryl group having 6 or 10 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. F1 R F2 and / or R F3 Substitution; preferably phenyl or naphthyl, especially phenyl;

[0279] Hetar E It 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 heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may be substituted with the same or different substituents R. F1 R F2 and / or R F3 Substitution; specifically, the heteroaryl group is a monocyclic heteroaryl group having 5 or 6 ring atoms, which may be unsubstituted or substituted with the same or different substituents R. F1 and / or R F2 Substitution; preferably, the heteroaryl group is selected from imidazolyl, 1H-imidazo-1-yl, 1H-imidazo-2-yl, each of which is unsubstituted or C-substituted. 1-4 -alkyl monosubstituted; pyridyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, each of which may be unsubstituted or monosubstituted with -F; pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; pyrazinyl, pyrazin-2-yl; pyridazinyl, pyridazin-3-yl; furanyl, pyrroleyl, pyrazolyl, oxazolyl, isoxazolyl; oxadiazolyl, triazolyl, thiazolyl, isothiazolyl;

[0280] Cyc E It is a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. G1 and / or R G2 Substitution: In particular, saturated monocyclic carbon rings having 3, 4, 5, or 6 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. G1 and / or R G2 Substitution; preferably cyclopropyl, cyclobutyl, or cyclohexenyl;

[0281] Hetcyc E It is a saturated or partially unsaturated monocyclic heterocycle having 4, 5, or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. G1 and / or R G2 Substitution; particularly saturated monocyclic heterocycles having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N and / or O and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R. G1 and / or R G2Substitution; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, each of which may be unsubstituted or monosubstituted with -OH; pyrrolyl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-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-dioxane; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl;

[0282] R Ea R Eb Representing H and C independently 1-4 -alkyl, -C(=O)-OC 1-4 -alkyl; in particular, both represent H or one represents H and the other represents C(=O)-O-tert-butyl;

[0283] R Ec Represents H or C 1-4 -alkyl, especially H or methyl;

[0284] R F1 R F2 and / or R F3 Each can independently represent a straight chain or a branch chain C. 1-6 -alkyl, the C 1-6 -Alkyl groups may be unsubstituted or replaced by -CN, OH, or -OC. 1-4 -Alkyl monosubstituted or substituted with 1, 2 or 3 halogens; straight-chain or branched C 1-4 -alkoxy, the C 1-4 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 halogens; straight-chain or branched-SC 1-4 -alkyl, the -SC 1-4 -The alkyl group may be unsubstituted or substituted with one, two, or three halogens; optionally substituted with halogens, OH, and / or C. 1-4 -alkyl-substituted C 3-7 -Cyclopropyl; F, Cl, Br, -CN, -S(=O)-C 1-3 -alkyl, S(=O)2-C 1-3 -alkyl, -NH2, -NH(C) 1-3 -alkyl)-N(C 1-3 -alkyl)2, -OH; especially methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; preferably, only R F1 R F2 and R F3 One of them exists and represents methyl or F;

[0285] And / or R attached to two different ring atoms of the aryl or heteroaryl group F1 R F2 R F3 The two in it form divalent C 1-6 -alkylene, wherein any one or two non-adjacent carbon units of the alkylene can be independently converted to O, NH, NC 1-4 -Alkyl substitution, especially -(CH2)4- and -CH2-O-(CH2)2-;

[0286] R G1 and / or R G2 Each of these elements independently represents a halogen, a hydroxyl group, and an unsubstituted or substituted C. 1-6 - Aliphatic, especially C2Cs that are optionally substituted with OH. 1-4 -alkyl, C 1-6 -Aliphatic oxygen groups, especially -OC 1-4 -alkyl, -C(=O)-OC 1-4 -alkyl, Hetar Y2 -CH2-Hetar Y2 Hetcyc Y2 Preferred R G1 and R G2 Only one of them exists and represents a hydroxyl group;

[0287] And / or R attached to the same ring atom of the carbon ring or heterocycle G1 and R G2 Formation of divalent C 2-6 -alkylene, wherein any one or two non-adjacent carbon units of the alkylene can be independently converted to carbon by O, NH, NC. 1-4 -Alkyl substitution, wherein the alkylene group may optionally be replaced by OH, C 1-4 -alkyl or -OC 1-4 -alkyl substitution, especially -(CH2)2-O-CH2-, -(CH2)2-O-(CH2)2-; and / or R attached to two different ring atoms of the carbide ring or heterocycle. G1 and R G2 Formation of divalent C 1-6 -alkylene, wherein any one or two non-adjacent carbon units of the alkylene can be independently converted to carbon by O, NH, NC. 1-4 -Alkyl substitution, especially -CH2-;

[0288] Cyc 2 It is a saturated monocyclic carbon ring having 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or independently substituted by R. D6 R D7 R D8R D9 and / or R D10 Substitution, wherein the carbon ring may optionally be replaced by Ar via two adjacent ring atoms. Z or Hetar Z Fusing, and wherein the fused carbon rings may optionally be further independently of each other by R C1 R C2 and / or R C3 replace;

[0289] Hetcyc 2 It is a saturated monocyclic heterocycle having 4, 5, or 6 ring atoms, wherein one or two of the ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or independently substituted by R. D6 R D7 R D8 R D9 and / or R D10 Substitution, wherein the heterocycle may optionally be replaced with Ar Z or Hetar Z Fusing, and wherein the fused heterocycles may optionally be further independently of each other by R C1 R C2 and / or R C3 replace;

[0290] R C1 R C2 R C3 Representing C 1-4 -alkyl;

[0291] R D6 R D7 R D8 R D9 R D10 Each of the following represents a halogen independently, especially F; a hydroxyl group; and a C that is optionally substituted with -OH and / or a halogen. 1-4 -alkyl, especially methyl, hydroxymethyl, 2-fluoroethyl; -OC 1-4 -alkyl groups, especially methoxy and ethoxy groups; Hetar Y1 -CH2-Hetar Y1 Cyc Y1 Hetcyc Y1 -CH2-Hetcyc Y1 ;

[0292] And / or R connected to the same ring atom of the carbon ring or heterocycle D6 R D7 R D8 R D9 R D10The two in it form divalent C 2-6 -alkylene, wherein optionally one or two non-adjacent carbon units of the alkylene can be independently converted to O, NH, NC 1-4 -Alkyl substitution, wherein the alkylene group may optionally be replaced by OH, C 1-4 -alkyl or -OC 1-4 -alkyl substitution, especially -(CH2)3-, -CH2-CH(OC2H5)-CH2-, -(CH2)2-O-(CH2)2-;

[0293] And / or R connected to two different ring atoms of the carbon ring or heterocycle D6 R D7 R D8 R D9 R D10 The two in it form divalent C 1-6 -alkylene, wherein optionally one or two non-adjacent carbon units of the alkylene can be independently converted to O, NH, NC 1-4 -Alkyl substitution, especially -CH2-, -(CH2)3-, -O-(CH2)2-, -O-(CH2)3-;

[0294] Ar Z It is benzo[a];

[0295] Hetar Y1 It is a 5- or 6-membered monocyclic heteroaryl group, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms. The heteroaryl group may be unsubstituted or substituted with F, or optionally substituted with OH. 1-4 -alkyl substitution; especially pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridyl, fluoropyridyl, methylpyridyl, pyrimidinyl, methylpyrimidinyl, pyrimidinyl, methylpyrimidinyl;

[0296] Hetar Y2 It is a 5- or 6-membered monocyclic heteroaryl group, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms selected from N, O, and / or S, and the remaining atoms are carbon atoms. The heteroaryl group may be unsubstituted or halogenated, and the C atoms may be optionally substituted with OH. 1-4 -alkyl substitution; particularly pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazoleyl, triazolyl, oxazolyl, hydroxymethyloxazolyl;

[0297] Hetar Z It is pyrrole, N-methylpyrrole, pyrazole, imidazole, triazole;

[0298] Cyc Y1It is a saturated monocyclic carbon ring with 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or substituted with halogens, OH, C 1-4 -Alkyl substitution, especially cyclopropyl;

[0299] Hetcyc Y1 It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms; in particular, tetrahydrofuranyl;

[0300] Hetcyc Y2 It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms; in particular tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl;

[0301] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below. It should be understood that specific embodiment PE5a comprises the compounds of the present invention, wherein R 2b Represents hydrogen and R 2c Represents a straight chain or a branch chain C 1-8 -alkyl, wherein one or two non-terminal and non-adjacent -CH2- (methylene) groups are replaced by -O-, -S- and / or one or two non-terminal and non-adjacent -CH2- or -CH- groups are replaced by -NH- or -N-.

[0302] In another specific implementation scheme of PE5aa, PE5aa...

[0303] R 2b Represents hydrogen,

[0304] R 2c Represents hydrogen; straight-chain or branched C 1-8 -alkyl group, which may be unsubstituted or may be the same or different R group. E1 R E2 R E3 R E4 and / or R E5 Replace; Cyc 2 Or Hetcyc 2 ,in

[0305] R E1 R E2 R E3 R E4 and / or R E5 They represent halogens independently of each other, especially F; -NR Ea R Eb -OH,OR Ec ArE Hetar E Cyc E Hetcyc E ;

[0306] Ar E It is a monocyclic or bicyclic aryl group having 6 or 10 ring carbon atoms, wherein the aryl group may be unsubstituted or may be substituted with the same or different substituents R. F1 R F2 and / or R F3 Substitution; preferably phenyl or naphthyl, especially phenyl;

[0307] Hetar E It 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 heteroatoms selected from N, O, and / or S, and the remainder are carbon atoms, wherein the heteroaryl may be unsubstituted or may be substituted with the same or different substituents R. F1 R F2 and / or R F3 Substitution; in particular, the heteroaryl group is a monocyclic heteroaryl group having 5 or 6 ring atoms, which may be unsubstituted or substituted with the same or different substituents R. F1 and / or R F2 Substitution; preferably, the heteroaryl group is selected from imidazolyl, 1H-imidazo-1-yl, 1H-imidazo-2-yl, each of which is unsubstituted or C-substituted. 1-4 -alkyl monosubstituted; pyridyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, each of which may be unsubstituted or monosubstituted with -F; pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; pyrazinyl, pyrazin-2-yl;

[0308] Cyc E It is a saturated or partially unsaturated monocyclic or bicyclic carbon ring having 3, 4, 5, 6, 7, or 8 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. G1 and / or R G2 Substitution: In particular, saturated monocyclic carbon rings having 3, 4, 5, or 6 ring carbon atoms, wherein the carbon ring may be unsubstituted or may be replaced by the same or different R atoms. G1 and / or R G2 Substitution; preferably cyclobutyl;

[0309] Hetcyc E It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S, and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or may be replaced by the same or different R atoms. G1 and / or RG2 Substitution; particularly saturated monocyclic heterocycles having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N and / or O and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R. G1 Monosubstituted; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, each of which may be unsubstituted or monosubstituted with -OH; pyrrolyl, pyrrolidine-1-yl, pyrrolidine-2-yl, pyrrolidine-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;

[0310] R Ea R Eb Representing H and C independently 1-4 -alkyl, -C(=O)-OC 1-4 -alkyl; in particular, both represent H or one represents H and the other represents C(=O)-O-tert-butyl;

[0311] R Ec Represents H or C 1-4 -alkyl, especially H or methyl;

[0312] R F1 R F2 and / or R F3 Each can independently represent a straight chain or a branch chain C. 1-6 -alkyl, the C 1-6 -alkyl groups can be unsubstituted or replaced by -CN OH, -OC 1-4 -Alkyl monosubstituted or substituted with 1, 2 or 3 halogens; straight-chain or branched C 1-4 -alkoxy, the C 1-4 -Alkyl groups may be unsubstituted or substituted with 1, 2, or 3 halogens; straight-chain or branched-SC 1-4 -alkyl, the -SC 1-4 -The alkyl group may be unsubstituted or substituted with one, two, or three halogens; optionally substituted with halogens, OH, and / or C. 1-4 -alkyl-substituted C 3-7 -Cyclopropyl; F, Cl, Br, -CN, -S(=O)-C 1-3 -alkyl, S(=O)2-C 1-3 -alkyl, -NH2, -NH(C) 1-3 -alkyl)-N(C 1-3 -alkyl)2, -OH; especially methyl, F; preferably only R F1 R F2 and R F3One of them exists and represents methyl or F;

[0313] R G1 and / or R G2 Each of these elements independently represents a halogen, a hydroxyl group, and an unsubstituted or substituted C. 1-4 -alkyl, -OC 1-4 -alkyl, especially hydroxyl; preferably R G1 and R G2 Only one of them exists and represents a hydroxyl group;

[0314] Cyc 2 It is a saturated monocyclic carbon ring with 3, 4, 5, 6, or 7 ring carbon atoms, wherein the carbon ring may be unsubstituted or substituted with R. D6 Monosubstitution, of which

[0315] R D6 It is an unsubstituted or monosubstituted C-type carbon. 1-4 -alkyl groups, especially -CH2OH;

[0316] Especially Cyc 2 It is cyclopropyl, cyclobutyl, or 1-hydroxymethyl-cyclobutyl;

[0317] Hetcyc 2 It is a saturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S and the remainder are carbon atoms, wherein the heterocycle may be unsubstituted or monosubstituted with hydroxyl groups; in particular tetrahydrofuran or hydroxytetrahydrofuran; preferably 4-hydroxytetrahydrofuran-3-yl;

[0318] In another specific implementation scheme of PE5, PE5b,

[0319] R 2b and R 2c Together with the nitrogen atoms attached to them, they form saturated or partially unsaturated heterocycles, which are optionally independently of each other by R Y1 R Y2 R Y3 R Y4 and / or R Y5 Substitution; wherein the heterocycle may optionally be replaced with Hetar Z Fused; and wherein the heterocycle is selected from: azahexacyclic butane, pyrrolidine, piperidine, piperazine, morpholine; wherein

[0320] R Y1 R Y2 R Y3 R Y4 R Y5 They represent halogens independently of each other, especially F; -NH2, -N(H)-C 1-4-alkyl, -N(H)-C(=O)-OC 1-4 -alkyl, -N(C) 1-4 -alkyl)2; -OH; optionally replaced by -OH, -OC 1-4 -alkyl, -OC 3-7 -cycloalkyl, -O-CH2-C 3-7 -Cycloalkyl-substituted C 1-4 -alkyl groups, especially methyl, -CH2OH, -(CH2)2OH, -(CH2)3OH, -CH2OCH3, -(CH2)2OCH3, cyclopropylmethoxy; -OC 1-4 -alkyl, especially methoxy; Hetar Y2 ;-CH2-Hetar Y2 Hetcyc Y2 ;

[0321] And / or R connected to the same ring atom of the heterocycle Y1 R Y2 R Y3 R Y4 R Y5 Two forms of divalent C 2-6 -alkylene, wherein one or two non-adjacent carbon units of the alkylene may be independently converted to carbon by O, NH, NC. 1-4 -Alkyl substitution, especially -(CH2)4-, -(CH2)2-O-(CH2)2-, -(CH2)2-O-(CH2)3-;

[0322] And / or R connected to two different ring atoms of the heterocycle Y1 R Y2 R Y3 R Y4 R Y5 The two in it form divalent C 1-6 - Alkylene, wherein optionally one or two non-adjacent carbon units of the alkylene can be independently converted to O, NH, NC 1-4 -Alkyl substitution, especially -(CH2)4-;

[0323] Ar Z It is benzo[a];

[0324] Hetar Y2 It is a 5- or 6-membered monocyclic heteroaryl group, wherein the 1st, 2nd, 3rd, and 4th ring atoms are heteroatoms selected from N, O, and / or S, and the remaining atoms are carbon atoms. The heteroaryl group may be unsubstituted or halogenated, and the C atoms may be optionally substituted with OH. 1-4 -alkyl substitution; particularly pyrrolyl, thiophenyl, pyrazolyl, imidazoleyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, and pyrimidinyl;

[0325] Hetar Z It is pyrrole, N-methylpyrrole, pyrazole, imidazole, triazole;

[0326] Hetcyc Y2 It is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of the ring atoms are heteroatoms selected from N, O and / or S, and the remainder are carbon atoms; particularly tetrahydrofuranyl, morpholinyl, and tetrahydropyranyl.

[0327] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0328] In PE5bb, another specific implementation scheme of PE5b

[0329] R 2b and R 2c Together with the nitrogen atoms to which they are attached, they form 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl, or 3-hydroxypiperidinyl rings.

[0330] In another specific implementation scheme of PE5, PE5c,

[0331] R 2b Represents either straight-chain or branched C that can be substituted with OH. 1-4 -alkyl; especially methyl, 2-hydroxyethyl;

[0332] and

[0333] R 2c Representing Cyc 2 Hetcyc 2 Straight chain or branched chain C 1-8 -alkyl groups, which may be unsubstituted or independently composed of the same or different R groups. E1 R E2 R E3 R E4 and / or R E5 Replace; where Cyc 2 Hetcyc 2 R E1 R E2 R E3 R E4 and R E5 As defined above for PE5a or PE5aa.

[0334] In another specific embodiment, PE6, the compound of the present invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0335] R 2 Representative - (CH2) x -NR 2d -C(=O)-R 2e -SR 2f -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i , -S(=O)2-OH, -S(=O)(=NR 2j -OH, -S(=O)(=NR 2j )-R 2g -S(=O)(=NR) 2k )-NR 2l R 2m -(CH2) z -NR 2d -S(=O)2-R 2g Especially -S-CH3, -S(=O)-R 2f -S(=O)2-R 2g -S(=O)2-NR 2h R 2i -S(=O)(=NR) 2j )-R 2g -S(=O)(=NR) 2k )-NR 2l R 2m -(CH2) z -NR 2d -S(=O)2-R 2g -C(=O)-N=S(=O)-R 2s R 2t -C(=O)-N=S(=NR) 2u )-R 2s R 2t ; Preferably -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-NHCH3, -S(=O)(=NH)-CH3, S(=O)(=NH)-N (CH3)2, -NH-S(=O)2-CH3, -N(CH3)-S(=O)2-CH3, -NH-S(=O)2-CH=CH2, -CH2-NH-S(=O)2-CH=CH2;

[0336] R 2e Representing H, C optionally substituted with -OH or a monocyclic 5- or 6-membered heteroaryl group. 1-6 -alkyl; 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;

[0337] R 2f R 2g Each independently represents either unsubstituted or substituted C. 1-8 -Aliphatic; especially C12 cells that are independent of each other. 1-4 -alkyl or C 2-4 -Alkenyl; preferably methyl or -CH=CH2, which are independent of each other:

[0338] R 2h R 2i Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic, aryl, heterocyclic, heteroaryl; or together with the nitrogen atom to which they are attached, forming unsubstituted or substituted saturated, partially unsaturated, or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O, or S and the remainder are carbon atoms; particularly C atoms that are independently substituted with H or optionally substituted with -OH. 1-4 -alkyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl or together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, which is optionally substituted with -OH and / or phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl;

[0339] R 2d R 2j R 2k Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic; especially H, methyl;

[0340] R 2l R 2m Each of them independently represents H, unsubstituted or substituted C. 1-8 - Aliphatic; or together with the nitrogen atoms to which they are attached, forming unsubstituted or substituted saturated, partially unsaturated, or aromatic heterocycles having 3, 4, 5, 6, or 7 ring atoms, wherein one of the ring atoms is the nitrogen atom and there is no or one additional ring atom is a heteroatom selected from N, O, or S and the remainder are carbon atoms; particularly C 1-4 -alkyl; preferably methyl;

[0341] R 2s R 2t Each of them independently represents a C that can be optionally substituted with -OH. 1-6 -alkyl, OC 1-4 -alkyl, NH2, NHC 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 to form a divalent C that may optionally be substituted with -NH2 or -CN. 3-4 -alkylene, or divalent C 2-5 -alkylene, wherein the C10 is optionally present 2-5 One of the carbon units of the -alkylene group can be O, NH, or NC. 1-4 -Alkyl substitution; especially –(CH2)3-, -CH2-C(NH2)H-CH2-, -CH2-C(CN)H-CH2-, -CH2-C(CH2-NH-CH2)-CH2-, –(CH2)4-;

[0342] R 2u Represents hydrogen or C 1-4 -alkyl;

[0343] x represents 0 or 1;

[0344] z is 0 or 1;

[0345] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0346] In another specific embodiment PE7, the compound of the present invention is a tricyclic heterocycle of formula I, or any N-oxide, solvate, tautomer or stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all ratios, wherein

[0347] in

[0348] Ring A represents a five-membered heteroaryl ring selected from the following ring subsets:

[0349]

[0350]

[0351]

[0352] Z 1 It is CH;

[0353] Z 2 It is CH;

[0354] R 1Representing 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)-phenyl-1-yl, 4-cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)thiophenyl, 4-(trifluoromethyl)thiophenyl, 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-Trifluoromethylthiophene-2-yl, 2-Trifluoromethyl-1,3-thiazolyl-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-Trifluoromethoxypyridin-2-yl, 4-Cyanopyridin-2-yl, 5-Trifluoromethylpyridin-2-yl, 6-Trifluoromethylpyridin-2-yl, 6-Trifluoromethylpyridin-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-methylthiopyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-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-cyclopentadien[b]pyridin-2-yl, 5,6,7,8-tetrahydroquinoline-2-yl, 5-oxo-5,6,7,8-tetrahydroquinoline-2-yl, Hydroquinoline-2-yl, 5H,6H,7H-cyclopentadien[b]pyridin-2-yl, quinoline-2-yl, isoquinoline-3-yl, 6-methylquinoline-2-yl, 8-methoxyquinoline-4-yl, furano[3,2-b]pyridin-5-yl, quinazoline-2-yl, 6-fluoroquinazoline-2-yl, 1,5-naphthidin-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]heptan-2-yl, 1H-indene-2-yl;Benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidone-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)phenylmethyl, 2-(prop-2-yn-1-yloxy) phenylmethyl, 3-(1,3-thiazolyl-2-yl)phenylmethyl, 3-(trifluoromethyl)thiophenylmethyl, 3-methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrolo-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)phenylmethyl 2-Fluoro-3-fluoromethoxyphenylmethyl, 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, naphth-1-ylmethyl, 5,6,7,8-tetrahydronaphth-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-dihydro-2H-1-benzopyran-8-ylmethyl, 2-phenylethyl, 2-(2-methyl-phenyl) 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-(propane-2-yl)-1,3-thiazolyl-2-ylmethyl, 2-methyl-1,3-thiazolyl-4-ylmethyl, 2-trifluoromethyl-1,3-thiazolyl-4-ylmethyl, 1-ethylpyrazole-5-ylmethyl, 1-(2-propyl)pyrazole-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazol-2-ylmethyl, 1-benzylimidazol-2-yl)methyl, 1-(2-methylpropyl)-1H-imidazol-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridine-2-ylmethyl, 2-methylpyridine- 4-ylmethyl, 4-trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)pyridin-2-ylmethyl, 6-trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophene-3-yl)ethyl, 5-trifluoromethylthiophene-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophene-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, 3-fluoro-3-phenylcyclobutylmethyl, cyclohexylmethyl, 4-methylcyclohexylmethyl, 4-trifluoromethylcyclohexylmethyl, 4-methoxycyclohexyl-methyl, 4,4-dimethylcyclohexylmethyl, 4,4-difluorocyclohexylmethyl, 3-trifluoromethyl - Bicyclo[1.1.1]pentan-1-ylmethyl, bicyclo[2.2.1]heptan-2-ylmethyl, bicyclo[2.2.2]octane-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothiazide-4-ylmethyl, 2-(thiazide-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl; and;

[0355] R 2Representing -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH3, -C(=O)-NH2, -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobut-1-yl, -C(=O)-N(H)-CH2CH2-OH, -C(=O)-N(H)-CH2CH2-OCH3, -C(=O)-N(H)-CH2-C(H)(OH)-CH3, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H -C(H)(CH3)-CH2OH, -C(=O)-N(H)-C(H)(CH2CH3)-CH2OH, -C(=O)-N(H)-C(H)(CH2OH)-CH2CH2-O-CH3, -C(=O)-N(H)-C(CH3)2CH2CH2OH, -C(=O)-N(H)-C(H)(CH2OH)-phenyl, -C(=O)-N(H)-C(CH3)(CH2OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH3)-phenyl, -C(=O)-N(H)-CH2-1H—1-methylimidazol-2-yl, -C(=O)-N(H)-(CH2 )2-1H-imidazol-1-yl, -C(=O)-N(H)-CH2-pyridin-2-yl, -C(=O)-N(H)-CH2-pyridin-3-yl, -C(=O)-N(H)-CH2-pyridin-4-yl, -C(=O)-N(H)-C(H)(CH2OH)-pyridin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-4-yl, -C(=O)-N(H)-CH2-pyridazin-2-yl, -C(=O)-NH-C(CH2OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidine-1-yl, -NH-C(=O)-CH=C H2, -NH-C(=O)-CF=CH2, -NH-C(=O)-CH2Cl, -NH-C(=O)-C≡CH, -CH2-NH-C(=O)-CH=CH2, -CH2-NH-C(=O)-CH2Cl, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2- OH, -S(=O)2-NH2, -S(=O)2-NHCH3, -S(=O)(=NH)-N(CH3)2, -S(=O)(=N-CH3)-N(CH3)2, -S(=O)(=N-CH3)-OH, -S(=O)(=NH)-CH3, -P(=O)(OH)2, F, -CN;Preferred types are -C(=O)-OH and -C(=O)-ONa.

[0356] In yet another specific embodiment, PE8, the compound of the present invention is a tricyclic heterocycle of formula IA, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0357] Ring A represents a five-membered heteroaryl ring selected from the following ring subsets:

[0358]

[0359]

[0360] Z 1 It is CH;

[0361] Z 2 It is CH;

[0362] Z 3 It is CH or N;

[0363] R 1Representing 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)-phenyl-1-yl, 4-cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)thiophenyl, 4-(trifluoromethyl)thiophenyl, 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-Trifluoromethylthiophene-2-yl, 2-Trifluoromethyl-1,3-thiazolyl-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-Trifluoromethoxypyridin-2-yl, 4-Cyanopyridin-2-yl, 5-Trifluoromethylpyridin-2-yl, 6-Trifluoromethylpyridin-2-yl, 6-Trifluoromethylpyridin-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-methylthiopyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-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-cyclopentadien[b]pyridin-2-yl, 5,6,7,8-tetrahydroquinoline-2-yl, 5-oxo-5,6,7,8-tetrahydroquinoline-2-yl, Hydroquinoline-2-yl, 5H,6H,7H-cyclopentadien[b]pyridin-2-yl, quinoline-2-yl, isoquinoline-3-yl, 6-methylquinoline-2-yl, 8-methoxyquinoline-4-yl, furano[3,2-b]pyridin-5-yl, quinazoline-2-yl, 6-fluoroquinazoline-2-yl, 1,5-naphthidin-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]heptan-2-yl, 1H-indene-2-yl;Benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidone-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)phenylmethyl, 2-(prop-2-yn-1-yloxy) phenylmethyl, 3-(1,3-thiazolyl-2-yl)phenylmethyl, 3-(trifluoromethyl)thiophenylmethyl, 3-methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrolo-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)phenylmethyl 2-Fluoro-3-fluoromethoxyphenylmethyl, 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, naphth-1-ylmethyl, 5,6,7,8-tetrahydronaphth-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-(propane-2-yl)-1,3-thiazolyl-2-ylmethyl, 2-methyl-1,3-thiazolyl-4-ylmethyl, 2-trifluoromethyl-1,3-thiazolyl-4-ylmethyl, 1-ethylpyrazole-5-ylmethyl, 1-(2-propyl)pyrazole-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazol-2-ylmethyl, 1-benzylimidazol-2-yl)methyl, 1-(2-methylpropyl)-1H-imidazol-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridine-2-ylmethyl, 2-methylpyridine- 4-ylmethyl, 4-trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)pyridin-2-ylmethyl, 6-trifluoromethylpyridin-2-ylmethyl, 2-(trifluoromethyl)pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophene-3-yl)ethyl, 5-trifluoromethylthiophene-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophene-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-yl Methyl, 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, 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]octane-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-dioxothiazide-4-ylmethyl, 2-(thiazide-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4,4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl;

[0364] R 2Representing -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH3, -C(=O)-NH2, -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutane-1-yl, -C(=O)-N(H)-CH2CH2-OH, -C(= O)-N(H)-CH2CH2-OCH3, -C(=O)-N(H)-CH2-C(H)(OH)-CH3, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)- N(H)-C(H)(CH3)-CH2OH, -C(=O)-N(H)-C(H)(CH2CH3)-CH2OH, -C(=O)-N(H)-C(H)(CH2OH)-CH2CH2 -O-CH3, -C(=O)-N(H)-C(CH3)2CH2CH2OH, -C(=O)-N(H)-C(H)(CH2OH)-phenyl, -C(=O)-N(H)-C(CH3)(CH2OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH3)-phenyl, -C(=O)-N(H)-CH2-1H—1-methylimidazol-2-yl, -C(=O)-N(H) -(CH2)2-1H-imidazol-1-yl, -C(=O)-N(H)-CH2-pyridin-2-yl, -C(=O)-N(H)-CH2-pyridin-3-yl, -C(=O)-N(H)-CH2-pyridin-4-yl, -C(=O)-N(H)-C(H)(CH2OH)-pyridin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH2-1,3-Pyrimidin-4-yl, -C(=O)-N(H)-CH2-pyridazin-2-yl, -C(=O)-NH-C(CH2OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidine-1-yl, -NH-C(=O)-CH=CH2, -NH-C(=O)-CF=CH2, -NH-C(=O)-CH2Cl, -NH-C(=O)-C≡CH, -CH2-NH-C(=O)-CH=CH2, -CH2-NH-C(=O)-CH2Cl, -CH2-NH- C(=O)-C≡CH, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-OH, -S(=O)2-NH2, -S(=O)2-NHCH3, -S(=O)(=NH)-N(CH3)2, -S( =O)(=N-CH3)-N(CH3)2, -S(=O)(=N-CH3)-OH, -S(=O)(=NH)-CH3, -P(=O)(OH)2, F, -CN; preferably -C(=O)-OH, -C(=O)-ONa. ,

[0365] In another specific embodiment of the invention, PE9, the compound of the invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, wherein

[0366] R 1 Selected from

[0367]

[0368]

[0369]

[0370] -CH3,

[0371] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0372] In the specific implementation scheme PE9a of PE9,

[0373] R 1 Selected from

[0374]

[0375] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below. In particular, R 1 yes (Specific implementation plan PE9aa).

[0376] In another specific embodiment of the invention, PE10, the compound of the invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, wherein

[0377] R 2 Selected from:

[0378] -COOH,-COONa,-COOCH3, -CN,-F,-CH2-CN,

[0379] -B(OH)2; -C(=O)-NH2,

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391] -S-CH3,-S(=O)-CH3,-S(=O)2-CH3,-S(=O)2-NH2,

[0392] (including R) Z2 );

[0393] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0394] In the specific implementation scheme PE10a of PE10,

[0395] The compounds of the present invention are tricyclic heterocycles of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0396] R 2 Selected from:

[0397] -COOH,-COONa,-COOCH3, (including R) Z2 );

[0398] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0399] In the specific implementation plan of PE10aa, PE10aa,

[0400] R 2 Selected from:

[0401] -COOH.

[0402] In the specific implementation scheme PE10b of PE10,

[0403] The compounds of the present invention are tricyclic heterocycles of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0404] R 2 Selected from:

[0405] -C(=O)-NH2,

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0418] In the specific implementation plan of PE10b, PE10bb

[0419] R 2 Selected from:

[0420] -C(=O)-NH2,

[0421]

[0422]

[0423] In another specific implementation scheme of PE10, PE10c,

[0424] The compounds of the present invention are tricyclic heterocycles of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein

[0425] R 2 Selected from:

[0426] -S-CH3,-S(=O)-CH3,-S(=O)2-CH3,-S(=O)2-NH2,

[0427]

[0428] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0429] In the specific implementation scheme PE10cc of PE10c

[0430] R 2 Selected from:

[0431] -S(=O)-CH3,

[0432] It is understandable that in the above implementation schemes PE9, PE9a, PE9aa, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, and PE10cc, the dashed lines... Used to indicate each group R 1 and R 2 They are attached to the remaining parts of the molecule, i.e., the positions of compounds of formula I or IA.

[0433] In another specific embodiment of the invention, PE11, the compound of the invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt thereof, including mixtures thereof in all proportions, wherein

[0434] R 1 Selected from the group described above for PE9; and

[0435] R 2 Selected from the group described above for PE10;

[0436] Furthermore, the remaining groups and residues are as defined above for formula IA or I, or any further specific embodiments described above or below.

[0437] This is the specific implementation plan PE11a for PE11, in which...

[0438] R 1 Selected from the group described above for PE9a, and especially PE9aa; and

[0439] R2 Selected from the group described above for PE10.

[0440] This is another specific implementation scheme of PE11, PE11b, in which...

[0441] R 1 Selected from the group described above for PE9a, and especially PE9aa; and

[0442] R 2 Selected from the group described above for PE10a, especially PE10aa.

[0443] This is another specific implementation scheme of PE11, PE11c, in which...

[0444] R 1 Selected from the group described above for PE9a, and especially PE9aa; and

[0445] R 2 Selected from the group described above for PE10b, especially PE10bb.

[0446] This is another specific implementation scheme of PE11, PE11d, in which...

[0447] R 1 Selected from the group described above for PE9a, and especially PE9aa; and

[0448] R 2 Selected from the group described above for PE10c, especially PE10cc.

[0449] This is yet another specific embodiment of the present invention, PE12, wherein...

[0450] Ring A is selected from one of the specific implementation schemes PE2, PE2a, PE2b, and PE2c; and

[0451] R 1 and R 2 The selection is as described for PE11.

[0452] In the specific implementation scheme PE12a of PE12, R 1 and R 2 The choice is as described for PE11a. In another specific implementation, PE12b, of PE12, R... 1 and R 2 The choice is as described for PE11b. In yet another specific implementation, PE12c, R... 1 and R 2 The choice is as described for PE11c. In yet another specific implementation, PE12d, R... 1and R 2 The selection is as described for PE11d.

[0453] In another specific embodiment, PE13, the compound of the present invention is a tricyclic heterocycle of formula IA or I, or any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein the compound is selected from Tables 1 and 1b below, particularly the compounds shown in Table 1. It should be understood that each individual compound described in Tables 1 and 1b, and any N-oxide, solvate, tautomer, or stereoisomer thereof, and / or any pharmaceutically acceptable salt of such compounds, represents a specific embodiment of the present invention.

[0454] As used herein, unless otherwise stated or explicitly defined elsewhere in the specification and / or claims, the following definitions shall apply.

[0455] As used herein, the term "aliphatic" or "aliphatic group" refers to a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic, bicyclic, or tricyclic hydrocarbon that is fully saturated or contains one or more unsaturated units, such as one or more C=C double bonds and / or C≡C triple bonds, but is not aromatic (also referred to herein as "carbocyclic," "alicyclic," or "cycloalkyl"), which typically, and unless otherwise defined in this specification or the appended claims, has a single attachment point to the remainder of the molecule. Unless otherwise stated, an aliphatic group contains 1-8 or 1-6 aliphatic carbon atoms (respectively "C..."). 1-8 -Aliphatic" and "C" 1-6 -Aliphatic". In some embodiments, the aliphatic group contains 1-5 aliphatic carbon atoms ("C"). 1-5 -Aliphatic". In other embodiments, the aliphatic group contains 1-4 aliphatic carbon atoms ("C"). 1-4 -Aliphatic". In other embodiments, the aliphatic group contains 1-3 aliphatic carbon atoms ("C"). 1-3 -Aliphatic), and in other embodiments, the aliphatic group contains 1-2 aliphatic carbon atoms ("C"). 1-2 - Alicyclic). In some embodiments, "alicyclic" ("cycloalkyl") refers to monocyclic C3-C7 hydrocarbons (i.e., monocyclic hydrocarbons having 3, 4, 5, 6 or 7 ring carbon atoms) or bicyclic C 5-8Hydrocarbons (i.e., bicyclic hydrocarbons having 5, 6, 7, or 8 ring carbon atoms), which are fully saturated or contain one or more unsaturated units but are not aromatic, have a single attachment point to the rest of the molecule. In another embodiment, the term "cycloaliphatic" or "carbocyclic" refers to a monocyclic or bicyclic alicyclic ring system fused to an aromatic, heteroaromatic, or heterocyclic ring system via two adjacent ring atoms; in other words, such a carbocyclic ring shares two ring atoms with the ring or ring system it is fused to, thus having two attachment points to the rest of the molecule. In another embodiment, the term "carbocyclic" refers to a bicyclic spirocyclic ring, wherein two monocyclic carbocyclic rings are fused to each other by the same single carbon atom. Generally, unless otherwise defined in a particular case, the term "aliphatic" includes, within the chemically possible range, straight-chain, i.e., unbranched, as well as branched hydrocarbon chains. Furthermore, unless otherwise defined in a particular case, the term generally includes, within the chemically possible range, both unsubstituted and substituted hydrocarbon moieties. Typical substituents of aliphatic groups include, but are not limited to, halogens, cyano groups, hydroxyl groups, alkoxy groups, unsubstituted or mono- or disubstituted amino groups; aryl groups, especially unsubstituted or substituted phenyl groups; heteroaryl groups, especially unsubstituted or substituted pyridyl or pyrimidinyl groups; and heterocyclic groups, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl, or morpholinyl groups. Suitable aliphatic groups include, but are not limited to, straight-chain or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0456] The term "alkyl" generally refers to a saturated aliphatic and acyclic moiety, while the term "alkenyl" generally refers to an unsaturated aliphatic and acyclic moiety having one or more C=C double bonds, and the term "alkynyl" generally refers to an aliphatic and acyclic moiety having one or more C≡C triple bonds. It should be understood that the term "alkenyl" includes all forms of isomers, namely E-isomers, Z-isomers, and mixtures thereof (E / Z-isomers). Exemplary aliphatic groups are straight-chain or branched, substituted or unsubstituted C- groups. 1-8 -alkyl, C 1-6 -alkyl, C 1-4 -alkyl, C 1-3 -alkyl, C 1-2 -alkyl, C 2-8 -Alkenyl, C 2-6 -Alkenyl, C 2-8 -Alynyl group, C 2-6 -Alynyl group, C 2-4 -Alynyl groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0457] Specifically, the term "C" 1-3"-alkyl" refers to an alkyl group having 1, 2, or 3 carbon atoms, i.e., a saturated acyclic aliphatic group. Example C 1-3 -alkyl groups are methyl, ethyl, propyl, and isopropyl. The term "C" 1-4 "-alkyl" refers to an alkyl group having 1, 2, 3, or 4 carbon atoms. Example C 1-4 Alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and tert-butyl. The term "C" is also used. 1-6 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, or 6 carbon atoms. Example C 1-6 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, and 2-hexyl. The term "C" is also used. 1-8 "-alkyl" refers to an alkyl group having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Example C 1-8 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, n-hexyl, 2-hexyl, n-heptyl, 2-heptyl, n-octyl, 2-octyl, and 2,2,4-trimethylpentyl. Each of these alkyl groups may be straight-chain or (except C1-alkyl and C2-alkyl) branched, and may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents, which may be the same or different, and may be selected from halogens, cyano, hydroxyl, alkoxy, unsubstituted or mono- or disubstituted amino groups, aryl, particularly unsubstituted or substituted phenyl groups, heteroaryl, particularly unsubstituted or substituted pyridyl or pyrimidinyl groups, heterocyclic groups, particularly unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazine, or morpholinyl groups.

[0458] In some cases, C 1-3 -alkyl, C 1-4 -alkyl, C 1-6 -alkyl, C 1-8 -alkyl groups may also include residues in which one or two of the non-terminal and non-adjacent -CH2- (methylene) groups are substituted with -O-, -S- and / or one or two non-terminal and non-adjacent -CH2- or -CH- groups are substituted with -NH- or -N-. These substitutions produce, for example, (modified) alkyl groups such as -CH2-CH2-O-CH3, -CH2-CH2-CH2-S-CH3, CH2-CH2-NH-CH2-CH3, CH2-CH2-O-CH2-CH2-O-CH3, CH2-CH2-N(CH3)-CH2-CH3, etc. Further and / or different substitutions of the -CH- and -CH2- groups may be defined for specific alkyl substituents or radicals elsewhere in the specification and / or claims.

[0459] Term "C" 3-7 "-Cycloalkyl" refers to alicyclic hydrocarbons as defined above that have 3, 4, 5, 6, or 7 ring carbon atoms. Similarly, the term "C"... 3-6 "-Cycloalkyl" refers to alicyclic hydrocarbons having 3, 4, 5, or 6 ring carbon atoms. C 3-7 -The cycloalkyl group may be unsubstituted or substituted with one, two, or three substituents (unless otherwise specified in this specification), the substituents may be the same or different, and unless otherwise specified in this specification, they are selected from C 1-6 -alkyl, OC 1-6 -alkyl (alkoxy), halogen, hydroxyl, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl. If substituted, C 3-7 -Cycloalkyl groups include all possible stereoisomers. Example C 3-7 -Cycloalkyl groups are cyclopropyl, 2-methyl-cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cycloheptenyl. The term "bicyclic C" is also mentioned. 5-8 "-Cycloalkyl" refers to a bicyclic alicyclic hydrocarbon having 5, 6, 7, or 8 ring carbon atoms as defined above; it includes spirocyclic systems, i.e., bicyclic C... 5-8 - A cycloalkyl ring system in which two carbon rings are linked to each other by the same carbon atom. Bicyclic C 5-8 -The cycloalkyl group may be unsubstituted or, unless otherwise specified herein, substituted with one, two, or three substituents that may be the same or different, and, unless otherwise specified herein, selected from C 1-6 -alkyl, OC 1-6 -alkyl (alkoxy), halogen, hydroxyl, unsubstituted or mono- or disubstituted amino groups. If substituted, the bicyclic C 5-8 -Cycloalkyl groups include all possible stereoisomers. Example bicyclic C 5-8 -Cycloalkyl groups are spiro[3.3]heptyl, bicyclo[2.2.1]hept-2-yl, bicyclo[2.2.2]oct-2-yl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, and bicyclo[3.1.1]hept-2-en-2-yl.

[0460] The term "aliphatic oxygen group" refers to a saturated or unsaturated aliphatic group or substituent, as defined above, attached to another structural moiety via an oxygen atom (-O-). The term "C" 1-6"-Aliphatic oxy group" refers to an aliphatic oxy group having 1, 2, 3, 4, 5, or 6 carbon atoms within an aliphatic group. The term "alkoxy group" refers to a specific subgroup of saturated aliphatic oxy groups, namely alkyl substituents and residues attached to another structural moiety via an oxygen atom (-O-). Sometimes, it is also called "O-alkyl," and more specifically "OC." 1-2 -alkyl", "OC" 1-3 -alkyl", "OC" 1-4 -alkyl", "OC" 1-6 -alkyl", "OC" 1-8 "-alkyl". Similar to similar alkyl groups, it can be straight-chain or (except for -O-C1-alkyl and -O-C2-alkyl) branched, and can be unsubstituted or substituted with 1, 2, or 3 substituents, which can be the same or different, and are selected from halogens, unsubstituted or mono- or di-substituted amino groups unless otherwise specified in this specification. Exemplary alkoxy groups are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, and n-pentoxy.

[0461] The term "alkylene" refers to a divalent (or divalent) aliphatic group, and particularly a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2). y - where y is a positive integer, preferably 1, 2, 3, 4, 5, or 6. In the context of this invention, "C" 1-3 "-alkylene" refers to alkylene moieties having 1, 2, and 3 -CH2- groups, respectively; however, the term "alkylene" includes not only straight-chain alkylene, i.e., "alkylene chains," but also branched-chain alkylene. The term "C..." 1-6 "-alkylene" refers to the alkylene moiety, which is either straight-chain (i.e., an alkylene chain) or branched and has 1, 2, 3, 4, 5, or 6 carbon atoms. The term "C"... 2-6 "-alkylene" refers to an alkylene moiety having 2, 3, 4, 5, or 6 carbon atoms, while "C" refers to a moiety having 2, 3, 4, 5, or 6 carbon atoms. 3-4 "-alkylene" refers to an alkylene moiety having 3 or 4 carbon atoms and "C 2-3 "-alkylene" refers to an alkylene moiety having 2 or 3 carbon atoms. A substituted alkylene is a group in which one or more methylene hydrogen atoms are replaced (or substituted by) a substituent. Suitable substituents include those described herein for substituted alkyl. In some cases, one or two methylene groups of the alkylene chain may be, for example, O, S and / or NH or NC. 1-4- Alkyl substitution. Exemplary alkylene groups are –CH2-, –CH2–CH2-, –CH2–CH2–CH2–CH2-, –O–CH2–CH2-, –O–CH2–CH2–CH2-, –CH2–O–CH2–CH2-, -O–CH2-O-, -O–CH2–CH2-O-, -O–CH2–CH2–CH2-O-, –O–CH2–CH2–CH2-O-, –CH2-NH–CH2–CH2-, –CH2-N(CH3)–CH2–CH2-.

[0462] The term "alkenyl" refers to a divalent alkenyl group. A substituted alkenyl chain is a polymethylene group containing at least one double bond, wherein one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described herein for substituted aliphatic groups. The term "alkenyl" refers not only to straight-chain divalent alkenyl groups, i.e., alkenyl chains, but also to branched alkenyl groups. The term "C" 2-6 "-Alkenyl" refers to alkenyl groups having 2, 3, 4, 5, or 6 carbon atoms.

[0463] The term "ynynyl" refers to a divalent ynyl group. A substituted ynynyl chain is a polymethylene group containing at least one triple bond, wherein one or more hydrogen atoms are replaced by substituents. Suitable substituents include those described herein for substituted aliphatic groups.

[0464] The term "halogen" refers to F, Cl, Br, or I.

[0465] The term “heteroatom” refers to one or more of oxygen (O), sulfur (S), or nitrogen (N), including any oxidized form of nitrogen or sulfur, such as N-oxides, sulfoxides, and sulfones; any basic nitrogen or quaternized form of substituted nitrogen in heterocyclic or heteroaromatic rings, such as N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidinyl), or N-SUB, wherein SUB is a suitable substituent (as in N-substituted pyrrolidinyl).

[0466] The term "aryl" as used alone or as part of a larger category such as "aralkyl," "ararylalkoxy," or "aryloxyalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system having a total of 5-14 ring members, wherein the ring members are carbon atoms, and at least one ring in the system is aromatic, i.e., it has (4n+2)π (π) electrons (where n is an integer selected from 0, 1, 2, 3), which are delocalized in the system, and wherein each ring in the system contains 3-7 ring members. Preferably, all rings or the entire ring system in the aryl system is aromatic. The term "aryl" is used interchangeably with the term "aromatic ring." In some embodiments of the invention, "aryl" refers to "aromatic ring system." More specifically, those aromatic ring systems can be monocyclic, bicyclic, or tricyclic with 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms. More specifically, these aromatic ring systems can be monocyclic or bicyclic with 6, 7, 8, 9, or 10 ring carbon atoms. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracene, etc., which can be unsubstituted or substituted with one or more of the same or different substituents. The scope of the term "aryl" or "aromatic ring system" as used herein also includes groups in which the aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimide, naphthimide, phenanthridine, or tetrahydronaphthyl. In the latter case, the "aryl" or substituent is attached to its side group via the aromatic portion of the ring system.

[0467] The term "benzo[a]" refers to a six-membered aromatic ring (having carbon ring atoms) fused to another ring via two adjacent carbon atoms; this ring is alicyclic, aromatic, heteroaromatic, or heterocyclic (heteroaliphatic) ring. The result is a cyclic system with at least two rings, where the benzo[a] ring shares two common carbon atoms with the other ring it is fused to. For example, if the benzo[a] ring is fused to a benzene ring, a naphthalene ring system is formed, while fusion of the benzo[a] ring to pyridine provides quinoline or isoquinoline; fusion of the benzo[a] ring to a cyclopentene ring yields an indene ring.

[0468] The terms "heteroaryl" and "heteroaryl-" used alone or as part of a larger portion, such as "heteroarylalkyl" or "heteroarylalkoxy," refer to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms (the atoms being carbon and heteroatoms), preferably 5, 6, 9, or 10 ring atoms; sharing 6, 10, or 14 π (pi) electrons in the cyclic array; and having 1, 2, 3, 4, or 5 heteroatoms in addition to the carbon atom. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of basic nitrogen. In other words, a "heteroaryl" ring or ring system can also be described as an aromatic heterocycle. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, furazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazinyl, purinyl, naphridinyl, pteridinyl, and pyrrolopyridinyl, particularly pyrrolo[2,3-b]pyridinyl. The terms “heteroaryl” and “heteroaryl-” as used herein also include groups in which the heteroaryl ring is fused to one or more aryl, alicyclic, or heterocyclic rings, wherein the attachment point or free radical is preferably on the heteroaryl ring, or, if present, on the aryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl (benzothiophene), benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 9H-carbazoleyl, dibenzofuranyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. For example, the indolyl ring may be attached via a ring atom of a six-membered aryl ring or via a ring atom of a five-membered heteroaryl ring. The heteroaryl group is optionally monocyclic, bicyclic, or tricyclic. The term “heteroaryl” is used interchangeably with the terms “heteroaryl ring,” “heteroaryl,” or “heteroaryl group,” and any of these terms includes an unsubstituted ring or a ring substituted with one or more of the same or different substituents. The term “heteroarylalkyl” refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are optionally substituted independently.

[0469] A heteroaryl ring can have its side groups attached to any of its heterocyclic or carbon ring atoms, and this attachment produces a stable structure or molecule: any ring atom can be unsubstituted or substituted.

[0470] The structure of a typical example of the "heteroaryl" substituent used in this invention is shown below:

[0471]

[0472]

[0473]

[0474]

[0475] Those heteroaryl substituents can attach to any side group via any ring atom suitable for such attachment.

[0476] As used herein, the terms “heterocyclic,” “heterocyclic group,” “heterocyclic moiety,” and “heterocyclic” are used interchangeably to refer to a stable monocyclic, bicyclic, or tricyclic heterocyclic moiety having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring atoms, wherein 1, 2, 3, 4, or 5 of the ring atoms are heteroatoms and wherein the heterocyclic moiety is saturated or partially unsaturated; a heterocyclic moiety that is an aromatic ring or a ring system is referred to as a “heteroaryl” moiety as described above. Preferably, the heterocyclic moiety 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.

[0477] When referring to the ring atom of a heterocycle, the term "nitrogen" includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur, or nitrogen, nitrogen is N (as in 3,4-dihydro-2H-pyrrole), NH (as in pyrrolidinyl), or N-SUB, where SUB is a suitable substituent (as in N-substituted pyrrolidinyl).

[0478] In the context of the term "heterocycle," the term "saturated" refers to a fully saturated heterocyclic system, such as pyrrolidinyl, piperidinyl, morpholinyl, piperidinoneyl, tetrahydrofuranyl, thiaalkyl, and dioxothialkyl. Regarding the term "heterocycle," the term "partially unsaturated" refers to a heterocyclic system (i) containing one or more unsaturated units, such as C=C or C= heteroatom bonds, but not aromatic, such as tetrahydropyridinyl; or (ii) in which a (saturated or unsaturated but non-aromatic) heterocycle is fused with an aromatic or heteroaromatic ring system, however, in which the "partially unsaturated heterocycle" is attached to the rest of the molecule (its side groups) through one of the ring atoms of the "heterocycle" portion of the system, rather than through the aromatic or heteroaromatic portion. This first type (i) "partially unsaturated" heterocycle may also be referred to as a "non-aromatic partially unsaturated" heterocycle. The second type (ii) “partially unsaturated” heterocycles, also known as (bicyclic or tricyclic) “partially aromatic” heterocycles, indicate that at least one ring of the heterocycle is a saturated or unsaturated but non-aromatic heterocycle that is fused with at least one aromatic or heteroaromatic ring system. Typical examples of these “partially aromatic” heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.

[0479] Heterocycles can be attached to their side groups at any heteroatom or carbon atom that produces a stable structure, and any ring atom can be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, thiaalkyl, dioxothiaalkyl, tetrahydrothiophenyl, pyrrolyl, piperidinyl, pyrrololinyl, morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolyl, piperazine, dioxalyl, dioxacyclopentyl, diazacycloheptyl, oxonitroheptanyl, thioazinoheptanyl, morpholinyl, and quininecycloyl. The terms “heterocyclic,” “heterocyclic group,” “heterocyclic ring,” “heterocyclic moiety,” and “heterocyclic group” are used interchangeably herein and also include those in which the heterocyclic ring is fused to one or more aryl, heteroaryl, or alicyclic rings, such as dihydroindolyl, 3H-indolyl, chromyl, phenanthrenediyl, or tetrahydroquinolinyl, wherein the attachment point or free radical is located on the heterocyclic ring. The heterocyclic group is optionally monocyclic, bicyclic, or tricyclic. The term “heterocyclic alkyl” refers to an alkyl group substituted with a heterocyclic group, wherein the alkyl group and the heterocyclic moiety are independently unsubstituted or substituted.

[0480] The term "carbohydrate-derived group" refers to a monovalent organic group derived from any kind of carbohydrate, such as aldoses and ketoses, as well as polyols, i.e., reduced carbohydrates, and carbohydrate acids, i.e., oxidized carbohydrates, derived from such aldoses and ketoses. This term includes monovalent groups of monosaccharides and their reduced and oxidized derivatives, including but not limited to D / L-glyceraldehyde, D-glyceraldehyde, L-glyceraldehyde, dihydroxyacetone, D / L-erythrose, D-erythrose, L-erythrose, D / L-threose, D-threose, L-threose, D / L-ribose, D-ribose, L-ribose, D / L-arabinose, D-arabinose, L-arabinose, D / L-xylose, D-xylose, L-xylose, D / L-Lysulose, D-Lysulose, L-Lysulose, D / L-Allose, D-Allose, L-Allose, D / L-Atroose, D-Atroose, L-Atroose, D / L-Glucose, D-Glucose, L-Glucose, D / L-Mannose, D-Mannose, L-Mannose, D / L-Guluose, D-Guluose, D-Guluose, D / L-Idulose, D-Idulose, L-Idulose, D / L-Galactose, D-Galactose L-galactose, D / L-tarose, D-tarose, L-tarose, D / L-fructose, D-fructose, L-fructose; D / L-sorbose, D-sorbose, L-sorbose; D / L-sorbitol, D-sorbitol, L-sorbitol, D / L-mannitol, D-mannitol, L-mannitol, D / L-aloteol, D-aloteol, L-aloteol, D / L-galactitol, D-galactitol, L-galactitol, D / L D-glucitol, L-glucitol, D / L-idutitol, D-idutitol, L-idutitol, D / L-atropitol, D-atropitol, L-atropitol; D / L-gluconic acid, D-gluconic acid, L-gluconic acid, D / L-mannitol, D-mannitol, L-mannitol, D / L-alendronic acid, D-alendronic acid, L-alendronic acid, D / L-glucuronic acid, D-glucuronic acid, L-glucuronic acid. It also contains monovalent groups of disaccharides and oligosaccharides, as well as their respective reducing and oxidizing derivatives, including sucrose, lactose, maltose, and cellobiose. These carbohydrate-derived groups can be used in their pure D- or L-form or as a mixture of D- and L-forms in every possible proportion. Similarly, each of these groups includes its open form and its cyclic form in pure form or in any proportion of a mixture. Each of these carbohydrate-derived groups can be further substituted with suitable substituents, such as halogens, cyano groups, unsubstituted, mono- or disubstituted amino groups, C... 1-6 Aliphatic group, C 1-6Aliphatic oxy groups, aryl groups, aralkyl groups, etc. Any carbohydrate-derived group can be attached to its side group at any heteroatom or carbon atom, resulting in a stable structure or molecule. Examples of carbohydrate-derived groups are D / L-fructose, D-fructose, D / L-glucose, D-glucose, D / L-glucuronic acid, D-glucuronic acid, and L-glucuronic acid.

[0481] The term "bioisostere," used alone or in combination with other terms such as "bioisosteric group," refers to a compound or group that produces a biological effect similar to that of another compound, group, base, part, or substituent, despite their structural differences. In a broader sense, "bioisosteres" can be understood as compounds or groups having nearly identical molecular shapes and volumes, substantially the same electron distribution, and exhibiting similar physical properties. A typical example of a bioisostere is a carboxylic acid bioisostere, which exhibits physicochemical properties similar to those of a carboxylic acid group ("carboxylic acid bioisosteres"). Such carboxylic acid bioisosteric groups or groups can be used to replace carboxylic acid groups or groups, thereby providing properties similar to those of a carboxylic acid group, but may exhibit some different properties compared to the carboxylic acid group, such as reduced polarity, increased lipophilicity, or enhanced pharmacokinetic properties. Typical examples of carboxylic acid bioisosteres include, but are not limited to, -CN, fluorine, amide, sulfonamide, sulfonylimide, and several aromatic and non-aromatic heterocycles, such as hydroxyl-substituted isoxazoles, sulfonamide-substituted oxadiazoles, and oxadiazoles, for example, 5-oxo-2,5-dihydro-1,2,4-oxadiazole, especially tetrazolium, such as 1H-1,2,3,4-tetrazolium and 2-methyl-2H-1,2,3,4-tetrazolium.

[0482] As used herein, the term "unsaturated" means that a part or group or substituent has one or more unsaturated units.

[0483] As used herein, with respect to any ring, ring system, ring moiety, etc., the term "partially unsaturated" refers to a ring moiety comprising at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple unsaturated sites. Specifically, it includes (i) unsaturated (monocyclic, bicyclic, or tricyclic) ring systems without any aromatic or heteroaromatic groups or moieties; and (ii) bicyclic or tricyclic systems in which one of the rings is an aromatic or heteroaromatic ring fused with another ring that is neither an aromatic nor a heteroaromatic ring, such as tetrahydronaphthyl or tetrahydroquinolinyl. The first type (i) "partially unsaturated" rings, ring systems, and ring moieties may also be referred to as "non-aromatic partially unsaturated" rings, ring systems, and ring moieties, while the second type (ii) may be referred to as "partially aromatic" rings, ring systems, and ring moieties.

[0484] As used herein, the terms “bicyclic,” “ring of a bicyclic,” or “bicyclic system” refer to any bicyclic system, i.e., a carbocyclic or heterocyclic system, saturated or having one or more unsaturated units (i.e., partially unsaturated) or aromatic, having one or more common atoms between the two rings of the system. Thus, the term includes any permissible ring fusion, such as ortho-fusion or spirocyclic. The term “heterobicyclic” as used herein is a subset of “bicyclic,” requiring one or more heteroatoms to be present in one or both rings of the bicyclic system. Such heteroatoms may be present at ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Similarly, the terms "tricyclic," "ring of tricyclic," or "tricyclic system" refer to any tricyclic system, i.e., a carbocyclic or heterocyclic system, saturated and or having one or more unsaturated units (i.e., partially unsaturated) or aromatic, wherein a bicyclic system (as defined above) is fused with another third ring. Therefore, the term includes any permissible ring fusion. The term "heterotricyclic" as used herein is a subset of "tricyclic," requiring one or more heteroatoms to be present in one or two rings of the tricyclic system. Such heteroatoms may be present at ring junctions and optionally substituted, and may be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms, such as sulfones and sulfonates), phosphorus (including oxidized forms, such as phosphates), boron, etc. In some embodiments, the tricyclic group has 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0485] As described herein, certain compounds of the present invention contain a “substituted” or “optionally substituted” moiety. Generally, the term “substituted,” whether or not preceded by the term “optionally,” means that one or more hydrogens of the specified moiety are replaced by a suitable substituent. “Substituted” applies to one or more hydrogens explicitly or implicitly present in the structure. Unless otherwise stated, a “substituted” or “optionally substituted” group has a suitable substituent at each substituted position of the group, and when more than one position in any given structure is replaced by more than one substituent selected from the specified group, the substituent is the same or different at each position. If a group, substituent, moiety, or radical is “monosubstituted,” it carries one (1) substituent. If it is “disubstituted,” it carries two (2) identical or different substituents; if it is “trisubstituted,” it carries three (3) substituents, wherein all three are identical, or two are identical and the third is different, or all three are different from each other. The combinations of substituents contemplated in the present invention are preferably those that result in the formation of stable or chemically viable compounds. As used herein, the term "stable" means a compound that remains substantially unchanged when subjected to conditions permissible for its production, testing, and, in some embodiments, its recovery, purification, and use for one or more purposes disclosed herein.

[0486] Unless otherwise stated elsewhere in the specification or appended claims, it should be understood that each optional substituent on the substituted carbon is independently selected from the following monovalent substituents: halogen; -(CH2). 0-4 R o ;-(CH2) 0- 4OR o ;-O(CH2) 0-4 R o -O-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ;-(CH2) 0-4 Ph, which can be generated by one or more R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be generated by one or more R o Substitution; -CH=CHPh, which can be replaced by one or more R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl group, which can be generated by one or more R o Substitution; -NO2; -CN; -N3; ​​-(CH2)0-4 N(R o )2;-(CH2) 0-4 N(R o )C(O)R o ;-N(R o )C(S)R o ;-(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2;-(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ;-(CH2) 0-4 C(O)R o ;-C(S)R o ;-(CH2) 0-4 C(O)OR o ;-(CH2) 0-4 C(O)SR o ;-(CH2) 0-4 C(O)OSiR o 3;-(CH2) 0-4 OC(O)R o ;-OC(O)(CH2) 0-4 SR-;SC(S)SR o ;-(CH2) 0-4 SC(O)R o ;-(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o ,-(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )Ro ;-(CH2) 0-4 SSR o ;-(CH2) 0-4 S(O)2R o ;-(CH2) 0-4 S(O)2OR o ;-(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2; -S(O)(NR o )R o ; -S(O)2N=C(NR) o 2)2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2; -N(R) o )S(O)2R o ;-N(OR) o )R o ;-C(NH)NR o 2; -P(O)2R o ;-P(O)R o 2; -OP(O)R o 2; -OP(O)(OR o )2; SiR o 3; -(C 1-4 (linear or branched alkylene)ON(R) o )2; or -(C 1-4 (straight-chain or branched alkylene)C(O)ON(R) o 2. It should be understood that "Ph" refers to phenyl; and "-(CH2)" refers to... 0-4 "" refers to an alkylene group that does not contain alkylene groups (if the subscript is "0" (zero)) or has 1, 2, 3 or 4 CH2 units.

[0487] Each R o Independently hydrogen, halogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2- (5-6 membered heteroaryl ring) or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen or sulfur, or, despite the above definition, two independently occurring R o Together with one or more of their inserted atoms, they form 3-12 saturated, partially unsaturated, or aryl monocyclic or bicyclic rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, which can be selected from =O and =S R oDivalent substituents on the saturated carbon atoms; or each R o Optionally substituted independently by a monovalent substituent selected from the following: halogen, -(CH2). 0-2 R · 、-(haloR · -(CH2) 0-2 OH, -(CH2) 0-2 OR · -(CH2) 0-2 CH(OR · )2、-O(haloR · -CN, -N3, -(CH2) 0-2 C(O)R · -(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · -(CH2) 0-2 SR · -(CH2) 0-2 SH, -(CH2) 0-2 NH2、-(CH2) 0-2 NHR · -(CH2) 0-2 NR · 2, -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · -(C 1-4 (straight-chain or branched alkylene)C(O)OR · or -SSR · It should be understood that "Ph" refers to phenyl; "halo" refers to halogen; and "-(CH2)" refers to... 0-2 "" refers to an alkylene group that does not contain alkylene groups (if the subscript is "0" (zero)) or has one or two CH2 units.

[0488] Each R · Selected independently from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, and wherein each R · It is unsubstituted or, when preceded by a halo, substituted only by one or more halogens; or wherein the optional substituents on the saturated carbon are independently selected from the following divalent substituents: =O, =S, =NNR. * 2、=NNHC(O)R * =NNHC(O)OR * =NNHS(O)2R* =NR * =NOR * -O(C(R) * 2)) 2-3 O- or -S(C(R) * 2)) 2-3 S-, or a divalent substituent bonded to an adjacent substituted carbon of the "optionally substituted" group, is -O(CR). * 2) 2-3 O-, where R appears independently each time * Selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6 saturated, partially unsaturated or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0489] When R * C 1-6 When aliphatic, R * Optional halogen, -R · 、(haloR · ), OH, -OR · -O(haloR) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2. Or -NO2 substitution, where each R · Selected independently from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, and wherein each R · It is either unsubstituted or, when preceded by halo, substituted by only one or more halogens.

[0490] The optional substituents on the substituted nitrogen are independently... or Each of them Independently hydrogen, C 1-6 Aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 independently selected heteroatoms chosen from nitrogen, oxygen, or sulfur, or two independently occurring rings. Together with one or more of their inserted atoms, they form unsubstituted 3-12 membered saturated, partially unsaturated, or aryl monocyclic or bicyclic rings having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur; wherein when C 1-6 When aliphatic, Optional halogen, -R · 、-(haloR · -OH, -OR · -O(haloR) · -CN, -C(O)OH, -C(O)OR · -NH2, -NHR · -NR · 2 or -NO2 substitution, where each R · Selected independently from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 member saturated, partially unsaturated, or aryl ring having 0-4 independent heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each R · It is either unsubstituted or, when preceded by "halo", substituted by only one or more halogens. It should be understood that "Ph" refers to phenyl and "halo" refers to a halogen.

[0491] The term "solvent" refers to the addition form of the compound of the present invention with a solvent, preferably a pharmaceutically acceptable solvent containing stoichiometric or non-stoichiometric amounts of the solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in a crystalline solid state, thus forming a solvate. If the solvent is water, the formed solvate is a hydrate, such as a hemihydrate, monohydrate, or dihydrate. If the solvent is an alcohol, the formed solvate is an alcohol, such as a methanol or ethanol. If the solvent is an ether, the formed solvate is an ether compound, such as a diethyl ether compound.

[0492] The term "N-oxide" refers to the compounds of the present invention containing an amine oxide moiety, i.e., oxides of tertiary amine groups.

[0493] Compounds of formulas IA and I may—and also depending on the nature of the substituents they may contain—have one or more chiral centers. Therefore, they can exist in a variety of enantiomeric and diastereomeric forms, as appropriate, and can be racemic or optically active forms. Thus, the invention also relates to optically active forms, enantiomers, racemates, diastereomers, and mixtures thereof in all proportions, collectively referred to for the purposes of the invention as “stereoisomers” of these compounds. Since the pharmaceutical activities of racemates or stereoisomers of compounds according to the invention may differ, it may be desirable to use specific stereoisomers, such as a specific enantiomer or diastereomer. In these cases, compounds according to the invention obtained as racemates or even intermediates can be isolated into stereoisomeric (enantiomeric, diastereomeric) compounds by chemical or physical methods known to those skilled in the art. Another method that can be used to obtain one or more specific stereoisomers of the compounds of the present invention in enriched or pure form utilizes stereoselective synthetic procedures, such as applying a stereoisomerically enriched or pure form of a starting material (e.g., using a pure or enriched (R)- or (S)-enantiomer of a specific starting material with a chiral center) or utilizing a chiral reagent or catalyst, particularly an enzyme. In the context of the present invention, the term "pure enantiomer" generally refers to an enantiomer with a relative purity of 95% or greater than that of another enantiomer (its enantiomer), preferably ≥98%, more preferably ≥98.5%, and even more preferably ≥99%.

[0494] Therefore, for example, compounds of the present invention having one or more chiral centers and existing as racemates or as mixtures of enantiomers or diastereomers can be fractionated or resolved by methods known per se into their optically pure or enriched isomers, i.e., enantiomers or diastereomers. The separation of compounds of the present invention can be carried out by chromatography, for example, column separation on a chiral or achiral phase, or by recrystallization from an optionally optically active solvent, or by using an optically active acid or base, or by derivatization with an optically active reagent (e.g., an optically active alcohol), followed by elimination of free radicals.

[0495] In the context of this invention, the term "tautomer" refers to the compounds of this invention that can exist in tautomeric form and exhibit tautomerism; for example, carbonyl compounds can exist in their ketone and / or their enol forms and exhibit ketone-enol tautomerism. These tautomers can exist in their individual forms, such as ketones or enols, or as mixtures thereof, and can be claimed individually and together as mixtures in any ratio. This also applies to cis / trans isomers, E / Z isomers, conformational isomers, etc.

[0496] In one embodiment, the compounds of the present invention are in the form of a free base or acid, which, depending on the circumstances, may be their non-salt (or salt-free) form. In another embodiment, the compounds of the present invention are in the form of a pharmaceutically acceptable salt, a pharmaceutically acceptable solvate, or a pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.

[0497] The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid, including inorganic bases or acids and organic bases or acids. In the case of compounds of the present invention containing one or more acidic or basic groups, the present invention also includes their corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing acidic groups (e.g., carboxyl groups) can exist in the form of salts and can be used according to the present invention, for example, as alkali metal salts, alkaline earth metal salts, aluminum salts, or ammonium salts. More precise examples of such salts include lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts, or salts with ammonia or organic amines (e.g., ethylamine, ethanolamine, diethanolamine, triethanolamine, piperidine, N-methylglutamine, or amino acids). These salts are readily available, for example, by reacting a compound having an acidic group with a suitable base, such as lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide, or barium hydroxide. Other basic salts of the compounds of the present invention include, but are not limited to, copper (I), copper (II), iron (II), iron (III), manganese (II), and zinc salts. Compounds of the present invention containing one or more basic groups (e.g., groups that can be protonated) may exist in salt form and, according to the present invention, may be used as addition salts of 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, neopentanoic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, pyruvic acid, mandelic acid, aminosulfonic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid, stearic acid, glutamic acid, or aspartic acid, and other acids known to those skilled in the art. The salts formed are, in particular, hydrochlorides, chlorides, hydrobromates, bromides, iodides, sulfates, phosphates, methanesulfonates, toluenesulfonates, carbonates, bicarbonates, formates, acetates, sulfoacetates, trifluoromethanesulfonates, oxalates, malonates, maleates, succinates, tartrates, malates, pyrates, mandelates, fumarates, lactates, citrates, glutarate, stearates, aspartate salts, and glutamates. Furthermore, the stoichiometry of the salts formed from the compounds of this invention can be an integer multiple or a non-integer multiple of one.

[0498] Compounds of the present invention containing a basic nitrogen-containing group can be quaternized using reagents such as (C1-C4) alkyl halides, such as methyl, ethyl, isopropyl, and tert-butyl chlorides, bromides, and iodides; di(C1-C4) alkyl sulfates, such as dimethyl, diethyl, and dipentyl sulfates; (C1-C4) alkyl halides. 10 -C 18 Alkyl halides, such as decyl, dodecyl, lauryl, tetradecyl and octadecyl chlorides, bromides and iodides; and aryl (C1-C4) alkyl halides, such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the invention can be prepared using such salts.

[0499] If the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes, in addition to the salt forms described herein, an inner salt or betaine (zwitterion). The corresponding salts can be obtained by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention that, due to their low physiological compatibility, are not directly applicable to pharmaceuticals, but can be used, for example, as intermediates in chemical reactions or for the preparation of pharmaceutically acceptable salts.

[0500] Therefore, the following items also conform to this invention:

[0501] (a) All stereoisomers or tautomers of the compound, including mixtures of all their ratios;

[0502] (b) Compounds and pharmaceutically acceptable salts of the items mentioned in (a);

[0503] (c) Compounds and pharmaceutically acceptable solvates of the items mentioned in (a) and (b);

[0504] (d) Compounds and N-oxides of the items mentioned in (a), (b) and (c).

[0505] It should be understood that all compounds mentioned above and below refer to pharmaceutically acceptable solvates of these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable salts thereof.

[0506] Furthermore, the compounds of the present invention are intended to include their isotopically labeled forms. Compounds of formula I or IA in the isotopically labeled form are identical to the compound, except that one or more atoms of the compound are replaced by atoms with atomic masses or mass numbers different from those normally found in nature. Examples of isotopes readily available commercially and that can be incorporated into the compounds of the present invention by known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example...2 H(D), 3 H, 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 33 S, 34 S, 35 S, 36 S, 18 F and 36 Cl. Compounds of Formula I or IA containing one or more of the above-mentioned isotopes and / or other isotopes of other atoms, or pharmaceutically acceptable salts thereof, are intended to be part of this invention. Compounds labeled with the isotopes of Formula I or IA can be used in many advantageous ways. For example, they may be doped with, for example, radioactive isotopes (e.g.,... 3 H or 14 The isotopically labeled compounds of the present invention (C) are suitable for drug and / or substrate tissue distribution assays. These radioisotopes (i.e., tritium) are... 3 H) and carbon-14 ( 14 C) is particularly preferred due to its simple preparation and excellent detectability. Heavier isotopes (e.g., deuterium) are used. 2 H)) Incorporation of compounds of formula I or IA offers therapeutic advantages due to the higher metabolic stability of the isotopically labeled compounds. Higher metabolic stability directly translates to an increased in vivo half-life or a lower dose, which in most cases represents a preferred embodiment of the invention. Isotopically labeled compounds of formula I or IA can generally be prepared by replacing non-isotopically labeled reactants with readily available isotopically labeled reactants using the synthetic schemes and procedures disclosed in the relevant descriptions in the Examples and Preparation sections of this document.

[0507] deuterium( 2 H;D) can also be incorporated into compounds of formula IA or I for the purpose of manipulating the oxidative metabolism of compounds via first-order kinetic isotope effects. First-order kinetic isotope effects are changes in the chemical reaction rate caused by the exchange of isotopic nuclei, which in turn are caused by changes in the ground-state energy necessary for the formation of covalent bonds after such exchange. Exchange of heavier isotopes typically leads to a decrease in the ground-state energy of chemical bonds, and thus a decrease in the rate-limiting bond breaking rate. If bond breaking occurs in or near a saddle point along the coordinates of a multi-product reaction, the product distribution can be significantly altered. To explain this: if deuterium is bonded to a carbon atom at a non-exchangeable position, the typical rate difference is k. M / k D=2-7. If this rate difference is successfully applied to oxidation-sensitive compounds of formula I or IA, the in vivo properties of the compound can be significantly altered, leading to improved pharmacokinetic properties.

[0508] When discovering and developing therapeutic agents, those skilled in the art seek to optimize pharmacokinetic parameters while maintaining desired in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic properties are sensitive to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information about this type of oxidative metabolic process, which in turn allows for the rational design of deuterated compounds of formula I or IA with improved stability through resistance to such oxidative metabolism. This results in significant improvements in the pharmacokinetic properties of compounds of formula I or IA, and can be determined based on the in vivo half-life (t1 / 2), maximum therapeutic concentration (C1 / 2), and other parameters. max The increase in the area under the dose-response curve (AUC) and F; and the reduction in clearance, dose, and material cost are expressed quantitatively.

[0509] The following aims to illustrate the above: Compounds of formula I or IA, possessing multiple potential attack sites for oxidative metabolism, such as benzyl hydrogen atoms and hydrogen atoms bonded to nitrogen atoms, are prepared into a series of analogs in which various combinations of hydrogen atoms are replaced by deuterium atoms, such that some, most, or all of these hydrogen atoms are replaced by deuterium atoms. Half-life determination allows for the advantageous and accurate determination of the degree of improvement in antioxidant metabolism. Thus, it is determined that the half-life of the parent compound can be extended by up to 100% due to this type of deuterium-hydrogen exchange.

[0510] The deuterium-hydrogen exchange in the compounds of the present invention can also be used to achieve advantageous modifications to the metabolite profile of the starting compound to reduce or eliminate undesirable toxic metabolites. For example, if toxic metabolites are generated by oxidative carbon-hydrogen (CH) bond cleavage, it is reasonable to assume that deuterated analogs will significantly reduce or eliminate the generation of unwanted metabolites, even if the specific oxidation is not a rate-determining step. Further information on prior art regarding deuterium-hydrogen exchange can be found, for example, in Hanzlik et al., J. Org. Chem. 55, 3992-3997, 1990; Reider et al., J. Org. Chem. 52, 3326-3334, 1987; Foster, Adv. Drug Res. 14, 1-40, 1985; Gillette et al., Biochemistry 33(10) 2927-2937, 1994; and Jarman et al., Carcinogenesis 16(4), 683-688, 1995.

[0511] Furthermore, the present invention relates to pharmaceutical compositions comprising at least one compound of formula I or IA as an active ingredient, or its N-oxide, solvate, tautomer or stereoisomer, and a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, and a pharmaceutically acceptable carrier.

[0512] For the purposes of this invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") refers to a composition or product comprising one or more active ingredients and one or more inert ingredients constituting a carrier, as well as any product produced directly or indirectly from the combination, complexation, or aggregation of any two or more ingredients, or from the dissociation of one or more ingredients, or from other types of reactions or interactions of one or more ingredients. Therefore, the pharmaceutical compositions of this invention include any composition prepared by mixing at least one compound of this invention with a pharmaceutically acceptable carrier. It may further comprise physiologically acceptable excipients, adjuvants, auxiliaries, diluents, and / or other pharmaceutically active substances besides the compounds of this invention.

[0513] Pharmaceutical compositions include those suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (eye), pulmonary (nasal or buccal inhalation), or nasal administration, although the most appropriate route in any given case will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They can be conveniently available in unit dosage forms and prepared by any method known in the pharmaceutical field.

[0514] The pharmaceutical compositions of the present invention may additionally comprise one or more other compounds as active ingredients (pharmaceuticals), such as one or more other compounds of the present invention. In certain embodiments, the pharmaceutical composition further comprises a second active ingredient or a derivative thereof, a prodrug, a solvate, a tautomer or stereoisomer, and a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in all proportions, wherein the second active ingredient is not a compound of formulas I and IA; preferably, the second active ingredient is a compound that can be used to treat, prevent, inhibit, and / or improve a medical condition or pathology, which may also be used by the compounds of the present invention, and which are listed elsewhere above or below. Such combinations of two or more active ingredients or pharmaceuticals may be safer or more effective than individual pharmaceuticals or active ingredients, or the combination may be safer or more effective than would be expected based on the additive properties of individual pharmaceuticals. Such one or more other pharmaceuticals may be administered via the route and amount typically used concurrently or sequentially with the compounds of the present invention. When the compounds of the present invention are used concurrently with one or more other pharmaceuticals or active ingredients, a combination product containing such one or more other pharmaceuticals and the compounds of the present invention is preferred, also referred to as a “fixed-dose combination.” However, combination therapies also include those in which the compounds of the present invention and one or more other drugs are administered at different overlapping schedules. It is anticipated that when used in combination with other active ingredients, the compounds of the present invention or other active ingredients, or both, can be used effectively at lower doses than when used individually. Therefore, in addition to the compounds of the present invention, the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients.

[0515] The compounds of the present invention—or their N-oxides, solvates, tautomers, or stereoisomers and / or pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all proportions—can be used as pharmaceuticals. They have been found to exhibit pharmacological activity by binding to TEAD and / or disrupting and / or inhibiting YAP-TEAD and / or TAZ-TEAD protein-protein interactions. It is presumed that through this activity, the compounds of the present invention can prevent or reverse dysfunction of the Hippo pathway. By preventing its dysfunction, the Hippo pathway may be able to exert its role as a tumor inhibitor. In addition to preventing or reversing Hippo pathway dysfunction and independent of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention can also be used in other pathophysiological conditions where inhibiting or disrupting TEAD binding and / or aberrant YAP-TEAD and / or aberrant TAZ-TEAD signaling would be beneficial.

[0516] Therefore, the compounds of the present invention, as TEAD binding agents and / or inhibitors of YAP-TEAD and / or TAZ-TEAD interactions, are particularly useful for treating, preventing, inhibiting, and / or improving hyperproliferative conditions and cancers, especially tumors, including solid tumors such as breast cancer, lung cancer, mesothelioma, epithelioid hemangioendothelioma, uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, and basal cell carcinoma. No specific theories or explanations are intended, but it can be hypothesized that the compounds may achieve this through direct action on cancer cells and / or indirectly by modulating the immune system's response to tumors. Furthermore, the compounds of the present invention can also be used to treat, prevent, inhibit, and / or improve non-cancerous conditions and diseases, such as cardiovascular diseases and fibrosis (e.g., liver fibrosis).

[0517] In specific embodiments, the compounds of the present invention are used for prevention and / or treatment, particularly for treating any of the conditions or diseases listed above, preferably cancer, especially tumors, including solid tumors, the specific types of cancer disclosed in the previous paragraph; or any non-cancerous condition or disease disclosed in the previous paragraph.

[0518] Another specific embodiment of the invention is a method for preventing and / or treating, preferably treating, conditions or diseases selected from: hyperproliferative conditions and cancers, particularly tumors, including solid tumors, specific types of cancer disclosed in the preceding paragraphs; or any non-cancerous conditions or diseases disclosed in the preceding paragraphs.

[0519] Another specific embodiment of the invention is the use of the compounds of the invention or derivatives thereof, N-oxides, prodrugs, solvates, tautomers or stereoisomers and / or pharmaceutically acceptable salts of each of the foregoing, including mixtures thereof in all proportions, for the manufacture of a medicament, particularly for the prevention and / or treatment, preferably for the treatment of conditions or diseases selected from: hyperproliferative conditions and cancers, particularly tumors, including solid tumors, the specific types of cancer disclosed in the preceding paragraphs; or any non-cancerous condition or disease disclosed in the preceding paragraphs.

[0520] Preferably, the present invention relates to compounds of the present invention for the prevention and / or treatment of diseases, or to methods for the prevention and / or treatment of diseases by administering an effective amount of the compounds of the present invention; or, in another alternative, to the use of the compounds of the present invention in the manufacture of medicaments for the prevention and / or treatment of diseases, wherein the disease is cancer, particularly tumors, including solid tumors, the specific types of cancer disclosed in the preceding paragraphs; and more preferably, the administration of said compound is performed simultaneously, sequentially, or alternately with the administration of at least one other active pharmaceutical agent.

[0521] The disclosed compounds of formula I or IA can be administered in combination with other known therapeutic agents, including anticancer agents. As used herein, the term "anticancer agent" refers to any pharmaceutical agent given to a patient with cancer for the purpose of treating cancer. Anticancer treatment as defined above can be used as a monotherapy, or may involve conventional surgery, radiation therapy, or drug therapy in addition to the compounds of formula IA or I disclosed herein. Such drug therapy (e.g., chemotherapy or targeted therapy) may include one or more (but preferably one) of the following antitumor agents:

[0522] Alkylating agents

[0523] Examples include hexamethylmelamine, bendamustine, busulfan, carmustine, chlorambucil, nitrogen mustard, cyclophosphamide, dacarbazine, ifosfamide, inprofen, p-toluenesulfonate, lomustine, melphalan, dibromomannitol, dibromoeusine, nimustine, ramustine, temozolomide, thiotepa, treoxan, nitrogen mustard, carboquinone, apaziquone, formostine, glucosamine, palifosfamide, piperobromophenazine, trazodine, uramustine, evofosfamide, and VAL-083. 4 ;

[0524] platinum compounds

[0525] For example, carboplatin, cisplatin, etaplatin, miplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, pyrazin, and saxaplatin;

[0526] DNA alteration agent

[0527] For example, amrubicin, bisacodyl, decitabine, mitoxantrone, procarbazine, trabectin, and clofarabine;

[0528] Acridine, brostallicin, pickaxanthin, laromustine [1],[3] ;

[0529] topoisomerase inhibitors

[0530] For example, etoposide, irinotecan, razorizine, sobuzosen, teniposide, and topotecan;

[0531] Aminopeptide, Belotticon, Elitidine, Voreloxin;

[0532] Microtubule modifier

[0533] For example, cabazitaxel, docetaxel, eribulin, ixaprone, paclitaxel, vincristine, vinorelbine, vindesine, vinflunine, fosbretabulin, tesetaxel;

[0534] Antimetabolites

[0535] For example, asparaginase [3] Azacitidine, Levofolate calcium, Capecitabine, Cladribine, Cytarabine, Enoxabine, Fluorouracil, Fludarabine, Fluorouracil, Gemcitabine, Mercaptopurine, Methotrexate, Nerapine, Pemetrexed, Prandtolex, Azathioprine, Thioguanine, Carmoflu, Deoxyfluorouridine, Esirapine, Raltitrexed, Sapacitabine, Tegafur [2],[3] Sanjiaqusha;

[0536] anticancer antibiotics

[0537] For example, bleomycin, actinomycin D, doxorubicin, epirubicin, idarubicin, levamisole, mitifone, mitomycin C, romidesin, strepzotocin, penoxuridine, fenofosine, zolpidem, daunorubicin, procainoxine; arubicin, pepromycin, pirarubicin;

[0538] Hormones / Antagonists

[0539] Examples include abaric, abiraterone, bicalutamide, busherin, carotestosterone, chlorestradiol, degarelic, dexamethasone, estradiol, flucloprodone, flutamide, fulvestrant, goserelin, histamine relin, leuprorelin, medroxyprogesterone acetate, mitotane, nafarelin, nandrolone, nilumet, octreotide, prednisolone, raloxifene, tamoxifen, thyroid-stimulating hormone alpha, toremifene, triplosterone, triptorelin, diethylstilbestrol, acolbifene, danazol, diloxacin, cyclothionol, orteronel, and enzalutamide. [1],[3] ;

[0540] Aromatase inhibitors

[0541] For example, aminoglutethimide, anastrozole, exemestane, fazodazole, letrozole, testosterone, and formexane;

[0542] Small molecule kinase inhibitors

[0543] Examples include crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxotinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib, gefitinib, axitinib, afatinib, aritinib, dabrafenib, dacomitinib, denaciline, dovirtinib, ensalistatin, nintedanib, lenvatinib, linifanib, linsitinib, masitinib, midotolin, motracenib, lenatatinib, orantinib, perifoxine, panatinib, radotinib, rigosertib, tepotinib, tepififib, tivantinib, tivozanib, trametinib, pimastinib, brivanib alaninate, sildenafil, and apatinib. [4] Cabozantinib S-malate [1],[3] Ibrutinib [1],[3] Icotinib [4] buparatinib [2] Ciprotinib [4] Cobitinib [1],[3] Alitinib [1],[3] fildatinib [1] tesevatinib;

[0544] photosensitizer

[0545] For example, methoxsalen [3] ; Porphyrin sodium, tarapofen, temopofen;

[0546] Antibody

[0547] Examples include alemtuzumab, bexolumab, bentuximab, cetuximab, denosumab, ipilimumab, oflambumab, panitumumab, rituximab, tosimoumab, trastuzumab, bevacizumab, and pertuzumab. [2],[3] Casulotuzumab, Elotuzumab, Iprazumab, Farletuzumab, Mocazumab, Nexituzumab, Nimotuzumab, Obinutuzumab, Ocaratuzumab, Ogovozabumab, Ramucirumab, Rilotumumab, Sestoximab, Tocilizumab, Zalutumumab, Zanolimumab, Matozumab, Dalotuzumab [1],[2],[3] ,onartuzumab [1],[3] racotumomab [1] tabalumab [1],[3] EMD-525797 [4] Atezolizumab, Drewalumab, Pembrolizumab, Nivolumab[1],[3] ;

[0548] Cytokines

[0549] For example, interleukin, interferon α2, interferon α2a [3] Interferon α2b [2],[3] ;

[0550] Simmo-interleukin, Tasonamin, Tisci-interleukin, Opi-re-interleukin [1],[3] Recombinant interferon β-1a [4] ;

[0551] Drug conjugates

[0552] Examples include interleukin-denis, teimomab, iodobenzylguanidine I123, prenimustine, trastuzumab, estrustine, gemtuzumab, ozomicin, aflibercept, cintredekin besudotox, edotuzumabozogamicin, naptumomab estafenatox, oportuzumab monatox, and technetium (99mTc) acipimomab. [1],[3] vintafolide [1],[3] ;

[0553] vaccine

[0554] For example, sipuleucel [3] ;vitespen [3] emepepimut-S [3] oncoVAX [3] ,rindopepimut [3] troVax [3] MGN-1601 [3] MGN-1703 [3] ;

[0555] Mixed

[0556] Alivetitanic acid, bexarotine, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, lentinan, methyltyrosine, mivastatin, pamidronate, pegaspargase, pentostatin, sipuleucel [3]Cizolam, Tamibarbitine, Tesirolimus, Thalidomide, Retinoic acid, Vimodil, Zoledronic acid, Vorinostat, Celecoxib, Silenjitide, Entenolide, Ethanidazole, Ganedodes, Iripalol, Iniparib, Ixazomib, Clonidamine, Nimoprazole, Pabistat, Doxorubicin, Plitidepsin, Pomalidomide, Procodazole, Desfolimus, Taquimod, Telotristat, Thymofasin, Tirazamine, Tosedostat, Trabedersen, Ubenimex, Vasopidazol, Gendicine [4] hemolytic streptococcal preparations [4] reolysin [4] retaspimycin hydrochloride [1],[3] trebananib [2],[3] , Verulin [4] Carfilzomi [1],[3] Endostatin [4] immucothel [4] Belistat [3] ;

[0557] PARP inhibitors

[0558] Olapani, Veliparib.

[0559] MCT1 inhibitors

[0560] AZD3965 [4] BAY-8002 [4] .

[0561] [1] Prop.INN (Proposed International Non-Property Name)

[0562] [2] Rec.INN (Recommended international non-proprietary name)

[0563] [3] USAN (the name used in the United States)

[0564] [4] No INN.

[0565] In another aspect of the invention, a kit or reagent kit is provided comprising a therapeutically effective amount of at least one compound of the present invention and / or at least one pharmaceutical composition described herein and a therapeutically effective amount of at least one other pharmacologically active substance other than a compound of the present invention. Preferably, the kit or reagent kit comprises the following individual packages:

[0566] a) an effective amount of compounds of formulas I and IA or any of their N-oxides, solvates, tautomers or stereoisomers, and pharmaceutically acceptable salts of each of the above, including mixtures thereof in all proportions, and

[0567] b) An effective amount of another active ingredient, which is neither a compound of formula I nor a compound of formula IA.

[0568] Other embodiments of the present invention are methods for manufacturing pharmaceutical compositions of the present invention, characterized in that one or more compounds according to the present invention and one or more compounds other than those according to the present invention, selected from solid, liquid or semi-liquid excipients, auxiliaries, adjuvants, diluents, carriers and pharmaceutically active agents, are converted in a suitable dosage form.

[0569] The pharmaceutical compositions (formulations) of the present invention can be administered in any manner to achieve their intended purpose. For example, administration can be via oral, parenteral, topical, enteral, intravenous, intramuscular, inhalation, nasal, intra-articular, intraspinal, tracheal, ocular, subcutaneous, intraperitoneal, percutaneous, or buccal routes. Alternatively, or concurrently, administration can be via oral route. The dosage will depend on the recipient's age, health and weight, the type of concurrent treatment (if any), the frequency of treatment, and the nature of the desired effect. Parenteral administration is preferred. Oral administration is particularly preferred.

[0570] Suitable dosage forms include, but are not limited to, capsules, tablets, pills, sugar-coated pills, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalers, injections, pastes, gels, tapes, eye drops, solutions, syrups, aerosols, suspensions, and emulsions, which can be prepared according to methods known in the art, such as those described below:

[0571] Tablets: A mixture of one or more active ingredients and excipients is compressed into tablets (direct compression), optionally with a portion of the mixture granulated prior to compression.

[0572] Capsules: One or more active ingredients and adjuvants are mixed to obtain a flowable powder, optionally granulated, the powder / granules are filled into an open capsule, and the capsule is capped.

[0573] Semi-solid (ointment, gel, cream): One or more active ingredients are dissolved / dispersed in an aqueous or fatty carrier; the aqueous / fatty phase is then mixed with a supplemental fatty / aqueous phase and homogenized (cream only).

[0574] Suppositories (rectal and vaginal): One or more active ingredients are dissolved / dispersed in a carrier material that is liquefied by heating (rectal: the carrier material is usually wax; vaginal: the carrier is usually a heated solution of a gelling agent), the mixture is cast into a suppository form, annealed, and the suppository is removed from the form.

[0575] Aerosol: One or more active agents are dispersed / dissolved in a propellant, and the mixture is bottled into a sprayer.

[0576] Typically, non-chemical approaches for producing pharmaceutical compositions and / or pharmaceutical formulations include processing steps on suitable mechanical devices known in the art, which transfer one or more compounds of the present invention into a dosage form suitable for administration to a patient requiring such treatment. Typically, transferring one or more compounds of the present invention into such a dosage form involves the addition of one or more compounds selected from carriers, excipients, adjuvants, and pharmaceutically active ingredients other than those of the present invention. Suitable processing steps include, but are not limited to, combining, grinding, mixing, granulating, dissolving, dispersing, homogenizing, casting, and / or pressing the respective active and inactive ingredients. Mechanical devices for performing these processing steps are known in the art, for example, from Ullmann's Encyclopedia of Industrial Chemistry, 5th edition. In this regard, the active ingredient is preferably at least one compound of the present invention and optionally one or more other compounds besides those of the present invention, exhibiting valuable pharmaceutical properties, preferably those pharmaceutically active agents other than those of the present invention disclosed herein.

[0577] Particularly suitable for oral administration are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices, or drops; suitable for rectal administration are suppositories; suitable for parenteral administration are solutions, preferably oil-based or aqueous solutions, as well as suspensions, emulsions, or implants; and suitable for topical administration are ointments, creams, or powders. The compounds of the present invention can also be lyophilized, and the resulting lyophilized products are used, for example, to prepare injectable formulations. These formulations may be sterile and / or contain adjuvants such as lubricants, preservatives, stabilizers and / or wetting agents, emulsifiers, salts for adjusting osmotic pressure, buffering substances, dyes, flavoring agents, and / or various other active ingredients, such as one or more vitamins.

[0578] Suitable excipients are organic or inorganic substances suitable for enteral (e.g., oral), parenteral, or topical administration and do not react with the compounds of the present invention, such as water, vegetable oils, benzyl alcohol, alkylene glycols, polyethylene glycol, triacetin, gelatin, carbohydrates such as lactose, sucrose, mannitol, sorbitol, or starch (corn starch, wheat starch, rice starch, potato starch), cellulose preparations and / or calcium phosphate (e.g., tricalcium phosphate or calcium hydrogen phosphate), magnesium stearate, talc, gelatin, tragacanth gum, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and / or petrolatum.

[0579] If desired, disintegrants such as the starches mentioned above, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginate or their salts, such as sodium alginate, may be added. Adjuvants include, but are not limited to, flow regulators and lubricants such as silica, talc, stearic acid or its salts, such as magnesium stearate or calcium stearate, and / or polyethylene glycol. The sugar-coated core is provided with a suitable coating that, if desired, is resistant to gastric juices. For this purpose, a concentrated sugar solution may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and / or titanium dioxide, lacquer solution, and a suitable organic solvent or solvent mixture. To produce a gastric juice-resistant coating or to provide a dosage form with the advantage of prolonged action, tablets, sugar-coated pills, or pellets may contain an internal dose component and an external dose component, the latter being a coating encapsulating the former. These two components may be separated by an enteric coating that resists disintegration in the stomach and allows the internal component to enter the duodenum intact or delays release. Various materials can be used for such enteric coatings or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, acetyl alcohol, or solutions of suitable cellulose formulations, such as acetylated cellulose phthalate, cellulose acetate, or hydroxypropyl methylcellulose phthalate. For example, to identify or characterize combinations of active compound dosages, dyes or pigments can be added to the coating of tablets or sugar-coated pills.

[0580] Suitable carrier substances are organic or inorganic materials suitable for enteral (e.g., oral) or parenteral administration or topical application and do not react with the novel compound, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates (e.g., lactose or starch), magnesium stearate, talc, and petrolatum. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops, or suppositories are used for enteral administration; solutions (preferably oily or aqueous solutions), suspensions, emulsions, or implants are used for parenteral administration; and ointments, creams, or powders are used for topical application. The compounds of the present invention can also be lyophilized, and the resulting lyophilized products can be used, for example, in the production of injectable formulations.

[0581] Other pharmaceutical formulations that can be taken orally include push-in capsules made of gelatin, and soft, sealed capsules made of gelatin and plasticizers (such as glycerin or sorbitol). Push-in capsules may contain the active compound in particulate form, which can be mixed with fillers (such as lactose), binders (such as starch), and / or lubricants (such as talc or magnesium stearate), and optionally, stabilizers. In soft capsules, the active compound is preferably dissolved or suspended in a suitable liquid (such as fatty oil or liquid paraffin). Furthermore, stabilizers may be added.

[0582] The novel compositions of the present invention can be incorporated into liquid forms for oral administration, including aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions containing edible oils (e.g., cottonseed oil, sesame oil, coconut oil, or peanut oil), as well as elixirs and similar pharmaceutical carriers. Suitable dispersants or suspending agents for aqueous suspensions include synthetic and natural gums, such as gum arabic, gum arabic, alginate, dextran, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone, or gelatin.

[0583] Suitable formulations for parenteral administration include aqueous solutions of the active compound in water-soluble form, such as water-soluble salts and alkaline solutions. Additionally, suspensions of the active compound can be administered as suitable oily injectable suspensions. Suitable lipophilic solvents or mediators include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or polyethylene glycol-400 (the compound is soluble in PEG-400).

[0584] Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, including, for example, sodium carboxymethyl cellulose, sorbitol and / or dextran; optionally, the suspension may also contain stabilizers.

[0585] For administration as an inhaled spray, a spray in which the active ingredient is dissolved or suspended in a propellant gas or a mixture of propellant gases (e.g., CO2 or chlorofluorocarbons) can be used. The active ingredient is advantageously used in a micronized form, in which case one or more other physiologically acceptable solvents, such as ethanol, may be present. The inhalation solution can be administered using a conventional inhaler.

[0586] Possible pharmaceutical formulations that can be used rectally include, for example, suppositories, which consist of a combination of one or more active compounds and a suppository matrix. Suitable suppository matrices are, for example, natural or synthetic triglycerides or alkanes. Alternatively, gelatin rectal capsules, which consist of a combination of active compounds and a matrix, can also be used. Possible matrix materials include, for example, liquid triglycerides, polyethylene glycol, or alkanes.

[0587] Pharmaceutical preparations can be used as medicines in humans and veterinary medicine. As used herein, the term "effective amount" means the amount of a drug or agent that will elicit a biological or medical response in a tissue, system, animal, or human, such biological or medical response being sought, for example, by an investigator or clinician. Furthermore, the term also includes, within its scope, "therapeutic effective amount," which means any amount that, compared to a corresponding subject who has not received such an amount, results in improved treatment, healing, prevention, or improvement of a disease, condition, or side effect, or a reduction in the rate of progression of the disease or condition, or improved treatment, healing, prevention, or improvement of symptoms associated with the disease or condition; it may also refer to the prevention of, or provision of, a disease or condition in a subject having or at risk of developing a disease disclosed herein. The term also includes, within its scope, amounts that effectively enhance normal physiological function. The therapeutically effective amounts of one or more compounds of the present invention are known to those skilled in the art or can be readily determined by standard methods known in the art.

[0588] As used herein, “treatment” or “curing” means the complete or partial relief of symptoms associated with a condition or disease, or the slowing or stopping of the further progression or worsening of those symptoms, or the prevention or avoidance of a disease or condition in a subject at risk of developing the disease or condition.

[0589] The compounds of the present invention and optional additional active substances are generally administered in a manner similar to commercial formulations. Typically, a therapeutically effective dose is between 0.0005 mg and 1000 mg per dose unit, preferably between 0.005 mg and 500 mg, and particularly between 0.5 mg and 100 mg. The daily dose is preferably between about 0.001 mg / kg and 10 mg / kg body weight.

[0590] Those skilled in the art will readily understand that dosage levels can vary depending on the specific compound, the severity of symptoms, and the subject's susceptibility to side effects. Some specific compounds are more effective than others. The preferred dosage of a given compound can be readily determined by those skilled in the art in various ways. A preferred method is to measure the physiological potency of the given compound.

[0591] However, the specific dosage for an individual patient, especially a human patient, depends on a variety of factors, such as the efficacy of the specific compound used, age, weight, general health status, sex, diet, timing and route of administration, excretion rate, type and dosage form of the drug, combination of drugs, and the severity of the specific condition addressed by the therapy. The specific therapeutically effective dosage for an individual patient can be readily determined through routine experimental procedures, such as by a physician or medical professional advising on or participating in therapeutic treatment.

[0592] The compounds of the present invention can be prepared using suitable materials according to the procedures of the following schemes and embodiments, and are further illustrated by the following specific examples. They can also be prepared by methods known per se, as described in the literature (e.g., in standard works, such as Houben-Weyl, Methodden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons, Inc., New York), precisely under known and suitable reaction conditions. Variations known per se but not mentioned in more detail herein can also be used.

[0593] Similarly, the starting materials used to prepare the compounds of the present invention can be prepared by the methods described in the examples or by methods known per se, such as those described in the literature of synthetic organic chemistry and those known to those skilled in the art, or can be commercially available. If desired, the starting materials for the claimed and / or used methods can also be formed in situ by immediately converting them further into the compounds or intermediate compounds of the present invention without separating them from the reaction mixture. On the other hand, the reaction can generally be carried out stepwise.

[0594] Preferably, the reaction of the compound is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), or dioxane; glycol ethers such as ethylene glycol monomethyl ether or ethylene glycol monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF), or N-methylpyrrolidone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of said solvents or mixtures with water.

[0595] The reaction temperature ranges from approximately -100°C to 300°C, depending on the reaction steps and the conditions used.

[0596] Reaction times typically range from a fraction of a minute to several days, depending on the reactivity of the corresponding compound and the relevant reaction conditions. A suitable reaction time can be readily determined using methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times are typically between 10 minutes and 48 hours.

[0597] Furthermore, other compounds of the invention claimed herein can be readily prepared using the procedures described herein in conjunction with common techniques in the art. However, the compounds illustrated in the examples should not be construed as forming the only class considered to be of the invention. The examples further detail the preparation of the compounds of the invention. Those skilled in the art will readily understand that known variations of the conditions and methods of the following preparation procedures can be used to prepare these compounds.

[0598] This invention also relates to a method for preparing compounds of the most general form of Formula I or IA described herein, and any specific embodiment of PE0, PE0a, PE0b, PE1, PE1a, PE1b, PE2, PE2a, PE2b, PE3, PE3a, PE3b, PE4, PE4a, PE5, PE5a, PE5aa, PE5b, PE5bb, PE5c, PE6, PE7, PE8, PE9, PE9a, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, PE10cc, PE11, PE11a, PE11b, PE11c, PE12, PE12a, PE12b, PE12c, PE12d, PE13, or their N-oxides, solvates, tautomers or stereoisomers, and pharmaceutically acceptable salts of each of the foregoing, characterized in that...

[0599] (a) Compounds of formula II-a or II-Aa

[0600]

[0601] Z 1 Z 2 Z 3 Ring A and R 2 As defined above and in the claims for compounds of formula I or IA, wherein R 2 It is neither -C(=O)-OH nor -C(=O)-OCat;

[0602] (a)(1) and compound of formula III

[0603] R 1 -Hal

[0604] III

[0605] Where R1 As defined above or in any of the claims for compounds of formula I or IA, and where Hal represents Cl, Br, or I, reacting in a CN crosslinking reaction under suitable reaction conditions;

[0606] or

[0607] (a)(2) First, under suitable reaction conditions, the compound is converted into a tricyclic compound of formula IV or IV-A in a CN crosslinking reaction.

[0608]

[0609] Then, under suitable reaction conditions, it reacts with compound of formula III in another CN crosslinking reaction.

[0610] R 1 -Hal

[0611] III;

[0612] supply

[0613] (a)(3) Compounds of formula I or IA as defined above or in any of the claims; and

[0614] Optional

[0615] (a)(4) If R is in a compound of formula I or IA 2 It is -C(=O)-OR 2a And R 2a Is it unsubstituted or substituted C? 1-8 -Aliphatic, then the compound of formula I or IA undergoes a saponification reaction under suitable conditions to provide the corresponding compound of formula I or IA, and R 2 It is -C(=O)-OH or -C(=O)-OCat;

[0616] or

[0617] (b) Compounds of formula II-b or II-Ab

[0618]

[0619] Z 1 Z 2 Z 3 Ring A and R 2 As defined above or in any of the claims for compounds of formula I or IA, wherein R 2 It is neither -C(=O)-OH nor -C(=O)-OCat;

[0620] (b)(1) and compound of formula V

[0621] R1 -NH2

[0622] V,

[0623] Where R 1 As defined above or in any of the claims for compounds of formula I or IA,

[0624] Reacting in a CN crosslinking reaction under suitable reaction conditions to provide

[0625] Compounds of formula I or IA as defined above or in any of the claims; and

[0626] Optional

[0627] (b)(2) If R is present in the compound of formula I or IA 2 It is -C(=O)-OR 2a And R 2a Is it unsubstituted or substituted C? 1-8 -Aliphatic, then the compound of formula I or IA undergoes a saponification reaction under suitable conditions to provide the corresponding compound of formula I or IA, and R 2 It is -C(=O)-OH or -C(=O)-OCat.

[0628] As will be understood by those skilled in the art of organic synthesis, the compounds of the present invention (particularly those of formulas I and IA) can be readily obtained by various synthetic routes, some of which are illustrated in the appended experimental section. To obtain the compounds of the present invention, in any particular case (wherever it is needed or useful), those skilled in the art will readily recognize which reagents and reaction conditions will be used and how to apply and adjust them. Furthermore, some compounds of the present invention can be readily synthesized by reacting other compounds of the present invention under suitable conditions, for example by applying standard synthetic methods, such as reduction, oxidation, addition, or substitution reactions, to convert one specific functional group present in the compounds of the present invention or their suitable precursor molecules into another; those methods are well known to those skilled in the art. Likewise, whenever needed or useful, those skilled in the art will apply synthetic protecting (or protective) groups; suitable protecting groups and 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 Uts, TW Greene, “Greene's Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

[0629] The following general synthetic routes, which can be used to prepare the compounds of the present invention, are described in more detail in schemes A, AA, B, and BA:

[0630]

[0631] Option A

[0632] (Z 1 Z 2 R 1 R 2 And ring A as defined in Formula I and the claims above.

[0633]

[0634] Plan AA

[0635] (Z 1 Z 2 Z 3 R 1 R 2 And ring A as defined in formula IA and the claims.

[0636] It should be understood that the interpretation of Scheme A below also applies similarly to Scheme AA; instead of compounds B, D, E, and I, Scheme AA and its interpretation refer to compounds BA, DA, EA, and IA. The synthetic procedures and methods used are the same as those in Schemes A and AA.

[0637] Scheme A above describes a general synthetic route for preparing the tricyclic heterocycle of Formula I. In reaction step a, boric acid B is readily available, for example, by first reacting the corresponding bromo-substituted aryl or heteroaryl group with a suitable organometallic base (such as n-butyllithium) and subsequently with a suitable borate ester such as B(OCH3)3. Boric acid B is then reacted with a 1-amino-2-bromo-substituted heterocycle C under typical CC crosslinking conditions, such as those typical of the Suzuki crosslinking reaction (e.g., by reacting a solution of B and C in a suitable solvent such as 1,4-dioxane with cesium carbonate in the presence of a palladium catalyst such as Pd(dppf)2Cl2 (1,1'-bis(diphenylphosphine)ferrocene]palladium(II) dichloride) to give compound D. It is understood that ring A in the 1-amino-2-bromo-substituted heterocycle C has the same meaning as "ring A" in the compounds of Formula I of the present invention, i.e., selected from the five-membered heteroaryl rings A-1 to A-24 as defined above and in the claims. For example, if ring A is chosen as ring A-1, then the corresponding compound C will have the following formula C-1:

[0638]

[0639] Compound D can then undergo an intramolecular CN crosslinking reaction (step b), for example, under typical Hartwig-Buchwald reaction conditions (e.g., reaction with cesium carbonate in a suitable solvent such as 1,4-dioxane in the presence of a suitable palladium catalyst such as di-tert-butyl[2',4',6'-tris(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine{2'-amino-[1,1'-biphenyl]-2-yl}palladium methanesulfonate) to produce a tricyclic heterocycle E. This heterocycle E can then be further reacted with bromide R. 1 -Br reacts with cesium carbonate in another CN coupling reaction (step c) under similar conditions, for example, in the presence of a suitable palladium catalyst (e.g., chloro(2-dicyclohexylphosphine-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride, XPhosPd G2), to provide the compound of formula I of the present invention. The reaction depends on the various substituents R. 1 R 2 The properties of R and ring A, and the optional conversion of Formula I compounds into other Formula I compounds. For example, if R 2 It is a carboxylic acid ester (-C(=O)-OR) 2a If the ester can be saponified using a suitable acid or base, then the corresponding carboxylic acid (R) can be provided. 2 =-C(=O)-OH) or its salts (e.g., R 2 =-C(=O)-OCat, where Cat is Li, Na, K or NH4).

[0640] In some cases, compound D (as shown in scheme A above and DA in scheme AA) – without undergoing subsequent reaction steps b and c, i.e., two consecutive CN coupling reactions – can be coupled with a suitable compound R. 1 -Br reacts in a CN coupling reaction (with a suitable base such as cesium carbonate or sodium hydride in the presence of a suitable palladium catalyst) to directly provide the corresponding compound of formula I (or IA in scheme AA).

[0641] Furthermore, it is readily understood that, starting from compound E, compounds of formula I (or starting from compound EA, compounds of formula IA) can be produced by using debrominated compounds R under suitable reaction conditions. 1 Suitable reactive complexes other than -Br are used for synthesis. For example, if R 1 Selected as L 1 -Ar or L 1 -Hetar 1 And L 1If the form is -S(=O)2-, then compound E can react with the corresponding thionyl chloride under suitable reaction conditions to produce the corresponding sulfonyl derivative of formula I (or IA).

[0642]

[0643] Option B

[0644] (Z 1 Z 2 R 1 R 2 And ring A is as defined above and in the claims for formula I.

[0645]

[0646] Solution BA

[0647] (Z 1 Z 2 Z 3 R 1 R 2 (And ring A as defined above and in the claims for IA.)

[0648] It should be understood that the interpretation of Scheme B below also applies similarly to Scheme BA; instead of compounds B, G, and I, Scheme BA and its interpretation refer to compounds BA, GA, and IA. The synthetic procedures and methods used are the same as those in Schemes B and BA.

[0649] Scheme B above describes another synthetic route for preparing the compounds of the present invention. Here, borate B (or a suitable borate ester) is reacted with a 1-chloro-2-iodide-substituted heterocyclic F in a CC crosslinking reaction under similar conditions as described in step a of Scheme A (step d), which yields a dichloro-substituted compound G. This G can then be prepared using a primary amine R in the presence of a suitable base such as cesium carbonate and a suitable palladium catalyst (as described in Scheme A). 1 -NH2 (step e) converts compound G into the desired compound of formula I (or IA of scheme BA) in the CN coupling reaction.

[0650] It is important to note that—unless specifically stated or the context provides a different meaning—the number of terms is generally used, i.e., their singular and plural forms, and they can be read interchangeably. For example, the singular term "compound" can also include or refer to the plural compound, and its plural form can also include or refer to the singular compound.

[0651] Examples and Experiments

[0652] The compounds of the present invention can be prepared using suitable materials according to the procedures of the following schemes and embodiments, and are further illustrated by the following specific examples. The compounds are shown in Table 1. Analytical data of the compounds prepared according to the following examples are also shown in Table 1.

[0653] The present invention will be described with reference to specific embodiments illustrated in the following examples, but is not limited thereto. Unless otherwise stated in the embodiments, variables have the same meaning as in the foregoing and claims.

[0654] Unless otherwise specified, all starting materials were obtained from commercial suppliers and used without further purification. Unless otherwise specified, all temperatures are in °C, and all reactions were carried out at room temperature (RT). Compounds were purified by silica gel chromatography or preparative HPLC.

[0655] 1 H NMR:

[0656] 1 H-NMR data are provided in Table 1 below. 1 ¹H NMR spectra were typically acquired under standard conditions on a Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300, or Bruker Avance III 700 MHz (equipped with a TXI cryogenic probe) NMR spectrometer, using TMS (tetramethylsilane) as an internal standard and DMSO-d6 as a standard solvent (unless otherwise reported). NS (number of scans): 32, SF (spectrometer frequency) as shown. TE (temperature): 297 K. Chemical shifts (δ) are reported in ppm relative to the TMS signal. 1 The following is a report of H NMR data: chemical shifts (multiplicity, coupling constant, and hydrogen number). Multiplicity is abbreviated as: s (singleton), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet), tt (triplet), td (triplet), br (broad peak). Coupling constants (J) are reported in Hz.

[0657] LC-MS:

[0658] The LC-MS data provided in Table 1 are given in terms of mass (m / z). The results can be obtained by one of the following methods.

[0659] synthesis

[0660] Example 1: 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid

[0661] Example 1-1: Synthesis of 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H-indole

[0662]

[0663] At ℃, 5-bromo-2,3-dimethyl-1H-indole (6.25 g; 27.89 mmol) in DMF (50 mL) was slowly added to a suspension of NaH (1.70 g; 42.50 mmol) in DMF (50 mL). The yellow-brown mixture was stirred at 0℃ for 1 hour, and then benzenesulfonyl chloride (6 g; 34 mmol) was added at 0℃. The mixture was then stirred at 25℃ for 2 hours. The reaction mixture was poured into water (500 mL) and extracted three times with EA (100 mL). The organic layer was washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated to give the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 4:1) to give the desired product (7.20 g; 71%; pink solid).

[0664] 1 H NMR (400MHz, CDCl3) δ8.06 (d, J = 8.4Hz, 1H), 7.73-7.70 (m, 2H), 7.55-7.52 (m, 1H), 7.49 (d ,J=2.0Hz,1H),7.44-7.40(m,2H),7.36(dd,J=8.8,2.0Hz,1H),2.51(s,3H),2.09(s,3H).

[0665] Examples 1-2: Synthesis of product 1-(benzenesulfonyl)-5-bromo-2,3-bis(bromomethyl)-1H-indole

[0666]

[0667] To a solution of 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H-indole (6.40 g; 17.57 mmol) in CCl4 (120 mL), 1-bromopyrrolidine-2,5-dione (6.40 g; 36 mmol) and 2-[2-(1-cyano-1-methylethyl)diazepine-1-yl]-2-methylpropionitrile (288 mg; 1.75 mmol) were added. The mixture was stirred at 80 °C under a nitrogen balloon at 1 bar for 3 hours to produce a yellow-brown solid. The reaction was filtered, and the filtrate was concentrated to give the crude product (8.15 g; 81%; yellow-brown solid).

[0668] 1 H NMR(400MHz, CDCl3)δ8.00(d,J=5.6Hz,1H),7.93-7.90(m,2H),7.75(d,J=2 .0Hz,1H),7.61-7.58(m,1H),7.50-7.45(m,3H),5.08(s,2H),4.59(s,2H).

[0669] Examples 1-3: Synthesis of 4-(benzenesulfonyl)-2-benzyl-7-bromo-1H,2H,3H,4H-pyrrolo[3,4-b]indole become

[0670]

[0671] At 80 °C, 1-phenylmethylamine (1.52 g; 14.19 mmol) in THF (280 mL) was slowly added to a solution of 1-(benzenesulfonyl)-5-bromo-2,3-bis(bromomethyl)-1H-indole (8.15 g; 14.21 mmol) and K₂CO₃ (6.68 g; 48.34 mmol) in THF (190 mL). The yellow-brown mixture was stirred at 80 °C under a 1 bar nitrogen balloon for 16 hours. The reaction was filtered, and the filtrate was concentrated to give the residue. The residue was purified by silica gel column chromatography (dichloromethane / EA = 5:1) to give the desired product (3.16 g; 41%; yellow-brown solid).

[0672] 1 H NMR (400MHz, CDCl3) δ7.85-7.79(m,3H),7.57-7.53(m,1H),7.46-7.24(m,9H),4.28-4.26(m,2H),4.01(s,2H),3.91-3.89(m,2H).

[0673] Examples 1-4: 4-(benzenesulfonyl)-2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid Ester Synthesis

[0674]

[0675] Potassium acetate (900 mg; 9.17 mmol) was added to a solution of 4-(benzyl)-2-benzyl-7-bromo-1H,2H,3H,4H-pyrrolo[3,4-b]indole (1.50 g; 2.73 mmol), tris(dibenzylacetone)dipalladium (300 mg; 0.33 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthium (190 mg; 0.33 mmol) in DMF (10 mL) and MeOH (10 mL) at 25 °C. The dark brown mixture was stirred at 90 °C under a 1 bar methanidylidyneoxidanium balloon for 16 hours. The reaction mixture was poured into water (50 mL) and extracted three times with EA (30 mL). The organic layer was concentrated to give the residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 5:1) to give the desired product. (510 mg; 39.8%; yellowish-brown solid).

[0676] 1H NMR (400MHz, CDCl3) δ8.03-8.01(m,2H),7.97-7.94(m,1H),7.86-7.84(m,2H),7.57-7.55(m,1H),7.48- 7.44(m,3H),7.40-7.37(m,3H),7.33-7.32(m,1H),4.31(s,2H),4.05(s,2H),3.98(s,2H),3.90(s,3H).

[0677] Examples 1-5: Synthesis of methyl 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylate become

[0678]

[0679] To a solution of methyl 4-(benzyl)-2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (84 mg; 0.19 mmol) in toluene (2 mL), 4,5-dichloro-3,6-dioxocyclohexane-1,4-diene-1,2-dicarboxynitrile (43 mg; 0.19 mmol) was added at 25 °C. The yellow-brown mixture was stirred at 25 °C for 3 hours. The reaction was filtered, and the filtrate was concentrated to give the crude product (60 mg; 67%; yellow-brown solid).

[0680] Examples 1-6: 4-(benzenesulfonyl)-2-benzyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid (Compound 1) Synthesis

[0681]

[0682] NaOH (13 mg; 0.33 mmol) was added to a solution of methyl 4-(benzyl)-2-benzyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylate (50 mg; 0.11 mmol) in iPrOH (3 mL) and water (0.6 mL) at 25 °C. The yellow-brown mixture was stirred at 70 °C for 16 hours. The reaction mixture was diluted with water (20 mL) and extracted three times with ethyl acetate (20 mL). The combined organic layers were concentrated to give the residue. The residue was purified by passing it through a C-18 column (ACN:water = 10%–95%) to give the desired product in 55% yield (25 mg; off-white solid).

[0683] 1H NMR(400MHz, DMSO-d6)δ12.86(brs,1H),8.15(d,J=1.6Hz,1H),8.03-8.01(m,1H),7.90-7.87(m,1H),7.80-7.78(m ,2H),7.63-7.61(m,1H),7.49-7.45(m,2H),7.38-7.35(m,2H),7.32-7.27(m,2H),7.24-7.22(m,3H),5.31(s,2H).

[0684] Example 2: 2-Methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0685] Example 2-1: Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazole-4-yl)-4-chlorobenzoate

[0686]

[0687] To a suspension of 2-chloro-5-(ethoxycarbonyl)phenylboronic acid (500 mg; 2.19 mmol) in dioxane (4 mL) and water (0.4 mL), 4-bromo-1-methyl-1H-pyrazole-3-amine (385 mg; 2.19 mmol), K₂CO₃ (605 mg; 4.38 mmol), and Pd(dppf)Cl₂ (160 mg) were added. The mixture was stirred at 60 °C for 6 hours under a nitrogen atmosphere. The mixture was poured into water (5 mL) and extracted with EA (6 mL x 3). The combined organic phases were collected and evaporated under vacuum. The residue was purified by C₁₈ column chromatography (ACN / H₂O = 5%–95%) to obtain a purified product (500 mg; 74%; white powder).

[0688] 1 H NMR(400MHz,DMSO)δ8.07(d,J=2.1Hz,1H),7.77(dd,J=8.4,2.2Hz,1H),7.67(s,1H),7.63 (d, J = 8.4Hz, 1H), 4.58 (s, 2H), 4.32 (q, J = 7.1Hz, 2H), 3.66 (s, 3H), 1.31 (t, J = 7.1Hz, 3H).

[0689] Example 2-2: Synthesis of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate

[0690]

[0691] To a suspension of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (300 mg; 1.1 mmol) in dioxane (15 mL), di-tert-butyl[2',4',6'-tris(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine{2'-amino-[1,1'-biphenyl]-2-yl}palladium methanesulfonate (85 mg; 0.11 mmol) and Cs₂CO₃ (699 mg; 2.14 mmol) were added. The mixture was stirred at 120 °C for 6 h under N₂ atmosphere. The mixture was poured into water (5 mL) and extracted with EA (6 mL x 3). The combined organic phases were collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H₂O = 5%–95%) to obtain the purified product (110 mg; 42%; white solid).

[0692] 1 H NMR (400MHz, DMSO) δ8.31(d,J=1.7Hz,1H),8.03(s,1H),7.83(dd,J=8.5,1.8Hz,1H ), 7.32 (d, J = 8.5Hz, 1H), 4.31 (q, J = 7.1Hz, 2H), 3.97 (s, 3H), 1.34 (t, J = 7.1Hz, 3H).

[0693] Examples 2-3: 2-Methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid Synthesis of ethyl ester

[0694]

[0695] Ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (85 mg; 0.35 mmol), 1-bromo-4-(trifluoromethyl)benzene (102 mg; 0.45 mmol), XPhosPd G2 (17 mg; 0.02 mmol), and Cs2CO3 (342 mg; 1.05 mmol) in dioxane (5 ml) were added to a sealed tube. The mixture was stirred at 100 °C for 2 hours under N2. The mixture was filtered and concentrated to give a crude product as a black oil. The crude product was purified by C18 (ACN / H2O = 5%–95%) to give a white solid product (92 mg; 62%; white solid).

[0696] 1H NMR (400MHz, DMSO) δ8.45(d,J=1.5Hz,1H),8.23(s,1H),8.08(d,J=8.5Hz,H),7.98(d,J=8.6Hz,2H),7 .93(d,J=1.8Hz,1H),7.80(d,J=8.7Hz,1H),4.35(d,J=7.1Hz,2H),4.04(s,3H),1.36(t,J=7.1Hz,2H).

[0697] Examples 2-4: 2-Methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid Synthesis

[0698]

[0699] To a solution of ethyl 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (90 mg; 0.21 mmol) in MeOH (40 mL), 1 M aqueous sodium hydroxide solution (1 mL) was added. The mixture was stirred at 60 °C for 6 hours under N2. The mixture was concentrated and adjusted to pH 1–2 with 1 N hydrochloric acid. The mixture was purified by C18 (0.1% TFA / H2O = 20%–95%) to give the product (59 mg; 73%; white solid).

[0700] 1 H NMR (400MHz, DMSO) δ12.74(s,1H),8.43(d,J=1.7Hz,1H),8.22(s,1H),8.08(d,J=8.5Hz,2 H), 7.98 (d, J = 8.6Hz, 2H), 7.93 (dd, J = 8.7, 1.8Hz, 1H), 7.78 (d, J = 8.7Hz, 1H), 4.03 (s, 3H).

[0701] Example 3: 2-Benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid

[0702] Example 3-1: Synthesis of methyl 2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate

[0703]

[0704] Methyl 4-(benzyl)-2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (460 mg; 1 mmol) (see Examples 1-4) was added to a solution of methyl 4-(benzyl)-2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (20 mL) at 25 °C. The mixture was stirred at 30 °C to form a yellow-brown solid for 16 hours. The reaction mixture was poured into water (100 mL) and extracted three times with EA (30 mL). The organic layer was concentrated to give a residue. The residue was purified by C18 (ACN / H2O = 10%-95%) to give the desired product (200 mg; 67%; yellow-brown solid).

[0705] Example 3-2 - Synthesis of methyl 2-benzyl-4-phenyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate become

[0706]

[0707] A suspension of methyl 2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (170 mg; 0.55 mmol), iodobenzene (140 mg; 0.69 mmol), and copper iodide (17 mg; 0.1 mmol) in DMSO (5 mL) was reacted with (2S)-pyrrolidine-2-carboxylic acid (17 mg; 0.15 mmol) and K₂CO₃ (150 mg; 1.1 mmol) at 25 °C. The dark brown mixture was stirred at 110 °C for 16 h under a nitrogen balloon at 1 bar. The reaction mixture was poured into water (30 mL) and extracted three times with EA (10 mL). The combined organic layers were concentrated to give the residue. The residue was purified by silica gel chromatography (petroleum ether / EA = 10:1) to give the desired product (200 mg; 91%; yellow-brown gel).

[0708] Example 3-3: Synthesis of methyl 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylate

[0709]

[0710] A solution of methyl 2-benzyl-4-phenyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (170 mg; 0.43 mmol.) in toluene (5 mL) was reacted with 4,5-dichloro-3,6-dioxocyclohexyl-1,4-diene-1,2-dicarboxynitrile (100 mg; 0.44 mmol.) at 25 °C. The yellow-brown mixture was stirred at 25 °C for 3 hours. The reaction was filtered and concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EA = 10:1) to give the desired product (34 mg; 20%; yellow-brown gel).

[0711] Examples 3-4: Synthesis of 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylic acid

[0712]

[0713] To a solution of methyl 2-benzyl-4-phenyl-2H,4H-pyrrolo[3,4-b]indole-7-carboxylate (34 mg; 0.1 mmol) in EtOH (5 mL) and H₂O (1 mL), NaOH (35 mg; 0.9 mmol) was added at 25 °C. The yellow-brown mixture was stirred at 70 °C for 16 hours. The reaction was concentrated and water (5 mL) was added. The aqueous phase was adjusted to pH ~5 and extracted three times with EA (10 mL). The combined organic layers were concentrated to give the residue. The residue was purified by passing it through a C18 column (ACN / H₂O = 10%–95%) to give the desired product (17 mg; 53%; gray-green solid).

[0714] 1 H NMR(400MHz,DMSO-d6)δ12.48(s,1H),8.33(d,J=1.6Hz,1H),7.84-7.82(m,1H),7.68- 7.66(m,2H),7.60-7.55(m,3H),7.39-7.27(m,7H),6.98(d,J=1.6Hz,1H),5.30(s,2H).

[0715] Example 4: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylic acid

[0716] Example 4-1: Synthesis of ethyl 3-(4-amino-1-methyl-1H-pyrazole-3-yl)-4-chlorobenzoate

[0717]

[0718] A mixture of 2-chloro-5-(ethoxycarbonyl)phenylboronic acid (1.20 g; 5.20 mmol), 3-bromo-1-methyl-1H-pyrazole-4-amine (915 mg; 5.20 mmol), Cs₂CO₃ (3.4 g; 10.40 mmol), and Pd(dppf)Cl₂ (380 mg; 0.52 mmol) in dioxane (20 ml) and water (2 ml) was stirred at 90 °C for 16 h under a nitrogen atmosphere. The mixture was filtered and concentrated to give a crude product as a black oil. The crude product was purified by C₁₈ (ACN / H₂O = 20%–95%) to obtain the final product (355 mg; 23%; light brown oil).

[0719] 1H NMR (400MHz, DMSO) δ7.97 (d, J=2.2Hz, 1H), 7.92¨C 7.87(m,1H),7.67(d,J=8.4Hz,1H),7.17(s,1H),4.32(d,J=7.1Hz,2H),3.76(s,3H),1.32(t,J=7.1Hz,3H).

[0720] Example 4-2: Synthesis of ethyl 2-methyl-2H,4H-pyrazolo[4,3-b]indole-7-carboxylate

[0721]

[0722] Ethyl 3-(4-amino-1-methyl-1H-pyrazole-3-yl)-4-chlorobenzoate (350 mg; 1.24 mmol), di-tert-butyl[2',4',6'-tris(prop-2-yl)-[1,1'-biphenyl]-2-yl]phosphine{2'-amino-[1,1'-biphenyl]-2-yl}palladium methane sulfonate (120 mg; 0.15 mmol), and Cs₂CO₃ (807 mg; 2.48 mmol) / dioxane (20 ml) were added to a sealed tube. The mixture was stirred at N₂ and 120 °C for 16 h. LCMS showed that the starting material did not disappear. Di-tert-butyl[2',4',6'-tris(propyl-2-yl)-[1,1'-biphenyl]-2-yl]phosphine{2'-amino-[1,1'-biphenyl]-2-yl}palladium methane sulfonate (120 mg; 0.15 mmol) was added to the mixture and stirred at 140 °C for 24 h. The mixture was filtered and concentrated to give a crude product as a black oil. The crude product was purified by C18 (ACN / H2O = 5%-95%) to give the final product (50 mg; 23%; white powder).

[0723] 1 H NMR (400MHz, DMSO) δ10.71(s,1H),8.38(d,J=1.6Hz,1H),7.89(dd,J=8.6,1.7Hz,1H),7.71(s ,1H),7.39(d,J=8.6Hz,1H),4.32(t,J=7.1Hz,2H),4.05(s,3H),1.35(dd,J=9.9,4.3Hz,3H).

[0724] Example 4-3: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylic acid Synthesis of ethyl ester

[0725]

[0726] Ethyl 2-methyl-2H,4H-pyrazolo[4,3-b]indole-7-carboxylate (65 mg; 0.25 mmol), 1-bromo-4-(trifluoromethyl)benzene (72 mg; 0.32 mmol), XPhosPd G2 (12 mg; 0.01 mmol), and Cs2CO3 (240 mg; 0.74 mmol) / dioxane (4 ml) were charged into a sealed tube. The mixture was stirred at 100 °C for 2 hours under N2. The mixture was filtered and concentrated to give a crude product, a black oil. The crude product was purified by C18 (ACN / H2O = 5%-95%) to give a white powder product (80 mg; 76%; white powder).

[0727] 1 H NMR(400MHz,DMSO)δ8.48(d,J=1.6Hz,1H),8.12(s,1H),8.01(dd,J=8.8,1.7Hz,1H),7.94 (s, 4H), 7.88 (d, J = 8.8Hz, 1H), 4.36 (q, J = 7.1Hz, 2H), 4.10 (s, 3H), 1.37 (t, J = 7.1Hz, 3H).

[0728] Example 4-4: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylic acid Synthesis

[0729]

[0730] A solution of ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylic acid (80 mg; 0.19 mmol) in EtOH (4 mL) was added to a solution of 1 M sodium hydroxide aqueous solution (1 mL). The mixture was stirred at 60 °C for 1.5 h. The mixture was concentrated and adjusted to pH 1–2 with 1 N hydrochloric acid (1 mL). The mixture was purified by HPLC to give 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylic acid (40 mg; 59%; white solid).

[0731] 1 H NMR (400MHz, DMSO) δ 8.44 (d, J = 1.4 Hz, 1H), 8.10 (s, 1H), 7.99 (d, J = 1.7 Hz, 1H), 7.94 (s, 4H), 7.84 (d, J = 8.8 Hz, 1H), 4.10 (s, 3H).

[0732] Example 5: 2-Methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5- Formic acid

[0733] Example 5-1: 2-Methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole- Synthesis of ethyl 5-carboxylate

[0734]

[0735] To a solution of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (220 mg; 0.81 mmol) in DMF (3 mL), NaH (49 mg; 2.04 mmol) was added at 0 °C. The solution was stirred at 0 °C for 30 min, and then 1-(bromomethyl)-4-(trifluoromethyl)benzene (230 mg; 0.96 mmol) was added. The solution was stirred at 25 °C for 3 h. The reaction mixture was filtered through a filter membrane. The filtrate was purified by a C-18 column (acetonitrile:water = 5% to 95%) to give the desired purified product (260 mg; 79%; off-white solid).

[0736] 1 H NMR (400MHz, CDCl3) δ8.44(d,J=1.6Hz,1H),7.98(dd,J=8.4,1.6Hz,1H),7.66(s,1H),7.53(d,J=8.4Hz,2H),7.3 4(d,J=8.0Hz,2H),7.12(d,J=8.4Hz,1H),5.44(s,2H),4.39(q,J=7.2Hz,2H),4.06(s,3H),1.41(t,J=7.2Hz,3H).

[0737] Example 5-2: 2-Methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole- Synthesis of 5-formic acid

[0738]

[0739] To a solution of ethyl 2-methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (120 mg; 0.30 mmol) in EtOH (40 mL) and water (1 mL), NaOH (36 mg; 0.90 mmol) was added at 25 °C. The yellow-brown solution was stirred at 70 °C for 3 hours. The solution was concentrated. Water (5 mL) was added to the resulting residue. The aqueous phase was adjusted to pH ~3 with 5 drops of 1N hydrochloric acid and concentrated. The resulting residue was suspended in pure water (10 mL) and filtered. The filter residue was washed three times with water (5 mL) and concentrated to obtain the desired purified product (101 mg; 88%; off-white solid).

[0740] 1H NMR(400MHz,DMSO-d6)δ12.49(s,1H),8.34(d,J=1.6Hz,1H),8.10(s,1H),7.85(dd,J =8.8,1.6Hz,1H),7.68(d,J=8.4Hz,2H),7.51-7.43(m,3H),5.52(s,2H),3.99(s,3H).

[0741] Example 6: 2-Methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0742] Example 6-1: 2-Methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid Synthesis of ethyl ester

[0743]

[0744] Ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-3-(trifluoromethyl)benzene (174 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol), and Cs2CO3 (629 mg; 1.93 mmol) were suspended in dioxane-1,4 (10 mL). The mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The mixture was filtered. The organic phase was concentrated and purified by silica gel (PE / EA = 10:1) to give a purified product as a grayish-white solid (230 mg; 88%).

[0745] 1 H NMR (400MHz, DMSO) δ8.45(s,1H),8.22(s,1H),8.17¨C8.08(m,2H),7.94(d,J=8.7Hz,1H),7.86(d,J=7.9Hz, 1H), 7.76 (d, J = 7.8Hz, 1H), 7.68 (d, J = 8.8Hz, 1H), 4.35 (q, J = 7.1Hz, 2H), 4.03 (s, 3H), 1.36 (t, J = 7.1Hz, 3H).

[0746] Example 6-2: 2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid synthesis

[0747]

[0748] To a solution of ethyl 2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (230 mg; 0.56 mmol) in EtOH (6 mL), 1 M sodium hydroxide aqueous solution (2 mL) was added. The reaction mixture was stirred at 60 °C for 2 h under a N2 atmosphere. The mixture was concentrated to dryness. Water (10 mL) was then added, and the mixture was adjusted to pH 1 with 1 N hydrochloric acid. The solution was filtered, and the residue was washed three times with H2O (10 mL). The residue was dried under vacuum to obtain the purified product (180 mg; 89%; off-white solid).

[0749] 1 H NMR (400MHz, DMSO) δ12.69(d,J=0.6Hz,1H),8.43(d,J=1.5Hz,1H),8.21(s,1H),8.13(d,J=12.1Hz,2H),7. 93(dd,J=8.7,1.7Hz,1H),7.86(t,J=7.9Hz,H),7.76(d,J=7.8Hz,1H),7.67(d,J=8.7Hz,1H),4.03(s,3H).

[0750] Example 7: 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0751] Example 7-1: Synthesis of ethyl 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate become

[0752]

[0753] A mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-3-fluorobenzene (135 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol), and Cs2CO3 (629 mg; 1.93 mmol) was added to dioxane-1,4 (10 mL). The mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The reaction mixture was filtered. The organic phase was concentrated and purified by silica gel (PE / EA = 5:1) to obtain a purified product (210 mg; 92%; off-white solid).

[0754] 1H NMR (400MHz, DMSO) δ8.43(d,J=1.4Hz,1H),8.21(s,1H),7.91(d,J=1.7Hz,1H),7.72(d,J=8.7Hz,1H),7.67(dd,J=6.5,2.6Hz,3H),7.28¨C 7.21 (m, H), 4.35 (d, J = 7.1 Hz, 2H), 4.03 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

[0755] Example 7-2: Synthesis of 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0756]

[0757] To a solution of ethyl 8-(3-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (210 mg; 0.59 mmol) in EtOH (6 ml), 2 ml of 1 M sodium hydroxide aqueous solution was added. The mixture was stirred at 60 °C for 2 h under N2 atmosphere. The mixture was concentrated to dryness. H2O (10 ml) was added to the residue, and the pH of the mixture was adjusted to 1-2 with 1 N hydrochloric acid. The solution was filtered. The residue was washed with H2O (3 x 10 ml) and dried under vacuum to obtain the crude product. Ethyl acetate / n-hexane = 1:1 (10 ml) was added, and the mixture was stirred for 30 min. The solution was then filtered, and the residue was dried under vacuum to obtain the purified product (120 mg; 65%; off-white solid).

[0758] 1 H NMR (400MHz, DMSO) δ12.68(s,1H),8.41(d,J=1.4Hz,1H),8.19(s,1H),7.92(dd,J=8.7,1.6Hz,1H),7.72¨C 7.63(m,4H),7.27¨C7.20(m,1H),4.03(s,3H).

[0759] Example 8: 2-Methyl-8-{[3-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5- Formic acid

[0760] Example 8-1: 2-Methyl-8-{[3-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole- Synthesis of ethyl 5-carboxylate

[0761]

[0762] To a solution of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (220 mg; 0.81 mmol) in DMF (3 mL), NaH (49 mg; 2.04 mmol) was added at 0 °C. The mixture was stirred at 0 °C for 30 min, and 1-(bromomethyl)-3-(trifluoromethyl)benzene (230 mg; 0.96 mmol) was added. The solution was stirred at 25 °C for 3 h. The reaction was filtered, concentrated under vacuum, and purified by C-18 column chromatography (ACN / H2O = 5%–95%) to obtain the product (213 mg; 64%; yellow-brown solid).

[0763] 1 H NMR (400MHz, CDCl3) δ8.44(d,J=2.0Hz,1H),7.98(dd,J=8.8,1.6Hz,1H),7.65(s,1H),7.57(s,1H),7.52-7.50(m,1H ),7.41-7.37(m,2H),7.12(d,J=9.2Hz,1H),5.43(s,2H),4.39(q,J=7.2Hz,2H),4.07(s,3H),1.41(t,J=7.2Hz,3H).

[0764] Example 8-2: 2-Methyl-8-{[3-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole- Synthesis of 5-formic acid

[0765]

[0766] To a solution of ethyl 2-methyl-8-{[3-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (210 mg; 0.51 mmol) in EtOH (4 mL) and water (1 mL), NaOH (63 mg; 1.58 mmol) was added at 25 °C. The yellow-brown mixture was stirred at 70 °C for 3 hours. The mixture was concentrated to dryness and water (5 mL) was added. The aqueous phase was adjusted to pH ~3 with 5 drops of 1 N hydrochloric acid and concentrated to dryness. Water (10 mL) was added to the residue and the mixture was filtered. The filtered residue was washed three times with water (5 mL) and concentrated to dryness. A purified product (150 mg; 78%; off-white solid) was obtained.

[0767] 1H NMR (400MHz, DMSO-d6) δ12.51(s,1H),8.34(d,J=1.6Hz,1H),8.10(s,1H),7.85(dd,J=8.8 ,2.0Hz,1H),7.72(s,1H),7.64-7.62(m,1H),7.56-7.47(m,3H),5.52(s,2H),3.99(s,3H).

[0768] Example 9: 2-Methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0769] Example 9-1: Ethyl 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate synthesis

[0770]

[0771] A mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-4-methylbenzene (132 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol), and Cs2CO3 (629 mg; 1.93 mmol) was added to dioxane-1,4 (10 mL). The mixture was stirred at 120 °C for 16 hours under a nitrogen atmosphere. The mixture was filtered. The organic phase was concentrated and purified by silica gel chromatography (PE / EA = 10:1) to give the product (207 mg; 91%; pale yellow solid).

[0772] 1 H NMR (400MHz, CDCl3) δ8.46(d,J=2.0Hz,1H),7.99(dd,J=8.7,2.4Hz,1H),7.67(d,J=3.8Hz,1H),7.63-7.57(m,2H),7.52-7. 46(m,1H),7.40-7.33(m,2H),4.45-4.38(m,2H),4.07(d,J=3.9Hz,3H),2.43(d,J=3.3Hz,3H),1.44(td,J=7.1,4.1Hz,3H).

[0773] Example 9-2: Synthesis of 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0774]

[0775] To a solution of ethyl 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (200 mg; 0.57 mmol) in EtOH (6 mL), 1 M sodium hydroxide aqueous solution (2 mL) was added. The mixture was stirred at 60 °C for 2 hours under a nitrogen atmosphere. The mixture was concentrated. H₂O (10 mL) was added to the residue, and the pH of the mixture was adjusted to 1 with 1 N hydrochloric acid. The precipitate was filtered. The crude product was washed three times with H₂O (15 mL). The filtered residue was dried under vacuum to obtain a purified product (160 mg; 87%; off-white solid).

[0776] 1 H NMR (400MHz, DMSO) δ12.60(s,1H),8.40(d,J=1.5Hz,1H),8.17(s,1H),7.89(dt,J=5.2,3.3Hz,1H ), 7.63 (d, J = 8.3Hz, 2H), 7.54 (d, J = 8.7Hz, 1H), 7.41 (d, J = 8.2Hz, 2H), 4.00 (s, 3H), 2.40 (s, 3H).

[0777] Example 10: 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0778] Example 10-1: Synthesis of ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate become

[0779]

[0780] A mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (200 mg; 0.64 mmol), 1-bromo-4-fluorobenzene (135 mg; 0.77 mmol), XPhosPd G2 (56 mg; 0.07 mmol), and Cs2CO3 (629 mg; 1.93 mmol) was added to dioxane-1,4 (10 mL). The mixture was stirred at 120 °C for 16 h under a nitrogen atmosphere. The mixture was filtered and the phases were separated. The organic phase was concentrated and purified by silica gel chromatography (PE / EA = 10:1). The purified product (186 mg; 81%; pale yellow solid) was obtained.

[0781] 1H NMR(400MHz, CDCl3)δ8.47(d,J=1.5Hz,1H),8.05-7.98(m,1H),7.74-7.66(m,3H),7.49-7.42(m, 1H), 7.26 (d, J = 3.6Hz, 2H), 4.42 (dd, J = 7.1, 3.5Hz, 2H), 4.07 (d, J = 3.4Hz, 3H), 1.47-1.41 (m, 3H).

[0782] Example 10-2: Synthesis of 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0783]

[0784] To a solution of ethyl 8-(4-fluorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (180 mg; 0.51 mmol) in EtOH (5 mL), 1 M sodium hydroxide aqueous solution (1.7 mL) was added. The mixture was stirred at 60 °C for 16 h under a N2 atmosphere. The mixture was concentrated to dryness. H2O (15 mL) was added to the residue and the pH was adjusted to 1 with 1 N hydrochloric acid. The precipitate was filtered off. The residue was washed three times with H2O (10 mL). Ethyl acetate (3 mL) and n-hexane (3 mL) were added to the residue and the mixture was stirred for 30 min. The suspension was filtered off and the residue was dried under vacuum. A purified product (100 mg; 62%; white solid) was obtained.

[0785] 1 H NMR (400MHz, DMSO) δ12.65(s,1H),8.41(d,J=1.4Hz,1H),8.18(s,1H),7.90(dd,J=8.7 ,1.6Hz,1H),7.83-7.77(m,2H),7.54(d,J=8.7Hz,1H),7.49-7.42(m,2H),4.01(s,3H).

[0786] Example 11: 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-methyl acid

[0787] Example 11-1: Ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate synthesis

[0788]

[0789] To a suspension of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (200 mg; 0.82 mmol) in acetone (5 mL), methyl cyclohexane (0.14 mL; 0.99 mmol) and KOH (138 mg; 2.47 mmol) were added. The mixture was stirred at 65 °C for 12 h under a nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted three times with EA (5 mL). The combined organic phases were collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H2O = 5%–95%), yielding the product (170 mg; 57%; yellow gel).

[0790] Example 11-2: Synthesis of 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0791]

[0792] To a suspension of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (170 mg; 0.47 mmol) in EtOH (24 mL), water (8 mL) and sodium hydroxide (320 mg; 8 mmol) were added. The mixture was stirred at 65 °C for 12 hours under a nitrogen atmosphere. The mixture was evaporated under vacuum. The residue was acidified with 1 N HCl solution and evaporated. The residue was purified by C18 column chromatography (ACN / H2O = 5%–95%), and the product (50 mg; 33%; white solid) was obtained.

[0793] 1 H NMR(400MHz,CDCl3)δ7.63(s,1H),7.31¨C 7.26(m,3H),4.09(s,3H),4.01(d,J=7.5Hz,2H),2.49(s,1H),2.01(s,1H),1.75-1.63(m,5H),1.26-1.15(m,3H),1.13-1.03(m,2H).

[0794] Example 12: 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0795] Example 12-1: Ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate synthesis

[0796]

[0797] To a suspension of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (300 mg; 1.23 mmol) in acetone (5 mL), bromomethylbenzene (0.18 mL; 1.48 mmol) and KOH (208 mg; 3.7 mmol) were added. The mixture was stirred at 65 °C for 12 h under a nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted three times with EA (5 mL). The combined organic phases were collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H2O = 5%–95%) to give the product (180 mg; 41%; off-white powder).

[0798] Example 12-2: Synthesis of 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0799]

[0800] Sodium hydroxide (320 mg; 8 mmol) and water (4 ml) were added to a suspension of ethyl 8-(benzyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (170 mg; 0.48 mmol) in EtOH (12 ml). The mixture was stirred at 65 °C for 12 hours under a N2 atmosphere. The residue was acidified with 1N HCl solution and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H2O = 5%-95%), and the product (60 mg; 41%; white solid) was obtained.

[0801] 1 H NMR (300MHz, DMSO) δ12.58-12.44(m,1H),8.35(d,J=1.4Hz,1H),8.12(s,1H),7.87(dd, J=8.5,1.6Hz,1H),7.52(d,J=8.6Hz,1H),7.39-7.24(m,6H),5.43(s,2H),4.02(s,3H).

[0802] Example 13: 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0803] Example 13-1: Synthesis of ethyl 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate become

[0804]

[0805] To a suspension of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (300 mg; 0.97 mmol) in dioxane-1,4 (10 mL), 1-bromo-4-chlorobenzene (222 mg; 1.16 mmol), XPhosPd G2 (84 mg; 0.11 mmol), and Cs2CO3 (944 mg; 2.90 mmol) were added. The mixture was stirred at 120 °C for 12 h under a nitrogen atmosphere. The mixture was poured into water (10 mL) and extracted three times with EA (5 mL). The combined organic phases were collected and evaporated under vacuum. The residue was purified by C18 column chromatography (ACN / H2O = 5%–95%), yielding a purified product (180 mg; 52%; off-white solid).

[0806] Example 13-2: Synthesis of 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0807]

[0808] To a suspension of ethyl 8-(4-chlorophenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (150 mg; 0.42 mmol) in EtOH (12 mL), hydroxide (320 mg; 8 mmol) and water (4 mL) were added. The mixture was stirred at 65 °C for 12 h under a nitrogen atmosphere. The mixture was evaporated under vacuum. The residue was acidified with 1 N HCl solution and evaporated. The residue was purified by C18 column chromatography (ACN / H2O = 5%–95%) to obtain a purified product (30 mg; 21%; white solid).

[0809] 1 H NMR (300MHz, DMSO) δ12.70(s,1H),8.44(d,J=1.4Hz,1H),8.22(s,1H),7.93(dd,J=8.7,1.7Hz ,1H),7.86(d,J=8.8Hz,2H),7.72(d,J=2.9Hz,1H),7.67(dd,J=7.1,4.0Hz,2H),4.04(s,3H).

[0810] Example 14: 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0811] Example 14-1: Ethyl 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate Synthesis

[0812]

[0813] In a microwave-safe vial, ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) / 1,4-dioxane (4 mL) were reacted with 4-bromoanisole (32 μl; 0.26 mmol), cesium carbonate (206 mg; 0.64 mmol), and XPhos Pd G4 (19 mg; 0.02 mmol) under argon atmosphere. The reaction mixture was stirred at 120 °C for 16 h. The reaction mixture was diluted with EA and extracted 3x with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative HPLC. The purified product was obtained (56 mg, 68%, beige solid).

[0814] Example 14-2: Synthesis of 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid become

[0815]

[0816] To ethyl 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (56 mg; 0.15 mmol) / ethanol (0.3 mL), sodium hydroxide solution c(NaOH) = 2 mol / L (0.2 mL) was added, and the mixture was stirred at 60 °C for 16 hours. The reaction mixture was evaporated to dryness, and the residue was purified by preparative HPLC. The purified product (19 mg, 40%, white solid) was obtained.

[0817] 1 H NMR (500MHz, DMSO-d6) δ12.58-12.54(m,1H),8.40-8.38(m,1H),8.15(s,1H),7.87(dd,J=8.6,1. 8Hz,1H),7.65-7.61(m,2H),7.44(d,J=8.7Hz,1H),7.18-7.14(m,2H),4.00(s,3H),3.85(s,3H).

[0818] Example 15: 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0819] Example 15-1: Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazole-4-yl)-4-chlorobenzoate

[0820]

[0821] In a microwave-safe vial under argon atmosphere, 4-bromo-1-methyl-1H-pyrazole-3-amine (462 mg; 2.63 mmol), potassium carbonate (726 mg; 5.25 mmol), and [1,1'-bis(diphenylphosphino)ferrocene]-palladium(II) dichloride, complexed with dichloromethane (214 mg), were added to a suspension of ethyl 3-boron-4-chlorobenzoate (600 mg; 2.63 mmol) in 1,4-dioxane (8 mL) and water (0.8 mL). The reaction was stirred at 60 °C for 16 h, and then diluted with EA at room temperature. The mixture was extracted three times with water, dried over Na₂SO₄, and evaporated to dryness. The residue was purified by rapid chromatography. A purified product (273 mg, 36% yield) as a brown oil was obtained.

[0822] Example 15-2: Ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate Synthesis

[0823]

[0824] In a microwave-safe vial, ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) / 1,4-dioxane (4 mL) was added under argon atmosphere to 4-bromophenethyl ether (35 μl; 0.25 mmol), cesium carbonate (0.62 mmol), and XPhos Pd G4 (19 mg; 0.02 mmol). The reaction was stirred at 120 °C for 16 h and diluted with EA at room temperature. The mixture was extracted three times with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative HPLC to give a purified product (10 mg, 12% yield) as a yellow solid.

[0825] Example 15-3: Synthesis of 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid become

[0826]

[0827] To ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (10 mg; 0.03 mmol) / ethanol (2 mL), sodium hydroxide solution c(NaOH) = 2 mol / L (2N) (76 μL; 0.15 mmol) was added, and the mixture was stirred at 60 °C for 16 h. When the reaction was incomplete, more sodium hydroxide solution c(NaOH) = 2 mol / L (2N) (76 μL; 0.15 mmol) was added, and the mixture was stirred at 60 °C for another 16 h. The reaction mixture was evaporated to dryness at room temperature, and the residue was purified by preparative HPLC column chromatography. The purified product was obtained as a grayish-white solid (13 mg, 99% yield).

[0828] Example 16: Methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxylate

[0829]

[0830] Methyl 3-(4-amino-1-methylpyrazol-3-yl)-4-chlorobenzoate (330 mg, 1.192 mmol), XPhos Pd G3 (99 mg, 0.115 mmol), Cs2CO3 (825 mg, 2.481 mmol), dioxane (160 mL), and 1-bromo-4-(trifluoromethyl)benzene (0.19 mL, 0.004 mmol) were mixed in a sealed tube at room temperature. The resulting mixture was stirred at 120 °C for 24 hours under an argon atmosphere. The mixture was then concentrated under vacuum. The crude product was purified by preparative HPLC to give methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxylate as a white solid (40 mg, 9%).

[0831] Example 17: N,2-Dimethyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide

[0832]

[0833] 2-Methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxylic acid (Examples 4-4) (70 mg, 0.189 mmol), HATU (153 mg, 0.393 mmol), DCM (6.80 mL), methylamine, 2M / THF (0.19 mL, 6.248 mmol), and DIEA (0.07 mL, 0.525 mmol) were added to a sealed tube at room temperature. The resulting mixture was stirred at 30 °C for 2 hours and then concentrated under vacuum. The crude product was purified by preparative HPLC to give N,2-dimethyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (41 mg, 58%) as a white solid.

[0834] 1 H NMR(400MHz,DMSO,ppm)δ8.52(d,J=4.6Hz,1H),8.46(d,J=1.8Hz,1H),8.10(s ,1H),7.93(s,5H),7.85(d,J=8.7Hz,1H),4.10(s,3H),2.83(d,J=4.4Hz,3H).

[0835] Example 18: 2-Methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0836] Example 18-1: 2-Methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-methyl Synthesis of ethyl acetate

[0837]

[0838] In a microwave-safe vial, ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) / 1,4-dioxane (4 mL) was added under argon atmosphere with 1-bromo-4-(trifluoromethoxy)-benzene (60 mg; 0.25 mmol), cesium carbonate (202 mg; 0.62 mmol), and XPos Pd G4 (18.7 mg; 0.02 mmol). The reaction mixture was stirred at 120 °C for 16 hours. At room temperature, the reaction mixture was diluted with EA and extracted three times with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative HPLC to give the product as a white solid (28 mg; 34%).

[0839] 1 H NMR(500MHz,DMSO-d6)δ8.45-8.43(m,1H),8.21(s,1H),7.94-7.90(m,3H),7.68-7.65 (m,1H),7.64-7.60(m,2H),4.35(q,J=7.1Hz,2H),4.02(s,3H),1.36(t,J=7.1Hz,3H).

[0840] Example 18-2: 2-Methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-methyl Acid Synthesis

[0841]

[0842] A solution of sodium hydroxide (c(NaOH) = 2 mol / L (2N)) (104 μL; 0.21 mmol) was added to a solution of ethyl 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (28 mg; 0.07 mmol) in ethanol (2 mL), and the mixture was stirred at 60 °C for 16 hours. The reactants were evaporated to dryness, and the residue was purified by preparative HPLC to give the product as a white solid (20 mg; 76%).

[0843] 1 H NMR (400MHz, DMSO-d6) δ12.67-12.62(m,1H),8.41(d,J=1.7Hz,1H),8.19(s,1H),7.95- 7.90(m,2H),7.93-7.88(m,1H),7.65(d,J=8.7Hz,1H),7.63-7.59(m,2H),4.02(s,3H).

[0844] Example 19: 2-Methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxynitrile

[0845] Example 19-1: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide become

[0846]

[0847] 2-Methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxylic acid (Example 4-4) (490 mg, 1.324 mmol), THF (25 mL), CDI (344 mg, 2.079 mmol), and NH4OH (30 mL) were combined in a sealed tube at room temperature. The resulting mixture was stirred at 30 °C for 3 hours. The reaction was quenched with water at room temperature. The aqueous layer was extracted with EtOAc (3 x 100 mL). The resulting mixture was concentrated under vacuum. This yielded 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (520 mg, 98%), as a white solid.

[0848] 1 H NMR (300MHz, DMSO, ppm) δ8.45(d,J=1.7Hz,1H),8.10(s,1H),8.04-7.95(m,1H),7.93(s,4H),7.86(d,J=8.8Hz,1H),4.09(s,3H),3.88(s,3H).

[0849] Example 19-2: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxynitrile

[0850]

[0851] 2-Methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (150 mg, 0.419 mmol), THF (7.5 mL), and POCl3 (0.15 mL) were added to a sealed tube at room temperature. The resulting mixture was stirred at room temperature for 3 hours. The reaction was quenched with ice at 0 °C. The aqueous layer was extracted with EtOAc (3 x 50 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC. This yielded 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxynitrile (37 mg, 25%) as a white solid.

[0852] 1 H NMR (300MHz, DMSO, ppm) δ8.44 (d, J = 1.7Hz, 1H), 8.15 (s, 1H), 7.95 (s, 4H), 8.02-7.87 (m, 1H), 7.85-7.75 (m, 1H), 4.12 (s, 3H).

[0853] Example 20: N-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]prop-2-ene amide

[0854] Example 20-1: Synthesis of 4-(2-chloro-5-nitrophenyl)-1-methylpyrazole-3-amine

[0855]

[0856] Pd(dppf)Cl2 (363 mg, 0.471 mmol) and K2CO3 (1.3 g, 8.936 mmol) were added to a solution of 2-chloro-5-nitrophenylboronic acid (1.0 g, 4.718 mmol) and 4-bromo-1-methylpyrazole-3-amine (437 mg, 2.359 mmol) in dioxane (10 mL) and H2O (2 mL). After stirring at 80 °C for 4 hours under nitrogen atmosphere, the resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1), to give 4-(2-chloro-5-nitrophenyl)-1-methylpyrazole-3-amine (190 mg, 15%) as a yellow solid.

[0857] Example 20-2: Synthesis of 2-methyl-5-nitro-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole

[0858]

[0859] To a stirred solution of 4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3-amine (330 mg, 1.124 mmol) and 1-bromo-4-(trifluoromethyl)benzene (346 mg, 1.461 mmol) in dioxane (10 mL), XPhos Pd G3 (50 mg, 0.056 mmol) and Cs2CO3 (1.16 g, 3.372 mmol) were added in portions at room temperature and under nitrogen atmosphere. The resulting mixture was stirred overnight at 120 °C under nitrogen atmosphere. The mixture was then concentrated under vacuum. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:2), to give 2-methyl-5-nitro-8-[4-(trifluoromethyl)phenyl]-pyrazolo[3,4-b]indole (460 mg, 95%) as a yellow solid.

[0860] Example 20-3: Synthesis of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-amine

[0861]

[0862] In a 250 mL round-bottom flask under a nitrogen atmosphere, Pd / C (10%, 450 mg) was added to a solution of 2-methyl-5-nitro-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole (450 mg, 1.048 mmol) in 20 mL MeOH. The mixture was hydrogenated at room temperature for 1 hour using a hydrogen balloon under a hydrogen atmosphere, filtered through a diatomaceous earth pad, and concentrated under reduced pressure. This yielded 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-amine (360 mg, 99%) as a yellow solid.

[0863] Example 20-4: N-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]propyl-2- Synthesis of enamides

[0864]

[0865] Acryloyl chloride (52 mg, 0.546 mmol) was added dropwise to a stirred solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-amine (160 mg, 0.463 mmol) and TEA (99 mg, 0.929 mmol) in DCM (5 mL) at room temperature and under nitrogen atmosphere. The resulting mixture was stirred at room temperature and under nitrogen atmosphere for 2 hours. The reaction was quenched with water / ice, and the resulting mixture was extracted with CH2Cl2 (3 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and preparative HPLC to give N-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]prop-2-enamide as a white solid (45 mg, 25%).

[0866] 1 H-NMR (400MHz, DMSO, ppm)10.20(s,1H),8.27(d,J=2.1Hz,1H),8.17(s,1H),8.08(d,J=8.5Hz,2H),7.92(d,J=8.5Hz,2H),7.74(d,J=8.9Hz ,1H),7.47(dd,J=8.9,2.1Hz,1H),6.47(dd,J=16.9,10.1Hz,1H),6.27(dd,J=16.9,2.1Hz,1H),5.75(dd,J=10.0,2.1Hz,1H),4.01(s,3H).

[0867] Example 21: N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methyl) Prop-2-enamide

[0868] Example 21-1: 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methylamine Synthesis

[0869]

[0870] Raney Ni (300 mg, 3.327 mmol) was added to a stirred mixture of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-carboxynitrile (Example 19) (300 mg, 0.882 mmol) and NH3(g) / MeOH (15 mL, 13%) in MeOH (30 mL) under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 6 hours under a hydrogen atmosphere, filtered, and the filter cake was washed with MeOH (5 x 15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with CH2Cl2(Et3N) / MeOH (24:1) to give 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methylamine (300 mg, 89%) as a pale yellow solid.

[0871] Example 21-2: N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methyl Synthesis of 2-propenamide

[0872]

[0873] Acryloyl chloride (38 mg, 0.399 mmol) / DCM was added dropwise to a stirred solution of 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methylamine (125 mg, 0.326 mmol) and DIPEA (133 mg, 0.979 mmol) in DCM (20 mL) under nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour under nitrogen atmosphere, and then concentrated under reduced pressure. The crude product was purified by preparative HPLC to give N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methyl)prop-2-enamide (62 mg, 48%) as a white solid.

[0874] 1 H-NMR (300MHz, DMSO-d6) δ8.64(t,J=5.8Hz,1H),8.13(s,1H),8.05(d,J=8.4Hz,2H),7.92(d,J=8.7Hz,2H),7.75-7.66(m,2H),7.22(dd,J=8. 5,1.9Hz,1H),6.29(dd,J=17.1,10.0Hz,1H),6.13(dd,J=17.1,2.4Hz,1H),5.61(dd,J=10.0,2.4Hz,1H),4.45(d,J=5.8Hz,2H),3.99(s,3H).

[0875] Example 22: 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid

[0876] Example 22-1: Ethyl 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate Synthesis

[0877]

[0878] In a microwave-safe vial under argon atmosphere, 1-bromo-4-cyclopentylbenzene (56 mg; 0.25 mmol), cesium carbonate (202 mg; 0.62 mmol), and XPhos Pd G4 (19 mg; 0.02 mmol) were added to a mixture of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-dioxane (4 mL). The reaction was stirred at 120 °C for 16 h. At room temperature, the reaction mixture was diluted with EA and extracted three times with water, dried over Na2SO4, and evaporated to dryness. The residue was purified by preparative HPLC to give a white solid product (15 mg; 18%).

[0879] Example 22-2: Synthesis of 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid become

[0880]

[0881] To ethyl 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (15 mg; 0.04 mmol) / ethanol (2 mL), sodium hydroxide solution c(NaOH) = 2 mol / L (2N) (57 μL; 0.11 mmol) was added, and the mixture was stirred at 60 °C for 2 days. The reactants were evaporated to dryness, and the residue was purified by preparative HPLC to give 14 mg (quantitative yield) of the desired product as a grayish-white solid.

[0882] Example 23: 2-Chloro-N-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]ethyl Synthesis of amides

[0883]

[0884] Chloroacetyl chloride (81 mg, 0.681 mmol) was added dropwise to a stirred solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-amine (Example 20-3) (170 mg, 0.492 mmol) and TEA (122 mg, 1.145 mmol) in DCM (5 mL) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred at room temperature for 1 hour. The reaction was quenched with water / ice and extracted with CH2Cl2 (3 x 40 mL). The combined organic layers were washed with brine (1 x 30 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2Cl2 / MeOH (10:1), and the crude product was purified by preparative HPLC to give 2-chloro-N-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]acetamide (45 mg, 22%), which was a grayish-white solid.

[0885] Example 24: 2-Chloro-N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl] Methylacetamide

[0886]

[0887] To a stirred solution of 1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methylamine (Example 21-1) (130 mg, 0.339 mmol) and DIPEA (139 mg, 1.022 mmol) in DCM (20 mL) under nitrogen atmosphere, chloroacetyl chloride (50 mg, 0.443 mmol) / DCM was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for 1 hour under nitrogen atmosphere and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1). The crude product was purified by preparative HPLC to give 2-chloro-N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methyl)acetamide (75 mg, 52%) as a white solid.

[0888] 1 H NMR (400MHz, DMSO-d6) δ8.77(t,J=5.9Hz,1H),8.15(s,1H),8.08(d,J=8.4Hz,2H),7.94(d,J=8.5Hz, 2H),7.77-7.69(m,2H),7.25(dd,J=8.5,1.9Hz,1H),4.43(d,J=5.8Hz,2H),4.15(s,2H),4.02(s,3H).

[0889] Example 25: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazo[4,5-b]indole-7-carboxylic acid

[0890] Example 25-1: Synthesis of methyl 3-bromo-4-[(2-methyl-1,3-thiazolyl-4-yl)amino]benzoate

[0891]

[0892] XantPhos (0.39 g, 0.640 mmol), Pd2(dba)3 (0.21 g, 0.213 mmol), and Cs2CO3 (2.94 g, 8.580 mmol) were added to a solution of methyl 4-amino-3-bromobenzoate (1.03 g, 4.268 mmol) and 4-bromo-2-methyl-1,3-thiazolyl (0.80 g, 4.268 mmol) in toluene (16 mL) at room temperature and under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave at 130 °C for 2 h and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (8:1) to give methyl 3-bromo-4-[(2-methyl-1,3-thiazolyl-4-yl)amino]benzoate (220 mg, 14%) as a pale yellow solid.

[0893] Example 25-2: Synthesis of 2-methyl-4H-[1,3]thiazo[4,5-b]indole-7-carboxylate

[0894]

[0895] To a mixture of methyl 3-bromo-4-[(2-methyl-1,3-thiazolyl-4-yl)amino]benzoate (1.01 g, 2.624 mmol) and neopentanoic acid (285 mg, 2.651 mmol) in xylene (45 mL), PCy3.HBF4 (153 mg, 0.395 mmol), Pd(AcO)2 (31 mg, 0.131 mmol), and Cs2CO3 (2.7 g, 7.872 mmol) were added at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 120 °C for 2 days under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give methyl 2-methyl-4H-[1,3]thiazo[4,5-b]indole-7-carboxylate (380 mg, 59%) as a pale yellow solid.

[0896] Example 25-3: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazo[4,5-b]indole-7-carboxylic acid Synthesis of methyl ester

[0897]

[0898] To a stirred mixture of methyl 2-methyl-4H-[1,3]thiazo[4,5-b]indole-7-carboxylate (230 mg, 0.934 mmol) and 1-bromo-4-(trifluoromethyl)benzene (332 mg, 1.402 mmol) in dioxane (10 mL), XPhos Pd G3 (83 mg, 0.093 mmol) and Cs₂CO₃ (960 mg, 2.799 mmol) were added at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred overnight at 100 °C under a nitrogen atmosphere and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluting with PE / EtOAc (1:1) to give methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazo[4,5-b]indole-7-carboxylate (230 mg, 63%) as a pale yellow solid.

[0899] Example 25-4: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazo[4,5-b]indole-7-carboxylic acid Synthesis

[0900]

[0901] A mixture of methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazo[4,5-b]indole-7-carboxylic acid (210 mg, 0.538 mmol) and LiOH (82 mg, 3.253 mmol) in THF (5 mL) and H₂O (5 mL) was stirred overnight at 50 °C. THF was removed under reduced pressure at room temperature. The residue was acidified to pH 4 with 1 M HCl (aqueous solution), and the resulting mixture was extracted with EtOAc (5 × 20 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to give 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazo[4,5-b]indole-7-carboxylic acid (57 mg, 28%) as a white solid.

[0902] 1 H NMR (300MHz, DMSO-d6) δ 8.50 (d, J = 1.7 Hz, 1H), 7.99 (s, 3H), 7.92 (dd, J = 8.8, 1.7 Hz, 2H), 7.70 (d, J = 8.8 Hz, 1H), 2.82 (s, 3H).

[0903] Example 26: 7-Fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole

[0904] Example 26-1: Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole

[0905]

[0906] To a stirred mixture of 2-bromo-5-fluorophenylboronic acid (700 mg, 3.039 mmol) and 3-bromo-1-methyl-4-nitropyrazole (700 mg, 3.330 mmol) in dioxane (28 mL) and H₂O (7 mL), NaHCO₃ (1.40 g, 15.832 mmol) and Pd(PPh₃)₄ (350 mg, 0.300 mmol) were added. The resulting mixture was stirred overnight at 110 °C under nitrogen atmosphere, and then concentrated under vacuum. The residue was extracted with EtOAc (3 × 30 mL), and the combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE / EtOAc (4:1) to give 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole (700 mg, 40%) as a white solid.

[0907] Example 26-2: Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methylpyrazole-4-amine

[0908]

[0909] Fe (609 mg, 10.360 mmol) was added to a stirred solution of 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole (650 mg, 1.133 mmol) and NH4Cl (580 mg, 10.301 mmol) in MeOH (13 mL) and H2O (6.5 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred at 70 °C for 2 hours and then diluted with water (20 mL). The resulting mixture was extracted with CH2Cl2 (3 x 50 mL). The combined organic layers were washed with brine (1 x 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This yielded 3-(2-bromo-5-fluorophenyl)-1-methylpyrazole-4-amine (500 mg, 100.00%) as a brown oil.

[0910] Example 26-3: Synthesis of 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole

[0911]

[0912] Cs₂CO₃ (1.20 g, 3.499 mmol) and XPhos Pd G₃ (161 mg, 0.181 mmol) were added to a stirred solution of 3-(2-bromo-5-fluorophenyl)-1-methylpyrazole-4-amine (500 mg, 1.133 mmol) and 1-bromo-4-(trifluoromethyl)benzene (460 mg, 1.942 mmol) in dioxane (15 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120 °C and then quenched with water. The mixture was extracted with EtOAc (3 × 20 mL). The combined organic layers were washed with brine (1 × 50 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC to obtain 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (26 mg, 7%), which was a white solid.

[0913] 1 H NMR (300MHz, DMSO-d6, ppm) 8.07 (s, 1H), 7.88 (s, 4H), 7.84-7.78 (m, 1H), 7.76-7.66 (m, 1H), 7.30-7.17 (m, 1H), 4.07 (s, 3H).

[0914] Example 27: N-cyclopropyl-2-methyl-8-[6-(trifluoromethyl)pyridin-3-yl]-2H,8H-pyrazolo[3,4- b] Indole-5-carboxamide

[0915] Example 27-1: N-cyclopropyl-2-methyl-8-[6-(trifluoromethyl)pyridin-3-yl]-2H,8H-pyrazolo[3, Synthesis of [4-b]indole-5-carboxamide

[0916]

[0917] Cyclopropylamine (21 μl; 0.29 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (75 mg; 0.39 mmol), 1-hydroxybenzotriazole hydrate (30 mg; 0.20 mmol), and 4-methylmorpholine (108 μl; 0.98 mmol) were added to 2-methyl-8-[6-(trifluoromethyl)pyridin-3-yl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (73 mg; 0.20 mmol) / DMF (4 mL). The reaction was stirred at room temperature for 16 hours and purified directly by HPLC to give the product as a white solid in 72% (58 mg) yield.

[0918] Example 28: 2-Methyl-N-[(pyridin-4-yl)methyl]-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazol [3,4-b]indole-5-carboxamide

[0919] Example 28-1: 2-Methyl-N-[(pyridin-4-yl)methyl]-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazole Synthesis of [3,4-b]indole-5-carboxamide

[0920]

[0921] Sodium 4-pyridinemethylamine (21 μl; 0.20 mmol), N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (50 mg; 0.26 mmol), 1-hydroxybenzotriazole hydrate (20 mg; 0.13 mmol), and 4-methylmorpholine (72 μl; 0.65 mmol) were added to 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8-pyrazolo[3,4-b]indole-5-carbodiimide sodium salt (50 mg; 0.13 mmol), DMF (3 mL). The reaction was stirred at room temperature for 16 hours. The reaction was directly purified by HPLC to give a 57% (34 mg) yield of a grayish-white solid product.

[0922] Example 29: N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H, 8H-pyrazolo[3,4-b]indole-5-carboxamide

[0923] Example 29-1: N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]- Synthesis of 2H,8H-pyrazolo[3,4-b]indole-5-carboxamide

[0924]

[0925] A solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carboxylic acid (150 mg, 0.42 mmol), DIEA (162 mg, 1.13 mmol), and HATU (191 mg, 0.45 mmol) in DMF (2 mL) was stirred at room temperature for 1 h. 2-Amino-2-(pyridin-2-yl)ethanol (87 mg, 0.57 mmol) was added to the mixture. The resulting mixture was stirred at room temperature for another 3 h. The crude product was purified by HPLC to give a product (82 mg, 41%) as a white solid.

[0926] Example 29-2: Separation of enantiomers

[0927]

[0928] The enantiomers of N-[2-hydroxy-1-(pyridin-2-yl)ethyl]-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxamide were separated on a YMC Cellulose-SC column by SCF eluent of CO2 / methanol = 60:40 at a flow rate of 5 mL / min. 50 mg of the racemic mixture provided 22 mg and 23 mg of the corresponding enantiomers.

[0929] Example 30: (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-{2-methyl-8-[4-(trifluoromethyl)benzene} ]-2H,8H-pyrazolo[3,4-b]indole-5-carbonyloxy}oxacyclohexane-2-carboxylic acid

[0930] Example 30-1: (2S,3S,4S,5R,6S)-3,4,5-trihydroxy-6-{2-methyl-8-[4-(trifluoromethyl)benzene} Synthesis of pyrazolo[3,4-b]indole-5-carbonyloxy}oxacyclohexane-2-carboxylic acid

[0931]

[0932] BnBr (4.60 g; 25.55 mmol) was added to a DMF (35 mL) solution of (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxetane-2-carboxylic acid (5 g; 24 mmol) and TBAF / THF (1 mol / L; 31 mL; 24 mmol) at 0 °C. The resulting mixture was stirred overnight at room temperature under a nitrogen atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxetane-2-carboxylic acid (4 g; 13.90 mmol; 57%) as a yellow oil.

[0933] HATU (4 g; 9.99 mmol) and NMM (2 g; 18.79 mmol) were added to a stirred solution of (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxacyclohexane-2-carboxylate (4 g; 13.90 mmol) and 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (2.50 g; 6.71 mmol) in dioxane-1,4 (80 mL) at room temperature and under a nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature. For post-treatment, the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 × 40 mL). The combined organic layers were washed with brine (3 × 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to obtain (2S,3R,4S,5S,6S)-6-[(benzyloxy)carbonyl]-3,4,5-trihydroxyoxacyclohexane-2-yl-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (500 mg; 0.70 mmol; 11%), as a yellow solid.

[0934] Triethylamine (0.50 ml; 3.66 mmol) and Pd(AcO)₂ (360 mg; 1.52 mmol) were added to a stirred solution of (2S,3R,4S,5S,6S)-6-[(benzyloxy)carbonyl]-3,4,5-trihydroxyoxacyclohexane-2-yl-2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (500 mg; 0.70 mmol) and tert-butyldimethylsilane (180 mg; 1.47 mmol) in a DCE (3 ml) at room temperature under a nitrogen atmosphere. The mixture was stirred at 60 °C for 2 hours and then filtered. The filter cake was washed with DCM (3 × 5 ml), and the filtrate was concentrated under reduced pressure. The residue was treated with TBAF / THF (1 M) (4 ml) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then acidified to pH 5 with HCl (aqueous solution), extracted with EtOAc (3 × 20 ml), and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give a product (53 mg; 15%) as a white solid.

[0935] Example 31: 2-Methyl-8-(4-methylphenyl)-5-(methylthio)-2H,8H-pyrazolo[3,4-b]indole

[0936] Example 31-1: 2-Methyl-8-(4-methylphenyl)-5-(methylthio)-2H,8H-pyrazolo[3,4-b]indole Synthesis

[0937]

[0938] 4-[2-chloro-5-(methylthio)phenyl]-1-methyl-1H-pyrazole-3-amine (500 mg; 1.9 mmol), 4-bromotoluene (661 mg; 3.9 mmol), and cesium carbonate (1.9 g; 5.8 mmol) were suspended in 1,4-dioxane (30 mL) and washed with argon. XPhos Pd G4 (175 mg; 0.2 mmol) was then added, and the mixture was stirred at 120 °C for two days. XPhos Pd G4 (175 mg; 0.2 mmol) was added again, and the mixture was stirred at 100 °C for two days. The reaction mixture was filtered through diatomaceous earth, and the residue was washed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude product was purified by chromatography. The product (385 mg; 62%) was given as a pale yellow solid.

[0939] Example 32: 7-Methanesulfinyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3- b) Indole

[0940] Example 32-1: 7-Methanesulfinyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4, [3-b] Synthesis of Indole

[0941]

[0942] H₂O₂ (0.11 mL; 30% / water) was added to a solution of 2-methyl-7-(methylthio)-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (400 mg, 0.7 mmol) in AcOH (400 mg) and CHCl₂ (20 mL) at 0 °C. The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. The reaction was quenched by adding water (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give the product (23 mg, 8%) as a white solid.

[0943] Example 33: 7-Methanesulfonyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b] Indole

[0944] Example 33-1: 7-Methanesulfonyl-2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3- b] Synthesis of indole

[0945]

[0946] MCPBA (22 mg, 0.089 mmol) was added to a stirred mixture of 2-methyl-7-(methylthio)-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (20 mg, 0.036 mmol) in DCM (1 mL) at room temperature. The resulting mixture was stirred at room temperature under air for 3 hours. The reaction mixture was diluted with water and washed with 10% aqueous sodium sulfite solution and saturated aqueous sodium bicarbonate solution. After phase separation and extraction of the aqueous phase with DCM, the combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give the product (48 mg, 17%) as a yellow solid.

[0947] Example 34: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-sulfonamide

[0948] Example 34-1: 2-Methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-sulfonyl Amine Synthesis

[0949]

[0950] 2-Methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (1.6 g, 4.8 mmol) was added to stirred HSO3Cl (25 mL) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred at 0 °C under a nitrogen atmosphere for 1 hour. The reaction was quenched by adding water / ice. The resulting mixture was extracted with CH2Cl2 (3 x 100 mL). The combined organic layers were concentrated under reduced pressure. This yielded crude 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonyl chloride (900 mg, 24%) as a yellow solid.

[0951] A mixture of NH3·H2O (3 mL) and THF (3 mL) was added dropwise to the reactant 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonyl chloride (140 mg, 0.18 mmol). The resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the product (47 mg, 68%) as a white solid.

[0952] Example 35: Imino(methyl){2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]} Indol-7-yl}-λ6-thionone

[0953] Example 35-1: Imino(methyl){2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3- Synthesis of indol-7-yl-λ6-thionone

[0954]

[0955] A mixture of 7-methanesulfinyl-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (300 mg, 0.674 mmol), MgO (1.14 g, 27 mmol), Rh2(OAc)4 (9 mg, 0.019 mmol), DIB (347 mg, 1.02 mmol), and BocNH2 (124 mg, 1 mmol) in CH2Cl2 (15 mL) was stirred at 40 °C for 8 hours. The reaction was quenched by adding water (100 mL) at room temperature. The mixture was extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with brine (2 × 100 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give N-[methyl([2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indol-7-yl])oxo-λ6-thionyl]carbamate tert-butyl ester (45 mg, 7%), as a brown solid.

[0956] A mixture of N-[methyl([2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indol-7-yl])oxo-λ6-thionyl]carbamate tert-butyl ester (40 mg, 0.04 mmol) in HCl (g) / MeOH (8 mL) was stirred at room temperature under air for 3 h. The reaction was quenched by adding water (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by HPLC to give the product (10 mg, 65%) as a white solid.

[0957] Example 36: N,N,2-Trimethyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7- sulfonoimidamide

[0958] Example 36-1: N,N,2-Trimethyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole- Synthesis of 7-sulfonylimine amide

[0959]

[0960] NaH (42 mg, 1.1 mmol) was added to a stirred solution of 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonamide (280 mg, 0.68 mmol) in THF (15) under a nitrogen atmosphere at 0 °C. The resulting mixture was stirred for 1 hour at room temperature under a nitrogen atmosphere. TBSCl (141 mg, 0.89 mmol) was added to the mixture in portions at 0 °C. The reaction mixture was stirred for another 2 hours at room temperature and quenched by the addition of saturated NH4Cl (aq.) at 0 °C. The resulting mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give N-(tert-butyldimethylsilyl)-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonamide (150 mg, 42%) as a grayish-white solid.

[0961] In a sealed tube, a solution of PPh3 (200 mg, 0.72 mmol) and CCl3 (181 mg, 0.73 mmol) in CHCl3 (2 mL) was stirred at 70 °C for 6 h under a nitrogen atmosphere. TEA (52 mg, 0.49 mmol) was added dropwise to the mixture at room temperature, and the mixture was stirred again at room temperature for 10 min. N-(tert-butyldimethylsilyl)-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonamide (130 mg, 0.24 mmol) / CHCl3 was added dropwise to the above mixture at 0 °C. The mixture was stirred at 0 °C for 20 min. Then, dimethylamine (35 mg, 0.74 mmol) / THF (0.37 mL) was added dropwise at 0 °C. The resulting mixture was stirred at 0 °C for another 30 min and then stirred overnight at room temperature. After vacuum concentration, the residue was dissolved in ACN (1 mL), and a solution of HCOOH (1 mL) in H2O (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. The residue was purified by silica gel column chromatography to give the product (46 mg, 40%) as a grayish-white solid.

[0962] Table 1

[0963] Table 1 below shows exemplary compounds of the present invention. They have been synthesized by methods as described in or similar to those described in the above embodiments.

[0964]

[0965]

[0966]

[0967]

[0968]

[0969]

[0970]

[0971]

[0972]

[0973]

[0974]

[0975]

[0976]

[0977]

[0978]

[0979]

[0980]

[0981]

[0982]

[0983]

[0984]

[0985]

[0986]

[0987]

[0988]

[0989]

[0990]

[0991]

[0992]

[0993]

[0994]

[0995]

[0996]

[0997]

[0998]

[0999]

[1000]

[1001]

[1002]

[1003]

[1004]

[1005]

[1006]

[1007]

[1008]

[1009]

[1010]

[1011]

[1012]

[1013]

[1014]

[1015]

[1016]

[1017]

[1018]

[1019]

[1020]

[1021]

[1022]

[1023]

[1024]

[1025]

[1026]

[1027]

[1028]

[1029]

[1030]

[1031]

[1032]

[1033]

[1034]

[1035]

[1036]

[1037]

[1038]

[1039]

[1040]

[1041]

[1042]

[1043]

[1044]

[1045]

[1046]

[1047]

[1048]

[1049]

[1050]

[1051]

[1052]

[1053]

[1054]

[1055]

[1056]

[1057]

[1058]

[1059]

[1060]

[1061]

[1062]

[1063]

[1064]

[1065]

[1066]

[1067]

[1068]

[1069]

[1070]

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079]

[1080]

[1081]

[1082]

[1083]

[1084]

[1085]

[1086]

[1087]

[1088]

[1089]

[1090]

[1091]

[1092]

[1093]

[1094]

[1095]

[1096]

[1097]

[1098]

[1099]

[1100]

[1101]

[1102]

[1103]

[1104]

[1105]

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114]

[1115]

[1116]

[1117]

[1118]

[1119]

[1120]

[1121]

[1122]

[1123]

[1124]

[1125]

[1126]

[1127]

[1128]

[1129]

[1130]

[1131]

[1132]

[1133]

[1134]

[1135]

[1136]

[1137]

[1138]

[1139]

[1140]

[1141]

[1142]

[1143]

[1144]

[1145]

[1146]

[1147]

[1148]

[1149]

[1150]

[1151]

[1152]

[1153]

[1154]

[1155]

[1156]

[1157]

[1158]

[1159]

[1160]

[1161]

[1162]

[1163]

[1164]

[1165]

[1166]

[1167]

[1168]

[1169]

[1170]

[1171]

[1172]

[1173]

[1174]

[1175]

[1176]

[1177]

[1178]

[1179]

[1180]

[1181]

[1182]

[1183]

[1184]

[1185]

[1186]

[1187] TFA = Trifluoroacetate

[1188] LC-MS conditions:

[1189] 1 Column: Waters XBridge C18 3.5μm, 50*4.6mm; 5-95%; Flow rate: 1.5mL / min; Analysis time: 6.5min; MS scan range: 100-1000; Mobile phase A: 0.02% NH4OAc / water; Mobile phase B: acetonitrile; Gradient: 0.15min: 5% B, 4.5min: 95% B, 6.0min: 95% B, 6.1min: 5% B, 6.5min: 5% B.

[1190] 2 24-column: Waters XBridge C18 3.5µm, 50*4.6mm; Solvent A: Water + 0.1% TFA; Solvent: ACN; Flow rate: 1.5ml / min; Time: 6.5min; Gradient: 0.15min: 10% B, 4.5min: 80% B, 4.6min: 95% B, 6.0min: 95% B, 6.1min: 5% B, 6.5min: 5% B.

[1191] 3 Column: Waters XBridge C18 3.5μm, 50*4.6mm; 20-70%; Flow rate: 1.5mL / min; Analysis time: 6.5min; MS scan range: 100-1000; Mobile phase A: 0.1% TFA / water; Mobile phase B: acetonitrile; Gradient: 0.15min: 20% B, 4.5min: 70% B, 4.6min: 95% B, 6.0min: 95% B, 6.1min: 5% B, 6.5min: 5% B

[1192] 4Column: Waters XBridge C18 3.5μm, 50*4.6mm; 30-95%; Flow rate: 1.5mL / min; Analysis time: 6.5min; MS scan range: 100-1000; Mobile phase A: 0.1% TFA / water; Mobile phase B: acetonitrile; Gradient: 0.15min: 30% B, 4.5min: 95% B, 4.6min: 95% B, 6.0min: 95% B, 6.1min: 5% B, 6.5min: 5% B

[1193] 5 Column: Waters XBridge C18 5µm, 50*4.6mm; Solvent A: Water + 0.1% TFA; Solvent: ACN; Flow rate: 1.5ml / min; Time: 6.5min; Gradient: 0.15min: 10% B, 4.5min o 80% B£ 4.6min:95%B, 6.0min:95%B, 6.1min:5%B, 6.5min:5%B

[1194] 6 Column: XBridge C18, 3.5μm, 3.0*30mm; Solvent A: Water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; Flow rate: 2ml / min; Gradient: 0min: 5% B, 8min: 100% B, 8.1min: 100% B, 8.5min: 5% B, 10min: 5% B.

[1195] 7 Column: Titank C18 1.8μm, 30*2.1mm; Column oven: 40°C; Mobile phase A: 0.04% NH4OH, Mobile phase B: ACN; Flow rate: 0.8mL / min; Gradient: 10% B to 95% B, 2.1min, hold for 0.6min; 254nm

[1196] 8 Agilent 1200 Series; Chromolith RP-18e 50-4.6 mm; 3.3 ml / min; Solvent A: Water + 0.05% HCOOH; Solvent B: Acetonitrile + 0.04% HCOOH; 220 nm; 0 to 2.0 min: 0% B to 100% B; 2.0 to 2.5 min: 100% B

[1197] 9Column: HALO, 3.0*30mm, 2µm; Column oven: 40℃; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.5mL / min; Gradient: 5% B to 100% B, 1.2min, hold for 0.5min

[1198] 10 Column: HALO C18, 3.0*30mm, 2.0µm; Column oven: 40℃; Mobile phase A: Water / 0.1% FA; Mobile phase B: Acetonitrile / 0.1% FA; Flow rate: 1.5mL / min; Gradient: 5% B to 100% B, 1.2min, hold for 0.6min

[1199] 11 Column: Shim-pack XR-ODS, 3.0*50mm, 2.2um; Mobile phase A: Water / 0.05% TFA, Mobile phase B: ACN / 0.05% TFA; Flow rate: 1.2mL / min; Gradient: 5% B to 100% B, 2.0min, hold for 0.7min.

[1200] 12 Column: HALO C18, 3.0*30mm, 2.0µm; Column oven: 40℃; Mobile phase A: Water / 0.1% FA, Mobile phase B: Acetonitrile / 0.1% TFA; Flow rate: 1.5mL / min; Gradient: 5% B to 100% B, 1.2min, hold for 0.5min; 254nm

[1201] 13 Column: Chromolith RP-18e 50-4,6mm; A:H2O+0,05% HCOOH|B:MeCN+0,04%HCOOH / 4%->100% B:0->2,8min|100% B:2,8->3,3min

[1202] 14 Waters Acquity UPLC; A:H2O+0,05% HCOOH|B:MeCN+0,04% HCOOH+1% H2OT:40℃|Flow rate: 0,9ml / min|Column: Kinetex EVO-C18 1,7μm 50-2,1mm 1%->99% B:0->1,0min|99% B:1,0->1,3min

[1203] 15Column: Poroshell HPH-C18 2.7µm, 3.0*50mm; Column oven: 40℃; Mobile phase A: Water / 5mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.2mL / min; Gradient: 10% B to 95% B, 2.1min, hold for 0.6min; 254nm

[1204] 16 Column: Kinetex EVO 2.6µm, 3.0*50mm; Column oven: 40℃; Mobile phase A: Water / 5mM NH4HCO3, Mobile phase B: Acetonitrile; Flow rate: 1.2mL / min; Gradient: 10% B to 95% B, 2.1min, hold for 0.6min; 254nm

[1205] 17 column: EVO C18 5.0μm 50-4.6mm; A: H2O + 0.05% HCOOH; B: MeCN + 0.04% HCOOH + 1% H2O; 1%->99% B: 0->0.8min; 99% B: 0.8->1.1min; T: 40℃; Flow rate: 3.3mL / min; MS: 61-1000 amu

[1206] 18 Kinetex EVO C18 5.0μm 50-4.6mm; A:H2O+0.1% TFA B:MeCN+0.1% TFA; 1%->99% B:0->1.8min; 99% B:1.8->2.1min; T:40℃; Flow rate: 3.3mL / min; MS: 61-1000amu positive

[1207] A: Column: Waters Cortecs C18 2.1*50mm, 1.6 μm particle size, column oven 45℃; Mobile phase A: Water / 0.1% FA, Mobile phase B: Acetonitrile / 0.1% FA; Flow rate: 0.8 mL / min; Gradient: 5% B to 95% B, 3 min, hold for 0.8 min, 254 nm

[1208] B: Column: Waters Xbridge C18 4.6*50mm, 5.0 μm particle size, column oven at room temperature; Mobile phase A: Water / 0.1% ammonium hydroxide, Mobile phase B: Acetonitrile / 0.1% ammonium hydroxide; Flow rate: 1.5 mL / min; Gradient: 5% B to 95% B, 5.5 min, hold for 1 min, 254 nm

[1209] Chiral HPLC / SFC:

[1210] aSFC; Column: ChiralPak IC; Eluent: CO2:ethanol (55:45); Wavelength: 220nm; Flow rate: 5mL / min.

[1211] b SFC: Column: YMC Cellulose-SC, Eluent CO2: Methanol 65:35, Wavelength 254 nm, Flow rate: 5 mL / min.

[1212] c SFC: Column: Lux Cellulose-2, eluent CO2:methanol 65:35, wavelength 270nm, flow rate: 5ml / min.

[1213] The melting points of the selected compounds in Table 1 were determined using a Tianjin Analytical Instrument RY-1 melting point detector, as shown in Table 1a below:

[1214] Table 1a

[1215]

[1216]

[1217] Table 1b

[1218] Table 1b below shows other exemplary compounds of the present invention. They can be synthesized by modifying the methods and procedures described in the above examples. LC-MS and chiral HPLC / SFC conditions are as defined above in Table 1.

[1219]

[1220]

[1221]

[1222]

[1223]

[1224]

[1225]

[1226]

[1227]

[1228]

[1229]

[1230]

[1231]

[1232]

[1233]

[1234]

[1235]

[1236]

[1237]

[1238]

[1239]

[1240]

[1241]

[1242]

[1243]

[1244]

[1245]

[1246]

[1247]

[1248]

[1249]

[1250]

[1251]

[1252]

[1253]

[1254]

[1255]

[1256]

[1257]

[1258]

[1259]

[1260]

[1261]

[1262]

[1263]

[1264]

[1265]

[1266]

[1267]

[1268]

[1269]

[1270]

[1271]

[1272]

[1273]

[1274]

[1275]

[1276]

[1277]

[1278]

[1279] Bioactivity

[1280] SK-HEP-1 reporter gene testing

[1281] To identify inhibitors of YAP-TEAD interaction, drive The 8x TEAD response element of the luciferase gene was stably integrated into SK-HEP-1 cells (ECACC#:91091816).

[1282] For this assay, cells were treated with the test compound in duplicate at 10-point doses, starting with a maximum concentration of 30 μM (the final concentration in the assay). After culturing for 24 hours at 37°C, 95% rH, and 5% CO2, the luciferase substrate / lysis reagent mixture (NanoGlo) was added. TM Promega was added to cells to quantify cytoluciferase activity.

[1283] Cell culture medium: Cells were cultured in the following medium: MEM, +10% FBS, +1x GlutaMAX, +1mM sodium pyruvate, +100μM non-essential amino acids, +0.1mg / ml hygromycin. The medium used for assays was: MEM (w / o phenol red), +10% FBS, +1x GlutaMAX, +1mM sodium pyruvate, +100μM non-essential amino acids, +0.5% Pen / Strep.

[1284] Reagents: The reagents used are as follows:

[1285]

[1286]

[1287] Cell culture: Cells were examined using an inverted microscope to assess health and cell density. To separate adherent cells, the monolayer was washed once with preheated PBS. After removing the PBS, 3 ml of preheated PBS was added... Add to the F75 flask, distribute evenly, and place the flask in the incubator for about 4-5 minutes.

[1288] Once a single-cell suspension is obtained, add 7 ml of preheated growth medium and resuspend the cells. Transfer the cell suspension to a sterile 15 ml conical centrifuge tube and centrifuge at 300 x g, RT for 5 minutes. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[1289] Determine the total cell count and add 20 μl of the desired cell count to each well of a 384-well plate using Multidrop Combi. The plate is then incubated at 37°C, 95% RH, and 5% CO2 for 24 hours.

[1290] Compound treatment: 24 hours after inoculation, the cells were treated with the compound.

[1291] Prepare a 1:333 dilution of the compound in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer the compound to the assay plate, 120 nmol was injected from a Labcyte low dead volume plate into a cell plate containing 20 μl of culture medium per well using an ECHO 555 liquid handling system. After treatment, 20 μl of freshly preheated assay medium was added to the cells using a Multidrop combi.

[1292] The assay plate was then incubated for another 24 hours at 37°C, 95% rH and 5% CO2.

[1293] Luciferase reading: 24 hours after treatment, remove the plate from the incubator and allow it to equilibrate to room temperature. In the dark, add 30 μl of... Add reagents to the plate. Shake the plate in the dark on a Teleshake (~1500 rpm) for 20 minutes. Then measure the luminescence using an EnVision microplate reader. (Genedata) Generate IC50 value.

[1294] Viability assays of NCI-H226 (Yap-dependent) and SW620 Yap KO (Yap-independent) cells

[1295] The ability of the YAP-TEAD inhibitor to suppress tumor cell growth was evaluated using two different cell lines: NCI-H226, a YAP-dependent cell line, and SW620 cells, in which YAP and TAZ were knocked out using CRISPR to generate a YAP-independent cell line.

[1296] For this assay, cells were treated with the test compound at 10-point doses, diluted 1:3 in duplicate, starting with a maximum concentration of 30 μM (the final concentration in the assay). After culturing for 96 hours at 37°C, 95% rH, and 5% CO2, the cell-permeable DNA of healthy cells was stained only with the dye. Promega is added to cells to quantify cell viability.

[1297] Cell culture medium: NCI-H226 cells were cultured in the following medium: RPMI 1640, +10% FBS, +1x GlutaMAX, +10mM HEPES, +0.5% Pen / Strep. SW620-KO cells were cultured in the following medium: DMEM / F-12, +10% FBS, +1x GlutaMAX, +10mM HEPES, +0.5% Pen / Strep.

[1298] Reagents: The reagents used are as follows:

[1299]

[1300] Cell culture: Use an inverted microscope to examine the cells to check their health status, cell density, etc. To separate the adherent cells, wash the monolayer of cells once with preheated PBS. After removing the PBS, add 3 ml of preheated Accutase to the F75 flask, disperse it evenly, and incubate the flask in an incubator for about 4-5 minutes.

[1301] Once a single-cell suspension is obtained, add 7 ml of preheated growth medium and resuspend the cells. Transfer the cell suspension to a sterile 15 ml conical centrifuge tube and centrifuge at 300 x g, RT for 5 minutes. Discard the supernatant and resuspend the pellet in 10 ml of preheated growth medium.

[1302] Determine the total cell count and add 20 μl of the desired cell count to each well of a 384-well plate using Multidrop Combi. The plate is then incubated at 37°C, 95% RH, and 5% CO2 for 24 hours.

[1303] Compound treatment: 24 hours after inoculation, the cells were treated with the compound.

[1304] Prepare a 1:333 dilution of the compound in DMSO to obtain a final concentration of 0.3% DMSO per well. To transfer the compound to the assay plate, 120 nmol was injected from a Labcyte low dead volume plate into a cell plate containing 20 μl of culture medium per well using an ECHO 555 liquid handling system. After treatment, 20 μl of freshly preheated assay medium was added to the cells using a Multidrop combi.

[1305] The assay plate was then incubated at 37°C, 95% rH and 5% CO2 for 96 hours.

[1306] Measurement

[1307] 96 hours after treatment, 30 μl of the solution was extracted using a Multidrop combi in the dark. Reagents were added to the assay plate. The plate was then incubated at 37°C, 95% rH, and 5% CO2 for 1 hour. Afterward, the assay plate was removed from the incubator and allowed to equilibrate to room temperature uncovered in the dark for 30 minutes. Finally, measurements were performed using an EnVision microplate reader with a FITC bottom readout program.

[1308] The experimental data for the SK-HEP-1 reporter gene assay of the compounds shown in Table 1 are shown in Table 2 below, and are divided into the following groups:

[1309]

[1310] The experimental data for the activity determination of the compounds shown in Table 1 are shown in Table 2 below, and are divided into the following groups:

[1311] for NCI-H226 Cell viability assay:

[1312]

[1313]

[1314] for SW620 Yap KO cells Viability determination in:

[1315]

[1316] ND = Cannot be determined across the entire range

[1317] Table 2

[1318]

[1319]

[1320]

[1321]

[1322]

[1323]

[1324]

[1325]

[1326]

[1327]

[1328]

[1329]

[1330]

[1331]

[1332]

[1333]

[1334]

[1335]

[1336]

[1337]

[1338]

[1339]

[1340] In vivo efficacy study of NCI-H226

[1341] 7-9 week old female H2d Rag2 mice (self-bred, Taconic-Denmark) were subcutaneously inoculated with 5 x 10^6 NCI-H226 human dermatoma tumor cells on the right side. Tumor growth and body weight were measured twice weekly using calipers. Tumor volume was calculated using the formula TV = L x W x W / 2.

[1342] When the tumor volume reaches approximately 75-150 mm 3 Animals were randomly assigned (day 0) to treatment groups (n = 9-10 / group) and treated orally for 29 days with either a carrier (20% hydroxypropyl β-cyclodextrin in 50 mM PBS pH 7.4) or compound 2 once daily (qd). Compound 2 was tested at dose levels of 1, 3, 10, 30, and 100 mg / kg. Results were obtained in... Figure 1 (Relationship between tumor growth and time in the carrier group and each dose group) and Figure 2 (Final tumor volume of the carrier group and each dose group) is described in (the final tumor volume of each dose group).

[1343] Compared with the carrier therapy group, significant tumor growth inhibition was achieved at all tested dose levels. Figure 1 -Curves b and c (p-value < 0.001) show the maximum inhibition at dose levels > 10 mg / kg. Statistical analysis of tumor volume between treatment groups was performed using repeated measures covariance analysis (RM-ANCOVA) in a linear mixed-effects model, followed by least-squares means pairwise comparisons.

[1344] The animal experiments were conducted in accordance with German animal welfare laws and the EU Directive on Laboratory Animals in the field of animal experiments.

[1345] The following examples involve drugs.

[1346] Example A: Injection vial

[1347] The solution of 100g of the active ingredient of formula I or IA with 5g of disodium hydrogen phosphate in 3 liters of double-distilled water was adjusted to pH 6.5 using 2N hydrochloric acid, aseptically filtered, transferred to injection vials, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each injection vial contains 5mg of the active ingredient.

[1348] Example B: Suppositories

[1349] Melt 20g of the active ingredient of formula I or IA with a mixture of 100g of soy lecithin and 1400g of cocoa butter, pour the mixture into a mold and cool. Each suppository contains 20mg of the active ingredient.

[1350] Example C: Solution

[1351] A solution was prepared from 1 g of the active ingredient of formula I or IA, 9.38 g of NaH2PO4·2H2O, 28.48 g of Na2HPO4·12H2O, and 0.1 g of benzalkonium chloride in 940 mL of double-distilled water. The pH was adjusted to 6.8, the solution was brought to a final volume of 1 liter, and the solution was sterilized by irradiation. This solution can be used as eye drops.

[1352] Example D: Ointment

[1353] Under aseptic conditions, 500 mg of the active ingredient of formula I or IA is mixed with 99.5 g of petrolatum.

[1354] Example E: Tablets

[1355] A mixture of 1 kg of active ingredient of formula I or IA, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and 0.1 kg of magnesium stearate is compressed in a conventional manner to obtain tablets, such that each tablet contains 10 mg of active ingredient.

[1356] Example F: Sugar-coated pills

[1357] Similar to Example E, the tablets were compressed and then coated in a conventional manner with a coating material consisting of sucrose, potato starch, talc, tragacanth gum, and dye.

[1358] Example G: Capsules

[1359] 2 kg of the active ingredient of Formula I or IA is introduced into hard gelatin capsules in a conventional manner, so that each capsule contains 20 mg of the active ingredient.

[1360] Example H: Ampoule

[1361] The solution of 1 kg of the active ingredient of Formula I or IA in 60 liters of double-distilled water is aseptically filtered, transferred to ampoules, lyophilized under aseptic conditions, and sealed under aseptic conditions. Each ampoule contains 10 mg of the active ingredient.

Claims

1. A compound of formula I-A, wherein Ring A is wherein R A1 represents H, C 1-3 -alkyl, -CH2-CN; R A2 represents H; Z 1 is CR Z1 ; Z 2 is CR Z2 ; Z 3 is CR Z3 ; R 1 selected from R 2 represents -C(=O)-OR 2a ; R 2a represents H, C 1-4 - alkyl or Cat; Cat represents a monovalent cation selected from lithium (Li), sodium (Na) and potassium (K); or R 2 represents S(=O)-R 2f , -S(=O)2-R 2g , -S(=O)2-NR 2h R 2i , -S(=O)(=NR 2j )-R 2g , -(CH2) z -NR 2d -S(=O)2-R 2g , -C(=O)-N=S(=O)-R 2s R 2t ; R 2f , R 2g independently of one another represent C 1-4 -alkyl or C 2-4 -alkenyl: R 2h , R 2i independently of one another represent H or C 1-4 -alkyl; R 2d , R 2j , R 2k independently represent H, methyl; R 2l , R 2m independently represent C 1-4 -alkyl; R 2s , R 2t independently represent a methyl group, an ethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group; R 2u represents hydrogen or C 1-4 - alkyl; z is 0 or 1 ; or R 2 represents -C(=O)-NR 2b R 2c , and (a) R 2b represents hydrogen, R 2c represents hydrogen; linear or branched C 1-8 - alkyl, which can be unsubstituted or substituted by R E1 , R E2 , R E3 , R E4 and / or R E5 ; Cyc 2 , wherein R E1 , R E2 , R E3 , R E4 and / or R E5 independently of one another represent F; -NR Ea R Eb , -OH, OR Ec , Ar E , Hetar E ; Ar E It is phenyl or naphthyl; Hetar E is a monocyclic heteroaryl selected from the group consisting of 1 H-imidazol-1 -yl, which is unsubstituted or monosubstituted by C 1-4 -alkyl; pyridinyl, which is unsubstituted; pyrimidinyl; pyrazinyl; R Ea , R Eb both represent H or one represents H and the other represents C(=O)-O-tert-butyl; R Ec represents H or methyl; Cyc 2 is cyclopropyl or 1-hydroxymethyl-cyclobutyl; or (b) R 2b and R 2c together with the nitrogen atom to which they are attached form 3-hydroxypyrrolidinyl or 2-methyl-3-hydroxypyrrolidinyl; R Z1 represents H; R Z2 represents H; R Z3 represents H; or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing.

2. The compound according to claim 1 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, wherein Ring A represents a five-membered heteroaromatic ring selected from the following ring moieties as defined in claim 1 : A-4； R A1 represents C 1-3 -alkyl, -CH2-CN; R A2 represents H.

3. The compound according to claim 1 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, wherein R 2 represents -C(=O)-OR 2a ; R 2a represents H, methyl, ethyl or Cat; Cat represents sodium (Na); or wherein R 2 represents S(=O)-R 2f , -S(=O)2-R 2g , -S(=O)2-NR 2h R 2i , -S(=O)(=NR 2j )-R 2g , -(CH2) z -NR 2d -S(=O)2-R 2g , -C(=O)-N=S(=O)-R 2s R 2t ; R 2f , R 2g independently of one another represent C 1-4 -alkyl or C 2-4 -alkenyl: R 2h , R 2i independently of one another represent H or C 1-4 -alkyl; R 2d , R 2j , R 2k independently represent H, methyl; R 2l , R 2m independently represent C 1-4 -alkyl; R 2s , R 2t independently represent a methyl group, an ethyl group, a 2-hydroxyethyl group, a 3-hydroxypropyl group; R 2u represents hydrogen or C 1-4 - alkyl; z is 0 or 1.

4. The compound according to claim 1 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, wherein R 2 represents -C(=O)-NR 2b R 2c ; and (a) R 2b represents hydrogen, R 2c represents hydrogen; linear or branched C 1-8 - alkyl, which can be unsubstituted or substituted by R E1 , R E2 , R E3 , R E4 and / or R E5 ; Cyc 2 , wherein R E1 , R E2 , R E3 , R E4 and / or R E5 independently of one another represent F; -NR Ea R Eb , -OH, OR Ec , Ar E , Hetar E ; Ar E It is phenyl or naphthyl; Hetar E is a monocyclic heteroaryl selected from the group consisting of 1 H-imidazol-1 -yl, which is unsubstituted or monosubstituted by C 1-4 -alkyl; pyridinyl, which is unsubstituted; pyrimidinyl; pyrazinyl; R Ea , R Eb both represent H or one represents H and the other represents C(=O)-O-tert-butyl; R Ec represents H or methyl; Cyc 2 is cyclopropyl or 1-hydroxymethyl-cyclobutyl; or (b) R 2b and R 2c form, together with the nitrogen atom to which they are attached, a 3-hydroxypyrrolidinyl or a 2-methyl-3-hydroxypyrrolidinyl.

5. The compound according to any one of claims 1 to 4 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, wherein Ring A represents a five-membered heteroaromatic ring selected from the following ring moieties: Z 1 is CH; Z 2 is CH; Z 3 is CH; R 1 represents 4-difluoromethylphenyl, 4-trifluoromethylphenyl, 4- difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 4- (trifluoromethyl)thiophenyl, 5-trifluoromethylthien-2-yl, 6- trifluoromethylpyridin-3-yl, 6-trifluoromethoxypyridin-3-yl, 4- methylcyclohexyl; and R 2 represents -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH3, -C(=O)-NH2, -C(=O)-NHCH3, -C(=O)-NHCH2CH3, -C(=O)-NH(CH2)2CH3, -C(=O)-N(H)-cyclopropyl, -C(=O)-N(H)-(1-hydroxymethyl)cyclobutane-1-yl, -C(=O)-N(H)-CH2CH2-OH, -C(=O)-N(H)-CH2CH2-OCH3, -C(=O)-N(H)-CH2-C(H)(OH)-CH3, -C(=O)-N(H)-CH2C(CH3)2OH, -C(=O)-N(H)-C(H)(CH3)-CH2OH, -C(=O)-N(H)-C(H)(CH2CH3)-CH2OH, -C(=O)-N(H)-C(H)(CH2OH)-CH2CH2-O-CH3, -C(=O)-N(H)-C(CH3)2CH2CH2OH, -C(=O)-N(H)-C(H)(CH2OH)-phenyl, -C(=O)-N(H)-C(CH3)(CH2OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH3)-phenyl, -C(=O)-N(H)-CH2-1H—1-methylimidazol-2-yl, -C(=O)-N(H)-(CH2)2-1H-imidazol-1-yl, -C(=O)-N(H)-CH2-pyridin-2-yl, -C(=O)-N(H)-CH2-pyridin-3-yl, -C(=O)-N(H)-CH2-pyridin-4-yl, -C(=O)-N(H)-C(H)(CH2OH)-pyridin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH2-1,3-pyrimidin-4-yl, -C(=O)-N(H)-CH2-pyridazin-2-yl, -C(=O)-NH-C(CH2OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -S(=O)-CH3, -S(=O)2-CH3, -S(=O)2-NH2, -S(=O)2-NHCH3, -S(=O)(=NH)-CH3.

6. The compound according to any one of claims 1 to 4 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, wherein R 1 is 4-trifluoromethylphenyl.

7. The compound according to any one of claims 1 to 4 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing, wherein Hetar E is a monocyclic heteroaryl selected from the group consisting of pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, each of which is unsubstituted; pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; pyrazin-2-yl.

8. A compound selected from Table 1 and Table 1b or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing. Table 1 Table 1b 9. Use of a compound according to any one of claims 1 to 8 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing for the manufacture of a medicament for the prevention and / or treatment of a medical condition or disease affected by the inhibition of the YAP-TEAD and / or TAZ-TEAD interaction, wherein the medical condition or disease is selected from the group consisting of tumors, including solid tumors of breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, kidney cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer; cardiovascular diseases and fibrosis.

10. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 8 or any stereoisomer thereof and / or any pharmaceutically acceptable salt of each of the foregoing as active ingredient, together with a pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, further comprising a second active ingredient or a pharmaceutically acceptable salt of any stereoisomer thereof and / or each of the foregoing, wherein the second active ingredient is not a compound of formula I-A as defined in any one of claims 1 to 7.

12. Process for the preparation of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt of any stereoisomer thereof and / or each of the foregoing, characterized in that (a) a compound of formula II-A-a wherein Z 1 , Z 2 , Z 3 , ring A and R 2 as defined for the compound of formula I-A in any one of claims 1 to 7, wherein R 2 is not -C(=0)-OH or -C(=0)-OCat; (a)(1) is converted to a tricyclic compound of formula IV-A R 1 -Hal III, wherein R 1 as defined for the compounds of formula I-A in any one of claims 1 to 7 and Hal represents Cl, Br or I, a C-N cross coupling reaction under suitable reaction conditions; or (a)(2) is first converted to a tricyclic compound of formula IV-A in a C-N cross-coupling reaction under suitable reaction conditions. under suitable reaction conditions in another C-N cross-coupling reaction with a compound of formula III R 1 -Hal III; Provided is (a)(3) a compound of formula I-A as defined in any one of claims 1-7; or (b) a compound of formula II-A-b wherein Z 1 , Z 2 , Z 3 , ring A and R 2 as defined for the compound of formula I-A in any one of claims 1 to 7, wherein R 2 is not -C(=0)-OH or -C(=0)-OCat; (b)(1) with a compound of formula V R 1 -NH2 Ⅴ, wherein R 1 as defined for the compound of formula I-A in any one of claims 1 to 7, under suitable reaction conditions to occur a C-N cross-coupling reaction to provide a compound of formula I-A as defined in any one of claims 1-7.

13. The method of claim 12, wherein in (a) the compound of formula I-A, wherein R 2 is -C(=0)-OR 2a and R 2a is C 1-4 -alkyl is subjected to a saponification reaction under suitable conditions to obtain the corresponding compound of formula I-A, wherein R 2 is -C(=0)-OH or -C(=0)-OCat.

14. The method of claim 12, wherein in (b), R 2 is -C(=O)-OR 2a and R 2a is C 1-4 -alkyl is subjected to a saponification reaction under suitable conditions to provide the corresponding R 2 is -C(=O)-OH or -C(=O)-OCat.

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