KR20230022861A - Tricyclic heterocycles useful as TEAD binders - Google Patents

Abstract

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

Description

Tricyclic heterocycles useful as TEAD binders

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

Recently, the Hippo pathway has been of interest for the treatment of hyperproliferative disorders and diseases, especially cancer (S.　A.　Smith et al., J. Med. Chem. 2019, 62, 1291-1305; K.　C .　Lin et al., Annu. Rev. Cancer Biol. 2018, 2: 59-79; C.-L. 　Kim et al., Cells (2019), 8, 468; K. Reviews 　Cancer, Vol.　13, 246-257 (2013)). The Hippo pathway regulates cell growth, proliferation and migration. In mammals, the Hippo pathway acts as a tumor suppressor, and it is assumed that dysfunction of Hippo signaling is frequently observed in human cancers.

In addition, since the Hippo pathway plays a role in several biological processes - eg, self-renewal and differentiation of stem and progenitor cells, wound healing and tissue regeneration, interaction 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; K. F. Harvey et al., Nature Reviews Cancer, Vol. 13, 246-257 (2013).

Several aspects of pathway activity and regulation are still the subject of further investigation, but in its “switch-on” state, the Hippo pathway binds two transcriptional co-activators in the cytoplasm, YAP (Yes-associated protein) and TAZ (PDZ). It has already been established that it is involved in a series of kinases (including Mst 1/2 and Lats 1/2) that result in the phosphorylation of transcriptional co-activators with a motif. Phosphorylation of YAP/TAZ results in their sequestration in the cytosol and ultimately their degradation. Conversely, when the Hippo pathway is “switched off” or dysfunctional, non-phosphorylated, activated YAP/TAZ co-activators translocate into the cell nucleus. Their main target transcription factors are four proteins of the transcription enhancing association domain (TEAD) family of transcription factors (TEAD1-4). Binding and activation of YAP or TAZ to TEAD (or other transcription factors) has been shown to induce the expression of a number of genes that mediate cell survival and proliferation. Thus, activated, non-phosphorylated YAP and TAZ can act as oncogenes, whereas activated, switch-on Hippo pathway can act as a tumor suppressor by inactivating, ie phosphorylating, YAP and TAZ.

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

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

Thus, inhibition of YAP, TAZ, TEAD, and YAP-TEAD or TAZ-TEAD protein-protein interactions by pharmacological intervention prevents and/or treats cancer and other hyperproliferative disorders and diseases associated with dysfunction of the Hippo pathway. It appears to be a reasonable and worthwhile strategy for

The present invention provides compounds useful for the prevention and/or treatment of medical conditions, disorders and/or diseases, particularly hyperproliferative disorders or diseases, wherein the compounds are TEAD binding agents and/or YAP-TEAD or TAZ-TEAD protein-protein interactions. It is an inhibitor of action.

The present invention relates in one embodiment to a compound of formula I-A

during the ceremony,

ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

during the ceremony,

R ^A1 represents H, D, C _1-6 -aliphatic, -CH ₂ -Ar ^A1 or -CH ₂ -CH ₂ -Ar ^A1 ;

R ^A2 represents H, D, halogen, C _1-6 -aliphatic, -CH ₂ -Ar ^A2 or -CH ₂ -CH ₂ -Ar ^A2 ;

R ^A3 represents H, D, C _1-6 -aliphatic, -CH ₂ -Ar ^A3 or -CH ₂ -CH ₂ -Ar ^A3 ;

Z ¹ is CR ^Z1 or N;

Z ² is CR ^Z2 or N;

Z ³ is CR ^Z3 or N;

at least two of Z ¹ , Z ² and Z ³ are not N;

R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , unsubstituted or substituted, straight chain or branched C _1-8 -represents an aliphatic;

R ² is -C(=O)-OR ^2a , -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _w -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _x - NR ^2d -C(=O)-R ^2e , -SR ^2f , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S(=O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , -S(=O)(=NR ^2k ) -NR ^2l R ^2m , F, Cl, Br, I, -CN, -(CH ₂ ) _v -CN, -P(=0)(OR ^2o )(OR ^2p ), -(CH ₂ ) _y -NR ^2q R ^2r , -(CH ₂ ) _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 ;

Ar ^A1 , Ar ^A2 , Ar ^A3 independently of each other represent unsubstituted or independently of each other phenyl which may be mono- or di-substituted with R ^A11 and/or R ^A12 ;

R ^Z1 represents H or halogen;

R ^Z2 represents H or halogen; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-;

R ^Z3 represents H or halogen;

R ^2a represents H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or a radical derived from a carbohydrate, or Cat ;

Cat represents a monovalent cation;

R ^2b , R ^2c , R ^2q , R ^2r independently represent H, unsubstituted or substituted C _1-8 -aliphatic, including C _3-7 -alicyclic; or

together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms; wherein said heterocycle may optionally be fused with Hetar ^Z ; or

one of R ^2b and R ^2c represents -CN, -NH ₂ , -OH, -OC _1-6 -alkyl, -S(=O) ₂ -R ^2g , Ar ² , Hetar ² , Cyc ² or Hetcyc ² while others represent H or unsubstituted or substituted C _1-8 -aliphatic;

R ^2d , R ^2j , R ^2k , R ^2o , R ^2p independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic;

R ^2e represents H, halogen, unsubstituted or substituted C _1-8 -aliphatic, heteroaryl;

R ^2f and R ^2g independently represent unsubstituted or substituted C _1-8 -aliphatic;

R ^2h , R ²ⁱ independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;

R ^2l , R ^2m independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;

R ^2s and R ^2t independently represent unsubstituted or substituted C _1-8 -aliphatic; or together form an unsubstituted or substituted divalent C _3-6 -alkylene radical;

R ^2u represents hydrogen or unsubstituted or substituted C _1-6 -aliphatic;

Ar ¹ is a mono-, bi-, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryls may be unsubstituted and may be the same or different; may be substituted with substituents R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;

Hetar ¹ is a mono-, bi- or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, wherein 1, 2, 3, 4, 5 are heteroatom(s) selected from N, O and/or S and the remainder are carbon atoms, heteroaryls are unsubstituted or substituents R ^B1 , R ^B2 , R ^B3 , R which may be the same or different ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;

Cyc ¹ is a saturated or partially unsaturated, mono-, bi- or tricyclic carboxyl having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms a bocycle, wherein the carbocycle may be unsubstituted or substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 R ^B12 and/or R ^B13 which may be the same or different; wherein a carbocycle may optionally be fused to Ar ^X via two adjacent ring atoms of said Ar ^X , and the fused carbocycle may further be unsubstituted or R ^C1 , R ^C2 , R ^C3 which may be identical or different. , R ^C4 , R ^C5 , R ^C6 ;

Hetcyc ¹ is a saturated or partially unsaturated, mono-, bi- 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, 5 of the ring atoms are heteroatom(s) selected from N, O and/or S and the others are carbon atoms, and the heterocycles may be unsubstituted or the same or different. may be substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 and/or R ^B13 ;

L ¹ is from the group consisting of -S(=0) ₂ -, -C(=0)-, unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene is a selected divalent radical, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-;

L ² is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene, in both of which the alkylene or alkenylene chain is One of the carbon units may be replaced by -O-;

R ^A11 , R ^A12 independently of each other represent halogen or unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic;

R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 , R ^B7 independently of each other are unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic, C _1-6 -aliphatoxy , -SC _1-6 -aliphatic; Halogen, -CN, -S(=O)-R ^b1 , S(=O) ₂ -R ^b1 , -NR ^b2 NR ^b3 , Ar ² , -CH ₂ -Ar ² , Hetar ² , Cyc ² , Hetcyc ² indicate;

and/or two adjacent R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 together form a divalent -C _2-4 -alkylene radical, wherein one of the alkylene carbon units is forms a carbonyl unit (which may be replaced by -C(=O)-), or a divalent -OC _1-3 -alkylene radical or a divalent -OC _1-3 -alkylene-O- radical;

R ^b1 represents unsubstituted or substituted C _1-8 -aliphatic;

R ^b2 , R ^b3 independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or

together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms;

R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 independently of each other represent halogen, unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, Ar ^Y ; and/or

two of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=0) group; and/or

2 of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , ^{R B13} or 4 of R ^B8 , R B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same sulfur atom of the heterocycle Dog forms a divalent oxo (=O) group to form a -S(=O)- or -S(=O) ₂ - moiety;

Ar ² is a mono- or bicyclic aryl having 5, 6, 7, 8, 9 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 ;

Hetar ² is a mono- or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are N, O and/or or heteroatom(s) selected from S, the remainder being carbon atoms, and the heteroaryl may be unsubstituted or substituted by substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 which may be identical or different. there is;

Cyc ² is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 ; wherein the carbocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused carbocycle may further be unsubstituted or R ^C1 which may be identical or different. , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;

Hetcyc ² is a saturated or partially unsaturated, monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein 1 or 2 of said ring atoms are selected from N, O and/or S and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 which may be the same or different; wherein the heterocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused heterocycle may further be unsubstituted or may be the same or different R ^C1 , R may be substituted with ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;

Ar ^X and Ar ^Z are each independently an unsubstituted or substituted benzo ring;

Ar ^Y is unsubstituted or mono- or di-substituted phenyl;

Hetar ^Y1 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH;

Hetar ^Z is a beach selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran a cyclic or substituted 5 or 6-membered heteroaryl ring;

Cyc ^Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by halogen, OH, C _1-4 -alkyl there is;

Hetcyc ^X 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 said ring atoms are N, O and/or heteroatom(s) selected from S, the remainder being carbon atoms, wherein the heterocycles may be unsubstituted or the same or different, R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , may be substituted with R ^X7 and/or R ^X8 , wherein the heterocycle is optionally a carboxylic acid bioisoster;

Hetcyc ^Y is a saturated, partially unsaturated or aromatic, monocyclic heterocycle having 3, 4, 5, 6 or 7 ring atoms, wherein 1, 2, 3 or 4 of said ring atoms are N, O and/or heteroatom(s) selected from S and the others being carbon atoms;

Hetcyc ^Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom;

R ^C1 , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;

R ^D1 , R ^D2 , R ^D3 , R ^D4 , R ^D5 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;

R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 independently of each other are unsubstituted or substituted C _1-6 -aliphatic, unsubstituted or substituted C _1-6 -alifatoxy, halogen, hydroxy ; Hetar ^Y1 , CH ₂ -Hetar ^Y1 , Cyc ^Y1 , Hetcyc ^Y1 , -CH ₂ -Hetcyc ^Y1 ; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to the same ring atom of said carbocycle or heterocycle may form a divalent C _2-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of the alkylene radical may optionally independently of each other be replaced by O, NH, or NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _1-4 -alkyl; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to different ring atoms of said carbocycle or heterocycle may form a divalent C _1-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of said alkylene radical may optionally, independently of each other be replaced by O, NH, or NC _1-4 -alkyl;

R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 are independently of each other unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, halogen , -OH, -NR ^2d -S(=0) ₂ -R ^2g , Hetcyc ^Y , O-Hetcyc ^Y ; and/or

two of R ^X1 , R ^X2 , R ^X3 , R ^X4 , R X5 , R ^X6 , ^{R X7 ,} R ^X8 attached to the same carbon atom of the heterocycle form a divalent oxo (=0) group; and/or two of R ^X1 , R ^X2 , R ^X3 , R X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 attached to ^the same sulfur atom of said heterocycle or R ^X1 , R ^X2 , R ^X3 , R ^{four of X4} , R ^X5 , R ^X6 , R ^X7 , R ^X8 form a divalent oxo (=0) group to form an -S(=0)- or -S(=0) ₂ - moiety;

halogen is F, Cl, Br, I;

v is 1 or 2;

w is 1 or 2;

x is 0, 1 or 2;

y is 0, 1 or 2;

z is 0, 1 or 2;

or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio.

In a further embodiment the present invention relates to a compound of formula I

during the ceremony,

ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

during the ceremony,

R ^A1 represents H, C _1-6 -aliphatic, -CH ₂ -Ar ^A1 or -CH ₂ -CH ₂ -Ar ^A1 ;

R ^A2 represents H, halogen, C _1-6 -aliphatic, -CH ₂ -Ar ^A2 or -CH ₂ -CH ₂ -Ar ^A2 ;

R ^A3 represents H, C _1-6 -aliphatic, -CH ₂ -Ar ^A3 or -CH ₂ -CH ₂ -Ar ^A3 ;

Z ¹ is CR ^Z1 or N;

Z ² is CR ^Z2 or N;

at least one of Z ¹ and Z ² is not N;

R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , unsubstituted or substituted, straight chain or branched C _1-8 -represents an aliphatic;

R ² is -C(=O)-OR ^2a , -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _w -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _x - NR ^2d -C(=O)-R ^2e , -SR ^2f , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S(=O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , -S(=O)(=NR ^2k ) -NR ^2l R ^2m , F, Cl, Br, I, -CN, -(CH ₂ ) _v -CN, -P(=0)(OR ^2o )(OR ^2p ), -(CH ₂ ) _y -NR ^2q R ^2r , -(CH ₂ ) _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 ;

Ar ^A1 , Ar ^A2 , Ar ^A3 independently of each other represent unsubstituted or independently of each other phenyl which may be mono- or di-substituted with R ^A11 and/or R ^A12 ;

R ^Z1 represents H or halogen;

R ^Z2 represents H or halogen; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-;

R ^2a represents H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or a radical derived from a carbohydrate, or Cat ;

Cat represents a monovalent cation;

R ^2b , R ^2c , R ^2q , R ^2r independently represent H, unsubstituted or substituted C _1-8 -aliphatic, including C _3-7 -alicyclic; or

together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms; wherein said heterocycle may optionally be fused with Hetar ^Z ; or

one of R ^2b and R ^2c represents -CN, -NH ₂ , -OH, -OC _1-6 -alkyl, -S(=O) ₂ -R ^2g , Ar ² , Hetar ² , Cyc ² or Hetcyc ² while others represent H or unsubstituted or substituted C _1-8 -aliphatic;

R ^2d , R ^2j , R ^2k , R ^2o , R ^2p independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic;

R ^2e represents H, halogen, unsubstituted or substituted C _1-8 -aliphatic, heteroaryl;

R ^2f and R ^2g independently represent unsubstituted or substituted C _1-8 -aliphatic;

R ^2h , R ²ⁱ independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;

R ^2l , R ^2m independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;

R ^2s and R ^2t independently represent unsubstituted or substituted C _1-8 -aliphatic; or together form an unsubstituted or substituted divalent C _3-6 -alkylene radical;

R ^2u represents hydrogen or unsubstituted or substituted C _1-6 -aliphatic;

Ar ¹ is a mono-, bi-, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryls may be unsubstituted and may be the same or different; may be substituted with substituents R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;

Hetar ¹ is a mono-, bi- or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, wherein 1, 2, 3, 4, 5 are heteroatom(s) selected from N, O and/or S and the remainder are carbon atoms, heteroaryls are unsubstituted or substituents R ^B1 , R ^B2 , R ^B3 , R which may be the same or different ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;

Cyc ¹ is a saturated or partially unsaturated, mono-, bi- or tricyclic carboxyl having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms a bocycle, wherein the carbocycle may be unsubstituted or substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 R ^B12 and/or R ^B13 which may be the same or different; wherein a carbocycle may optionally be fused to Ar ^X via two adjacent ring atoms of said Ar ^X , and the fused carbocycle may further be unsubstituted or R ^C1 , R ^C2 , R ^C3 which may be identical or different. , R ^C4 , R ^C5 , R ^C6 ;

Hetcyc ¹ is a saturated or partially unsaturated, mono-, bi- 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, 5 of the ring atoms are heteroatom(s) selected from N, O and/or S and the others are carbon atoms, and the heterocycles may be unsubstituted or the same or different. may be substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 and/or R ^B13 ;

L ¹ is from the group consisting of -S(=0) ₂ -, -C(=0)-, unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene is a selected divalent radical, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-;

L ² is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene, in both of which the alkylene or alkenylene chain is One of the carbon units may be replaced by -O-;

R ^A11 , R ^A12 independently of each other represent halogen or unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic;

R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 , R ^B7 independently of each other are unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic, C _1-6 -aliphatoxy , -SC _1-6 -aliphatic; Halogen, -CN, -S(=O)-R ^b1 , S(=O) ₂ -R ^b1 , -NR ^b2 NR ^b3 , Ar ² , -CH ₂ -Ar ² , Hetar ² , Cyc ² , Hetcyc ² indicate;

and/or two adjacent R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 together form a divalent -C _2-4 -alkylene radical, wherein one of the alkylene carbon units is forms a carbonyl unit (which may be replaced by -C(=O)-), or a divalent -OC _1-3 -alkylene radical or a divalent -OC _1-3 -alkylene-O- radical;

R ^b1 represents unsubstituted or substituted C _1-8 -aliphatic;

R ^b2 , R ^b3 independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or

together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms;

R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 independently of each other represent halogen, unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, Ar ^Y ; and/or

two of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=0) group; and/or

2 of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , ^{R B13} or 4 of R ^B8 , R B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same sulfur atom of the heterocycle Dog forms a divalent oxo (=O) group to form a -S(=O)- or -S(=O) ₂ - moiety;

Ar ² is a mono- or bicyclic aryl having 5, 6, 7, 8, 9 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 ;

Hetar ² is a mono- or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are N, O and/or or heteroatom(s) selected from S, the remainder being carbon atoms, and the heteroaryl may be unsubstituted or substituted by substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 which may be identical or different. there is;

Cyc ² is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 ; wherein the carbocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused carbocycle may further be unsubstituted or R ^C1 which may be identical or different. , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;

Hetcyc ² is a saturated or partially unsaturated, monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein 1 or 2 of said ring atoms are selected from N, O and/or S and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 which may be the same or different; wherein the heterocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused heterocycle may further be unsubstituted or may be the same or different R ^C1 , R may be substituted with ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;

Ar ^X and Ar ^Z are each independently an unsubstituted or substituted benzo ring;

Ar ^Y is unsubstituted or mono- or di-substituted phenyl;

Hetar ^Y1 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH;

Hetar ^Z is a beach selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran a cyclic or substituted 5 or 6-membered heteroaryl ring;

Cyc ^Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by halogen, OH, C _1-4 -alkyl there is;

Hetcyc ^X 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 said ring atoms are N, O and/or heteroatom(s) selected from S, the remainder being carbon atoms, wherein the heterocycles may be unsubstituted or the same or different, R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , may be substituted with R ^X7 and/or R ^X8 , wherein the heterocycle is optionally a carboxylic acid bioisoster;

Hetcyc ^Y is a saturated, partially unsaturated or aromatic, monocyclic heterocycle having 3, 4, 5, 6 or 7 ring atoms, wherein 1, 2, 3 or 4 of said ring atoms are N, O and/or heteroatom(s) selected from S and the others being carbon atoms;

Hetcyc ^Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom;

R ^C1 , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;

R ^D1 , R ^D2 , R ^D3 , R ^D4 , R ^D5 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;

R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 independently of each other are unsubstituted or substituted C _1-6 -aliphatic, unsubstituted or substituted C _1-6 -alifatoxy, halogen, hydroxy ; Hetar ^Y1 , CH ₂ -Hetar ^Y1 , Cyc ^Y1 , Hetcyc ^Y1 , -CH ₂ -Hetcyc ^Y1 ; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to the same ring atom of said carbocycle or heterocycle may form a divalent C _2-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of the alkylene radical may optionally independently of each other be replaced by O, NH, or NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _1-4 -alkyl; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to different ring atoms of said carbocycle or heterocycle may form a divalent C _1-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of said alkylene radical may optionally, independently of each other be replaced by O, NH, or NC _1-4 -alkyl;

R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 are independently of each other unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, halogen , -OH, -NR ^2d -S(=0) ₂ -R ^2g , Hetcyc ^Y , O-Hetcyc ^Y ; and/or

two of R ^X1 , R ^X2 , R ^X3 , R ^X4 , R X5 , R ^X6 , ^{R X7 ,} R ^X8 attached to the same carbon atom of the heterocycle form a divalent oxo (=0) group; and/or two of R ^X1 , R ^X2 , R ^X3 , R X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 attached to ^the same sulfur atom of said heterocycle or R ^X1 , R ^X2 , R ^X3 , R ^{four of X4} , R ^X5 , R ^X6 , R ^X7 , R ^X8 form a divalent oxo (=0) group to form an -S(=0)- or -S(=0) ₂ - moiety;

halogen is F, Cl, Br, I;

v is 1 or 2;

w is 1 or 2;

x is 0, 1 or 2;

y is 0, 1 or 2;

z is 0, 1 or 2;

or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio.

In general, all moieties, radicals, substituents, groups, moieties, variables, etc. occurring two or more times may be the same or different, i.e., independent of each other. Above and below, moieties and parameters have the meanings indicated for Formulas I-A and I, unless expressly indicated otherwise. Accordingly, the present invention particularly relates to compounds of formulas I-A and I, wherein at least one of said moieties, radicals, substituents, variables has one of the preferred meanings indicated above.

Any of these specific or even preferred embodiments of the invention specified below and in the claims, unless indicated otherwise, are compounds of formulas I-A and I as well as their N-oxides, solvates, tautomers or stereoisomers. We refer to pharmaceutically acceptable salts of each of the above, including isomers as well as mixtures thereof in all proportions.

In certain embodiments, a compound of the present invention

Z ¹ is CR ^Z1 ;

Z ² is CR ^Z2 ;

Z ³ is CR ^Z3 or N;

R ^Z1 is H or F; is preferably H;

R ^Z2 is H or F; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-; is preferably H;

R ^Z3 is H or F; preferably H,

A tricyclic heterocycle of Formula I-A, or any pharmaceutically acceptable pharmaceutically acceptable of each of the foregoing, including any N-oxides, solvates, tautomers or stereoisomers thereof and/or mixtures thereof in all proportions. is a possible salt.

In another specific embodiment of PE0, PE0a,

Z ³ is N.

In yet another specific embodiment of PE0, PE0b,

Z ³ is CR ^Z3 ;

R ^Z3 is H.

It will be understood that this specific embodiment (PE0b) is the same as the specific embodiment (PE1) as described below. That is, the compound of formula (IA) can also be described as a compound of formula (I), wherein when Z ³ represents CR ^Z3 in formula (IA), then R ^Z3 is H.

In a specific embodiment, PE1, a compound of the invention

Z ¹ is CR ^Z1 ;

Z ² is CR ^Z2 ;

R ^Z1 is H or F;

R ^Z2 is H or F; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-;

The remaining radicals and moieties are tricyclic heterocycles of formula I, as defined for formula I above or for any of the additional specific embodiments described herein below, or any N-oxides, solvates thereof , tautomers or stereoisomers and/or mixtures thereof in any ratio.

In another particular embodiment of PE1, PE1a, at least one of R ^Z1 and R ^Z2 is H. In another particular embodiment of PE1a, PE1b, both R ^Z1 and R ^Z2 are H.

In a further specific embodiment, PE2, a compound of the invention

ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

R ^A1 represents C _1-6 -aliphatic, -CH ₂ -Ar ^A1 ;

R ^A2 represents H, C _1-6 -aliphatic;

R ^A3 represents H, C _1-6 -aliphatic;

Ar ^A1 represents phenyl which may be unsubstituted or monosubstituted with R ^A11 ;

R ^A11 represents halogen;

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In another specific embodiment of PE2, PE2a,

R ^A1 represents C _1-3 -alkyl optionally substituted by 1, 2 or 3 F atoms or CN, C _2-4 -alkynyl (in particular -CH ₂ -C≡CH), -CH ₂ -Ar ^A1 ;

R ^A2 represents H, C _1-6 -aliphatic, in particular H, C _1-3 -alkyl optionally substituted by 1, 2 or 3 F atoms;

R ^A3 represents H;

Ar ^A1 represents phenyl which may be unsubstituted or monosubstituted with R ^A11 ;

R ^A11 represents F;

The remaining radicals and moieties are as defined for formulas I-A or I above or for any of the further specific embodiments described herein above or below.

In another particular embodiment of PE2 or PE2a, PE2b, ring A is ring A-1, A-4, A-7, A-9, A-10, A-12, A-13, A-15, A It is selected from the group consisting of -17, A-23 and A-24. In another specific embodiment of PE2 or PE2a, PE2c, ring A is ring A-4, wherein preferably R ^A1 is methyl, ethyl, n-propyl, or -CH ₂ -C≡CH, more preferably methyl, and R ^A2 is H.

In a further specific embodiment, PE3, a compound of the invention

R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , unsubstituted or substituted, straight chain or branched represents C _1-6 -alkyl, C _2-6 -alkenyl or C _2-6 -alkynyl; during the ceremony

Ar ¹ is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryl is unsubstituted or may be the same or different substituents R ^B1 , may be substituted with R ^B2 and/or R ^B3 ;

Hetar ¹ 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 N, O and/or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being unsubstituted or substituents which may be the same or different R ^B1 , may be substituted with R ^B2 and/or R ^B3 ; Preferably heteroaryl may be unsubstituted or substituted with substituents R ^B1 and/or R ^B2 which may be the same or different;

Cyc ¹ is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^B8 and/or R ^B9 ; wherein a carbocycle may optionally be fused to Ar ^X through two adjacent ring atoms of said Ar ^X , and the fused carbocycle may be further unsubstituted by R ^C1 and/or R ^C2 which may be identical or different. can be substituted;

Hetcyc ¹ is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N, O and/or S and the remainder being carbon atoms, the heterocycle may be unsubstituted or substituted with R ^B8 and/or R ^B9 which may be the same or different; When one of the heteroatoms is S, the heterocycle may also be substituted with R ^B8 , R ^B9 , R ^B10 and R ^B11 ;

L ¹ is a divalent radical selected from the group consisting of -S(=0) ₂ -, unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene; In c, one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-;

L ² is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene, in both of which the alkylene or alkenylene chain is One of the carbon units may be replaced by -O-;

R ^B1 , R ^B2 , R ^B3 are independently of each other straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl is unsubstituted or mono-substituted with —CN or substituted with 1, 2 or 3 halogens. may be), straight-chain or branched C _1-4 -alkoxy (the C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens), -O-CH-C≡CH, straight-chain or branched -SC _1-4 -alkyl, wherein -SC _1-4 -alkyl 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 , -CH ₂ -Ar ² , _Hetar ² , Cyc ² , represents Hetcyc ² ;

or two adjacent R ^B1 , R ^B2 and/or R ^B3 together represent a divalent -C _3-4 -alkylene radical wherein one of the alkylene carbon units is replaced by a carbonyl unit (-C(=O)-) can be), or 2 forms an -OC _2-3 -alkylene radical;

Ar ² is phenyl;

Hetar ² is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O and/or S; the rest are carbon atoms;

Cyc ² is cyclopropyl, cyclobutyl, cyclopentyl, each of which may be unsubstituted or monosubstituted with R ^D6 or disubstituted with R ^D6 and R ^D7 independently of each other; in particular unsubstituted or monosubstituted with R ^D6 ;

Hetcyc ² is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or monosubstituted with R ^D6 or disubstituted with R ^D6 and R ^D7 independently of each other; in particular unsubstituted or monosubstituted with R ^D6 ;

R ^B8 , R ^B9 are independently of each other F, C _1-2 -alkyl (the C _1-2 -alkyl may be unsubstituted or substituted with 1, 2 or 3 F ), C _1-2 -alkoxy, represents Ar ^Y ; or

R ^B8 and R ^B9 are attached to the same carbon atom of the carbocycle Cyc ¹ or the heterocycle Hetcyc ¹ and form a divalent oxo (=0) group; or

R ^B8 and R ^B9 and R ^B10 and R ^B11 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=0) groups to form an -S(=0) ₂ - moiety;

Ar ^X is an unsubstituted benzo ring;

Ar ^Y is phenyl;

R ^C1 and R ^C2 independently of each other represent C _1-6 -alkyl, which may be independently substituted with 1, 2 or 3 F atoms;

R ^D6 , R ^D7 are independently of each other C _1-6 -alkyl which may be substituted with 1, 2, or 3 F atoms or 1 hydroxy group; or hydroxy;

halogen is F, Cl, Br;

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In another specific embodiment of PE3, PE3a,

R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , straight-chain or branched C _1-6 -alkyl; C _2-6 -alkenyl or C _2-6 -alkynyl, said C _1-6 -alkyl, C _2-6 -alkenyl or C _2-6 -alkynyl being unsubstituted or 1, 2 or 3 substituted with two halogens; during the ceremony

Ar ¹ is phenyl or naphthalenyl, especially phenyl, which may be unsubstituted or substituted by substituents R ^B1 and or R ^B2 which may be the same or different;

Hetar ¹ is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2 or 3 of the ring atoms are N, O and/or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being unsubstituted or substituents R ^B1 which may be the same or different and/or may be substituted with R ^B2 ;

Cyc ¹ is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^B8 and/or R ^B9 ; wherein a carbocycle may optionally be fused to Ar ^X through two adjacent ring atoms of said Ar ^X , and the fused carbocycle may be further unsubstituted by R ^C1 and/or R ^C2 which may be identical or different. can be substituted;

Hetcyc ¹ is a saturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one of said ring atoms is a heteroatom selected from O and S and the others are carbon atoms, and the heterocycle is unsubstituted or the same as or R ^B8 and/or R ^B9 which may be different; When one of the heteroatoms is S, the heterocycle may also be substituted with R ^B8 , R ^B9 , R ^B10 and R ^B11 ;

L ¹ is -S(=0) ₂ -, -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -C(CH ₃ )H-, -CH ₂ -CH ₂ -C(CH ₃ ) is a divalent radical selected from the group consisting of ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH=CH-;

L ² is a divalent radical selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -;

R ^B1 , R ^B2 independently of one another are straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl may be unsubstituted or mono-substituted with —CN or substituted with 1, 2 or 3 halogens; , eg -CF ₃ , straight-chain or branched C _1-4 -alkoxy (the C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens), eg - OCF ₃ , -O-CH ₂ -C≡CH, straight-chain or branched -SC _1-4 -alkyl, which -SC _1-4 -alkyl 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 , -CH ₂ -Ar ² , Hetar ² , Cyc ² , Hetcyc ² ;

or two adjacent R ^B1 , R ^B2 together represent a divalent -C _3-4 -alkylene radical, wherein one of the alkylene carbon units may be replaced by a carbonyl unit (-C(=O)-); or 2 forms an -OC _2-3 -alkylene radical;

Ar ² is phenyl;

Hetar ² is a monocyclic heteroaryl having 5 ring atoms, wherein one of the ring atoms is N and the other are carbon atoms, or one of the ring atoms is N and one of the ring atoms is S and the remainder are carbon atoms;

Cyc ² is cyclopropyl, 1-trifluoromethylcyclopropyl, cyclopentyl;

Hetcyc ² is pyrrolidinyl;

R ^B8 , R ^B9 are independently of each other F, C _1-2 -alkyl (the C _1-2 -alkyl may be unsubstituted or substituted with 1, 2 or 3 F ), C _1-2 -alkoxy, represents Ar ^Y ; or

R ^B8 and R ^B9 are attached to the same carbon atom of the carbocycle Cyc ¹ or the heterocycle Hetcyc ¹ and form a divalent oxo (=0) group; or

R ^B8 and R ^B9 and R ^B10 and R ^B11 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=0) groups to form an -S(=0) ₂ - moiety;

Ar ^X is an unsubstituted benzo ring;

Ar ^Y is phenyl;

R ^C1 and R ^C2 independently of each other represent C _1-2 -alkyl, which may be independently substituted with 1, 2 or 3 F atoms;

halogen is F, Cl, Br;

The remaining radicals and moieties are as defined for formulas I-A or I above or for any of the further specific embodiments described herein above or below.

In another specific embodiment of PE3 or PE3a, PE3b,

R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , 2,2-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; during the ceremony

Ar ¹ is phenyl which may be unsubstituted or substituted with substituents R ^B1 and or R ^B2 which may be the same or different;

Hetar ¹ is furanyl, in particular furan-2-yl; thiophenyl, in particular thiophen-2-yl, thiophen-3-yl; thiazolyl, in particular 1,3-thiazol-2-yl or 1,3-thiazol-4-yl; pyrazolyl, in particular pyrazol-5-yl (1H-pyrazol-5-yl); imidazolyl, in particular imidazol-2-yl (1H-imidazol-2-yl), imidazol-5-yl (1H-imidazol-5-yl); oxazolyl, especially 1,3-oxazol-2-yl; pyridinyl (pyridyl), especially pyridin-2-yl, pyridin-3-yl, pyridin-4-yl; 5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl; pyrimidinyl, especially pyrimidin-2-yl; indolyl, in particular 1H-indol-6-yl; quinolinyls, 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; benzothiophenyl, especially 1-benzothiophen-3-yl; isoquinolinyl, especially isoquinolin-3-yl; furo[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, pyrazolo[1,5-a]pyridin-7-yl; imidazo[1,2-a]pyridinyl, especially imidazo[1,2-a]pyridin-3-yl, imidazo[1,2-a]pyridin-5-yl; imidazo[1,5-a]pyridinyl, especially 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, in particular pyrazolo[1,5-c]pyrimidin-3-yl; quinazolinyl, especially quinazolin-2-yl; naphthyridinyl, in particular heteroaryl selected from the group consisting of 1,5-naphthyridin-2-yl; wherein said heteroaryl may be unsubstituted or substituted with substituents R ^B1 and/or R ^B2 which may be the same or different;

Cyc ¹ is cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, spiro[3.3]heptanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, is selected from the group consisting of bicyclo[2.2.1]heptenyl, methylbicyclo[3.1.1]heptenyl, wherein the carbocycle is unsubstituted or substituted with R ^B8 and/or R ^B9 which may be the same or different can be; wherein a carbocycle may optionally be fused to Ar ^X through two adjacent ring atoms of said Ar ^X , and the fused carbocycle may be further unsubstituted by R ^C1 and/or R ^C2 which may be identical or different. can be substituted;

Hetcyc ¹ is selected from the group consisting of pyrrolidinyl, tetrahydrofuranyl and thianyl, wherein the heterocycle may be unsubstituted or substituted with R ^B8 and/or R ^B9 which may be the same or different; When one of the heteroatoms is S, the heterocycle may also be substituted with R ^B8 , R ^B9 , R ^B10 and R ^B11 ;

L ¹ is -S(=0) ₂ -, -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -C(CH ₃ )H-, -CH ₂ -CH ₂ -C(CH ₃ ) ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH=CH - is a divalent radical selected from the group consisting of;

L ² is a divalent radical selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -;

R ^B1 , R ^B2 are independently of each other methyl, ethyl, n-propyl, 2-propyl, tert.-butyl, cyanomethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2- trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, -O-CH ₂ -C≡CH, straight or branched -S-methyl, -S-CF _3, F, Cl, Br , -CN, -S(=O)-methyl, S(=O) ₂ -methyl, -N(CH ₃ ) ₂ , phenyl, -CH ₂ -phenyl (benzyl), -O-CH ₂ -phenyl (benzyl oxy), pyrrolyl, thiazolyl, cyclopropyl, cyclopentyl, pyrrolidinyl;

or two adjacent R ^B1 , R ^B2 together -CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -CH 2 -CH ₂ -CH 2 -, -O-CH _{2 -CH 2 -} , -O-CH ₂ -CH ₂ -CH ₂ -, -C(=O)-CH ₂ -CH ₂ -, -C(=O)-CH ₂ -CH ₂ -CH ₂ - forms a divalent radical selected from the group consisting of do,

R ^B8 , R ^B9 independently of each other represent F, methyl, ethyl, fluoromethyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, or phenyl; or

R ^B8 and R ^B9 are attached to the same carbon atom of the carbocycle Cyc ¹ or the heterocycle Hetcyc ¹ to form a divalent oxo (=0) group; or

R ^B8 and R ^B9 and R ^B10 and R ^B11 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=0) groups to form an -S(=0) ₂ - moiety;

Ar ^X is an unsubstituted benzo ring;

Ar ^Y is phenyl;

R ^C1 and R ^C2 independently represent CF ₃ ;

The remaining radicals and moieties are as defined for formulas I-A or I above or for any of the further specific embodiments described herein above or below.

In a further specific embodiment, PE4, a compound of the invention

R ² represents -C(=0)-OR ^2a or Hetcyc ^X ;

R ^2a represents H, straight-chain or branched, unsubstituted or substituted C _1-4 -alkyl or Cat;

Cat represents a monovalent cation selected from the group consisting of lithium (Li), sodium (Na) and potassium (K);

Hetcyc ^X is 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-on-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3-chloro-4,5-dihydro-1,2-oxazol-5-yl, 3-(1H- 1,2,3-triazol-1-yl)-4,5-dihydro-1,2-oxazol-5-yl, 3-(2H-1,2,3-triazol-2-yl) -4,5-dihydro-1,2-oxazol-5-yl, 3-(pyrimidin-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3 -Hydroxy-oxetan-3-yl, 5-hydroxy-4H-pyran-4-one-2-yl, 3,3-difluoropyrrolidin-2-one-4-yl, 3,3 -Difluoropyrrolidin-2-one-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-one-4-yl, 3,3-difluoro represents -2,3-dihydro-1H-pyrrol-2-one-5-yl;

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In another specific embodiment of PE4, PE4a,

R ² represents -C(=0)-OR ^2a ;

R ^2a represents H, methyl, ethyl or Cat;

Cat represents a monovalent sodium cation;

The remaining radicals and moieties are as defined for formulas I-A or I above or for any of the further specific embodiments described herein above or below.

In yet another specific embodiment of PE4, PE4b,

R ² represents -C(=0)-OR ^2a ;

R ^2a is -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S( C _1-4 - substituted with =O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , -S(=O)(=NR ^2k )-NR ^2l R ^2m represents alkyl, wherein R ^2f , R ^2g , R ^2h , R ²ⁱ , R ^2j , R ^2k , R ^2l , and R ^2m are as defined above and below in the specification for Formulas IA or I;

The remaining radicals and moieties are as defined for formulas I-A or I above or for any of the further specific embodiments described herein above or below.

In a further specific embodiment, PE5, a compound of the invention

R ² represents -C(=0)-NR ^2b R ^2c ;

R ^2b and R ^2c independently of each other represent H or straight-chain or branched C _1-8 -aliphatic which may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents which may be the same or different ;

or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom , wherein 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms; wherein said heterocycle may optionally be fused with Hetar ^Z as defined in any one of claims 1 to 7; in particular forming a pyrrolidinyl ring or a piperidinyl ring, each of which is unsubstituted or mono-substituted with —OH or independently of one another disubstituted with C _1-4 -alkyl and/or —OH;

or one of R ^2b and R ^2c represents H and the other represents Cyc ² or Hetcyc ² ; In particular it represents cyclopropyl or cyclobutyl, each of which is unsubstituted or substituted with -CH ₂ OH or tetrahydrofuranyl, which is unsubstituted or monosubstituted with -OH;

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In another specific embodiment of PE5, PE5a,

R ^2b represents hydrogen,

R ^2c is hydrogen; represents straight-chain or branched C _1-8 -alkyl, Cyc 2 or Hetcyc ² which may be unsubstituted or substituted ^by R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 , which may be the same or different, wherein ,

R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 are independently of each other halogen, in particular F; -NR ^Ea R ^Eb , -OH, OR ^Ec , Ar ^E , Hetar ^E , Cyc ^E , Hetcyc ^E ;

Ar ^E is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; preferably phenyl or naphthalenyl, especially phenyl;

Hetar ^E is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are N, O and / or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being an unsubstituted substituent which may be the same or different R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; In particular heteroaryl is unsubstituted or may be the same or different substituents R ^F1 and / or monocyclic heteroaryl having 5 or 6 ring atoms which may be substituted by R ^F2 ; Preferably heteroaryl is imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, each of which is unsubstituted or monosubstituted with C _1-4 -alkyl; pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, each of which is 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, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; It is selected from the group consisting of oxadiazolyl, triazolyl, thiazolyl, and isothiazolyl;

Cyc ^E is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^G1 and/or R ^G2 ; In particular a saturated monocyclic carbocycle having 3, 4, 5, or 6 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by R ^G1 and/or R ^G2 which may be the same or different. there is; preferably cyclopropyl, cyclobutyl, cyclohexenyl;

Hetcyc ^E 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 ( s) and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^G1 and/or R ^G2 which may be the same or different; especially saturated monocyclic heterocycles having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N and/or O and the others are carbon atoms, wherein heteroatoms the cycle may be unsubstituted or substituted with R ^G1 and/or R ^G2 ; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); Piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, each of which may be unsubstituted or monosubstituted with -OH ); morpholinyl, morpholin-1-yl, morpholin-2-yl, each of which may be unsubstituted or monosubstituted with methyl; 1,4-dioxanil; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl;

R ^{E a} , R ^Eb independently of each other represents H, C _1-4 -alkyl, -C(=O)-OC _1-4 -alkyl; in particular both represent H or one represents H and the other represents C(=0)-O-tert.-butyl;

R ^Ec represents H or C _1-4 -alkyl, in particular H or methyl;

R ^F1 , R ^F2 and/or R ^F3 are, independently of each other, straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl is unsubstituted or monosubstituted by -CN, OH, -OC _1-4 -alkyl or 1 , which may be substituted with 2 or 3 halogens), straight-chain or branched C _1-4 -alkoxy (the C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens), straight-chain or branched -SC _1-4 -alkyl, wherein -SC _1-4 -alkyl may be unsubstituted or substituted with 1, 2 or 3 halogens; C _3-7 -cyclopropyl optionally substituted by halogen, OH and/or C _1-4 -alkyl; F, Cl, Br, -CN, -S(=O)-C _1-3 -alkyl, S(=O) ₂ -C _1-3 -alkyl, -NH ₂ , -NH(C _1-3 -alkyl ) -N(C _1-3 -alkyl) ₂ , -OH; especially methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; Preferably R ^F1 , only one of R ^F2 and R ^F3 is present and represents methyl or F;

and/or two of R ^F1 , R ^F2 , R ^F3 attached to two different ring atoms of the aryl or heteroaryl form a divalent C _1-6 -alkylene radical, optionally 1 or 2 of the alkylene radical two non-adjacent carbon units independently of each other may be replaced by O, NH, NC _1-4 -alkyl, in particular -(CH ₂ ) ₄ -, -CH ₂ -O-(CH ₂ ) ₂ -;

R ^G1 and/or R ^G2 are independently of each other halogen, hydroxy, unsubstituted or substituted C _1-6 -aliphatic, in particular C _1-4 -alkyl optionally substituted by OH, C _1-6 -alifatoxy , in particular -OC _1-4 -alkyl, -C(=O)-OC _1-4 -alkyl, Hetar ^Y2 , -CH ₂ -Hetar ^Y2 , Hetcyc ^Y2 ; preferably only one of R ^G1 and R ^G2 is present and represents hydroxy;

and/or R ^G1 and R ^G2 attached to the same ring atom of the carbocycle or heterocycle form a divalent C _2-6 -alkylene radical, wherein optionally 1 or 2 non-adjacent carbon units of the alkylene radical may independently of one another be replaced by O, NH, NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _1-4 -alkyl, in particular -(CH ₂ ) ₂ -O-CH ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -; and/or R ^G1 and R attached to two different ring atoms of the carbocycle or heterocycle. ^G2 forms a divalent C _1-6 -alkylene radical, optionally 1 or 2 non-adjacent carbon units of the alkylene radical being independently of one another O, NH, NC _1-4 -alkyl, in particular -CH ₂ - can be replaced;

Cyc ² is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycles are unsubstituted or independently of each other R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 , wherein the carbocycles may optionally be fused to Ar ^Z or Hetar ^Z through two adjacent ring atoms and the fused carbocycles are optionally independently of each other R ^C1 , R ^C2 and / or may be further substituted with R ^C3 ;

Hetcyc ² is a saturated monocyclic heterocycle having 4, 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N, O and/or S and the others are carbon atom, and the heterocycle may be unsubstituted or substituted independently of each other by R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 , wherein the heterocycle may optionally be fused to Ar ^Z or Hetar ^Z and The fused heterocycles may optionally be further substituted independently of each other with R ^C1 , R ^C2 and/or R ^C3 ;

R ^C1 , R ^C2 , R ^C3 represent C _1-4 -alkyl;

R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 independently of each other represent halogen, in particular F; hydroxy; -C _1-4 -alkyl optionally substituted by OH and/or halogen, in particular methyl, hydroxymethyl, 2-fluoroethyl; -OC _1-4 -alkyl, in particular methoxy, ethoxy; Hetar ^Y1 , -CH ₂ -Hetar ^Y1 , Cyc ^Y1 , Hetcyc ^Y1 , -CH ₂ -Hetcyc ^Y1 ;

and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to the same ring atom of the carbocycle or heterocycle form a divalent C _2-6 -alkylene radical, wherein optionally 1 or 2 non-adjacent carbon units of an alkylene radical can independently of each other be replaced by O, NH, NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _{1 -4} -alkyl, in particular -(CH ₂ ) ₃ -, -CH ₂ -CH(OC ₂ H ₅ )-CH ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -; ;

and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to two different ring atoms of the carbocycle or heterocycle form a divalent C _1-6 -alkylene radical; Optionally 1 or 2 non-adjacent carbon units of the alkylene radical are, independently of each other, O, NH, NC _1-4 -alkyl, in particular -CH ₂ -, -(CH ₂ ) ₃ -, -O-(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -;

Ar ^Z is benzo;

Hetar ^Y1 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is C _1-4 -alkyl which is unsubstituted or optionally substituted with F, OH; In particular, pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl , methylpyrimidinyl;

Hetar ^Y2 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH; in particular pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl;

Hetar ^Z is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole;

Cyc ^Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by halogen, OH, C _1-4 -alkyl and, in particular, cyclopropyl;

Hetcyc ^Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom; in particular tetrahydrofuranyl;

Hetcyc ^Y2 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom; in particular tetrahydrofuranyl, morpholinyl, tetrahydropyranyl;

The remaining radicals and moieties are as defined for formulas IA or I above or for any of the further specific embodiments described herein above or below. This particular embodiment PE5a is wherein R ^2b represents hydrogen and R ^2c represents straight-chain or branched C _1-8 -alkyl, wherein one or two of the non-terminal and non-adjacent -CH ₂ - (methylene) groups are -O -, -S- and/or 1 or 2 of the non-terminal and non-adjacent -CH ₂ - or -CH - groups are replaced by -NH - or -N-. .

In yet another specific embodiment of PE5a, PE5aa,

R ^2b represents hydrogen,

R ^2c is hydrogen; represents straight-chain or branched C _1-8 -alkyl, Cyc 2 or Hetcyc ² which may be unsubstituted or substituted ^by R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 , which may be the same or different, wherein ,

R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 are independently of each other halogen, in particular F; -NR ^Ea R ^Eb , -OH, OR ^Ec , Ar ^E , Hetar ^E , Cyc ^E , Hetcyc ^E ;

Ar ^E is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; preferably phenyl or naphthalenyl, especially phenyl;

Hetar ^E is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are N, O and / or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being an unsubstituted substituent which may be the same or different R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; In particular heteroaryl is unsubstituted or may be the same or different substituents R ^F1 and / or monocyclic heteroaryl having 5 or 6 ring atoms which may be substituted by R ^F2 ; Preferably heteroaryl is imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, each of which is unsubstituted or monosubstituted with C _1-4 -alkyl; pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, each of which is unsubstituted or monosubstituted with -F; pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; It is selected from the group consisting of pyrazinyl and pyrazin-2-yl;

Cyc ^E is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^G1 and/or R ^G2 ; In particular a saturated monocyclic carbocycle having 3, 4, 5, or 6 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by R ^G1 and/or R ^G2 which may be the same or different. there is; preferably cyclobutyl;

Hetcyc ^E is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N, O and/or S and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^G1 and/or R ^G2 which may be the same or different; especially saturated monocyclic heterocycles having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N and/or O and the others are carbon atoms, wherein heteroatoms the cycle may be unsubstituted or substituted with R ^G1 ; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); Piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, each of which may be unsubstituted or monosubstituted with -OH ); morpholinyl, morpholin-1-yl, morpholin-2-yl;

R ^{E a} , R ^Eb independently of each other represents H, C _1-4 -alkyl, -C(=O)-OC _1-4 -alkyl; in particular both represent H or one represents H and the other represents C(=0)-O-tert.-butyl;

R ^Ec represents H or C _1-4 -alkyl, in particular H or methyl;

R ^F1 , R ^F2 and/or R ^F3 are, independently of each other, straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl is unsubstituted or monosubstituted by -CN, OH, -OC _1-4 -alkyl or 1 , which may be substituted with 2 or 3 halogens), straight-chain or branched C _1-4 -alkoxy (the C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens), straight-chain or by branched -SC _1-4 -alkyl, wherein -SC _1-4 -alkyl may be unsubstituted or substituted with 1, 2 or 3 halogens, halogen, OH and/or C _1-4 -alkyl optionally substituted C _3-7 -cyclopropyl, F, Cl, Br, -CN, -S(=O)-C _1-3 -alkyl, S(=O) ₂ -C _1-3 -alkyl, -NH ₂ , -NH(C _1-3 -alkyl) -N(C _1-3 -alkyl) ₂ , -OH; especially methyl, F; Preferably R ^F1 , only one of R ^F2 and R ^F3 is present and represents methyl or F;

R ^G1 and/or R ^G2 independently of each other represent halogen, hydroxy, unsubstituted or substituted C _1-4 -alkyl, -OC _1-4 -alkyl, in particular hydroxy; preferably only one of R ^G1 and R ^G2 is present and represents hydroxy;

Cyc ² is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted with R ^D6 , wherein

R ^D6 is C _1-4 -alkyl unsubstituted or mono-substituted by -OH, in particular -CH ₂ OH;

in particular Cyc ² is cyclopropyl, cyclobutyl or 1-hydroxymethylcyclobutyl;

Hetcyc ² is a saturated monocyclic heterocycle having 5 or 6 ring atoms, 1 or 2 of which are heteroatom(s) selected from N, O and/or S and the others are carbon atoms; , wherein the heterocycle may be unsubstituted or monosubstituted with hydroxy; in particular tetrahydrofuranyl or hydroxytetrahydrofuranyl; preferably 4-hydroxytetrahydrofuran-3-yl;

In yet another specific embodiment of PE5, PE5b,

R ^2b and R ^2c together with the nitrogen atom to which they are attached form, independently of each other, a saturated or partially unsaturated heterocycle optionally substituted with R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 and/or R ^Y5 ; wherein the heterocycle may optionally be fused to Hetar ^Z ; the heterocycle is selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, and morpholine; during the ceremony

R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 , R ^Y5 are independently of each other halogen, in particular F; -NH ₂ , -N(H)-C _1-4 -alkyl, -N(H)-C(=O)-OC _1-4 -alkyl, -N(C _1-4 -alkyl) ₂ ; -OH; C _1-4 -alkyl optionally substituted with -OH, -OC _1-4 -alkyl, -OC _3-7 -cycloalkyl, -O-CH ₂ -C _3-7 -cycloalkyl, in particular methyl, -CH ₂ OH, -(CH ₂ ) ₂ OH, -(CH ₂ ) ₃ OH, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , cyclopropylmethoxy; -OC _1-4 -alkyl, in particular methoxy; Hetar ^Y2 ; -CH ₂ -Hetar ^Y2 ; represents Hetcyc ^Y2 ;

and/or two of R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 , R ^Y5 attached to the same ring atom of the heterocycle form a divalent C _2-6 -alkylene radical, optionally 1 of an alkylene radical. or two non-adjacent carbon units independently of each other are O, NH, NC _1-4 -alkyl, in particular -(CH ₂ ) ₄ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₃ -;

and/or two of R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 , R ^Y5 attached to two different ring atoms of the heterocycle form a divalent C _1-6 -alkylene radical, optionally an alkylene radical 1 or 2 non-adjacent carbon units of may independently of each other be replaced by O, NH, NC _1-4 -alkyl, in particular -(CH ₂ ) ₄ -;

Ar ^Z is benzo;

Hetar ^Y2 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH; in particular pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl;

Hetar ^Z is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole;

Hetcyc ^Y2 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom; in particular tetrahydrofuranyl, morpholinyl, tetrahydropyranyl;

The remaining radicals and moieties are as defined for formulas I-A or I above or for any of the further specific embodiments described herein above or below.

In yet another specific embodiment of PE5b, PE5bb,

R ^2b and R ^2c together with the nitrogen atom to which they are attached form a 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl or 3-hydroxypiperidinyl ring.

In yet another specific embodiment of PE5, PE5c,

R ^2b is a straight chain of branched C _1-4 -alkyl optionally substituted with OH; especially methyl, 2-hydroxyethyl;

R ^2c is straight-chain or branched C _1-8 which may be independently of each other substituted with Cyc ² , Hetcyc ² or R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 which may be unsubstituted or identical or different - represents alkyl; wherein Cyc ² , Hetcyc ² , R ^E1 , R ^E2 , R ^E3 , R ^E4 and R ^E5 are as defined herein above for PE5a or PE5aa.

In a further specific embodiment, PE6, a compound of the invention

R ² is -(CH ₂ ) _x -NR ^2d -C(=O)-R ^2e , -SR ^2f , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S( =O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S(=O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , - S(=0)(=NR ^2k )-NR ^2l R ^2m , -(CH ₂ ) _z -NR ^2d -S(=0) ₂ -R ^2g ; In particular, -S-CH ₃ , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O)(= NR ^2j )-R ^2g , -S(=O)(=NR ^2k )-NR ^2l R ^2m , -(CH ₂ ) _z -NR ^2d -S(=O) ₂ -R ^2g , -C(=O) -N=S(=O)-R ^2s R ^2t , -C(=O)-N=S(=NR ^2u )-R ^2s R ^2t ; Preferably, -S(=O)-CH ₃ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -NH ₂ , -S(=O) ₂ -NHCH ₃ , -S( =O)(=NH)-CH ₃ , S(=O)(=NH)-N(CH ₃ ) ₂ , -NH-S(=O) ₂ -CH ₃ , -N(CH ₃ )-S( =0) ₂ -CH ₃ , -NH-S(=0) ₂ -CH=CH ₂ , -CH ₂ -NH-S(=0) ₂ -CH=CH ₂ ;

R ^2e is C _1-6 -alkyl optionally substituted with H, -OH or monocyclic 5- or 6-membered heteroaryl; C _3-7 -cycloalkyl, monocyclic 5- or 6-membered heteroaryl; In particular H, methyl, hydroxymethyl, methylpyridin-2-yl, methylpyridin-3-yl, methylpyridin-4-yl, cyclopropyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl represents;

R ^2f and R ^2g are each independently unsubstituted or substituted C _1-8 -aliphatic; in particular independently of one another C _1-4 -alkyl or C _2-4 -alkenyl _: preferably independently of one another methyl or -CH=CH ₂ denote:

R ^2h , R ²ⁱ independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms; in particular independently of each other represents C _1-4 -alkyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl, optionally substituted by H or -OH or together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, wherein the ring is optionally substituted with -OH and/or phenyl and represents pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl;

R ^2d , R ^2j , R ^2k independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, in particular H, methyl;

R ^2l , R ^2m independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms; in particular C _1-4 -alkyl; preferably represents methyl;

R ^2s , R ^2t are independently of each other C _1-6 -alkyl, OC _1-4 -alkyl, NH ₂ , NHC _1-4 -alkyl, N(C _1-4 -alkyl) which may be optionally substituted with —OH ₂ , pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl; especially methyl, ethyl, 2-hydroxyethyl, 3-hydroxy propyl, 2-aminoethyl, 3-(N,N-dimethylamino)propyl; or together form a divalent C _3-4 -alkylene radical optionally substituted by -NH ₂ , -CN , or a divalent C _2-5 -alkylene radical, wherein optionally said C _2-5 -alkylene One of the carbon units of the radical may be replaced by O, NH or NC _1-4 -alkyl; In particular -(CH ₂ ) ₃ -, -CH ₂ -C(NH ₂ )H-CH ₂ -, -CH ₂ -C(CN)H-CH ₂ -, -CH ₂ -C(CH ₂ -NH-CH ₂ )-CH ₂ -, -(CH ₂ ) ₄ -;

R ^2u represents hydrogen or C _1-4 -alkyl;

x represents 0 or 1;

z is 0 or 1;

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In yet a further specific embodiment, PE7, a compound of the invention

ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

Z ¹ is CH;

Z ² is CH;

R ¹ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoro Methylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4 -Cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl , 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl , 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2- 1, 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-methylsulfanylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl Midin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano- 6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5 ,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2- yl, quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazoline -2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]phetan-1-yl, cyclohexyl, 4-methylcyclo Hexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-difluorospiro[3.3]heptane-2 -yl, 1H-inden-2-yl; Benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidine- 1-yl) phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)-phenylmethyl, 3-tert-butylphenylmethyl, 3-(difluoromethyl Toxy)-phenylmethyl, 2-(difluoromethyl)phenylmethyl, 3-(difluoromethyl)phenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenyl]methyl , 2-(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3 -Methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrol-1-yl)phenylmethyl, 2-methyl-3-methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl , 2-methyl-3- (trifluoromethyl) phenylmethyl, 3-trifluoromethyl-4-fluorophenylmethyl, 2-fluoro-5- (trifluoromethoxy) phenylmethyl, 2-methoxy -3-trifluoromethoxyphenylmethyl, 2-fluoro-3-methoxyphenylmethyl, 2-fluoro-3-(trifluoromethyl)phenyl]methyl, 2-fluoro-3-fluoromethoxyphenylmethyl , 2-trifluoromethoxy-5-fluorophenylmethyl, 2-fluoro-5-chloro-phenylmethyl, 3-fluoro-5-methylphenyl) methyl, 3,5-difluorophenylmethyl, 5-fluoro Rho-2- (trifluoromethyl) phenylmethyl, 3-fluoro-5- (trifluoromethyl) phenylmethyl, 2-chloro-3- (trifluoromethyl) phenylmethyl, naphthalin-1-yl Methyl, 5,6,7,8-tetrahydronaphthalen-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-dihydro-2H-1-benzopyran- 8-ylmethyl, 2-phenylethyl, 2-(2-methylphenyl)-ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl) ) Ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2-(2,4-difluorophenyl) ethyl, 2 -(difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl-3-phenylbutyl, 2-(benzyloxy)ethyl; 5-ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazol-2-ylmethyl, 2-methyl -1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2-propyl) Pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazol-2-ylmethyl, 1-benzimidazole -2-yl)methyl, 1-(2-methylpropyl)-1H-imidazol-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridin- 2-ylmethyl, 2-methylpyridin-4-ylmethyl, 4-trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)-pyridin-2-ylmethyl, 6-trifluoromethylpyridine -2-ylmethyl, 2-(trifluoromethyl)-pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5-trifluoro Methylthiophen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H- Pyrrolo[1,2-b]pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imi polyzo[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, pyra zolo[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]phetan-1-ylmethyl, bicyclo[2.2.1]heptane- 2-ylmethyl, bicyclo[2.2.2]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept -2-en-2-yl] methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4 Represents 4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl,

R ² is -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH ₃ , -C(=O)-NH ₂ , -C(=O)-NHCH ₃ , -C(=O)-NHCH ₂ CH ₃ , -C(=O)-NH(CH ₂ ) ₂ CH ₃ , -C(=O)-N(H)-cyclopropyl, -C(=O) -N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH ₂ CH ₂ -OH, -C(=O)-N(H) -CH ₂ CH ₂ -OCH ₃ , -C(=O)-N(H)-CH ₂ -C(H)(OH)-CH ₃ , -C(=O)-N(H)-CH ₂ C (CH ₃ ) ₂ OH, -C(=0)-N(H)-C(H)(CH ₃ )-CH ₂ OH, -C(=0)-N(H)-C(H)(CH ₂ CH ₃ )-CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-CH ₂ CH ₂ -O-CH ₃ , -C(=O)-N( H)-C(CH ₃ ) ₂ CH ₂ CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-phenyl, -C(=O)-N(H) -C(CH ₃ )(CH ₂ OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH ₃ )-phenyl, -C(=O)-N( H)-CH ₂ -1H-1-methylimidazol-2-yl, -C(=O)-N(H)-(CH ₂ ) ₂ -1H-imidazol-1-yl, -C(= O)-N(H)-CH ₂ -pyridin-2-yl, -C(=O)-N(H)-CH ₂ -pyridin-3-yl, -C(=O)-N(H)- CH ₂ -pyridin-4-yl, -C(=O)-N(H)-C(H)(CH ₂ OH)-pyridin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-4-yl, -C(=O)-N(H) -CH ₂ -pyridazin-2-yl, -C(=O)-NH-C(CH ₂ OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -NH-C(=O)-CH=CH ₂ , -NH-C(=O)-CF=CH ₂ , -NH-C(=O)-CH ₂ Cl, -NH-C(=O)- C≡CH, -CH ₂ -NH-C(=O)-CH=CH ₂ , -CH ₂ -NH-C(=O)-CH ₂ Cl, -S(=O)-CH ₃ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -OH, -S(=O) ₂ -NH ₂ , -S(=O) ) ₂ -NHCH ₃ , -S(=O)(=NH)-N(CH ₃ ) ₂ , -S(=O)(=N-CH ₃ )-N(CH ₃ ) ₂ , -S(=O )(=N-CH ₃ )-OH, -S(=O)(=NH)-CH ₃ , -P(=O)(OH) ₂ , F, -CN; preferably represents -C(=O)-OH, -C(=O)-ONa,

Tricyclic heterocycles of formula I, or any pharmaceutically acceptable pharmaceutically acceptable of each of the foregoing, including any N-oxides, solvates, tautomers or stereoisomers thereof and/or mixtures thereof in all proportions. is a possible salt.

In yet a further specific embodiment, PE8, a compound of the invention

ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

Z ¹ is CH;

Z ² is CH;

Z ³ is CH or N;

R ¹ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoro Methylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4 -Cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl , 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl , 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2- 1, 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-methylsulfanylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl Midin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano- 6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5 ,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2- yl, quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazoline -2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]phetan-1-yl, cyclohexyl, 4-methylcyclo Hexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-difluorospiro[3.3]heptane-2 -yl, 1H-inden-2-yl; Benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidine- 1-yl) phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)-phenylmethyl, 3-tert-butylphenylmethyl, 3-(difluoromethyl Toxy)-phenylmethyl, 2-(difluoromethyl)phenylmethyl, 3-(difluoromethyl)phenylmethyl, 3-(trifluoromethyl)phenylmethyl, 4-(trifluoromethyl)phenyl]methyl , 2-(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3 -Methanesulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrol-1-yl)phenylmethyl, 2-methyl-3-methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl , 2-methyl-3- (trifluoromethyl) phenylmethyl, 3-trifluoromethyl-4-fluorophenylmethyl, 2-fluoro-5- (trifluoromethoxy) phenylmethyl, 2-methoxy -3-trifluoromethoxyphenylmethyl, 2-fluoro-3-methoxyphenylmethyl, 2-fluoro-3-(trifluoromethyl)phenyl]methyl, 2-fluoro-3-fluoromethoxyphenylmethyl , 2-trifluoromethoxy-5-fluorophenylmethyl, 2-fluoro-5-chloro-phenylmethyl, 3-fluoro-5-methylphenyl) methyl, 3,5-difluorophenylmethyl, 5-fluoro Rho-2- (trifluoromethyl) phenylmethyl, 3-fluoro-5- (trifluoromethyl) phenylmethyl, 2-chloro-3- (trifluoromethyl) phenylmethyl, naphthalin-1-yl Methyl, 5,6,7,8-tetrahydronaphthalen-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-dihydro-2H-1-benzopyran- 8-ylmethyl, 2-phenylethyl, 2-(2-methylphenyl)-ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl) ) Ethyl, 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2-(4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2-(2,4-difluorophenyl) ethyl, 2 -(difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl-3-phenylbutyl, 2-(benzyloxy)ethyl; 5-ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazol-2-ylmethyl, 2-methyl -1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2-propyl) Pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazol-2-ylmethyl, 1-benzimidazole -2-yl)methyl, 1-(2-methylpropyl)-1H-imidazol-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridin- 2-ylmethyl, 2-methylpyridin-4-ylmethyl, 4-trifluoromethylpyridin-2-ylmethyl, 6-(fluoromethyl)-pyridin-2-ylmethyl, 6-trifluoromethylpyridine -2-ylmethyl, 2-(trifluoromethyl)-pyridin-4-ylmethyl, 4-methylpyrimidin-2-ylmethyl, 2-(thiophen-3-yl)ethyl, 5-trifluoro Methylthiophen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H- Pyrrolo[1,2-b]pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imi polyzo[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, pyra zolo[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]phetan-1-ylmethyl, bicyclo[2.2.1]heptane- 2-ylmethyl, bicyclo[2.2.2]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept -2-en-2-yl] methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4 Represents 4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl,

R ² is -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH ₃ , -C(=O)-NH ₂ , -C(=O)-NHCH ₃ , -C(=O)-NHCH ₂ CH ₃ , -C(=O)-NH(CH ₂ ) ₂ CH ₃ , -C(=O)-N(H)-cyclopropyl, -C(=O) -N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH ₂ CH ₂ -OH, -C(=O)-N(H) -CH ₂ CH ₂ -OCH ₃ , -C(=O)-N(H)-CH ₂ -C(H)(OH)-CH ₃ , -C(=O)-N(H)-CH ₂ C (CH ₃ ) ₂ OH, -C(=0)-N(H)-C(H)(CH ₃ )-CH ₂ OH, -C(=0)-N(H)-C(H)(CH ₂ CH ₃ )-CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-CH ₂ CH ₂ -O-CH ₃ , -C(=O)-N( H)-C(CH ₃ ) ₂ CH ₂ CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-phenyl, -C(=O)-N(H) -C(CH ₃ )(CH ₂ OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH ₃ )-phenyl, -C(=O)-N( H)-CH ₂ -1H-1-methylimidazol-2-yl, -C(=O)-N(H)-(CH ₂ ) ₂ -1H-imidazol-1-yl, -C(= O)-N(H)-CH ₂ -pyridin-2-yl, -C(=O)-N(H)-CH ₂ -pyridin-3-yl, -C(=O)-N(H)- CH ₂ -pyridin-4-yl, -C(=O)-N(H)-C(H)(CH ₂ OH)-pyridin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-4-yl, -C(=O)-N(H) -CH ₂ -pyridazin-2-yl, -C(=O)-NH-C(CH ₂ OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -NH-C(=O)-CH=CH ₂ , -NH-C(=O)-CF=CH ₂ , -NH-C(=O)-CH ₂ Cl, -NH-C(=O)- C≡CH, -CH ₂ -NH-C(=O)-CH=CH ₂ , -CH ₂ -NH-C(=O)-CH ₂ Cl, -CH ₂ -NH-C(=O)-C≡CH, -S(=O)-CH ₃ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -OH, -S(=O) ₂ -NH ₂ , -S(=O) ₂ -NHCH ₃ , -S(=O)(=NH)-N(CH ₃ ) ₂ , -S(=O)(=N- CH ₃ )-N(CH ₃ ) ₂ , -S(=O)(=N-CH ₃ )-OH, -S(=O)(=NH)-CH ₃ , -P(=O)(OH) ₂ , F, -CN; preferably represents -C(=O)-OH, -C(=O)-ONa,

A tricyclic heterocycle of Formula I-A, or any pharmaceutically acceptable pharmaceutically acceptable of each of the foregoing, including any N-oxides, solvates, tautomers or stereoisomers thereof and/or mixtures thereof in all proportions. is a possible salt.

In yet another specific embodiment of the present invention, PE9, the compound of the present invention

R ¹ is selected from the group consisting of:

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In certain embodiments of PE9, PE9a,

R ¹ is selected from the group consisting of

이다 (특정 구현예 PE9aa).The remaining radicals and moieties are as defined for formulas IA or I above or for any of the further specific embodiments described herein above or below. In particular, R ¹ is

(specific embodiment PE9aa).

In yet another specific embodiment of the present invention, PE10, the compound of the present invention

R ² is selected from the group consisting of

(R^Z2 와 함께);

(with R ^Z2 );

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In certain embodiments of PE10, PE10a,

Compounds of the present invention

R ² is selected from the group consisting of

(R^Z2 와 함께);

(with R ^Z2 );

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In certain embodiments of PE10a, PE10aa,

R ² is selected from the group consisting of -COOH.

In certain embodiments of PE10, PE10b,

Compounds of the present invention

R ² is selected from the group consisting of

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In certain embodiments of PE10b, PE10bb,

R ² is selected from the group consisting of:

In another specific embodiment of PE10, PE10c,

Compounds of the present invention

R ² is selected from the group consisting of

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

In certain embodiments of PE10c, PE10cc,

R ² is selected from the group consisting of:

) 위에 나타낸 PE9, PE9a, PE9aa, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, 및 PE10cc 는 개개의 라디칼 R¹ 및 R² 각각이 분자의 나머지, 즉 화학식 I 또는 I-A 의 화합물에 부착되는 위치를 나타내기 위해 사용된다는 것을 이해한다.In an embodiment, the dotted line (

) PE9, PE9a, PE9aa, PE10, PE10a, PE10aa, PE10b, PE10bb, PE10c, and PE10cc indicate the positions at which each of the individual radicals R ¹ and R ² are attached to the rest of the molecule, ie the compound of formula I or IA understand that it is used to indicate

In yet another specific embodiment of the present invention, PE11, the compound of the present invention

R ¹ is selected from the group described for PE9 above;

R ² is selected from the group described for PE10 above;

The remaining radicals and moieties are tricyclic heterocycles of formula I-A or I, as defined for formulas I-A or I above or for any of the additional specific embodiments described above or below herein, or any N thereof -a pharmaceutically acceptable salt of any of each of the foregoing, including oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio.

This is a specific embodiment of PE11, PE11a, wherein

R ¹ is selected from the group described above for PE9a, in particular PE9aa;

R ² is selected from the group described for PE10 above.

This is another specific embodiment of PE11, PE11b, wherein

R ¹ is selected from the group described above for PE9a, in particular PE9aa;

R ² is selected from the groups described above for PE10a, in particular for PE10aa.

This is yet another specific embodiment of PE11, PE11c, wherein

R ¹ is selected from the group described above for PE9a, in particular PE9aa;

R ² is selected from the group described above for PE10b, in particular for PE10bb.

This is another specific embodiment of PE11, PE11d, wherein

R ¹ is selected from the group described above for PE9a, in particular PE9aa;

R ² is selected from the group described above for PE10c, in particular for PE10cc.

This is yet another specific embodiment of the present invention, PE12, wherein

ring A is selected from one of the specific embodiments PE2, PE2a, PE2b, PE2c;

R ¹ and R ² are selected as described for PE11.

In certain embodiments of PE12, PE12a, R ¹ and R ² are selected as described for PE11a. In another specific embodiment of PE12, PE12b, R ¹ and R ² are selected as described for PE11b. In yet another specific embodiment of PE12, PE12c, R ¹ and R ² are selected as described for PE11c. In yet a further specific embodiment of PE12, PE12d, R ¹ and R ² are selected as described for PE11d.

In yet another specific embodiment, PE13, the compounds of the present invention are tricyclic heterocycles of formula I-A or I, or any N-oxides, solvates, tautomers or stereoisomers thereof and/or in all ratios. A pharmaceutically acceptable salt of any of the foregoing, including mixtures thereof, wherein the compound is selected from the compounds set forth in Tables 1 and 1b below, in particular Table 1 below. Each single compound shown in Table 1 and Table 1b, as well as any N-oxide, solvate, tautomer or stereoisomer thereof and/or any pharmaceutically acceptable salt of such compound, is a specific embodiment of the present invention. It is understood to represent

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

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 units of unsaturation, or fully saturated. or contains one or more unsaturated units, such as one or more C=C double bond(s) and/or C≡C triple bond(s), but is not aromatic (also referred to herein as a "carbocycle", "alicyclic" or "cycloalkyl"), i.e., generally and unless otherwise defined in the specification or claims, a monocyclic hydrocarbon or bicyclic hydrocarbon or tricyclic hydrocarbon having a single point of attachment to the rest of the molecule. it means. Unless otherwise specified, aliphatic groups contain 1-8 or 1-6 aliphatic carbon atoms (“C _1-8 -aliphatic” and “C _1-6 -aliphatic” respectively). In some embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms (“C _1-5 -aliphatic”). In another embodiment, an aliphatic group contains 1-4 aliphatic carbon atoms (“C _1-4 -aliphatic”). In another embodiment, an aliphatic group contains 1-3 aliphatic carbon atoms (“C _1-3 -aliphatic”), and in another embodiment, an aliphatic group contains 1-2 aliphatic carbon atoms (“C 1-3 -aliphatic”). _1-2 -aliphatic"). In some embodiments, “cycloaliphatic” (“cycloalkyl”) is a monocyclic C ₃ -C ₇ hydrocarbon that is fully saturated or contains one or more unsaturation units that have a single point of attachment to the rest of the molecule, but are not aromatic ( ie monocyclic hydrocarbons having 3, 4, 5, 6 or 7 ring carbon atoms) or bicyclic C _5-8 hydrocarbons (ie bicyclic hydrocarbons having 5, 6, 7 or 8 ring carbon atoms). hydrocarbons). In another embodiment, the term "alicyclic" or "carbocycle" refers to an aromatic, heteroaromatic or heterocyclic ring or ring system through two adjacent ring atoms of the aromatic, heteroaromatic or heterocyclic ring or ring system. means a monocyclic or bicyclic alicyclic ring system fused to; In other words, these carbocycles share two ring atoms with the ring or ring system to which they are fused, thus having two points of attachment to the rest of the molecule. In another embodiment, the term "carbocycle" refers to a bicyclic spirocycle in which two monocyclic carbocycles are fused to each other via the same single carbon atom. In general, the term “aliphatic” includes branched hydrocarbon chains as well as chemically feasible straight-chain, ie unbranched, chains, unless otherwise defined in a particular instance. Also generally, the term includes unsubstituted and substituted hydrocarbon moieties, to the extent chemically possible, unless defined otherwise in a particular instance. Typical substituents for aliphatic groups are halogen, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, particularly unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. Suitable aliphatic groups include linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkyl. including, but not limited to, kenyl.

The term "alkyl" generally refers to saturated aliphatic and acyclic moieties, whereas the term "alkenyl" generally refers to unsaturated aliphatic and acyclic moieties having at least one C=C double bond, and the term "alky "Nyl" generally refers to aliphatic and acyclic moieties having at least one C≡C triple bond. The term “alkenyl” is understood to include all forms of isomers, ie E-isomer, Z-isomer and mixtures thereof (E/Z-isomer). Exemplary aliphatic groups are linear or branched, substituted or unsubstituted C _1-8 -alkyl, C _1-6 -alkyl, C _1-4 -alkyl, C _1-3 -alkyl, C _1-2 -alkyl, C _{2 -8} -alkenyl, C _2-6 -alkenyl, C _2-8 -alkynyl, C _2-6 -alkynyl, C _2-4 -alkynyl, groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

In particular, the term “C _1-3 -alkyl” refers to an alkyl group having 1, 2 or 3 carbon atoms, ie a saturated acyclic aliphatic group. Exemplary C _1-3 alkyl groups are methyl, ethyl, propyl and isopropyl. The term “C _1-4 -alkyl” means an alkyl group having 1, 2, 3 or 4 carbon atoms. Exemplary C _1-4 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl. The term “C _1-6 -alkyl” means an alkyl group having 1, 2, 3, 4, 5 or 6 carbon atoms. Exemplary 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 _1-8 -alkyl” means an alkyl group having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Exemplary C _1-8 -alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n - pentyl, 2-pentyl, n - hexyl, 2-hexyl, n-heptyl, 2-heptyl , n-octyl, 2-octyl, and 2,2,4-trimethylpentyl. Each of these alkyl groups may be straight chain or - except for C ₁ -alkyl and C ₂ -alkyl - branched chain, and may be unsubstituted or substituted with 1, 2, 3, 4 or 5 substituents which may be the same or different. and, unless otherwise specified elsewhere in the specification and/or claims, halogen, cyano, hydroxy, alkoxy, unsubstituted or mono- or di-substituted amino, aryl, especially unsubstituted or substituted phenyl, heteroaryl, especially unsubstituted or substituted pyridyl or pyrimidinyl, heterocyclyl, especially unsubstituted or substituted pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl. It can be.

In some cases, C _1-3 -alkyl, C _1-4 -alkyl, C _1-6 -alkyl, C _1-8 -alkyl groups also contain one or two non - terminal and non - adjacent -CH ₂ - (methylene) may contain those residues in which the group is replaced by -O-, -S- and/or one or two non-terminal and non - adjacent -CH ₂ - or -CH - groups are replaced by -NH - or -N- there is. Such replacement can be for example a (modified) alkyl group such as -CH ₂ -CH ₂ -O-CH ₃ , -CH ₂ -CH ₂ -CH ₂ -S-CH ₃ , CH ₂ -CH ₂ -NH - CH ₂ Calculate -CH ₃ , CH ₂ -CH ₂ -O-CH ₂ -CH ₂ -O-CH ₃ , CH ₂ -CH ₂ -N(CH ₃ )-CH ₂ -CH ₃ and the like. Additional and/or different substitutions of the -CH- and -CH ₂ - groups may be defined for specific alkyl substituents or radicals elsewhere in the specification and/or claims.

The term "C _3-7 -cycloalkyl" means an alicyclic hydrocarbon as defined above, having 3, 4, 5, 6 or 7 ring carbon atoms. Likewise, the term "C _3-6 -cycloalkyl" means an alicyclic hydrocarbon, having 3, 4, 5, or 6 ring carbon atoms. C _3-7 -cycloalkyl groups are unsubstituted - unless specified elsewhere - can be the same or different - unless specified elsewhere - C _1-6 -alkyl, OC _1-6 - 1, 2 or 3 substituents selected from the group consisting of alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino, aryl, in particular unsubstituted or substituted phenyl can be replaced with When substituted, C _3-7 -cycloalkyl includes all possible stereoisomers. Exemplary C _3-7 -cycloalkyl groups are cyclopropyl, 2-methylcyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl am. The term “bicyclic C _5-8 -cycloalkyl” refers to a bicyclic cycloaliphatic hydrocarbon as defined above having 5, 6, 7, or 8 ring carbon atoms; This includes spirocyclic ring systems, ie ring systems in which two carbocycles of bicyclic C _5-8 -cycloalkyl are attached to each other through the same carbon atom. Bicyclic C _5-8 -cycloalkyl groups are unsubstituted - unless specified otherwise elsewhere in this specification - can be the same or different - unless specified elsewhere in this specification - C _1-6 -alkyl, OC _1-6 -alkyl (alkoxy), halogen, hydroxy, unsubstituted or mono- or di-substituted amino. When substituted, bicyclic C _5-8 -cycloalkyl includes all possible stereoisomers. Exemplary bicyclic C _5-8 -cycloalkyls are spiro[3.3]heptanyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.2]octan-2-yl, bicyclo[2.2 .1]hept-5-en-2-ylmethyl, bicyclo[3.1.1]hept-2-en-2-yl.

The term "aliphatoxy" refers to a saturated or unsaturated aliphatic group or substituent as defined above linked to another structural moiety through an oxygen atom (-O-). The term "C _1-6 -alifatoxy" means an alipatoxy radical having 1, 2, 3, 4, 5 or 6 carbon atoms in the aliphatic group. The term "alkoxy" refers to a specific subgroup of moieties and alkyl substituents linked to another structural moiety through a saturated alipatoxy, ie oxygen atom (-O-). Sometimes it is also "O-alkyl", more specifically "OC _1-2 -alkyl", "OC _1-3 -alkyl", "OC _1-4 -alkyl", "OC _1-6 -alkyl" , as “OC _1-8 -alkyl”. Like similar alkyl groups, it can be straight-chain or - except for -OC ₁ -alkyl and -OC ₂ -alkyl - branched, and can be the same or different, unless otherwise specified elsewhere in the specification; It may be unsubstituted or substituted with 1, 2 or 3 substituents selected from the group comprising halogen, unsubstituted or mono- or di-substituted amino. Exemplary alkoxy groups are methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, n - propoxy, iso-propoxy, n-butoxy, sec-part oxy, tert-butoxy, n-pentoxy.

The term "alkylene" refers to a divalent (or divalent) aliphatic group, particularly a divalent alkyl group. An "alkylene chain" is a polymethylene group, ie -(CH ₂ ) _y - (where y is a positive integer, preferably 1, 2, 3, 4, 5 or 6). In the context of the present invention, “C _1-3 -alkylene” refers to an alkylene moiety having 1, 2 and 3 —CH ₂ — groups, respectively; The term "alkylene" includes branched alkylene groups as well as linear alkylene groups, i.e., "alkylene chains". The term “C _1-6 -alkylene” refers to an alkylene moiety that is linear, ie an alkylene chain or branched, and has 1, 2, 3, 4, 5 or 6 carbon atoms. The term "C _2-6 -alkylene" means an alkylene moiety having 2, 3, 4, 5 or 6 carbon atoms, "C _3-4 -alkylene" having 3 or 4 carbon atoms "C _2-3 -alkylene" means an alkylene moiety having 2 or 3 carbon atoms. A substituted alkylene is a group in which one or more methylene hydrogen atoms have been replaced by (or with) a substituent. Suitable substituents include those described herein for substituted alkyl groups. In some cases, 1 or 2 methylene groups of an alkylene chain may be replaced by, for example, O, S and/or NH or N - C _1-4 -alkyl. Exemplary alkylene groups are -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -CH 2 -CH 2 -, -O-CH _{2 -CH 2 -} , -O-CH ₂ -CH ₂ -CH ₂ -, -CH ₂ -O-CH ₂ -CH ₂ -, -O-CH ₂ -O-, -O-CH ₂ -CH ₂ -O-, -O-CH ₂ -CH ₂ -CH ₂ -O-,-CH ₂ -NH-CH ₂ -CH ₂ -, -CH ₂ -N(CH ₃ )-CH ₂ -CH ₂ -.

The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described herein for substituted aliphatic groups. The term “alkenylene” refers to a straight-chain divalent alkenylene radical, ie alkenylene chains, as well as branched alkenylene groups. The term "C _2-6 -alkenylene" means an alkenylene radical having 2, 3, 4, 5 or 6 carbon atoms.

The term "alkynylene" refers to a divalent alkynyl group. A substituted alkynylene chain is a polymethylene group containing at least one triple bond in which one or more hydrogen atoms have been replaced with a substituent. Suitable substituents include those described herein for substituted aliphatic groups.

The term “halogen” means F, Cl, Br or I.

The term "heteroatom" refers to one or more of oxygen (O), sulfur (S), or nitrogen (N) (any oxidized form of nitrogen or sulfur, such as N - oxides, sulfoxides and sulfones; any Quaternized forms of basic nitrogen or substitutable nitrogens of heterocyclic or heteroaromatic rings, such as N (as in 3,4-dihydro-2 H -pyrrolyl), NH (as in pyrrolidinyl) ) or N - SUB, where SUB is a suitable substituent, including (as in N-substituted pyrrolidinyl)).

The term "aryl", used alone or as part of a larger moiety, as in "aralkyl", "aralkoxy" or "aryloxyalkyl", means a ring member having a total of 5 to 14 ring members (the ring members being carbon atoms). atoms), at least one ring in the system is aromatic, i.e. it has (4n+2) π (pi) electrons, where n is 0, 1 , an integer selected from 2 and 3), the electrons are delocalized throughout the system, and each ring in the system contains 3 to 7 ring members. Preferably, all rings within the aryl system or total ring system are aromatic. The term “aryl” is used interchangeably with the term “aryl ring”. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system. More specifically, these aromatic ring systems may be mono-, bi- or tricyclic having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring carbon atoms. Even more specifically, these aromatic ring systems may be mono- or bicyclic having 6, 7, 8, 9, or 10 ring carbon atoms. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl, and the like, which may be unsubstituted or substituted with one or more identical or different substituents. As used herein, a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, and the like, also includes the term " aryl" or "aromatic ring system". In the latter case, the “aryl” group or substituent is attached to its pendant group through the aromatic portion of the ring system.

The term "benzo" refers to a six-membered aromatic ring (having carbocyclic ring atoms) fused to another ring through two adjacent carbon atoms, which is a cycloaliphatic, aromatic, heteroaromatic or heterocyclic (heteroaliphatic) ring ego; The result is a ring system with at least two rings that share two common carbon atoms with the other ring to which the benzo ring is fused. For example, fusing a benzo ring to a phenyl ring forms a naphthaline ring system, while fusing a benzo ring to a pyridine gives a quinoline or isoquinoline; Fusing a benzo ring to a cyclopentene ring provides an indene ring.

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl" or "heteroaralkoxy", refer to 3, 4, 5, 6, has 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, which atoms are carbon and heteroatoms, preferably 5, 6, 9 or 10 ring atoms; have 6, 10 or 14 π electrons shared in a cyclic arrangement; represents a group having, in addition to carbon atoms, 1, 2, 3, 4 or 5 heteroatoms. The term "heteroatom" refers to nitrogen, oxygen or sulfur, and includes any oxidized form of nitrogen or sulfur, and the quaternized form of basic nitrogen. That is, a “heteroaryl” ring or ring system may also be described as an aromatic heterocycle. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl , furazanil, pyridyl (pyridinyl), pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, pteridinyl, and pyrrolopyridinyl, especially pyrrolo[2,3 -b] pyridinyl. As used herein, the terms “heteroaryl” and “heteroar-” also refer to groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the radical or point of attachment is a heteroaromatic or , on the aryl ring, if present). Non-limiting examples include indolyl, isoindolyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, Cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4 H -quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydro isoquinolinyl, 9H-carbazolyl, dibenzofuranil and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. For example, an indolyl ring may be attached through one of the ring atoms of a 6-membered aryl ring or through one of the ring atoms of a 5-membered heteroaryl ring. Heteroaryl groups are optionally mono-, bi- or tricyclic. The term "heteroaryl" is used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic" (any of the above terms includes rings that are unsubstituted or substituted with one or more identical or different substituents). used interchangeably. The term “heteroaralkyl” refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl moieties are independently optionally substituted.

A heteroaryl ring can be attached to its pendant group at any hetero or carbocyclic ring atom to create a structure or molecule in which the attachment is stable: any ring atom can be unsubstituted or substituted.

The structure of a typical example of a "heteroaryl" substituent used in the present invention is depicted below:

Such heteroaryl substituents may be attached to any pendant group through any of its ring atoms suitable for such attachment.

As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and are 5, 6, 7, 8, 9, refers to a stable mono-bi- or tricyclic heterocyclic moiety having 10, 11, 12, 13, 14 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatoms , the heterocyclic moiety is saturated or partially unsaturated; Heterocyclic moieties that are aromatic rings or ring systems are referred to as "heteroaryl" moieties, as described above. Preferably, the heterocycle is a stable saturated or partially unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic or It is an 11-, 12-, 13- or 14-membered tricyclic heterocyclic moiety.

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

The term "saturated" in the context of the term "heterocycle" refers to fully saturated heterocyclic groups such as pyrrolidinyl, piperidinyl, morpholinyl, piperidinonyl, tetrahydrofuranyl, thianyl, and dioxothianil. Refers to the click system. In relation to the term "heterocycle", the term "partially unsaturated" means (i) a heterocyclic system that contains at least one unsaturated unit, for example a C=C or C=heteroatom bond, but is not aromatic, such as For example tetrahydropyridinyl; or (ii) a (saturated or unsaturated but non-aromatic) heterocyclic ring is fused with an aromatic or heteroaromatic ring system, but the "partially unsaturated heterocycle" does not go through an aromatic or heteroaromatic portion and is a "heterocyclic ring" of the system. Refers to a heterocyclic system that is attached to the rest of the molecule (its pendant group) through one of the ring atoms of the "cyclic" moiety. "Partially unsaturated" heterocycles of this first class (i) may also be referred to as "non-aromatic partially unsaturated" heterocycles. Such "partially unsaturated" heterocycles of this second class (ii) may also be referred to as (bicyclic or tricyclic) "partially aromatic" heterocycles, provided that at least one of the rings of the heterocycle is represents a saturated or unsaturated but non-aromatic heterocycle fused with at least one aromatic or heteroaromatic ring system. Typical examples of such “partially aromatic” heterocycles are 1,2,3,4-tetrahydroquinolinyl and 1,2,3,4-tetrahydroisoquinolinyl.

A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom to create a stable structure and any ring atom can be unsubstituted or substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, but are not limited to, tetrahydrofuranyl, tetrahydropyranyl, thianyl, dioxothianyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl , morpholinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinil, dioxanil, dioxolanil, diazepinil, oxazepinil, thiazepi nyl, morpholinyl and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic radical" are used interchangeably herein; Also groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or alicyclic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl, wherein the radical or point of attachment is hetero on the cyclyl ring). Heterocyclyl groups are optionally mono-, bi- or tricyclic. The term “heterocyclylalkyl” refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently unsubstituted or substituted.

The term "carbohydrate-derived radical" refers to monovalent organic radicals derived from carbohydrate compounds of any kind, such as aldoses and ketosis, as well as polyols derived from such aldoses and ketosis, i.e. reduced carbohydrates, and carbohydrate acids, i.e. oxidized refers to carbohydrates. This term includes D/L-glyceraldehyde, D-glycerol aldehyde, L-glycerol aldehyde, dihydroxy acetone, 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-Lysose, D-Lysose, L-Lysose, D/L-Allose, D-Allose, L-Allose, D/L-Altro Oose, D-altrose, L-altrose, D/L-glucose, D-glucose, L-glucose, D/L-mannose, D-mannose, L-mannose, D/L-gulose, D -Gulose, D-gulose, D/L-idose. D-idose, L-idose, D/L-galactose, D-galactose, L-galactose, D/L-talose, D-talose, L-talose, D/L-fructose, D -fructose, L-fructose; D/L-sorbose, D-sorbose, L-sorbose; D/L-sorbit, D-sorbit, L-sorbit, D/L-maninite, D-maninite, L-maninite, D/L-alit, D-alit, L-alit , D/L-galasheet, D-galasheet, L-galasheet, D/L-glusheet, D-glusheet, L-glusheet, D/L-idite, D-idite, L-idite alt, D/L-altrite, D-altrite, L-altrite; of monosaccharides, including but not limited to D/L-gluconic acid, D-gluconic acid, L-gluconic acid, D/L-mannonic acid, D/L-gluconic acid, D-gluconic acid, and L-gluconic acid. monovalent radicals and their reduced and oxidized derivatives. It also includes monovalent radicals of disaccharides and oligosaccharides and their respective reduced and oxidized derivatives including sucrose, lactose, maltose, cellobiose. These carbohydrate derived radicals can be used in their pure D- or L-forms or as a mixture of D- and L-forms in any possible ratio. Likewise, each of these radicals includes their open form as well as their cyclic form in pure form or as a mixture in any proportion. Each of these carbohydrate derived radicals is a suitable substituent, eg halogen, cyano, unsubstituted, mono- or di-substituted amino, C _1-6 aliphatic, C _1-6 aliphatoxy, aryl, arylalkyl etc. may be further substituted. Any carbohydrate-derived radical can be attached to its pendant group at any hetero or carbon atom to create a structure or molecule in which the attachment is stable. Examples of carbohydrate derived radicals are D/L-fructose, D-fructose, D/L-glucose, D-glucose, D/L-glucoronic acid, D-glucoronic acid, L-glucoronic acid.

The term "bioisostere", when used alone or in combination with other terms, such as "bioisostere radicals", refers to another compound, group, radical, moiety or substituent that is structurally different from one another but Refers to compounds or groups, radicals, moieties, substituents, etc. that induce similar biological effects. In a broad sense, a “bioisomer” can be understood as a compound or group that has approximately the same molecular shape and volume, approximately the same distribution of electrons, and exhibits similar physical properties. A typical example of a bioisoster is a carboxylic acid bioisoster ("carboxylic acid bioisoster") that exhibits physiochemical properties similar to carboxylic acid groups. Such carboxylic acid bioisosteric groups or radicals can be used in place of carboxylic acid groups or radicals, thereby providing properties similar to those of carboxylic acid groups, but potentially with some different properties when compared to carboxylic acid groups. properties such as reduced polarity, increased lipophilicity, or improved pharmacokinetic properties. Typical examples of carboxylic acid bioisosteres include, but are not limited to -CN, fluoro, amides, sulfonamides, sulfonimides, and hydroxy-substituted isoxazoles, sulfonamido-substituted oxadiazoles and oxadia several aromatic and non-aromatic heterocycles such as sols, such as 5-oxo-2,5-dihydro-1,2,4-oxadiazoles, and especially tetrazoles, such as 1H-1,2 ,3,4-tetrazole, 2-methyl-2H-1,2,3,4-tetrazole.

As used herein, the term “unsaturated” refers to a moiety or group having one or more units of unsaturation or a cyclic group.

As used herein with reference to any ring, ring system, ring moiety, etc., the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term “partially unsaturated” is intended to include rings having multiple sites of unsaturation. In particular, they include (i) non-saturated (mono-, bi- or tricyclic) ring systems that are free of any aromatic or heteroaromatic moieties or moieties; and (ii) bi- or tricyclic where one of the rings of the ring system is an aromatic or heteroaromatic ring fused with another ring that is not an aromatic or heteroaromatic ring, for example tetrahydronaphthyl or tetrahydroquinolinyl. contains a ring system. "Partially unsaturated" rings, ring systems, ring moieties of the first class (i) may also be referred to as "non-aromatic partially unsaturated" rings, ring systems, ring moieties, and those of the second class ( ii) may be referred to as a "partially aromatic" ring, ring system, ring moiety.

As used herein, the term "bicyclic", "bicyclic ring" or "bicyclic ring system" refers to any bicyclic ring system, i.e., saturated or having one or more units of unsaturation, i.e., partially unsaturated or aromatic, a ring system Refers to a carbocyclic or heterocyclic group having at least one atom in common between the two rings of . Thus, this term includes any permissible ring fusion, such as ortho-fused or spirocyclic. As used herein, the term "heterobicyclic" is a subset of "bicyclic" which requires that at least one heteroatom be present in one or both rings of the bicycle. These heteroatoms may be present at ring junctions and may be optionally substituted, nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including phosphates) including oxidized forms), boron, and the like. In some embodiments, bicyclic groups have 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Likewise, the term “tricyclic”, “tricyclic ring” or “tricyclic ring system” refers to any tricyclic ring system, i.e., saturated or having one or more units of unsaturation, i.e. partially unsaturated or aromatic, and bicyclic ring system ( as defined above) is fused with another, second ring. Thus, the term includes any permissible ring fusion. As used herein, the term "heterotricyclic" is a subset of "tricyclic" which requires that at least one heteroatom be present in one or both rings of the tricycle. These heteroatoms may be present at ring junctions and may be optionally substituted, nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including phosphates) including oxidized forms), boron, and the like. In some embodiments, tricyclic groups have 10-14 ring members and 0-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

As described herein, certain compounds of the invention contain “substituted” or “optionally substituted” moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety have been replaced with a suitable substituent. "Substituted" applies to one or more hydrogens, either explicit or implicit from the structure. Unless otherwise indicated, a "substituted" or "optionally substituted" group has a suitable substituent at each substitutable position of the group, and any When more than one position in a given structure of is substituted with more than one substituent selected from a particular group, the substituents are the same or different at each position. When a particular group, substituent, moiety or radical is "monosubstituted", it has one (1) substituent. if it is "di-substituted" it has two (2) substituents and is the same or different; "Tri-substituted" has three (3) substituents, where all three are identical or two are identical and the third is different or all three are different. Combinations of substituents devised by the present invention are preferably those that lead to the formation of stable or chemically feasible compounds. As used herein, the term “stable” means substantially modified when applied to conditions that permit its preparation, detection, and, in certain embodiments, its recovery, purification, and use for one or more of the purposes disclosed herein. Indicates a compound that does not.

Unless indicated otherwise anywhere in the specification or appended claims, each optional substituent on a substitutable carbon may be halogen; -(CH ₂ ) _0-4 R°; -(CH ₂ ) _0-4 OR°; -O(CH ₂ ) _0-4 R°, -O-(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 CH(OR°) ₂ ; -(CH ₂ ) _0-4 SR°; -(CH ₂ ) _0-4 Ph (which may be substituted by one or more R°); -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 Ph (which may be substituted by one or more R°); -CH=CHPh (which may be substituted by one or more R°); -(CH ₂ ) _0-4 O(CH ₂ ) _0-1 -pyridyl (which may be substituted by one or more R°); -NO ₂ ; -CN; -N ₃ ; -(CH ₂ ) _0-4 N(R°) ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)R°; -N(R°)C(S)R°; -(CH ₂ ) _0-4 N(R°)C(O)NR° ₂ ; -N(R°)C(S)NR° ₂ ; -(CH ₂ ) _0-4 N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR° ₂ ; -N(R°)N(R°)C(O)OR°; -(CH ₂ ) _0-4 C(O)R°; -C(S)R°; -(CH ₂ ) _0-4 C(O)OR°; -(CH ₂ ) _0-4 C(O)SR°; -(CH ₂ ) _0-4 C(O)OSiR° ₃ ; -(CH ₂ ) _0-4 OC(O)R°; -OC(O)(CH ₂ ) _0-4 SR-, SC(S)SR°; -(CH ₂ ) _0-4 SC(O)R°; -(CH ₂ ) _0-4 C(O)NR° ₂ ; -C(S)NR° ₂ ; -C(S)SR°; -SC(S)SR°, -(CH ₂ ) _0-4 OC(O)NR° ₂ ; -C(O)N(OR°)R°; -C(O)C(O)R° -C(O)CH ₂ C(O)R°; -C(NOR°)R°; -(CH ₂ ) _0-4 SSR°; - (CH ₂ ) _0-4 S(O) ₂ R°; -(CH ₂ ) _0-4 S(O) ₂ OR°; -(CH ₂ ) _0-4 OS(O) ₂ R°; -S(O) ₂ NR° ₂ ; - S(O)(NR°)R°; -S(O) ₂ N=C(NR° ₂ ) ₂ ; -(CH ₂ ) _0-4 S(O)R°; -N(R°)S(O) ₂ NR° ₂ ; -N(R°)S(O) ₂ R°; -N(OR°)R°; -C(NH)NR° ₂ ; -P(O) ₂ R°; -P(O)R° ₂ ; -OP(O)R° ₂ ; -OP(O)(OR°) ₂ ; SiR° ₃ ; -(C _1-4 straight or branched alkylene)ON(R°) ₂ ; or -(C _1-4 straight or branched alkylene)C(O)ON(R°) ₂ . “Ph” means phenyl; “-(CH ₂ ) _0-4 ” is understood to mean an alkylene group without an alkylene group or having 1, 2, 3 or 4 CH ₂ units, if the subscript is “0” (zero).

each R° is independently hydrogen, halogen, C _1-6 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, -CH ₂ -(5-6 membered heteroaryl ring), or 5 -6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the above definition, two independent occurrences of R° 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, taken together with their intervening atom(s); , which may be substituted by a divalent substituent on a saturated carbon atom of R° selected from =O and =S; or each R° is halogen, -(CH ₂ ) _0-2 R ^● , -(haloR ^● ), -(CH ₂ ) _0-2 OH, -(CH ₂ ) _0-2 OR ^● , -(CH ₂ ) _0-2 CH(OR ^● ) ₂ ; O(haloR ^● ), -CN, -N ₃ , -(CH ₂ ) _0-2 C(O)R ^● , -(CH ₂ ) _0-2 C(O)OH, -(CH ₂ ) _0-2 C(O)OR ^● , -(CH ₂ ) _0-2 SR ^● , -(CH ₂ ) _0-2 SH, -(CH ₂ ) _0-2 NH ₂ , -(CH ₂ ) _0-2 NHR ^● , -(CH ₂ ) _0-2 ^NR ₂ , -NO ₂ , -SiR ³ , -OSiR ₃ ^, C(O)SR ^, _- (C _1-4 straight or branched alkylene ₎ C(O) optionally substituted with a monovalent substituent independently selected from OR ^● , or -SSR ^● . “Ph” means phenyl; "halo" means halogen; “-(CH ₂ ) _0-2” is understood to mean no alkylene group or an alkylene group having 1 or 2 CH ₂ units if the subscript is “0” (zero).

each R ^● is independently C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) _0-1 Ph, or 5-6-membered saturated, partially unsaturated, or from nitrogen, oxygen, or sulfur aryl rings having 0-4 independently selected heteroatoms, wherein each R ^● is unsubstituted or substituted only with one or more halogens when preceded by halo; or any substituent on a saturated carbon =O, =S, =NNR ^* ₂ , =NNHC(O)R ^* , =NNHC(O)OR ^* , =NNHS(O) ₂ R ^* , =NR ^* , = a divalent substituent independently selected from NOR ^* , -O(C(R ^* ₂ )) _2-3 O-, or -S(C(R ^* ₂ )) _2-3 S-, or "optionally substituted " The divalent substituent attached to the adjacent substitutable carbon of the group is -O(CR ^* ₂ ) _2-3 O-, wherein each independent occurrence of R ^* is hydrogen, C _1-6 aliphatic or unsubstituted 5-6-membered saturated, partially unsaturated, or 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur It is selected from aryl rings having

When R ^* is C _1-6 aliphatic, R ^* is optionally halogen, -R ^● , (haloR ^● ), OH, -OR ^● , -O(haloR ^● ), -CN, -C(O)OH, - C(O)OR ^● , -NH ₂ , -NHR ^● , -NR ^● ₂ , or -NO ₂ , wherein each R ^● is independently C _1-4 aliphatic, -CH ₂ Ph, -O( CH ₂ ) _0-1 Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein each R ^● is unsubstituted or substituted only with one or more halogens when preceded by halo.

Any substituent on a substitutable nitrogen is independently -R ^† , -NR ^† ₂ , -C(O)R ^† , -C(O)OR ^† , -C(O)C(O)R ^† , -C( O)CH ₂ C(O)R ^† , -S(O) ₂ R ^† , -S(O) ₂ NR ^† ₂ , -C(S)NR ^† ₂ , -C(NH)NR ^† ₂ , or - N(R ^† )S(O) ₂ R ^† ; wherein each R ^† is independently hydrogen, C _1-6 aliphatic, unsubstituted —OPh, or unsubstituted 5-6-membered saturated, partially unsaturated, or 0 independently selected from nitrogen, oxygen, or sulfur. Aryl rings with -4 heteroatoms, or two independent occurrences of R ^† , taken together with their intervening atom(s), form an unsubstituted 3-12-membered saturated, partially unsaturated, or nitrogen, oxygen , or an aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from sulfur; When R ^† is C _1-6 aliphatic, R ^† is optionally halogen, -R ^● , -(haloR ^● ), -OH, -OR ^● , -O(haloR ^● ), -CN, -C(O)OH , -C(O)OR ^● , -NH ₂ , -NHR ^● , -NR ^● ₂ , or -NO ₂ , each R ^● is C _1-4 aliphatic, -CH ₂ Ph, -O(CH ₂ ) independently selected from _0-1 Ph, or 5-6 membered saturated, partially unsaturated, or aryl rings having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, each R ^● is unsubstituted or substituted only with one or more halogens when preceded by halo. “Ph” means phenyl; “Halo” is understood to mean halogen.

The term "solvate" refers to an addition form of a compound of the present invention and a pharmaceutically acceptable solvent containing a solvent, preferably a stoichiometric or non-stoichiometric amount of the solvent. Some compounds tend to trap a fixed molar ratio of solvent molecules in the crystalline solid state and thus form solvates. When the solvent is water, the solvate formed is a hydrate, for example a hemi-, mono- or dihydrate. When the solvent is an alcohol, the solvate formed is an alcoholate, for example a methanolate or ethanolate. When the solvent is an ether, the solvate formed is an etherate, for example diethyl etherate.

The term “N - oxide” refers to those compounds of the present invention that contain an amine oxide moiety, ie an oxide of a tertiary amine group.

Compounds of formulas I-A and I may have - also depending on the nature of the substituents they may have - one or more chiral centers. They may thus optionally occur in various enantiomeric and diastereomeric forms, and may be in racemic or optically active form. Accordingly, the present invention also relates to optically active forms, enantiomers, racemates, diastereomers, mixtures thereof in all proportions, collectively: "stereoisomers" for the purposes of the present invention of these compounds. . As the pharmacological activity of the racemates or stereoisomers of the compounds according to the present invention may differ, it may be desirable to use a particular stereoisomer, eg one particular enantiomer or diastereomer. In this case, the compounds according to the invention obtained as racemates or even intermediates thereof can be separated into stereoisomeric (enantiomers, diastereomers) compounds by chemical or physical measurements known to those skilled in the art. Another approach that can be applied to obtain one or more specific stereoisomers of the compounds of the present invention in enriched or pure form is stereoselective synthetic procedures, for example (e.g., pure or The starting materials are applied in stereoisomerically enriched or pure form (using enriched (R)- or (S)-enantiomers), or using chiral reagents or catalysts, especially enzymes. In the context of the present invention, the term "pure enantiomer" usually means at least 95%, preferably ≥ 98%, more preferably ≥ 98.5%, still more preferably ≥ 99% of the other enantiomer (its opposite). Refers to the relative purity of one enantiomer for

Thus, for example, compounds of the invention which have at least one chiral center and which occur as racemates or as mixtures of enantiomers or diastereomers, by methods known per se, are optically pure or enriched isomers, i.e. enantiomers. It can be resolved or resolved into isomers or diastereomers. Separation of the compounds of the present invention may be accomplished by chromatographic methods, for example column separation on a chiral or achiral phase, or optionally by recrystallization from an optically active solvent, or by use of an optically active acid or base, or derivatization with an optically active reagent, such as an optically active alcohol, and subsequent removal of the radical.

In the context of the present invention, the term "tautomer" means a compound of the present invention that exists in tautomeric form and is capable of exhibiting tautomerism; For example, carbonyl compounds can exist in their keto and/or their enol forms and exhibit keto-enol tautomerism. These tautomers may occur in their individual forms, eg the keto or enol forms, or as mixtures thereof, and are claimed individually and together as a mixture in any proportion. The same applies to cis/trans isomers, E/Z isomers, conformers, etc.

In one embodiment, the compounds of the present invention may be in free base or acid form - as the case may be - ie non-salt (or no-salt) form. In another embodiment, a compound of the present invention is in the form of a pharmaceutically acceptable salt, pharmaceutically acceptable solvate, or pharmaceutically acceptable solvate of a pharmaceutically acceptable salt.

The term "pharmaceutically acceptable salt" refers to a salt prepared from a pharmaceutically acceptable base or acid including an inorganic base or acid and an organic base or acid. When a compound of the present invention contains one or more acidic or basic groups, the present invention also includes its corresponding pharmaceutically acceptable salts. Thus, compounds of the present invention containing acidic groups such as carboxyl groups may exist in salt form and may 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 are lithium salts, sodium salts, potassium salts, calcium salts, magnesium salts, barium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, diethanolamine, triethanolamine, salts with peridine, N-methylglutamine or amino acids. These salts are readily obtained, for example, by reacting a compound having an acidic group with a suitable base, for example lithium hydroxide, sodium hydroxide, sodium propoxide, potassium hydroxide, potassium ethoxide, magnesium hydroxide, calcium hydroxide or barium hydroxide. possible. Other base 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, for example groups capable of being protonated, may exist in salt form and may be used according to the present invention in the form of their addition salts with inorganic or organic acids. Examples of suitable acids are hydrogen chloride, hydrogen bromide, hydrogen iodide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, sulfoacetic acid, trifluoroacetic acid, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid , carbonic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, malonic acid, maleic acid, malic acid, embonic acid, mandelic acid, sulfamic acid, phenylpropionic acid, gluconic acid, ascorbic acid , isonicotinic acid, citric acid, adipic acid, taurocholic acid, glutaric acid. stearic acid, glutamic acid or aspartic acid, and other acids known to those skilled in the art. The salts formed are inter alia hydrochloride, chloride, hydrobromide, bromide, iodide, sulfate, phosphate, methanesulfonate (mesylate), tosylate, carbonate, bicarbonate, formate, acetate, Sulfoacetate, triflate, oxalate, malonate, maleate, succinate, tartrate, malate, embonate, mandelate, fumarate, lactate, citrate, glutarate, stearate, aspartate and It is glutamate. The stoichiometry of the salts formed from the compounds of the present invention may also be integer multiples or non-integer multiples of 1.

Compounds of the present invention containing basic nitrogen-containing groups include (C ₁ -C ₄ )alkyl halides such as methyl, ethyl, isopropyl and tert-butyl chlorides, bromides and iodides; di(C ₁ -C ₄ )alkyl sulfates such as dimethyl, diethyl and diamyl sulfate; (C ₁₀ -C ₁₈ )alkyl halides such as decyl, dodecyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; and aryl(C ₁ -C ₄ )alkyl halides such as benzyl chloride and phenethyl bromide. Both water-soluble and oil-soluble compounds according to the present invention can be prepared using these salts.

When the compounds of the present invention contain both acidic and basic groups in the molecule, the present invention also includes internal salts or betaines (zwitterions) in addition to the salt forms mentioned. Each salt can be obtained by conventional methods known to those skilled in the art, for example by contacting them with organic or inorganic acids or bases in a solvent or dispersant, or by anion exchange or cation exchange with other salts. In addition, the present invention provides all salts of the compounds of the present invention that are not directly suitable for use in medicine because of their poor physiological compatibility, but can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts. include

Therefore, the following items are also according to the present invention:

(a) including all stereoisomers or tautomers of the compound and mixtures thereof in all proportions;

(b) pharmaceutically acceptable salts of the compounds and items mentioned in (a);

(C) pharmaceutically acceptable solvates of the compounds and items mentioned in (a) and (b);

(d) N-oxides of the compounds and items mentioned in (a), (b), and (c).

All references to compounds above and below should be understood to include pharmaceutically acceptable solvates of these items, in particular pharmaceutically acceptable solvates of the compounds, or pharmaceutically acceptable salts thereof.

Also, the compounds of the present invention are intended to include isotopically-labeled forms thereof. Isotopically-labeled forms of the compounds of Formula I or IA are identical to those compounds except for the fact that one or more atoms of the compound are replaced by an atom having an atomic mass or mass number that is usually different from the atomic mass or mass number of the naturally occurring atom. Examples of isotopes that are readily commercially available and that can be incorporated into the compounds of the present invention by well-known methods include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as ² H ( D), ³ H, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³³ S, ³⁴ S, ³⁵ S, ³⁶ S, ¹⁸ F and ³⁶ CI, respectively. Compounds of Formula I or IA, or pharmaceutically acceptable salts thereof, which contain one or more of the aforementioned isotopes and/or other isotopes of other atoms are intended to be part of this invention. Isotopically-labeled compounds of Formula I or IA can be used in a number of beneficial ways. For example, isotopically-labeled compounds of the present invention incorporating radioactive isotopes such as ³ H or ¹⁴ C are suitable for pharmaceutical and/or matrix tissue distribution assays. These radioactive isotopes, namely tritium ( ³ H) and carbon-14 ( ¹⁴ C), are particularly preferred because of their simple preparation and good detectability. Incorporation of heavier isotopes, such as deuterium ( ² H), into compounds of Formula I or IA has therapeutic advantages due to the higher metabolic stability of these isotopically-labeled compounds. Higher metabolic stability directly leads to increased half-life in vivo or reduced dosage, which under most circumstances will represent a preferred embodiment of the present invention. Isotopically-labeled compounds of Formula I or IA typically replace non-isotopically-labeled reactants with readily available isotopically-labeled reactants, such as synthetic schemes and related descriptions, examples section and It can be prepared by carrying out the procedure described in the preparation section.

Deuterium ( ² H; D) may also be incorporated into compounds of formula I or IA for the purpose of manipulating the oxidative metabolism of the compound by first order kinetic isotope effects. The primary kinetic isotope effect is a change in rate for a chemical reaction due to exchange of isotope nuclei caused by a change in the ground state energy required for covalent bond formation after such isotope exchange. The exchange of heavier isotopes usually results in lower ground state energies for chemical bonds, thus causing a decrease in the rate at rate-limiting bond breakage. When bond breakage occurs within or near the saddle point region along the coordinates of a multi-product reaction, the product distribution ratio can be substantially altered. For clarification: When deuterium bonds to a carbon atom in a non-exchangeable position, a rate difference of k _M /k _D = 2-7 is typical. If this rate differential is successfully applied to compounds of formula I or IA that are susceptible to oxidation, the profile of such compounds in vivo can be drastically modified, resulting in improved pharmacokinetic properties.

When discovering and developing therapeutics, those skilled in the art attempt to optimize pharmacokinetic parameters while maintaining desirable in vitro properties. It is reasonable to assume that many compounds with poor pharmacokinetic profiles are susceptible to oxidative metabolism. Currently available in vitro liver microsomal assays provide valuable information during this type of oxidative metabolism, which allows rational design of deuterated compounds of Formula I or IA with improved stability through resistance to such oxidative metabolism. make it possible A significant improvement in the pharmacokinetic profile of the compound of formula I or IA is thereby obtained, an increase in half-life in vivo (t1/2), concentration at maximal therapeutic effect (C _max ), area under the dose response curve ( AUC), and in terms of F; and quantified in terms of reduced clearance, dosage and material cost.

The following is intended to illustrate the above: Compounds of formula I or I-A having a number of potential attack sites for oxidative metabolism, for example a hydrogen atom bonded to a benzylic hydrogen atom and a nitrogen atom, Various combinations are prepared as a series of analogues in which deuterium atoms are replaced, so that some, most or all of these hydrogen atoms have been replaced with deuterium atoms. Half-life determination makes it possible to determine advantageously and accurately the degree to which an improvement in resistance to oxidative metabolism is improved. In this way, it is determined that the half-life of the parent compound can be extended by up to 100% as a result of this type of deuterium-hydrogen exchange.

Deuterium-hydrogen exchange in the compounds of the present invention can also be used to achieve desirable modifications of the metabolite spectrum of the starting compounds to reduce or eliminate undesirable toxic metabolites. For example, if a toxic metabolite occurs through oxidative carbon-hydrogen (CH) bond cleavage, the deuterated analog will greatly reduce the production of the unwanted metabolite, even if the specific oxidation is not the rate-determining step, or It may be reasonable to assume that it will be eliminated. Further information on the state of the 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.

The present invention relates to at least one compound of formula I or I-A as an active ingredient, or N-oxides, solvates, tautomers or stereoisomers thereof, as well as pharmaceutically acceptable salts of each thereof (in all proportions thereof). It relates to a pharmaceutical composition comprising (including a mixture of) together with a pharmaceutically acceptable carrier.

For the purposes of the present invention, the term "pharmaceutical composition" (or "pharmaceutical formulation") refers to a composition or product comprising one or more active ingredients and one or more inactive ingredients constituting a carrier, as well as any, directly or indirectly, Refers to any product that results from the combination, complexation or aggregation of two or more components, or from the dissociation of one or more components, or from other types of reactions or interactions of one or more components. Thus, the pharmaceutical composition of the present invention includes any composition prepared by mixing one or more compounds of the present invention and a pharmaceutically acceptable carrier. It may further contain physiologically acceptable excipients, adjuvants, adjuvants, diluents and/or additional pharmacologically active substances other than the compounds of the present invention.

Pharmaceutical compositions include compositions and pharmaceutical preparations suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular and intravenous), ocular (ophthalmic), pulmonary (nasal or oral inhalation), or nasal administration, but any The route most suitable for a given case of will depend on the nature and severity of the condition being treated and the nature of the active ingredient. They may conveniently be presented in unit dosage form and may be prepared by any method well known in the art of pharmacy.

The pharmaceutical composition of the present invention may further comprise one or more other compounds, such as one or more additional compounds of the present invention, as an active ingredient (drug). In certain embodiments, the pharmaceutical composition comprises a second active ingredient or its derivatives, prodrugs, solvates, tautomers or stereoisomers, as well as mixtures thereof in all proportions, including pharmaceutically acceptable salts of each of the foregoing. further comprising, wherein the second active ingredient is other than a compound of Formulas I and I-A; Preferably the second active ingredient is a compound for which a compound of the present invention is also useful and is useful for the treatment, prevention, inhibition and/or amelioration of a medical condition or pathology listed above or elsewhere herein below. Such combinations of two or more active ingredients or drugs may be safer or more effective than either drug or active ingredient alone, or the combination may be safer or more effective than would be expected based on the additive properties of the individual drugs. These other drug(s) can be administered by a route and in an amount commonly used either simultaneously or sequentially with the compound of the present invention. When a compound of the present invention is used concomitantly with one or more other drugs or active ingredients, a combination product containing such other drug(s) and a compound of the present invention - also referred to as a "fixed dose combination" - is preferred. However, combination therapy also includes therapy in which a compound of the present invention and one or more other drugs are administered on different overlapping schedules. When used in combination with other active ingredients, it is contemplated that the compounds of the present invention or the other active ingredients or both can be effectively used in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those containing, in addition to the compounds of the present invention, one or more other active ingredients.

The compounds of the present invention - or pharmaceutically acceptable salts of each of them, including their N-oxides, solvates, tautomers or stereoisomers and/or mixtures thereof in any ratio - can be used as medicaments. . They have been found to exert their pharmacological activity by binding to TEAD and/or disrupting and/or inhibiting YAP-TEAD and/or TAZ-TEAD protein-protein interactions. This activity presumes that the compounds of the present invention can prevent or reverse the dysfunction of the Hippo pathway. By preventing its dysfunction, the Hippo pathway can fulfill its role as a tumor suppressor. Apart from preventing or reversing dysfunction of the Hippo pathway, and independent of upstream Hippo regulation, the pharmacological activity of the compounds of the present invention may also inhibit TEAD binding and/or aberrant YAP-TEAD and/or aberrant TAZ-TEAD signaling. It may be useful in other pathophysiological scenarios where inhibition or disruption is beneficial.

Thus, compounds of the present invention which are TEAD binders and/or inhibitors of the YAP-TEAD and/or TAZ-TEAD interaction are particularly useful in hyperproliferative disorders and cancers, particularly tumors including solid tumors, breast cancer, lung cancer, mesothelioma, epithelial vascular endothelial uveal melanoma, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colon cancer, pancreatic cancer, schwannoma, meningioma, glioma, basal cell carcinoma. . Without being bound by any particular theory or explanation, it can be assumed that the compounds may achieve this by direct effect on cancer cells and/or indirectly by modulating the immune system's response to tumors. In addition, the compounds of the present invention may also be useful for the treatment, prevention, inhibition and/or amelioration of non-cancerous disorders and diseases, such as cardiovascular disease and fibrosis (such as liver fibrosis).

In certain embodiments, the compounds of the present invention are useful in treating the disorders or diseases listed above, preferably cancer, especially tumors, including solid tumors, certain types of cancers described in the previous paragraph; or for use in the prevention and/or treatment of any non-cancerous disorder or disease described in the previous paragraph.

Another particular embodiment of the present invention is for treating hyperproliferative disorders and cancers, especially tumors, including solid tumors, certain types of cancers described in the previous paragraph; or for the prevention and/or treatment, preferably treatment, of a disorder or disease selected from the group consisting of any non-cancerous disorder or disease disclosed in the previous paragraph.

Yet another particular embodiment of the present invention comprises a compound of the present invention - or a derivative, N-oxide, prodrug, solvate, tautomer or stereoisomer thereof and/or a mixture thereof in all proportions as described above. of each pharmaceutically acceptable salt - hyperproliferative disorders and cancers, especially tumors, including solid tumors, certain types of cancers disclosed in the previous paragraph; or for the manufacture of a medicament, in particular for preventing and/or treating, preferably treating, a disorder or disease selected from the group consisting of any of the non-cancerous disorders or diseases described in the previous paragraph.

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

The disclosed compounds of Formula I or I-A can be administered in combination with other known therapeutic agents, including anti-cancer agents. As used herein, the term "anti-cancer agent" relates to any agent administered to a patient suffering from cancer for the purpose of treating cancer. The anti-cancer treatment as defined above may be applied as a monotherapy or may include conventional surgery or radiation therapy or drug therapy in addition to the compounds of formula (I-A) or (I) disclosed herein. Such drug therapy, eg chemotherapy or targeted therapy, may include one or more of the following anti-tumor agents, but preferably one of the following anti-tumor agents:

alkylating agent

For example, altretamine, bendamustine, busulfan, carmustine, chlorambucil, chlormethine, cyclophosphamide, dicarbazine, ifosfamide, improsulfan, tosylate, lomustine, melphalan, mitobronitol, mitolactol, nimustine, ranimustine, temozolomide, thiotepa, threosulfan, mechlorethamine, carboquone; Apaziquone, fotemustine, gluphosphamide, palifosphamide, pipobroman, trophosphamide, uramustine, evophosphamide, VAL-083 ^[4] ;

platinum compound

For example, carboplatin, cisplatin, eftaplatin, myriplatin hydrate, oxaliplatin, lobaplatin, nedaplatin, picoplatin, satraplatin;

DNA modifier

For example, amrubicin, bisantrene, decitabine, mitoxantrone, procarbazine, trabectedin, clofarabine;

Amsacrine, Brostalysin, Pixantrone, Laromustine ^[1],[3] ;

topoisomerase inhibitors

eg etoposide, irinotecan, razoxane, sotrizoxane, teniposide, topotecan;

amonafide, belotecan, elliptinium acetate, boreloxin;

microtubule modifier

For example, cabazitaxel, docetaxel, eribulin, ixabepilone, paclitaxel, vinblastine, vincristine, vinorelbine, vindesine, vinflunine; phosbretabulin, tesetaxel;

antimetabolites

For example, asparaginase ^[3] , azacitidine, calcium levopolynate, capecitabine, cladribine, cytarabine, enocitabine, floxuridine, fludarabine, fluorouracil, gemcitabine, mer captopurine, methotrexate, nelarabine, pemetrexed, pralatrexate, azathioprine, thioguanine, carmofur; doxifluridine, elacitalabine, raltitrexed, sapacitabine, tegafur ^{[2], [3]} , trimetrexate;

anticancer antibiotics

For example, bleomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, levamisole, miltefosin, mitomycin C, romidepsin, streptozocin, valrubicin, zinostatin, zorubicin, daunurovicin, plicama isin; Aclarubicin, peplomycin, pirarubicin;

hormone/antagonist

For example, abarelix, abiraterone, bicalutamide, buserelin, calusterone, chlorotrianisene, degarelix, dexamethasone, estradiol, fluocortolone, fluoxymesterone, flutamide, fulvestrant , goserelin, histrelin, leuprorelin, megestrol, mitotane, naparelin, nandrolone, nilutamide, octreotide, prednisolone, raloxifene, tamoxifen, thyrotropin alfa, toremifene, trilostane , triptorelin, diethylstilbestrol; acolbifene, danazol, deslorelin, epithiostanol, orteronel, enzalutamide ^{[1], [3];}

aromatase inhibitor

eg aminoglutethimide, anastrozole, exemestane, fadrozole, letrozole, testolactone; formestane;

small molecule kinase inhibitors

For example, crizotinib, dasatinib, erlotinib, imatinib, lapatinib, nilotinib, pazopanib, regorafenib, ruxolitinib, sorafenib, sunitinib, vandetanib, vemurafenib, bosutinib , gefitinib, axitinib; Afatinib, alisertib, dabrafenib, dacomitinib, dinaciclib, dovitinib, enzastaurin, nintedanib, lenvatinib, linipanib, lincitinib, mastinib, midostaurin, motesanib Alaninate , cediranib, afatinib ^[4] , cabozantinib S-malate ^[1],[3] , ibrutinib ^[1],[3] , icotinib ^[4] , bupafliplib ^[2] , sipatinib ^[4] , cobimetinib ^[1],[3] , idelalisib ^[1],[3] , fedratinib ^[1] , tesebatinib;

photosensitizer

For example, methoxsalen ^[3] ; porfimer sodium, talaporfin, temoporfin;

antibody

Examples include alemtuzumab, becillesomab, blenduximab vedotin, cetuximab, denosumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, trastuzumab, beva Cijumab, Pertuzumab ^[2],[3] ; Catumaxomab, elotuzumab, epratuzumab, parletuzumab, mogamulizumab, nesitumumab, nimotuzumab, obinutuzumab, ocaratuzumab, oregobomab, ramucirumab, rilotumumab , Siltuximab, Tocilizumab, Zalutumumab, Zanolimumab, Matuzumab, Dalotuzumab ^[1],[2],[3] , Onartuzumab ^[1],[3] , Lakotumomab ^[1] , tabalumab ^[1],[3] , EMD-525797 ^[4] , atezolizumab, durvalumab, pembrolizumab, nivolumab ^[1],[3] ;

cytokines

For example, aldesleukin, interferon alpha 2, interferon alpha 2a ^[3] , interferon alpha 2b ^{[2], [3]} ; Cellmoryukin, Tasonermin, Teseryukin, Oprelbekin ^[1],[3] , Recombinant interferon beta-1a ^[4] ;

drug conjugate

eg, denileukin diptitox, ibritumomab tiuxetan, iobenguan I 123, prednimustine, trastuzumab emtansine, estramustine, gemtuzumab, ozogamicin, aflibercept; Sintredecin Besudotox, Edotreotide, Inotuzumab Ozogamicin, Naptumomab Estafenatox, Ofortuzumab Monatox, Technetium (99mTc) Arsitumomab ^[1],[3] , Binta polyd ^[1],[3] ;

vaccine

For example, Sipuleucel ^[3] ; Vitespen ^[3] , Emepepimut-S ^[3] , OncoVAX ^[4] , Lindopepimut ^[3] , TroVax ^[4] MGN-1601 ^[4] , MGN-1703 ^[4] ;

etc

alitretinoin, bexarotene, bortezomib, everolimus, ibandronic acid, imiquimod, lenalidomide, retinan, methirosine, mifamurtide, pamidronic acid, pegaspargase, pentostatin, sipuleucel ^[3] , sizopyran, tamibarrotene, temsirolimus, thalidomide, tretinoin, vismodegib, zolendronic acid, vorinostat; selcoxib, cilengitide, entinostat, etanidazole, ganetespip, idronoxil, iniparib, ixazomib, lonidamine, nimorazole, panobinostat, ferretinoin, plitidepsin, pomalidomide, Procodazole, ridaforolimus, tasquinimod, telotristat, timalfacin, tirapazamine, tosedostat, travedersen, ubenimex, valspodar, gendisin ^[4] , fishbanil ^{[ 4]} , leolysin ^[4] , letaspimycin hydrochloride ^[1],[3] , trevananib ^[2],[3] , virulizin ^[4] , carfilzomib ^[1],[3] , Endostatin ^[4] , Imukotel ^[4] , Velinostat ^[3] ;

PARP inhibitor

Olaparib, Veliparib.

MCT1 inhibitor

AZD3965 ^[4] , BAY-8002 ^[4] .

^[1] Prop. INN ( Proposed International N onproprietary Name )

^[2] Rec. INN ( Recommended International N onproprietary Names )

^[3] USAN ( United States A dopted Name )

^[4] no INN.

In another aspect of the present invention, a therapeutically effective amount of at least one compound of the present invention and/or at least one pharmaceutical composition described herein and at least one additional pharmacologically active substance other than a therapeutically effective amount of a compound of the present invention A set or kit comprising a is provided. This set or kit preferably includes individual packs of:

a) an effective amount of a compound of formula I and formula I-A, or any N-oxide, solvate, tautomer or stereoisomer thereof, as well as mixtures thereof in all proportions, each pharmaceutically acceptable possible salts; and

b) a further active ingredient in an effective amount, which is not a compound of formula I and is not a compound of formula I-A.

A further embodiment of the present invention relates to at least one compound according to the present invention and at least one selected from the group consisting of solid, liquid or semi-liquid excipients, adjuvants, adjuvants, diluents, carriers and pharmaceutically active agents other than the compounds according to the present invention. A method for preparing a pharmaceutical composition of the present invention, characterized in that the compound is converted into a suitable dosage form.

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

Suitable dosage forms include capsules, tablets, pellets, dragees, semi-solids, powders, granules, suppositories, ointments, creams, lotions, inhalants, injectables, cataplasms, gels, tapes, eye drops, solutions, syrups, aerosols. , suspensions, emulsions, including but not limited to, which may be prepared according to methods known in the art, for example as described below:

Tablets: mixing of the active ingredient(s) and auxiliaries, compression of the mixture into tablets (direct compression), optionally granulation of a portion of the mixture prior to compression.

Capsule: Mixing of the active ingredient(s) and auxiliaries to obtain a flowable powder, optionally granulation of the powder, filling of the powder/granule into an open capsule, capping of the capsule.

Semi-solids (ointments, gels, creams): solubility/dispersion of the active ingredient(s) in an aqueous or fatty carrier; Subsequent mixing with the complementary fat/aqueous phase of the aqueous/fatty phase, homogenization (cream only).

Suppositories (rectal and vaginal): dissolution/dispersion of the active ingredient(s) in a thermally liquefied carrier material (rectal: carrier material, usually a wax; vagina: carrier, usually a heated solution of a gelling agent), Casting into suppository form, annealing and recovery of suppository from form.

Aerosol: Dispersion/dissolution of the active agent(s) in a propellant, bottling the mixture into an atomizer.

Generally, non-chemical routes for the preparation of pharmaceutical compositions and/or pharmaceutical formulations are suitable mechanical routes known in the art that deliver one or more compounds of the present invention in a dosage form suitable for administration to a patient in need of such treatment. Include a processing step for the means. Generally, delivery of one or more compounds of the present invention in such dosage forms involves the addition of one or more compounds selected from the group consisting of carriers, excipients, adjuvants and pharmaceutically active ingredients other than the compounds of the present invention. Suitable processing steps include, but are not limited to, combining, milling, mixing, granulating, dissolving, dispersing, homogenizing, casting and/or compacting the respective active and inactive ingredients. Mechanical means for carrying out this processing step 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 additional compounds other than the compound of the present invention, which exhibit valuable pharmacological properties and are preferably compounds of the present invention disclosed herein. other than pharmaceutically active agents.

Particularly suitable for oral use are tablets, pills, coated tablets, capsules, powders, granules, syrups, juices or drops, suitable for rectal use are suppositories, suitable for parenteral use are solutions, preferably oil-based or aqueous solutions, moreover suspensions, emulsions or implants; suitable for topical use are ointments, creams or powders. The compounds of the present invention may also be lyophilized, and the obtained lyophilizates have been used, for example, in the preparation of injectable preparations. The formulations shown may be sterile and/or may contain lubricants, preservatives, stabilizers and/or wetting agents, emulsifiers, salts to modify osmotic pressure, buffer substances, dyes, flavors and/or a plurality of further active ingredients, for example Supplements such as one or more vitamins may be included.

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

If desired, disintegrating agents such as the aforementioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate may be added. Auxiliaries include, without limitation, flow-regulating agents and lubricants such as silica, talc, stearic acid or salts thereof such as magnesium stearate or calcium stearate, and/or polyethylene glycol. Dragee cores are provided with suitable coatings, which, if desired, are resistant to gastric juices. For this purpose, concentrated saccharide solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. To produce a coating that is resistant to gastric fluids or to provide a dosage form that provides the benefit of prolonged action, tablets, dragees or pills may contain internal dosage and external dosage ingredients, the latter being an envelope over the former. It is the form of an envelope. The two components can be separated by an enteric layer, which is resistant to disintegration in the stomach and allows intact passage of the internal components into the duodenum or delayed release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and suitable cellulose preparations such as shellac, acetyl alcohol, acetyl-cellulose phthalate, cellulose acetate or hydroxypropylmethyl-cellulose phthalate. Such materials, including mixtures with materials such as solutions of Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize combinations of active compound doses.

Suitable carrier materials are organic or inorganic substances suitable for enteral (eg oral) or parenteral administration or topical administration and which do not react with the novel compounds, such as water, vegetable oils, benzyl alcohol, polyethylene glycol, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc and petroleum jelly. In particular, tablets, coated tablets, capsules, syrups, suspensions, drops or suppositories are used for enteral administration, solutions, preferably oily or aqueous solutions, also suspensions, emulsions or implants are used for parenteral administration, ointments , creams or powders are used for topical application. The compounds of the present invention may also be lyophilized and the obtained lyophilizate may be used, for example, in the preparation of injectable preparations.

Other pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules may contain the active ingredients in the form of granules, which may be mixed with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compound is dissolved or suspended in a suitable liquid, such as a fatty oil, or liquid paraffin. Stabilizers may also be added.

Liquid forms in which the novel compositions of this invention may be incorporated for oral administration include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil; and elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginates, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.

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

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

For administration as an inhalation spray, a spray may be used in which the active ingredient is dissolved or suspended in a propellant gas or propellant gas mixture (eg CO ₂ or a chlorofluorocarbon). The active ingredient is advantageously used here in micronized form, in which case one or more further physiologically acceptable solvents may be present, for example ethanol. Inhalation solutions can be administered with the aid of a conventional inhaler.

Possible pharmaceutical preparations that can be used rectally include, for example, suppositories consisting of a combination of one or more active compounds with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, or paraffinic hydrocarbons. In addition, gelatin rectal capsules consisting of a combination of active compound and base may also be used. Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffinic hydrocarbons.

Pharmaceutical preparations can be used as medicines in human medicine and veterinary medicine. As used herein, "effective amount" means an amount of a drug or agent that will elicit a biological or medical response in a tissue, system, animal or human being sought, for example by a researcher or clinician. In addition, the term also includes within its scope a "therapeutically effective amount", which is an improved treatment, cure, prevention or amelioration of a disease, disorder or side effect compared to a corresponding subject not receiving such amount. , or any amount that results in a decrease in the rate of progression of a disease or disorder, or in symptoms associated with such a disease or disorder; It can also refer to preventing or providing prophylaxis against a disease or disorder in a subject having or at risk of developing a disease disclosed herein. The term also includes within its scope amounts effective to enhance normal physiological function. Such therapeutically effective amounts of one or more compounds of the invention are known to those skilled in the art or can be readily determined by standard methods known in the art.

As used herein, “treating” or “treatment” means relief of all or some of the symptoms associated with a disorder or disorder, or delay or halting further progression or worsening of such symptoms, or risk of developing the disorder or disorder. Prevention or prevention of a disease or disorder in a subject is meant.

The compounds of the present invention and any additional active substances are generally administered similarly to commercial formulations. Usually, a suitable therapeutically effective dosage is in the range of 0.0005 mg to 1000 mg, preferably 0.005 mg to 500 mg, in particular 0.5 mg to 100 mg per dosage unit. The daily dosage is preferably about 0.001 mg/kg to 10 mg/kg body weight.

Those skilled in the art will readily appreciate that dosage levels may vary depending on the particular compound, the severity of the symptoms and the subject's susceptibility to side effects. Some of the specific compounds are more powerful than others. Preferred dosages for a given compound are readily determined by one skilled in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.

However, the specific dosage for an individual patient, in particular for an individual human patient, depends on a number of factors, such as the potency of the specific compound used, age, weight, general state of health, sex, type of diet, time and route of administration, excretion. The rate, type and form of administration administered, pharmaceutical combination and regimen will depend on the severity of the particular disorder involved. A particular therapeutically effective dosage for an individual patient can be readily determined by routine experimentation advising or conducting therapeutic treatment, for example by a physician or physician.

The compounds of the present invention may be prepared according to the procedures in the schematics and examples below using appropriate materials, as further illustrated by the specific examples below. They are also suitable for the above reactions and accurate under known reaction conditions, according to literature (eg Houben-Weyl, Methoden der Organischen Chemie [Methods of Organic Chemistry], Georg Thieme Verlag, Stuttgart; Organic Reactions, John Wiley & Sons , Inc., New York), it can be prepared by a method known per se. Variations known per se, but not mentioned in more detail herein, may also be used.

Likewise, the starting materials for the preparation of the compounds of the present invention may be prepared by methods as described in the examples, or methods known per se, as described in the literature of synthetic organic chemistry and known to the skilled person, or obtained commercially. It can be. The starting materials for the claimed and/or utilized methods, if desired, may also be formed in situ, without isolation from the reaction mixture, but instead immediately further converting them to compounds of the present invention or intermediate compounds. . Meanwhile, in general, it is possible to carry out the above reaction step by step.

Preferably, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, without limitation, hydrocarbons such as hexane, petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons such as trichlorethylene, 1,2-dichloroethane, tetrachloromethane, chloroform or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methyl phyllolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate, or mixtures of these solvents or mixtures with water.

The reaction temperature is about -100°C to 300°C depending on the reaction step and the conditions used.

The reaction time generally ranges from minutes to several days depending on the reactivity of each compound and each reaction condition. Suitable reaction times can be readily determined by methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times are generally in the range of 10 minutes to 48 hours.

Moreover, using the procedures described herein in conjunction with ordinary knowledge in the art, additional compounds of the invention claimed herein can be readily prepared. However, the compounds exemplified in the examples are not to be construed as forming the only genus considered as the present invention. The examples further elucidate details of the preparation of the compounds of the present invention. Those skilled in the art will readily appreciate that known modifications of the procedures and conditions of the following preparatory procedures may be used to prepare such compounds.

The present invention also relates to compounds of formula I or I-A in their most general form, as well as specific embodiments described herein: 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, A process for the preparation of any of PE12c, PE12d, PE13, or N-oxides, solvates, tautomers or stereoisomers thereof, and pharmaceutically acceptable salts of each of the foregoing, said process characterized by do

(a) Compounds of Formula II-a or II-A-a

wherein Z ¹ , Z ² , Z ³ , rings A and R ² are as defined above and in the claims for the compound of formula I or IA, and R ² is -C(=0)-OH or -C( =O)-not OCat;

(a) (1) reacting with a compound of formula III in a C-N cross-coupling reaction under suitable reaction conditions;

R ¹ -Hal

III,

wherein R ¹ is as defined above or in any claim for a compound of formula I or IA and Hal represents Cl, Br or I;

or

(a) (2) In a C-N cross-coupling reaction under suitable reaction conditions, first converting to a tricyclic compound of formula IV or IV-A

;

;

Then in another C-N cross-coupling reaction under suitable reaction conditions, by reacting with a compound of formula III

R ¹ -Hal

III,

(a) (3) providing a compound of Formula I or I-A as defined above and in any claim; and

optionally

(a) (4) In the compound of formula I or IA, when R ² is -C(=O)-OR ^2a , wherein R ^2a is unsubstituted or substituted C _1-8 -aliphatic, this formula subjecting a compound of I or IA to saponification under suitable conditions to give a compound of the respective formula I or IA, wherein R ² is -C(=0)-OH or -C(=0)-OCat ;

or

(b) Compounds of Formula II-b or II-A-b

wherein Z ¹ , Z ² , Z ³ , rings A and R ² are as defined above and in any claims for the compounds of formula I or IA, and R ² is -C(=0)-OH or - not C(=O)-OCat;

(b) (1) reacted with a compound of formula V in a C-N cross-coupling reaction under suitable reaction conditions

R ¹ -NH ₂

V,

wherein R ¹ is as defined for the compound of formula I or IA above or in any claim,

providing a compound of Formula I or I-A as defined above and in any claim; and

optionally

(b) (2) In the compound of formula I or IA, when R ² is -C(=O)-OR ^2a , wherein R ^2a is unsubstituted or substituted C _1-8 -aliphatic, this formula subjecting a compound of I or IA to saponification under suitable conditions to give a compound of the respective formula I or IA, wherein R ² is -C(=0)-OH or -C(=0)-OCat .

As will be appreciated by those skilled in the art of synthetic organic compounds of the present invention, in particular the compounds of formulas I and I-A are readily accessible by a variety of synthetic routes, some of which are exemplified in the appended experimental section. One skilled in the art will readily recognize what kind of reagents and reaction conditions must be used to obtain the compounds of this invention and how they should be applied and adapted in any particular instance - whenever necessary or useful. In addition, some of the compounds of the present invention may react with other compounds of the present invention under suitable conditions, for example, reducing, oxidizing, adding or substituting a specific functional group or a suitable precursor molecule thereof present in the compound of the present invention. can be easily synthesized by applying the same standard synthetic methods to transform one into another; These methods are well known to those skilled in the art. Likewise, the skilled person will - whenever necessary or useful - apply synthetic protective (or protective) groups; Suitable protecting groups as well as methods for introducing and removing them are well known to those skilled in the art of chemical synthesis, for example P.G.M. Wuts, T.W. Greene, "Greene's Protective Groups in Organic Synthesis", 4th edition (2006) (John Wiley & Sons).

The following general synthetic routes that can be used to prepare the compounds of the present invention are described in more detail in Schemes A, A-A, B and B-A below:

Scheme A

(Z ¹ , Z ² , R ¹ , R ² and Ring A are as defined for Formula I above and in the claims.)

Scheme A-A

(Z ¹ , Z ² , Z ³ , R ¹ , R ² and Ring A are as defined for Formula IA above and in the claims.)

The following description of Scheme A also applies analogously to Schemes A-A; Instead of compounds B, D, E, and I, Scheme A-A and its description will be understood to refer to compounds B-A, D-A, E-A, and I-A. The synthetic procedures and methods used are the same in Schemes A and A-A.

Scheme A above depicts a general synthetic route for preparing tricyclic heterocycles of Formula I. In the reaction step, for example, by first reacting the respective bromo-substituted aryl or heteroaryl with a suitable organometallic base such as n-butyl lithium and then reacting with a suitable boric acid ester such as B(OCH ₃ ) ₃ A readily available boronic acid B is reacted with a 1-amino-2-bromo-substituted heterocycle C under typical C-C cross-coupling conditions, e.g. under conditions typical of Suzuki cross-coupling reactions (e.g. , a solution of B and C in a suitable solvent, such as 1,4-dioxane, with cesium carbonate and Pd(dppf) ₂ Cl ₂ (1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloride. reaction in the presence of the same palladium catalyst) to give compound D. 1-amino-2-bromo-substituted heterocycle C has the same meaning as "Ring A" for the compounds of the present invention of formula I is selected from the 5-membered heteroaromatic rings A-1 to A-24 as defined above and in the claims. For example, when ring A is selected to be ring A-1, each Compound C of will have the formula C-1:

Compound D is then subjected to an intra-molecular CN cross-coupling reaction (step b), for example, a Hartwig-Buchwald reaction (eg di-tert-butyl[2',4',6'-tris (Propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'-biphenyl]-2-yl}palladium ylium methanesulfonate reaction with cesium carbonate in a suitable solvent such as 1,4-dioxane in the presence of a suitable palladium catalyst such as This heterocycle E is then reacted under similar conditions, for example, by a suitable palladium catalyst (eg chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'- Another CN coupling with cesium carbonate in the presence of biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II), X-Phos aminobiphenyl palladium chloride, XPhosPd G2) In reaction (step c) it can be reacted with the bromide R ¹ -Br in turn to give the compounds of formula I of the invention. Depending on the nature of the various substituents R ¹ , R ² and ring A, these compounds of formula I may optionally be converted to further compounds of formula I. For example, when R ² is a carboxylic ester (-C(=O)-OR ^2a ), this ester is subjected to a saponification reaction using a suitable acid or base, such that the respective carboxylic acid (R ² = - C(=O)-OH) or a salt thereof (eg, R ² = -C(=O)-OCat, wherein Cat is Li, Na, K or NH ₄ ).

In some cases, compound D as shown in Scheme A above (and DA in Scheme AA) (and instead of being subjected to subsequent reaction steps b and c, i.e., two consecutive CN coupling reactions) is a CN coupling reaction under (with a suitable base such as cesium carbonate or sodium hydride in the presence of a suitable palladium catalyst) with a suitable compound R ¹ -Br to directly give the respective compound of formula I (or IA in Scheme AA).

It is also well understood that starting from compound E of formula I (or from compound EA of formula IA), under suitable reaction conditions, may be synthesized by using a suitable reaction partner other than the bromo-substituted compound R ¹ -Br. . For example, when R ¹ is selected to be L ¹ -Ar or L ¹ -Hetar ¹ , wherein L ¹ is -S(=O) ₂ -, compound E under suitable reaction conditions can be a compound of the respective thionyl chloride to yield the respective sulfonyl derivative of formula I (or IA).

Scheme B

(Z ¹ , Z ² , R ¹ , R ² and Ring A are as defined for Formula I above and in the claims.)

Scheme B-A

(Z ¹ , Z ² , Z ³ , R ¹ , R ² and Ring A are as defined for Formula IA above and in the claims.)

The following description of Scheme B also applies analogously to Scheme B-A; Instead of compounds B, G, and I, Scheme B-A and its description will be understood to refer to compounds B-A, G-A, and I-A. The synthetic procedures and methods used are the same in Schemes B and B-A.

Scheme B above depicts another synthetic route for preparing the compounds of the present invention. wherein boronic acid B (or a suitable boronic acid ester) is reacted with a 1-chloro-2-iodo-substituted heterocycle F (step d) in a CC cross-coupling reaction under similar conditions described for step a in Scheme A. reacted, and the reaction yielded the dichloro-substituted compound G. Compound G is then subjected to a CN coupling reaction (step e) with a primary amine R ¹ -NH ₂ in the presence of a suitable base such as cesium carbonate and a suitable palladium catalyst (as described for Scheme A) to the desired compound of formula I (or IA for Scheme BA).

It should be noted that, unless specifically stated or the context gives a different meaning, generally a number of terms, i.e. singular and plural, are used and can be read interchangeably. For example, the term “compound” in the singular form can also include or refer to plural compounds, and the term “compounds” in the plural form can also include or refer to a singular compound.

EXAMPLES AND EXPERIMENTAL PARTS

The compounds of the present invention can be prepared according to the procedures in the schematics and examples below using appropriate materials and are further illustrated by the specific examples below. Compounds are shown in Table 1. Table 1 also shows analytical data of compounds prepared according to the following examples.

The present invention will be illustrated with reference to specific embodiments set forth in the Examples below, but not limited thereto. Unless otherwise indicated in the diagram, variables have the same meanings as set forth above and in the claims.

Unless otherwise specified, all starting materials were obtained from commercial sources and used without further purification. Unless otherwise specified, all temperatures are expressed in °C and all reactions are conducted at room temperature (RT). The compound was purified by silica chromatography or preparative HPLC.

^One H NMR:

¹ H-NMR data are provided in Table 1 below. ¹ H NMR spectra, unless otherwise reported, were performed on a Bruker Avance DRX 500, Bruker Avance 400, Bruker DPX 300 or Bruker Avance III 700 MHz (equipped with a TXI cryoprobe) NMR spectrometer with TMS (tetramethylsilane) as an internal reference and It was obtained under standard conditions using DMSO-d6 as a standard solvent. NS (number of scans): 32, indicated SF (spectrometer frequency). TE (temperature): 297 K. Chemical shifts (δ) are reported in ppm for the TMS signal. ¹ H NMR data are reported as follows: chemical shifts (multiplicity, coupling constant and number of hydrogens). Multiplicity is abbreviated as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets), tt (triplet of triplets). line), td (triple of doublets) br (broad) and coupling constants (J) are reported in Hz.

LC-MS:

LC-MS data provided in Table 1 are given in mass in m/z units. Results may be obtained by one of the methods described below.

synthesis

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

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

To a suspension of NaH (1.70 g; 42.50 mmol) in DMF (50 ml) was added 5-bromo-2,3-dimethyl-1H-indole (6.25 g; 27.89 mmol) in DMF (50 ml) slowly at 0°C. did After the tan mixture was stirred at 0°C for 1 hour, benzenesulfonyl chloride (6 g, 34 mmol) was added at 0°C. After that, the mixture was stirred at 25° C. for 2 hours. The reaction was poured into water (500 mL) and extracted 3 times with EA (100 mL). The organic layer was washed with brine (50 mL), dried over Na ₂ SO ₄ , filtered, and concentrated to give a 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).

^1H NMR (400 MHz, CDCl ₃ ) δ 8.06 (d, J = 8.4 Hz, 1H), 7.73 - 7.70 (m, 2H), 7.55 - 7.52 (m, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.44 - 7.40 (m, 2H), 7.36 (dd, J = 8.8, 2.0 Hz, 1H), 2.51 (s, 3H), 2.09 (s, 3H).

Example 1-2: Synthesis of product 1-(benzenesulfonyl)-5-bromo-2,3-bis(bromomethyl)-1H-indole

To a solution of 1-(benzenesulfonyl)-5-bromo-2,3-dimethyl-1H-indole (6.40 g; 17.57 mmol) in CCl ₄ (120 ml) was added 1-bromopyrrolidine-2,5- Dione (6.40 g; 36 mmol) and 2-[2-(1-cyano-1-methylethyl)diazen-1-yl]-2-methylpropanenitrile (288 mg; 1.75 mmol) were added at 80°C. did The tan mixture was stirred at 80° C. under a nitrogen balloon at 1 bar for 3 hours. The reaction was filtered and the filtrate was concentrated to give the crude product (8.15 g; 81%; tan solid).

^1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 5.6 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.61 - 7.58 (m, 1H) ), 7.50 - 7.45 (m, 3H), 5.08 (s, 2H), 4.59 (s, 2H).

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

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

¹ H NMR (400 MHz, CDCl3) δ 7.85 - 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).

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

4-(benzenesulfonyl)-2-benzyl-7-bromo-1H,2H,3H,4H-pyrrolo[3,4-b]indole (1.50 g) in DMF (10 ml) and MeOH (10 ml) ; To this was added potassium acetate (900 mg; 9.17 mmol) at 25°C. The dark-brown mixture was stirred at 90° C. under a metanidylidineoxidanium balloon at 1 bar for 16 hours. The reaction was poured into water (50 mL) and extracted 3 times with EA (30 mL). The organic layer was concentrated to give a residue. The residue was purified by silica gel column chromatography (petroleum ether/EA = 5:1) to give the desired product. (510 mg; 39.8%; tan solid).

¹ H NMR (400 MHz, CDCl3) δ 8.03 - 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) .

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

Methyl 4-(benzenesulfonyl)-2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (84 mg; 0.19 mmol) in toluene (2 ml) To a solution of 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (43 mg; 0.19 mmol) was added at 25°C. The tan mixture solution 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%; tan solid).

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

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

^1H NMR (400 MHz, DMSO-d6) δ 12.86 (brs, 1H), 8.15 (d, J = 1.6 Hz, 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).

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

Example 2-1: Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate

To a suspension of 2-chloro-5-(ethoxycarbonyl)phenyl]boronic acid (500 mg; 2.19 mmol) in dioxane (4 ml) and water (0.4 ml) was added 4-bromo-1-methyl-1H- Pyrazol-3-amine (385 mg; 2.19 mmol), K ₂ CO ₃ (605 mg; 4.38 mmol) and Pd(dppf)Cl ₂ (160 mg) were added. The mixture was stirred at 60° C. under N ₂ atmosphere for 6 hours. The mixture was poured into water (80 mL) then extracted with EA (6 ml*3). The combined organic phases were collected and evaporated under vacuum. The residue could be purified by C18 column chromatography (ACN/H ₂ O = 5% - 95%) to give the purified product (500 mg; 74%; white powder).

^1H NMR (400 MHz, DMSO) 8.07 (d, J = 2.1 Hz, 1H), 7.77 (dd, J = 8.4, 2.2 Hz, 1H), 7.67 (s, 1H), 7.63 (d, J = 8.4 Hz , 1H), 4.58 (s, 2H), 4.32 (q, J = 7.1 Hz, 2H), 3.66 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H).

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

Di-tert-butyl [ 2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'-biphenyl]- 2-yl}palladiumylium methanesulfonate (85 mg; 0.11 mmol) and Cs ₂ CO ₃ (699 mg; 2.14 mmol) were added. The mixture was stirred at 120° C. under N ₂ atmosphere for 6 hours. The mixture was poured into water (80 mL) then extracted with EA (6 ml*3). The combined organic phases were collected and evaporated under vacuum. The residue could be purified by C18 column chromatography (ACN/H ₂ O = 5% - 95%) to give the purified product. (110 mg; 42%; white solid).

^1H NMR (400 MHz, DMSO) δ 8.31 (d, J = 1.7 Hz, 1H), 8.03 (s, 1H), 7.83 (dd, J = 8.5, 1.8 Hz, 1H), 7.32 (d, J = 8.5 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.97 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H).

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

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

^1H NMR (400 MHz, DMSO) δ 8.45 (d, J = 1.5 Hz, 1H), 8.23 (s, 1H), 8.08 (d, J = 8.5 Hz, H), 7.98 (d, J = 8.6 Hz, 2H), 7.93 (d, J = 1.8 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1H), 4.35 (d, J = 7.1 Hz, 2H), 4.04 (s, 3H), 1.36 (t, J = 7.1 Hz, 2H).

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

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

^1H NMR (400 MHz, DMSO) δ 12.74 (s, 1H), 8.43 (d, J = 1.7 Hz, 1H), 8.22 (s, 1H), 8.08 (d, J = 8.5 Hz, 2H), 7.98 ( d, J = 8.6 Hz, 2H), 7.93 (dd, J = 8.7, 1.8 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H).

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

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

Methyl 4-(benzenesulfonyl)-2-benzyl-1H,2H,3H,4H-pyrrolo[3,4-b]indole-7-carboxylate (460 mg; 1 mmol) in MeOH (20 ml) To a solution of Cs ₂ CO ₃ (2.68 g; 8.23 mmol) was added at 25 °C. The tan mixture was stirred at 30° C. for 16 hours. The reaction was poured into water (100 mL) and extracted 3 times with EA (30 mL). The organic layer was concentrated to give a residue. The residue was purified by C18 (ACN/H ₂ O = 10% - 95%) to give the desired product. (200 mg; 67%; tan solid).

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

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

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

To 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) 4 ,5-Dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (100 mg; 0.19 mmol) was added at 25°C. The tan 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%; tan gel).

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

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

^1H NMR (400 MHz, DMSO-d6) δ 12.48 (s, 1H), 8.33 (d, J = 1.6 Hz, 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 = 1.6 Hz, 1H), 5.30 (s, 2H).

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

Example 4-1: Synthesis of ethyl 3-(4-amino-1-methyl-1H-pyrazol-3-yl)-4-chlorobenzoate

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

^1H NMR (400 MHz, DMSO) δ 7.97 (d, J = 2.2 Hz, 1H), 7.92 ¨C 7.87 (m, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.17 (s, 1H) , 4.32 (d, J = 7.1 Hz, 2H), 3.76 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H).

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

In a sealed tube, ethyl 3-(4-amino-1-methyl-1H-pyrazol-3-yl)-4-chlorobenzoate (350 mg; 1.24 mmol) in dioxane (20 ml), di-tert- Butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphane {2'-amino-[1,1'-biphenyl ]-2-yl}palladiumylium methanesulfonate (120 mg; 0.15 mmol) and Cs ₂ CO ₃ (807 mg; 2.48 mmol) were added. The mixture was stirred under N ₂ at 120° C. for 16 h. LCMS showed that the starting material was not lost. Di-tert-butyl[2',4',6'-tris(propan-2-yl)-[1,1'-biphenyl]-2-yl]phosphan {2'-amino-[1 ,1′-biphenyl]-2-yl}palladiumylium methanesulfonate (120 mg; 0.15 mmol) was added and stirring was continued at 140° C. for 24 hours. The mixture was filtered and concentrated to give the crude product as a black oil. The crude product was purified by C18 (ACN/H ₂ O = 5% - 95%) to give the product. (50 mg; 23%; white powder).

^1H NMR (400 MHz, DMSO) δ 10.71 (s, 1H), 8.38 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 8.6, 1.7 Hz, 1H), 7.71 (s, 1H), 7.39 (d, J = 8.6 Hz, 1H), 4.32 (t, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.35 (dd, J = 9.9, 4.3 Hz, 3H).

Example 4-3: Synthesis of ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylate

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

^1H NMR (400 MHz, DMSO) δ 8.48 (d, J = 1.6 Hz, 1H), 8.12 (s, 1H), 8.01 (dd, J = 8.8, 1.7 Hz, 1H), 7.94 (s, 4H), 7.88 (d, J = 8.8 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 4.10 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

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

Ethyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-carboxylate (80 mg; 0.19 mmol) was added with 1 M aqueous sodium hydroxide 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 1N hydrochloric acid (1ml). 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) was obtained.

^1H NMR (400 MHz, 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).

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

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

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) was added NaH (49 mg; 2.04 mmol). It was added at 0°C. The solution was stirred at 0° C. for 30 min then 1-(bromomethyl)-4-(trifluoromethyl)benzene (230 mg, 0.96 mmol) was added. The solution was stirred at 25° C. for 3 hours. The reaction mixture was filtered through a filter membrane. The filtrate was purified by C-18 column (acetonitrile: water = 5% to 95%) to give the desired purified product (260 mg; 79%; off-white solid).

^1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 1.6 Hz, 1H), 7.98 (dd, J = 8.4, 1.6 Hz, 1H), 7.66 (s, 1H), 7.53 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H), 7.12 (d, J = 8.4 Hz, 1H), 5.44 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 4.06 ( s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

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

Ethyl 2-methyl-8-{[4-(trifluoromethyl)phenyl]methyl}-2H,8H-pyrazolo[3,4-b]indole-5 in EtOH (40 ml) and water (1 ml) - To a solution of carboxylate (120 mg; 0.30 mmol) was added NaOH (36 mg; 0.90 mmol) at 25°C. The tan 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 1N aqueous hydrochloric acid solution (5 drops) and concentrated. The resulting residue was suspended in pure water (10 mL) and filtered. The filter residue was washed 3 times with water (5 mL) and concentrated to give the desired purified product. (101 mg; 88%; off-white solid).

^1H NMR (400 MHz, DMSO-d6) δ 12.49 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 7.85 (dd, J = 8.8, 1.6 Hz, 1H) ), 7.68 (d, J = 8.4 Hz, 2H), 7.51 - 7.43 (m, 3H), 5.52 (s, 2H), 3.99 (s, 3H).

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

Example 6-1: Synthesis of ethyl 2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate

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 Cs ₂ CO ₃ (629 mg; 1.93 mmol) were suspended in dioxane-1,4 (10 ml). The mixture was stirred at 120° C. under N ₂ atmosphere for 16 hours. The mixture was filtered. The organic phase was concentrated and purified by silica gel (PE/EA = 10:1) to give the purified product as an off-white solid. (230 mg; 88%).

^1H NMR (400 MHz, DMSO) δ 8.45 (s, 1H), 8.22 (s, 1H), 8.17 ¨C 8.08 (m, 2H), 7.94 (d, J = 8.7 Hz, 1H), 7.86 (d, J = 7.9 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.68 (d, J = 8.8 Hz, 1H), 4.35 (q, J = 7.1 Hz, 2H), 4.03 (s, 3H) , 1.36 (t, J = 7.1 Hz, 3H).

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

Ethyl-2-methyl-8-[3-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (230 mg; 0.56 mmol) of 1 M aqueous sodium hydroxide solution (2 ml) was added. The reaction mixture was stirred at 60° C. for 2 hours under N ₂ atmosphere. The mixture was concentrated to dryness. Water (10 ml) was then added and the mixture was adjusted to pH = 1 with 1N hydrochloric acid. The solution was filtered and the residue was washed 3 times with H ₂ O (10ml). The residue was dried under vacuum to give the purified product. (180 mg; 89%; off-white solid).

^1H NMR (400 MHz, DMSO) δ 12.69 (d, J = 0.6 Hz, 1H), 8.43 (d, J = 1.5 Hz, 1H), 8.21 (s, 1H), 8.13 (d, J = 12.1 Hz, 2H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 7.86 (t, J = 7.9 Hz, H), 7.76 (d, J = 7.8 Hz, 1H), 7.67 (d, J = 8.7 Hz, 1H), 4.03 (s, 3H).

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

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

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 Cs ₂ CO ₃ (629 mg; 1.93 mmol) was added to dioxane-1,4 (10 ml). The mixture was stirred at 120° C. under N ₂ atmosphere for 16 hours. The reaction mixture was filtered. The organic phase was concentrated and purified by silica gel (PE/EA = 5:1) to give the purified product (210 mg; 92%; off-white solid).

^1H NMR (400 MHz, DMSO) δ 8.43 (d, J = 1.4 Hz, 1H), 8.21 (s, 1H), 7.91 (d, J = 1.7 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.67 (dd, J = 6.5, 2.6 Hz, 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).

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

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) To this was added 1 M sodium hydroxide aqueous solution (2 ml). The mixture was stirred at 60° C. for 2 hours under N ₂ atmosphere. The mixture was concentrated to dryness. H ₂ O (10 ml) was added to the residue and the mixture was adjusted to pH = 1-2 with 1N hydrochloric acid. The solution was filtered. The residue was washed with H ₂ O (3 * 10 ml) and dried under vacuum to give crude product. Ethyl acetate/N-hexane = 1:1 (10ml) was added and the mixture was stirred for 30 minutes. The solution was then filtered and the residue was dried under vacuum to give the purified product. (120 mg; 65%; off-white solid).

^1H NMR (400 MHz, DMSO) δ 12.68 (s, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.19 (s, 1H), 7.92 (dd, J = 8.7, 1.6 Hz, 1H), 7.72 ¨C 7.63 (m, 4H), 7.27 ¨C 7.20 (m, 1H), 4.03 (s, 3H).

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

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

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 hours. The reaction could be filtered, concentrated in vacuo and purified by C-18 column chromatography (ACN/H ₂ O = 5% - 95%) to give the product (213 mg; 64%; tan solid).

^1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 2.0 Hz, 1H), 7.98 (dd, J = 8.8, 1.6 Hz, 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 = 9.2 Hz, 1H), 5.43 (s, 2H), 4.39 (q, J = 7.2 Hz, 2H), 4.07 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H).

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

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

^1H NMR (400 MHz, DMSO-d6) δ 12.51 (s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.10 (s, 1H), 7.85 (dd, J = 8.8, 2.0 Hz, 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).

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

Example 9-1: Synthesis of ethyl 2-methyl-8-(4-methylphenyl)-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate

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 Cs ₂ CO ₃ (629 mg; 1.93 mmol) was added to dioxane-1,4 (10 ml). The mixture was stirred at 120° C. under N ₂ atmosphere for 16 hours. 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).

^1H NMR (400 MHz, CDCl3) δ 8.46 (d, J = 2.0 Hz, 1H), 7.99 (dd, J = 8.7, 2.4 Hz, 1H), 7.67 (d, J = 3.8 Hz, 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 = 3.9 Hz, 3H), 2.43 (d, J = 3.3 Hz, 3H), 1.44 (td, J = 7.1, 4.1 Hz, 3H).

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

1 M 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) Aqueous sodium hydroxide solution (2 ml) was added. The mixture was stirred at 60° C. for 2 hours under N ₂ atmosphere. The mixture was concentrated. H ₂ O (10 ml) was added to the residue and the mixture was adjusted to pH = 1 with 1N hydrochloric acid. The precipitate was filtered. The resulting crude product was washed 3 times with H ₂ O (15 ml). The filtered residue could be dried under vacuum to give the purified product (160 mg; 87%; off-white solid).

^1H NMR (400 MHz, DMSO) δ 12.60 (s, 1H), 8.40 (d, J = 1.5 Hz, 1H), 8.17 (s, 1H), 7.89 (dt, J = 5.2, 3.3 Hz, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 4.00 (s, 3H), 2.40 (s, 3H).

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

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

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 Cs ₂ CO ₃ (629 mg; 1.93 mmol) was added to dioxane-1,4 (10 ml). The mixture was heated at 120° C. under N ₂ atmosphere. Stir for 16 hours. The mixture was filtered and the phases were separated. The organic phase was concentrated and purified by silica gel chromatography (PE/EA = 10:1). A purified product was obtained (186 mg; 81 %; pale yellow solid).

^1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 1.5 Hz, 1H), 8.05 - 7.98 (m, 1H), 7.74 - 7.66 (m, 3H), 7.49 - 7.42 (m, 1H), 7.26 (d, J = 3.6 Hz, 2H), 4.42 (dd, J = 7.1, 3.5 Hz, 2H), 4.07 (d, J = 3.4 Hz, 3H), 1.47 - 1.41 (m, 3H).

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

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) To this was added 1 M sodium hydroxide aqueous solution (1.7 ml). The mixture was stirred at 60° C. under N ₂ atmosphere for 16 hours. The mixture was concentrated to dryness. H ₂ O (15 ml) was added to the residue and the pH was adjusted to 1 with 1N hydrochloric acid. The precipitate was filtered. The residue was washed 3 times with H ₂ O (10 ml). Ethyl acetate (3 ml) and n-hexane (3 ml) were added to the residue, and the mixture was stirred for 30 minutes. The suspension was filtered and the residue was dried under vacuum. A purified product was obtained (100 mg; 62 %; white solid).

^1H NMR (400 MHz, DMSO) δ 12.65 (s, 1H), 8.41 (d, J = 1.4 Hz, 1H), 8.18 (s, 1H), 7.90 (dd, J = 8.7, 1.6 Hz, 1H), 7.83 - 7.77 (m, 2H), 7.54 (d, J = 8.7 Hz, 1H), 7.49 - 7.42 (m, 2H), 4.01 (s, 3H).

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

Example 11-1: Synthesis of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate

Bromomethylcyclohexane to a suspension of ethyl 2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (200 mg; 0.82 mmol) in propan-2-one (5 ml) (0.14 ml; 0.99 mmol) and KOH (138 mg; 2.47 mmol.) were added. The mixture was stirred at 65° C. under N ₂ atmosphere for 12 hours. The mixture was poured into water (10 mL) then extracted 3 times with EA (5 ml). The combined organic phases were collected and evaporated under vacuum. The residue could be purified by C18 column chromatography (ACN/H ₂ O = 5% - 95%) to give the product (170 mg; 57 %; yellow gel).

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

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) in water (8 ml) and sodium hydroxide (320 mg; 8 mmol) were added. The mixture was stirred at 65° C. under N ₂ atmosphere for 12 hours. The mixture was evaporated under vacuum. The residue was acidified with 1N HCl solution and evaporated. The residue could be purified by C18 column chromatography (ACN/H ₂ O = 5% - 95%) to give the product (50 mg; 33 %; white solid).

^1H NMR (400 MHz, CDCl3) δ 7.63 (s, 1H), 7.31 ¨C 7.26 (m, 3H), 4.09 (s, 3H), 4.01 (d, J = 7.5 Hz, 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).

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

Example 12-1: Synthesis of ethyl 8-(cyclohexylmethyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate

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

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

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

^1H NMR (300 MHz, DMSO) δ 12.58 - 12.44 (m, 1H), 8.35 (d, J = 1.4 Hz, 1H), 8.12 (s, 1H), 7.87 (dd, J = 8.5, 1.6 Hz, 1H) ), 7.52 (d, J = 8.6 Hz, 1H), 7.39 - 7.24 (m, 6H), 5.43 (s, 2H), 4.02 (s, 3H).

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

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

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) was added 1- Bromo-4-chlorobenzene (222 mg; 1.16 mmol), XPhosPd G2 (84 mg; 0.11 mmol) and Cs ₂ CO ₃ (944 mg; 2.90 mmol) were added. The mixture was stirred at 120° C. under N ₂ atmosphere for 12 hours. The mixture was poured into water (10 mL) then extracted 3 times with EA (5 ml). The combined organic phases were collected and evaporated under vacuum. The residue could be purified by C18 column chromatography (ACN/H ₂ O = 5% - 95%) to give the purified product (180 mg; 52 %; off-white solid).

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

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) Sodium hydroxide (320 mg; 8 mmol) and water (4 ml) were added. The mixture was stirred at 65° C. under N ₂ atmosphere for 12 hours. The mixture is evaporated under vacuum. The residue was acidified with 1N HCl solution and evaporated. The remainder could be purified by C18 column chromatography (ACN/H2O = 5% - 95%) to give the purified product (30 mg; 21 %; white solid).

^1H NMR (300 MHz, DMSO) δ 12.70 (s, 1H), 8.44 (d, J = 1.4 Hz, 1H), 8.22 (s, 1H), 7.93 (dd, J = 8.7, 1.7 Hz, 1H), 7.86 (d, J = 8.8 Hz, 2H), 7.72 (d, J = 2.9 Hz, 1H), 7.67 (dd, J = 7.1, 4.0 Hz, 2H), 4.04 (s, 3H).

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

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

Ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-dioxane (4 ml) was placed in a microwave vial with argon. 4-bromoanisole (32 μl; 0.26 mmol), cesium carbonate (206 mg; 0.64 mmol) and XPhos Pd G4 (19 mg; 0.02 mmol) were added under The reaction was stirred at 120° C. for 16 hours. The reaction mixture was diluted with EA, extracted three times with water, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by preparative HPLC. A purified product could be obtained. (56 mg; 68 %; beige solid).

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

Ethyl 8-(4-methoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (56 mg; 0,15 mmol) in ethanol (0.3 ml) Sodium hydroxide solution c(NaOH) = 2 mol/l (0.2 ml) was added thereto, and the mixture was stirred at 60°C for 16 hours. The reaction was evaporated to dryness and the residue was purified by preparative HPLC. A purified product was obtained (19 mg; 40 %, white solid).

¹ H NMR (500 MHz, DMSO-d6) δ 12.58 - 12.54 (m, 1H), 8.40 - 8.38 (m, 1H), 8.15 (s, 1H), 7.87 (dd, J = 8.6, 1.8 Hz, 1H) , 7.65 - 7.61 (m, 2H), 7.44 (d, J = 8.7 Hz, 1H), 7.18 - 7.14 (m, 2H), 4.00 (s, 3H), 3.85 (s, 3H).

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

Example 15-1: Synthesis of ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate

To a suspension of ethyl 3-borono-4-chlorobenzoate (600 mg; 2.63 mmol) in 1,4-dioxane (8 ml) and water (0.8 ml) was added with dichloromethane (214 mg) in a microwave vial under argon. A complex of 4-bromo-1-methyl-1H-pyrazol-3-amine (462 mg; 2.63 mmol), potassium carbonate (726 mg; 5.25 mmol) and [1,1'-bis(diphenylphosphino) ) ferrocene]-dichloropalladium(II) was added. The reaction was stirred at 60° C. for 16 hours, then diluted with EA at room temperature. The mixture was extracted 3x with water, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by flash chromatography. The purified product could be obtained as a brown oil (273 mg, 36% yield).

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

Ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-dioxane (4 ml) was placed in a microwave vial with argon. 4-bromophenetol (35 μl; 0.25 mmol), cesium carbonate (0.62 mmol) and XPhos Pd G4 (19 mg; 0.02 mmol) were added under The reaction was stirred at 120° C. for 16 hours, then diluted with EA at room temperature. The mixture was extracted 3x with water, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by preparative HPLC and the purified product could be obtained as a yellow solid (10 mg, 12% yield).

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

Ethyl 8-(4-ethoxyphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (10 mg; 0,03 mmol) in ethanol (2 ml) Sodium hydroxide solution c(NaOH) = 2 mol/l (76 μl; 0.15 mmol) was added thereto, and the mixture was stirred at 60° C. for 16 hours. The reaction was not complete so more sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (76 μl; 0.15 mmol) was added and stirred at 60° C. for an additional 16 h. The reaction was dried at room temperature. Evaporated and the residue was purified by preparative HPLC column chromatography. The purified product could be obtained as an off-white solid (13 mg, 99% yield).

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

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 combined at room temperature. The resulting mixture was stirred under an argon atmosphere at 120° C. for 24 hours. The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC to give the product methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxylate as a white solid (40 mg, 9%).

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

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

¹ H NMR (400 MHz, DMSO, ppm) 8.52 (d, J = 4.6 Hz, 1 H), 8.46 (d, J = 1.8 Hz, 1 H), 8.10 (s, 1 H), 7.93 (s, 5 H), 7.85 (d, J = 8.7 Hz, 1 H), 4.10 (s, 3 H), 2.83 (d, J = 4.4 Hz, 3 H).

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

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

Ethyl 3-(3-amino-1-methyl-1H-pyrazol-4-yl)-4-chlorobenzoate (60 mg; 0.21 mmol) in 1,4-dioxane (4 ml) was placed in a microwave vial with argon. 1-Bromo-4-(trifluoromethoxy)-benzene (60 mg; 0.25 mmol), cesium carbonate (202 mg; 0.62 mmol) and XPhos Pd G4 (18.7 mg; 0.02 mmol) were added under The reaction was stirred at 120° C. for 16 hours. At room temperature the reaction mixture was diluted with EA, extracted three times with water, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by preparative HPLC and the product was obtained as a white solid (28 mg, 34%).

¹ H NMR (500 MHz, DMSO-d6) 8.45 - 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 = 7.1 Hz, 2H), 4.02 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H).

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

Ethyl 2-methyl-8-[4-(trifluoromethoxy)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (28 mg; 0 ,07 mmol) was added sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (104 μl; 0.21 mmol), and the mixture was stirred at 60° C. for 16 hours. The reaction was evaporated to dryness and the residue was purified by preparative HPLC to give the product as a white solid (20 mg, 76%).

^1H NMR (400 MHz, DMSO-d6) 12.67 - 12.62 (m, 1H), 8.41 (d, J = 1.7 Hz, 1H), 8.19 (s, 1H), 7.95 - 7.90 (m, 2H), 7.93 - 7.88 (m, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.63 - 7.59 (m, 2H), 4.02 (s, 3H).

Example 19: 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carbonitrile

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

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), NH ₄ OH (30 mL). The obtained 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 (3x100 mL). The resulting mixture was concentrated under vacuum. The result was 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (520 mg, 98%) as a white solid.

¹ H NMR (300 MHz, DMSO, ppm) 8.45 (d, J = 1.7 Hz, 1 H), 8.10 (s, 1 H), 8.04 - 7.95 (m, 1 H), 7.93 (s, 4 H), 7.86 (d, J = 8.8 Hz, 1 H), 4.09 (s, 3 H), 3.88 (s, 3 H).

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

2-Methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carboxamide (150 mg, 0.419 mmol), THF (7.5 mL) and POCl ₃ (0.15 mL) were added. The resulting mixture was stirred for 3 h at room temperature. The reaction was quenched on ice at 0 °C. The aqueous layer was extracted with EtOAc (3x50 mL). The resulting mixture was concentrated under vacuum. The crude product was purified by Prep-HPLC. The result was 2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-carbonitrile (37 mg, 25%) as a white solid.

¹ H NMR (300 MHz, DMSO, ppm) 8.44 (d, J = 1.7 Hz, 1 H), 8.15 (s, 1 H), 7.95 (s, 4 H), 8.02 - 7.87 (m, 1 H), 7.85 - 7.75 (m, 1 H), 4.12 (s, 3 H).

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

Example 20-1: Synthesis of 4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3-amine

2-chloro-5-nitrophenylboronic acid (1.0 g, 4.718 mmol) and 4-bromo-1-methylpyrazol-3-amine (437 mg) in dioxane (10 mL) and H ₂ O (2 mL) , 2.359 mmol) was added Pd(dppf)Cl ₂ (363 mg, 0.471 mmol) and K ₂ CO ₃ (1.3 g, 8.936 mmol). After stirring for 4 hours at 80° C. under a 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-methylpyrazol-3-amine (190 mg, 15 %) was obtained as a yellow solid.

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

4-(2-chloro-5-nitrophenyl)-1-methylpyrazol-3-amine (330 mg, 1.124 mmol) and 1-bromo-4-(trifluoromethyl) in dioxane (10 mL) To a stirred solution of benzene (346 mg, 1.461 mmol) was added XPhos Pd G3 (50 mg, 0.056 mmol), Cs ₂ CO ₃ (1.16 g, 3.372 mmol) portionwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120° C. under a 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 2-methyl-5-nitro-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4 -b]indole (460 mg, 95%) was obtained as a yellow solid.

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

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 in a 250 mL round bottom flask was added with Pd/C (10%, 450 mg) under a nitrogen atmosphere. The mixture was hydrogenated for 1 hour at room temperature under a hydrogen atmosphere using a hydrogen balloon, filtered through a pad of celite and concentrated under reduced pressure. This resulted in 2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-amine (360 mg, 99%) as a yellow solid.

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

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) of acryloyl chloride (52 mg, 0.546 mmol) was added dropwise at room temperature under a nitrogen atmosphere. The resulting mixture was stirred under a nitrogen atmosphere at room temperature for 2 hours. The reaction was quenched with water/ice and the resulting mixture was extracted with CH ₂ Cl ₂ (3×30 mL). The combined organic layers were washed with brine (1x30 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and purified by Prep-HPLC to obtain N-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole- 5-yl]prop-2-enamide was obtained as a white solid (45 mg, 25%).

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

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

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

2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indole-5-carbonitrile (Example 19) (300 mg, 0.882 mmol) in MeOH (30 mL) and NH ₃ (g) in MeOH (15 mL, 13%) was added Raney Ni (300 mg, 3.327 mmol) under nitrogen atmosphere. The resulting mixture was filtered for 6 hours at room temperature under a hydrogen atmosphere, and the filter cake was washed with MeOH (5x15 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with CH ₂ Cl ₂ (Et ₃ N) / MeOH (24:1) to give 1-[2-methyl-8-[4-(trifluoromethyl)phenyl Obtained ]pyrazolo[3,4-b]indol-5-yl]methanamine (300 mg, 89%) as a pale yellow solid.

Example 21-2: N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methyl)prop-2-ene synthesis of amides

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

^1H -NMR (300 MHz, DMSO-d6) 8.64 (t, J = 5.8 Hz, 1H), 8.13 (s, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.92 (d, J = 8.7 Hz, 2H), 7.75 - 7.66 (m, 2H), 7.22 (dd, J = 8.5, 1.9 Hz, 1H), 6.29 (dd, J = 17.1, 10.0 Hz, 1H), 6.13 (dd, J = 17.1, 2.4 Hz, 1H), 5.61 (dd, J = 10.0, 2.4 Hz, 1H), 4.45 (d, J = 5.8 Hz, 2H), 3.99 (s, 3H).

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

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

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) in a microwave vial. To this was added 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) under argon. The reaction was stirred at 120° C. for 16 hours. At room temperature the reaction was diluted with EA, extracted three times with water, dried over Na ₂ SO ₄ and evaporated to dryness. The residue was purified by preparative HPLC and the product was obtained as a white solid (15 mg, 18%).

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

Ethyl 8-(4-cyclopentylphenyl)-2-methyl-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (15 mg; 0,04 mmol) in ethanol (2 ml) To this was added sodium hydroxide solution c(NaOH) = 2 mol/l (2 N) (57 μl; 0.11 mmol), and the mixture was stirred at 60° C. for 2 days. The reaction was evaporated to dryness and the residue was purified by preparative HPLC to give 14 mg (quantitative yield) of the desired product as an off-white solid.

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

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

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

1-[2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl]methanamine in DCM (20 mL) (Example 21-1) (130 mg, 0.339 mmol) and DIPEA (139 mg, 1.022 mmol) was added chloroacetyl chloride (50 mg, 0.443 mmol) dropwise in DCM at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 1 h at 0° C. under a 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 Prep-HPLC to give 2-chloro-N-([2-methyl-8-[4-(trifluoromethyl)phenyl]pyrazolo[3,4-b]indol-5-yl] Methyl)acetamide (75 mg, 52%) was obtained as a white solid.

^1H NMR (400 MHz, DMSO-d6) 8.77 (t, J = 5.9 Hz, 1H), 8.15 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.94 (d, J = 8.5 Hz) , 2H), 7.77 - 7.69 (m, 2H), 7.25 (dd, J = 8.5, 1.9 Hz, 1H), 4.43 (d, J = 5.8 Hz, 2H), 4.15 (s, 2H), 4.02 (s, 3H).

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

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

To a solution of methyl 4-amino-3-bromobenzoate (1.03 g, 4.268 mmol) and 4-bromo-2-methyl-1,3-thiazole (0.80 g, 4.268 mmol) in toluene (16 mL) XantPhos (0.39 g, 0.640 mmol), Pd ₂ (dba) ₃ (0.21 g, 0.213 mmol) and Cs ₂ CO ₃ (2.94 g, 8.580 mmol) were added at room temperature under a nitrogen atmosphere. The final reaction mixture was irradiated with microwave radiation at 130° C. for 2 hours 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-thiazol-4-yl)amino] Benzoate (220 mg, 14%) (220 mg, 14%) was obtained as a pale yellow solid.

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

Methyl 3-bromo-4-[(2-methyl-1,3-thiazol-4-yl)amino]benzoate (1.01 g, 2.624 mmol) and pivalic acid (285 mg, 2.651 mmol) was added PCy ₃ .HBF ₄ (153 mg, 0.395 mmol), Pd(AcO) 2 (31 mg, 0.131 mmol) and Cs ₂ CO ₃ (2.7 g, 7.872 mmol) at room temperature under a nitrogen atmosphere. did The resulting mixture was stirred under a nitrogen atmosphere at 120° C. for 2 days 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]thiazolo[4,5-b]indole-7-carboxyl Yield (380 mg, 59%) was obtained as a pale yellow solid.

Example 25-3: Synthesis of methyl 2-methyl-4-[4-(trifluoromethyl)phenyl]-[1,3]thiazolo[4,5-b]indole-7-carboxylate

Methyl 2-methyl-4H-[1,3]thiazolo[4,5-b]indole-7-carboxylate (230 mg, 0.934 mmol) and 1-bromo-4- in dioxane (10 mL) To a stirred mixture of (trifluoromethyl)benzene (332 mg, 1.402 mmol) was added XPhos Pd G3 (83 mg, 0.093 mmol) and Cs ₂ CO ₃ (960 mg, 2.799 mmol) at room temperature 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]thiazolo[ 4,5-b] indole-7-carboxylate (230 mg, 63%) was obtained as a pale yellow solid.

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

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

^1H NMR (300 MHz, DMSO-d6) 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).

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

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

2-bromo-5-fluorophenylboronic acid (700 mg, 3.039 mmol) and 3-bromo-1-methyl-4-nitropyrazole (in dioxane (28 mL) and H ₂ O (7 mL)) To a stirred mixture of 700 mg, 3.330 mmol) was added NaHCO ₃ (1.40 g, 15.832 mmol) and Pd(PPh ₃ ) ₄ (350 mg, 0.300 mmol). The resulting mixture was stirred overnight at 110° C. under a nitrogen atmosphere and then concentrated under vacuum. The residue was extracted with EtOAc (3 x 30 mL) and the combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (4:1) to give 3-(2-bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole (700 mg , 40%) as a white solid.

Example 26-2: Synthesis of 3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4-amine

3-(2 _- bromo-5-fluorophenyl)-1-methyl-4-nitropyrazole (650 mg, 1.133 mmol) and NH ₄ Cl ( To a stirred solution of 580 mg, 10.301 mmol) was added Fe (609 mg, 10.360 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred for 2 h at 70° C. then diluted with water (20 mL). Extract the resulting mixture with CH ₂ Cl ₂ (3 x50 mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4-amine (500 mg, 100.00%) as a brown oil.

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

3-(2-bromo-5-fluorophenyl)-1-methylpyrazol-4-amine (500 mg, 1.133 mmol) and 1-bromo-4-(trifluoro To a stirred solution of methyl)benzene (460 mg, 1.942 mmol) was added Cs ₂ CO ₃ (1.20 g, 3.499 mmol) and XPhos Pd G3 (161 mg, 0.181 mmol) at room temperature under a nitrogen atmosphere. The resulting mixture was stirred overnight at 120° C. then quenched with water. This mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1x50 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC to give 7-fluoro-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (26 mg, 7%) Calculated as a white solid.

¹ H NMR (300 MHz, 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).

Example 27: N-Cyclopropyl-2-methyl-8-[6-(trifluoromethyl)pyridin-3-yl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxa mid

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

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

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

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

Sodium 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylate (50 mg; 0.13 mmol) in 4-picolylamine (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. The reaction was stirred at room temperature for 16 hours. The reaction was purified directly by HPLC to give the product as an off-white solid in 57% (34 mg) yield.

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

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

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) were stirred for 1 h at RT. To the mixture was added 2-amino-2-(pyridin-2-yl)ethanol (87 mg, 0.57 mmol). The resulting mixture was stirred at room temperature for an additional 3 h. The crude product was purified by HPLC to give the product (82 mg, 41%) as a white solid.

Example 29-2: Separation of Enantiomers

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

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

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

(2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylic acid (5 g; 24 mmol) in THF (1 Mol/L; 31 ml; 24 mmol) ) and TBAF in DMF (35 ml) at 0 °C was added BnBr (4.60 g; 25.55 mmol). The resulting mixture was stirred overnight at RT under N2 atmosphere. The mixture was then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylate (4 g; 13.90 mmol; 57%) as a yellow oil.

Benzyl (2S,3S,4S,5R,6R)-3,4,5,6-tetrahydroxyoxane-2-carboxylate (4 g; 13.90 mmol) in dioxane-1,4 (80 ml) and To a stirred solution of 2-methyl-8-[4-(trifluoromethyl)phenyl]-2H,8H-pyrazolo[3,4-b]indole-5-carboxylic acid (2.50 g; 6.71 mmol) HATU (4 g; 9.99 mmol) and NMM (2 g; 18.79 mmol) were added at RT under N ₂ atmosphere. The resulting mixture was stirred overnight at room temperature. For workup, the reaction was quenched with water. The resulting mixture was extracted with EtOAc (3 x 40 ml). The combined organic layers were washed with brine (3 x 100ml) and dried over anhydrous Na ₂ SO ₄ . 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 -trihydroxyoxan-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.

(2S,3R,4S,5S,6S)-6-[(benzyloxy)carbonyl]-3,4,5-trihydroxyoxan-2-yl 2-methyl-8-[ in DCE (3 ml) 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) ) was added triethylamine (0.50 ml; 3.66 mmol) and Pd(AcO) ₂ (360 mg; 1.52 mmol) at RT under N ₂ atmosphere. The mixture was stirred at 60° C. for 2 hours and then filtered. The filter cake was washed with DCM (3 x 5 ml) and the filtrate was concentrated under reduced pressure. The residue was treated with TBAF (4 ml) in THF (1 M) at room temperature. The resulting mixture was stirred at room temperature for 1 hour, then acidified to pH 5 with HCl (aq.), extracted with EtOAc (3 x 20 ml) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC to give the product (53 mg, 15%) as a white solid.

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

Example 31-1: Synthesis of 2-methyl-8-(4-methylphenyl)-5-(methylsulfanyl)-2H,8H-pyrazolo[3,4-b]indole

4-[2-chloro-5-(methylsulfanyl)phenyl]-1-methyl-1H-pyrazol-3-amine (500 mg; 1.9 mmol), 4-bromotoluene (661 mg; 3.9 mmol) and Cesium carbonate (1.9 g; 5.8 mmol) was suspended in 1,4-dioxane (30 ml), flushed with argon, then XPhos Pd G4 (175 mg; 0.2 mmol) was added and heated to 120° C. over the weekend. was stirred at. XPhos Pd G4 (175 mg; 0.2 mmol) was then added again and stirred at 100° C. for 2 days. The reaction was filtered over celite, the residue was washed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude was purified by chromatography to give the product (385 mg, 62%) as a pale yellow solid.

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

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

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

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

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

Stirring of 2-methyl-7-(methylsulfanyl)-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (20 mg, 0.036 mmol) in DCM (1 mL) To the mixture was added MCPBA (22 mg, 0.089 mmol) at RT. The resulting mixture was stirred for 3 hours at RT under an air atmosphere. The reaction mixture was diluted with water and washed with 10% aqueous sodium sulfite solution and saturated aqueous sodium hydrogen carbonate 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 Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC to give the product (48 mg, 17%) as a yellow solid.

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

Example 34-1: Synthesis of 2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-sulfonamide

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

NH ₃ .H ₂ O (3 mL) and THF (3 mL) was added dropwise. The resulting mixture was stirred at RT for 30 min. 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.

Example 35: imino(methyl){2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indol-7-yl}-lambda6 -Sulfanone

Example 35-1: Imino(methyl){2-methyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indol-7-yl}- Synthesis of lambda 6-sulfanone

7-Methanesulfinyl-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole (300 mg, 0.674 mmol) in CH ₂ Cl ₂ (15 mL); A mixture of MgO (1.14 g, 27 mmol), Rh ₂ (OAc) ₄ (9 mg, 0.019 mmol), DIB (347 mg, 1.02 mmol) and BocNH ₂ (124 mg, 1 mmol) was stirred for 8 h at 40 °C. Stir. The reaction was quenched at RT by addition of water (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl N-[methyl([2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7 -yl])oxo-lambda 6-sulfanylidene]carbamate (45 mg, 7%) was obtained as a brown solid.

tert-Butyl N-[methyl([2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7- in HCl (g) in MeOH (8 mL) yl]) A mixture of oxo-lambda 6-sulfanylidene]carbamate (40 mg, 0.04 mmol) was stirred for 3 h at RT under an air atmosphere. The reaction was quenched at RT by addition of water (50 mL). The resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (50 mL) and dried over anhydrous Na ₂ SO ₄ . After filtration, the filtrate was concentrated under reduced pressure. The crude was purified by HPLC to give the product (10 mg, 65%) as a white solid.

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

Example 36-1: N,N,2-trimethyl-4-[4-(trifluoromethyl)phenyl]-2H,4H-pyrazolo[4,3-b]indole-7-sulfonoimidamide synthesis of

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) was (42 mg, 1.1 mmol) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at RT under a nitrogen atmosphere. TBSCl (141 mg, 0.89 mmol) was added portionwise at 0°C to the mixture. The reaction mixture was stirred at room temperature for an additional 2 hours and quenched at 0 °C by addition of saturated NH ₄ Cl (aq.). The resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography to obtain N-(tert-butyldimethylsilyl)-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[ 4,3-b]indole-7-sulfonamide (150 mg, 42%) as an off-white solid.

In a sealed tube, a solution of PPh3 (200 mg, 0.72 mmol) and CCl ₃ CCl ₃ (181 mg, 0.73 mmol) in CHCl ₃ (2 mL) was stirred at 70° C. for 6 h under nitrogen atmosphere. TEA (52 mg, 0.49 mmol) was added dropwise to the mixture at room temperature and stirred at room temperature for an additional 10 minutes. N-( _tert -butyldimethylsilyl)-2-methyl-4-[4-(trifluoromethyl)phenyl]pyrazolo[4,3-b]indole-7-sulfonamide (130 mg, 0.24 mmol) was added dropwise at 0°C. The mixture was stirred at 0 °C for 20 minutes. Dimethylamine (35 mg, 0.74 mmol) in THF (0.37 mL) was then added dropwise at 0°C. The resulting mixture was stirred at 0° C. for an additional 30 min and at RT overnight. After concentration in vacuo, the residue was isolated in ACN (1 mL) and a solution of HCOOH (1 mL) in H ₂ O (1 mL) was added dropwise at 0 °C. The resulting mixture was stirred for 1 hour at room temperature and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give the product (46 mg, 40%) as an off-white solid.

Table 1

Table 1 below shows exemplary compounds of the present invention. These were synthesized as or similarly described in the Examples above.

TFA = trifluoroacetate

LC-MS conditions:

¹ column: Waters XBridge C18 3.5 μm, 50*4.6 mm; 5-95 %: flow rate: 1.5 mL/min; Assay time: 6.5 min; MS scan range: 100-1000; Mobile Phase A: 0.02% NH4OAc in water; Mobile phase B: acetonitrile; Gradient: 0.15 min: 5 % B, 4.5 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B.

² 24 columns: Waters XBridge C18 3.5 um, 50*4.6 mm; Solvent A: water+0.1% TFA; Solvent: ACN; Flow: 1.5 ml/min; time: 6.5 min; Gradient: 0.15 min: 10 % B, 4.5 min: 80 % B, 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B.

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

⁴ column: Waters XBridge C18 3.5 μm, 50*4.6 mm; 30-95 %: flow rate: 1.5 mL/min; Assay time: 6.5 min; MS scan range: 100-1000; Mobile Phase A: 0.1% TFA in water; Mobile phase B: acetonitrile; Gradient: 0.15 min: 30 % B, 4.5 min: 95 % B, 4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B

⁵ columns: waters XBridge C18 5um, 50*4.6mm; Solvent A: water+0.1% TFA; Solvent: ACN; flow: 1.5 ml/min; time:6.5 min; Gradient :0.15 min: 10 % B, 4.5 min￡º80 % B￡￢4.6 min: 95 % B, 6.0 min: 95 % B, 6.1 min: 5% B, 6.5 min: 5% B

⁶ column: XBridge C18, 3.5 μm, 3.0 * 30 mm; Solvent A: water + 0.1% TFA; Solvent B: ACN + 0.1% TFA; flow: 2 ml/min; Gradient: 0 min: 5 % B, 8 min: 100 % B, 8.1 min: 100 % B, 8.5 min: 5% B, 10 min: 5% B.

⁷ column: Titank C18 1.8 μm, 30*2.1 mm; Column Oven: 40 C; Mobile Phase A: 0.04% NH4OH, Mobile Phase B: ACN; flow rate: 0.8 mL/min; Gradient: 10% B to 95% B in 2.1 min, hold 0.6 min; 254 nm

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

⁹ column: HALO, 3.0*30mm, 2um; Column Oven: 40° C.; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; flow rate: 1.5 mL/min; Gradient: 5%B to 100%B in 1.2 min, hold 0.5 min

¹⁰ column: HALO C18, 3.0*30mm, 2.0um; Column Oven: 40° C.; Mobile phase A: water/0.1% FA; Mobile Phase B: Acetonitrile/0.1% FA; flow rate: 1.5 mL/min; Gradient: 5%B to 100%B in 1.2 min, hold 0.6 min

¹¹ column: Shim-pack XR-ODS, 3.0*50 mm, 2.2um; Mobile Phase A: Water/0.05% TFA, Mobile Phase B: ACN/0.05% TFA; flow rate: 1.2 mL/min; Gradient: 5%B to 100%B in 2.0 min, hold 0.7 min

¹² column: HALO C18, 3.0*30mm, 2.0um; Column Oven: 40° C.; Mobile Phase A: Water/0.1% FA, Mobile Phase B: Acetonitrile/0.1% TFA; flow rate: 1.5 mL/min; Gradient: 5% B to 100% B in 1.2 min, hold 0.5 min; 254 nm

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

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

¹⁵ column: Poroshell HPH-C18 2.7um, 3.0*50 mm; Column Oven: 40° C.; Mobile phase A: water/5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.2 mL/min; Gradient: 10% B to 95% B in 2.1 min, hold 0.6 min; 254 nm

¹⁶ columns: Kinetex EVO 2.6um, 3.0*50 mm; Column Oven: 40° C.; Mobile phase A: water/5 mM NH4HCO3, mobile phase B: acetonitrile; flow rate: 1.2 mL/min; Gradient: 10% B to 95% B in 2.1 min, hold 0.6 min; 254 nm

¹⁷ column: Kinetex® EVO C18 5.0 μm 50-4.6 mm; A: H2O+0.05% HCOOH; B: MeCN+0.04% HCOOH+1% H2O; 1% -> 99% B: 0 ->0.8min; 99% B: 0.8 -> 1.1 min; T: 40° C.; Flow: 3.3 mL/min; MS: 61-1000 amu positive

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

A: Column: Waters Cortecs C18 2.1*50 mm, 1.6 micron particle size, column oven 45 ^o C; 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 in 3 min, hold 0.8 min, 254 nm

B: Column: Waters Xbridge C18 4.6*50 mm, 5.0 micron particle size, column oven 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 in 5.5 min, hold 1 min, 254 nm

Chiral HPLC/SFC:

^a SFC; Column: ChiralPak IC; Eluent: CO ₂ :ethanol (55:45); Wavelength: 220 nm; Flow: 5 mL/min.

^b SFC: Column: YMC Cellulose-SC, eluent CO ₂ : methanol 65:35, wavelength 254, flow: 5 mL/min.

^c SFC: Column: Lux Cellulose-2, eluent CO ₂ : methanol 65:35, wavelength 270 nm, flow: 5 ml/min.

Melting points of selected compounds of Table 1 were determined using a Tianjin Analytical Instrument RY-1 melting point detector and are shown in Table 1a below:

Table 1a

Table 1b

Table 1b below further shows exemplary compounds of the present invention. These can be synthesized by applying the methods and procedures described in the Examples above. LC-MS and chiral HPLC/SFC conditions are as defined above for Table 1.

biological activity

SK-HEP-1 reporter assay

To identify inhibitors of the YAP-TEAD interaction, an 8x TEAD responsive element inducing the NanoLuc® luciferase gene was stably integrated into SK-HEP-1 cells (ECACC #: 91091816).

For the assay, cells were treated in duplicate with the test compound at a 10-point dose, with the highest concentration starting at 30 μM (final concentration in the assay). After 24 hours incubation at 37° C., 95% rH, and 5% CO ₂ , a luciferase substrate/lysis reagent mix (NanoGlo™, Promega) was added to the cells to allow quantification of cellular luciferase activity.

Cell medium: Cells were cultured in the following medium: MEM, +10% FBS, +1x GlutaMAX, +1 mM sodium-pyruvate, + 100 μM non-essential amino acids, +0.1 mg/ml hygromycin. The medium used for the assay was as follows: MEM (w/o Phenol Red), +10% FBS, +1x GlutaMAX, +1 mM sodium-pyruvate, + 100 μM non-essential amino acids, +0.5% Pen/ Strep

Reagents: The reagents used are listed below:

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

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

Total cell count was determined and 20 μl of the desired cell count was added to each well of a 384 well plate using the Multidrop Combi. Plates were then incubated for 24 hours at 37° C., 95% rH, and 5% CO ₂ .

Compound treatment: 24 hours after seeding, cells were treated with compounds.

A 1:333 dilution of compound, diluted in DMSO, was made to a final concentration of 0.3% DMSO per well. To transfer compounds to assay plates, 120 nl were injected from Labcyte low dead volume plates into ECHO 555 liquid handling system into cell plates containing 20 μl media/well.

After treatment, cells were supplied with 20 μl of fresh pre-warmed assay medium using Multidrop combi.

The assay plate was then incubated for another 24 hours at 37° C., 95% rH, and 5% CO ₂ .

Luciferase Reading: After 24 hours of treatment, the plate was removed from the incubator and allowed to equilibrate to RT. 30 μl of NanoGlo® reagent was added to the plate in the dark. The plate was shaken for 20 minutes on a Teleshake (~1500 rpm) in the dark. Luminescence was then measured using an EnVision microplate reader. IC50 values were generated using Genedata Screener®.

Viability assay in NCI-H226 (Yap-dependent) and SW620 Yap KO (Yap independent) cells

The ability of YAP-TEAD inhibitors to inhibit tumor cell growth was evaluated using two different cell lines: NCI-H226, which is a YAP-dependent cell line, and SW620 cells, which knock out YAP and TAZ using CRISPR to achieve YAP-independent Cell lines were generated.

For the assay, cells were treated in duplicate with test compounds at 10-point doses, 1:3 dilution steps, at the highest concentration starting at 30 μM (final concentration in the assay). After 96 hours incubation at 37°C, 95% rH, and 5% CO ₂ , a cell-permeable DNA-binding dye that stains only healthy cells (CyQUANT®, Promega) was added to the cells to allow quantification of cell viability. .

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

Reagents: The reagents used are listed below:

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

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

Total cell count was determined and 20 μl of the desired cell count was added to each well of a 384 well plate using the Multidrop Combi. Plates were then incubated for 24 hours at 37° C., 95% rH, and 5% CO ₂ .

Compound treatment: 24 hours after seeding, cells were treated with compounds.

A 1:333 dilution of compound, diluted in DMSO, was made to a final concentration of 0.3% DMSO per well. To transfer compounds to assay plates, 120 nl were injected from Labcyte low dead volume plates into ECHO 555 liquid handling system into cell plates containing 20 μl media/well.

After treatment, cells were supplied with 20 μl of fresh pre-warmed assay medium using Multidrop combi.

The assay plate was then incubated for 96 hours at 37° C., 95% rH, and 5% CO ₂ .

CyQuant® measurement

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

The experimental data in the SK-HEP-1 reporter assay of the compounds shown in Table 1 are shown in Table 2 below and are classified into the following groups:

Group A IC ₅₀ is in the range of 1 nM to 10 nM

Group B IC ₅₀ is in the range of >10 nM to 100 nM

Group C IC ₅₀ is in the range of >100 nM to 10000 nM

Group D IC ₅₀ is in the range of >10000 nM

The experimental data in the viability assay of the compounds shown in Table 1 are shown in Table 2 below and are classified into the following groups:

For viability assay in NCI-H226 cells:

Group A IC ₅₀ is in the range of 1 nM to 100 nM

Group B IC ₅₀ is in the range of >100 nM to 1000 nM

Group C IC ₅₀ is in the range of >1000 nM to 10000 nM

Group D IC ₅₀ is in the range of >10000 nM

For the viability assay in SW620 Yap KO cells :

Group A IC ₅₀ is in the range of 0.1 μM to 1 μM

Group B IC ₅₀ is in the range of >1 μM to 10 μM

Group C IC ₅₀ is in the range of >10 μM to 30 μM

Group D IC ₅₀ is in the range of >30 μM

ND = cannot be determined within full range

Table 2

NCI-H226 in vivo efficacy study

7-9-week-old H2d Rag2 female mice (autologous sarcoma, Taconic-Denmark) were inoculated subcutaneously with 5 x 10^6 NCI-H226 human mesothelioma tumor cells into the right flank. Tumor growth and body weight were measured twice a week using calipers. Tumor volume was calculated using the formula TV = L x W x W /2.

When tumor volume reached approximately 75-150 mm³, animals were randomized into treatment groups (n = 9-10/group) (Day 0) and treated with vehicle (20% hydroxypropyl β in 50 mM PBS pH 7.4). -cyclodextrin) or compound no.2 orally (po) once a day for 29 days. Compound no.2 was tested at dosage levels of 1, 3, 10, 30, and 100 mg/kg, respectively. The results are shown in FIG. 1 (tumor growth over time for vehicle group and each dose group) and FIG. 2 (final tumor volume for vehicle group and each dose group).

Significant tumor growth inhibition was achieved compared to the vehicle treated group for all tested dose levels (FIG. 1 - graphs b and c; p-value < 0.001), indicating maximal inhibition at dose levels greater than 10 mg/kg. indicates Statistical analysis of tumor volume between treatment groups was performed using repeated measures analysis of covariance (RM-ANCOVA) followed by least square mean pairwise comparisons in a linear mixed effects model.

Animal experiments were conducted in accordance with EU laboratory animal guidelines for animal testing areas under the regulation of the German Animal Welfare Act.

The following examples relate to medicines:

Example A: injection vial

A solution of 100 g of the active ingredient of formula I or I-A and 5 g of disodium hydrogenphosphate in 3 l of double distilled water is adjusted to pH 6.5 with 2 N hydrochloric acid, sterile filtered and transferred to an injection vial, Lyophilized under sterile conditions and sealed under sterile conditions. Each injection vial contains 5 mg of active ingredient.

Example B: suppositories

A mixture of 20 g of the active ingredient of formula I or I-A, 100 g of soybean lecithin and 1400 g of cocoa butter is melted, poured into molds and allowed to cool. Each suppository contains 20 mg of active ingredient.

Example C: solution

1 g of active ingredient of formula I or IA, 9.38 g of NaH ₂ PO ₄ 2 H ₂ O, 28.48 g of Na ₂ HPO ₄ 12 H ₂ O and 0.1 g of benzalkonium in 940 mL of double distilled water. A solution was prepared from chloride. The pH is adjusted to 6.8, the solution is made up to 1 l and sterilized by irradiation. This solution may be used in the form of eye drops.

Example D: Ointment

500 mg of the active ingredient of formula I or I-A are mixed under aseptic conditions with 99.5 g of Vaseline.

Example E: refine

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

Example F: Dragee

After the tablets are compressed similarly to example E, they are coated in the customary manner with a coating of sucrose, potato starch, talc, tragacanth and dye.

Example G: capsule

2 kg of active ingredient of formula I or I-A are introduced into hard gelatine capsules in the customary manner, in such a way that each capsule contains 20 mg of active ingredient.

Example H: ample

A solution of 1 kg of active ingredient of formula I or I-A in 60 l of double distilled water is sterile filtered, transferred into ampoules, lyophilized under sterile conditions and sealed under sterile conditions. Each ampoule contains 10 mg of active ingredient.

Claims (21)

Compounds of Formula IA

during the ceremony,
Ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

during the ceremony,
R ^A1 represents H, D, C _1-6 -aliphatic, -CH ₂ -Ar ^A1 or -CH ₂ -CH ₂ -Ar ^A1 ;
R ^A2 represents H, D, halogen, C _1-6 -aliphatic, -CH ₂ -Ar ^A2 or -CH ₂ -CH ₂ -Ar ^A2 ;
R ^A3 represents H, D, C _1-6 -aliphatic, -CH ₂ -Ar ^A3 or -CH ₂ -CH ₂ -Ar ^A3 ;
Z ¹ is CR ^Z1 or N;
Z ² is CR ^Z2 or N;
Z ³ is CR ^Z3 or N;
at least two of Z ¹ , Z ² and Z ³ are not N;
R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , unsubstituted or substituted, straight chain or branched C _1-8 -represents an aliphatic;
R ² is -C(=O)-OR ^2a , -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _w -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _x - NR ^2d -C(=O)-R ^2e , -SR ^2f , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S(=O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , -S(=O)(=NR ^2k ) -NR ^2l R ^2m , F, Cl, Br, I, -CN, -(CH ₂ ) _v -CN, -P(=0)(OR ^2o )(OR ^2p ), -(CH ₂ ) _y -NR ^2q R ^2r , -(CH ₂ ) _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 ;
Ar ^A1 , Ar ^A2 , Ar ^A3 independently of each other represent unsubstituted or independently of each other phenyl which may be mono- or di-substituted with R ^A11 and/or R ^A12 ;
R ^Z1 represents H or halogen;
R ^Z2 represents H or halogen; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-;
R ^Z3 represents H or halogen;
R ^2a represents H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or a radical derived from a carbohydrate, or Cat ;
Cat represents a monovalent cation;
R ^2b , R ^2c , R ^2q , R ^2r independently represent H, unsubstituted or substituted C _{1-8 -aliphatic, including C 3-7 -alicyclic} ; or
together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms; wherein said heterocycle may optionally be fused with Hetar ^Z ; or
one of R ^2b and R ^2c represents -CN, -NH ₂ , -OH, -OC _1-6 -alkyl, -S(=O) ₂ -R ^2g , Ar ² , Hetar ² , Cyc ² or Hetcyc ² while others represent H or unsubstituted or substituted C _1-8 -aliphatic;
R ^2d , R ^2j , R ^2k , R ^2o , R ^2p independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic;
R ^2e represents H, halogen, unsubstituted or substituted C _1-8 -aliphatic, heteroaryl;
R ^2f and R ^2g independently represent unsubstituted or substituted C _1-8 -aliphatic;
R ^2h , R ²ⁱ independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;
R ^2l , R ^2m independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;
R ^2s and R ^2t independently represent unsubstituted or substituted C _1-8 -aliphatic; or together form an unsubstituted or substituted divalent C _3-6 -alkylene radical;
R ^2u represents hydrogen or unsubstituted or substituted C _1-6 -aliphatic;
Ar ¹ is a mono-, bi-, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryls may be unsubstituted and may be the same or different; may be substituted with substituents R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;
Hetar ¹ is a mono-, bi- or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, wherein 1, 2, 3, 4, 5 are heteroatom(s) selected from N, O and/or S and the remainder are carbon atoms, heteroaryls are unsubstituted or substituents R ^B1 , R ^B2 , R ^B3 , R which may be the same or different ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;
Cyc ¹ is a saturated or partially unsaturated, mono-, bi- or tricyclic carboxyl having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms a bocycle, wherein the carbocycle may be unsubstituted or substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 R ^B12 and/or R ^B13 which may be the same or different; wherein a carbocycle may optionally be fused to Ar ^X via two adjacent ring atoms of said Ar ^X , and the fused carbocycle may further be unsubstituted or R ^C1 , R ^C2 , R ^C3 which may be identical or different. , R ^C4 , R ^C5 , R ^C6 ;
Hetcyc ¹ is a saturated or partially unsaturated, mono-, bi- 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, 5 of the ring atoms are heteroatom(s) selected from N, O and/or S and the others are carbon atoms, and the heterocycles may be unsubstituted or the same or different. may be substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 and/or R ^B13 ;
L ¹ is from the group consisting of -S(=0) ₂ -, -C(=0)-, unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene is a selected divalent radical, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-;
L ² is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene, in both of which the alkylene or alkenylene chain is One of the carbon units may be replaced by -O-;
R ^A11 , R ^A12 independently of each other represent halogen or unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic;
R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 , R ^B7 independently of each other are unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic, C _1-6 -aliphatoxy , -SC _1-6 -aliphatic; Halogen, -CN, -S(=O)-R ^b1 , S(=O) ₂ -R ^b1 , -NR ^b2 NR ^b3 , Ar ² , -CH ₂ -Ar ² , Hetar ² , Cyc ² , Hetcyc ² indicate;
and/or two adjacent R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 together form a divalent -C _2-4 -alkylene radical, wherein one of the alkylene carbon units is forms a carbonyl unit (which may be replaced by -C(=O)-), or a divalent -OC _1-3 -alkylene radical or a divalent -OC _1-3 -alkylene-O- radical;
R ^b1 represents unsubstituted or substituted C _1-8 -aliphatic;
R ^b2 , R ^b3 independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or
together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms;
R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 independently of each other represent halogen, unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, Ar ^Y ; and/or
two of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=0) group; and/or
2 of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , ^{R B13} or 4 of R ^B8 , R B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same sulfur atom of the heterocycle Dog forms a divalent oxo (=O) group to form a -S(=O)- or -S(=O) ₂ - moiety;
Ar ² is a mono- or bicyclic aryl having 5, 6, 7, 8, 9 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 ;
Hetar ² is a mono- or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are N, O and/or or heteroatom(s) selected from S, the remainder being carbon atoms, and the heteroaryl may be unsubstituted or substituted by substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 which may be identical or different. there is;
Cyc ² is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 ; wherein the carbocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused carbocycle may further be unsubstituted or R ^C1 which may be identical or different. , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;
Hetcyc ² is a saturated or partially unsaturated, monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein 1 or 2 of said ring atoms are selected from N, O and/or S and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 which may be the same or different; wherein the heterocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused heterocycle may further be unsubstituted or may be the same or different R ^C1 , R may be substituted with ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;
Ar ^X and Ar ^Z are each independently an unsubstituted or substituted benzo ring;
Ar ^Y is unsubstituted or mono- or di-substituted phenyl;
Hetar ^Y1 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH;
Hetar ^Z is a beach selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran a cyclic or substituted 5 or 6-membered heteroaryl ring;
Cyc ^Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by halogen, OH, C _1-4 -alkyl there is;
Hetcyc ^X 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 said ring atoms are N, O and/or heteroatom(s) selected from S, the remainder being carbon atoms, wherein the heterocycles may be unsubstituted or the same or different, R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , may be substituted with R ^X7 and/or R ^X8 , wherein the heterocycle is optionally a carboxylic acid bioisoster;
Hetcyc ^Y is a saturated, partially unsaturated or aromatic, monocyclic heterocycle having 3, 4, 5, 6 or 7 ring atoms, wherein 1, 2, 3 or 4 of said ring atoms are N, O and/or heteroatom(s) selected from S and the others being carbon atoms;
Hetcyc ^Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom;
R ^C1 , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;
R ^D1 , R ^D2 , R ^D3 , R ^D4 , R ^D5 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;
R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 independently of each other are unsubstituted or substituted C _1-6 -aliphatic, unsubstituted or substituted C _1-6 -alifatoxy, halogen, hydroxy ; Hetar ^Y1 , CH ₂ -Hetar ^Y1 , Cyc ^Y1 , Hetcyc ^Y1 , -CH ₂ -Hetcyc ^Y1 ; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to the same ring atom of said carbocycle or heterocycle may form a divalent C _2-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of the alkylene radical may optionally independently of each other be replaced by O, NH, or NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _1-4 -alkyl; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to different ring atoms of said carbocycle or heterocycle may form a divalent C _1-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of said alkylene radical may optionally, independently of each other be replaced by O, NH, or NC _1-4 -alkyl;
R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 are independently of each other unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, halogen , -OH, -NR ^2d -S(=0) ₂ -R ^2g , Hetcyc ^Y , O-Hetcyc ^Y ; and/or
two of R ^X1 , R ^X2 , R ^X3 , R ^X4 , R X5 , R ^X6 , ^{R X7 ,} R ^X8 attached to the same carbon atom of the heterocycle form a divalent oxo (=0) group; and/or two of R ^X1 , R ^X2 , R ^X3 , R X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 attached to ^the same sulfur atom of said heterocycle or R ^X1 , R ^X2 , R ^X3 , R ^{four of X4} , R ^X5 , R ^X6 , R ^X7 , R ^X8 form a divalent oxo (=0) group to form an -S(=0)- or -S(=0) ₂ - moiety;
halogen is F, Cl, Br, I;
v is 1 or 2;
w is 1 or 2;
x is 0, 1 or 2;
y is 0, 1 or 2;
z is 0, 1 or 2;
or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to claim 1,
Z ¹ is CR ^Z1 ;
Z ² is CR ^Z2 ;
Z ³ is CR ^Z3 or N;
R ^Z1 is H or F; is preferably H;
R ^Z2 is H or F; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-; is preferably H;
R ^Z3 is H or F; preferably H,
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. compound of formula I

during the ceremony,
Ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

during the ceremony,
R ^A1 represents H, C _1-6 -aliphatic, -CH ₂ -Ar ^A1 or -CH ₂ -CH ₂ -Ar ^A1 ;
R ^A2 represents H, halogen, C _1-6 -aliphatic, -CH ₂ -Ar ^A2 or -CH ₂ -CH ₂ -Ar ^A2 ;
R ^A3 represents H, C _1-6 -aliphatic, -CH ₂ -Ar ^A3 or -CH ₂ -CH ₂ -Ar ^A3 ;
Z ¹ is CR ^Z1 or N;
Z ² is CR ^Z2 or N;
at least one of Z ¹ and Z ² is not N;
R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , unsubstituted or substituted, straight chain or branched C _1-8 -represents an aliphatic;
R ² is -C(=O)-OR ^2a , -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _w -C(=O)-NR ^2b R ^2c , -(CH ₂ ) _x - NR ^2d -C(=O)-R ^2e , -SR ^2f , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S(=O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , -S(=O)(=NR ^2k ) -NR ^2l R ^2m , F, Cl, Br, I, -CN, -(CH ₂ ) _v -CN, -P(=0)(OR ^2o )(OR ^2p ), -(CH ₂ ) _y -NR ^2q R ^2r , -(CH ₂ ) _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 ;
Ar ^A1 , Ar ^A2 , Ar ^A3 independently of each other represent unsubstituted or independently of each other phenyl which may be mono- or di-substituted with R ^A11 and/or R ^A12 ;
R ^Z1 represents H or halogen;
R ^Z2 represents H or halogen; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-;
R ^2a represents H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heteroaryl, saturated or partially unsaturated heterocyclyl, or a radical derived from a carbohydrate, or Cat ;
Cat represents a monovalent cation;
R ^2b , R ^2c , R ^2q , R ^2r independently represent H, unsubstituted or substituted C _{1-8 -aliphatic, including C 3-7 -alicyclic} ; or
together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms; wherein said heterocycle may optionally be fused with Hetar ^Z ; or
one of R ^2b and R ^2c represents -CN, -NH ₂ , -OH, -OC _1-6 -alkyl, -S(=O) ₂ -R ^2g , Ar ² , Hetar ² , Cyc ² or Hetcyc ² while others represent H or unsubstituted or substituted C _1-8 -aliphatic;
R ^2d , R ^2j , R ^2k , R ^2o , R ^2p independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic;
R ^2e represents H, halogen, unsubstituted or substituted C _1-8 -aliphatic, heteroaryl;
R ^2f and R ^2g independently represent unsubstituted or substituted C _1-8 -aliphatic;
R ^2h , R ²ⁱ independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;
R ^2l , R ^2m independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms;
R ^2s and R ^2t independently represent unsubstituted or substituted C _1-8 -aliphatic; or together form an unsubstituted or substituted divalent C _3-6 -alkylene radical;
R ^2u represents hydrogen or unsubstituted or substituted C _1-6 -aliphatic;
Ar ¹ is a mono-, bi-, or tricyclic aryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 ring carbon atoms, wherein the aryls may be unsubstituted and may be the same or different; may be substituted with substituents R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;
Hetar ¹ is a mono-, bi- or tricyclic heteroaryl having 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 ring atoms, wherein 1, 2, 3, 4, 5 are heteroatom(s) selected from N, O and/or S and the remainder are carbon atoms, heteroaryls are unsubstituted or substituents R ^B1 , R ^B2 , R ^B3 , R which may be the same or different ^B4 , R ^B5 , R ^B6 and/or R ^B7 ;
Cyc ¹ is a saturated or partially unsaturated, mono-, bi- or tricyclic carboxyl having 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 ring carbon atoms a bocycle, wherein the carbocycle may be unsubstituted or substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 R ^B12 and/or R ^B13 which may be the same or different; wherein a carbocycle may optionally be fused to Ar ^X via two adjacent ring atoms of said Ar ^X , and the fused carbocycle may further be unsubstituted or R ^C1 , R ^C2 , R ^C3 which may be identical or different. , R ^C4 , R ^C5 , R ^C6 ;
Hetcyc ¹ is a saturated or partially unsaturated, mono-, bi- 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, 5 of the ring atoms are heteroatom(s) selected from N, O and/or S and the others are carbon atoms, and the heterocycles may be unsubstituted or the same or different. may be substituted with R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 and/or R ^B13 ;
L ¹ is from the group consisting of -S(=0) ₂ -, -C(=0)-, unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene is a selected divalent radical, in both of which one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-;
L ² is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene, in both of which the alkylene or alkenylene chain is One of the carbon units may be replaced by -O-;
R ^A11 , R ^A12 independently of each other represent halogen or unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic;
R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 , R ^B7 independently of each other are unsubstituted or substituted, straight-chain or branched C _1-6 -aliphatic, C _1-6 -aliphatoxy , -SC _1-6 -aliphatic; Halogen, -CN, -S(=O)-R ^b1 , S(=O) ₂ -R ^b1 , -NR ^b2 NR ^b3 , Ar ² , -CH ₂ -Ar ² , Hetar ² , Cyc ² , Hetcyc ² indicate;
and/or two adjacent R ^B1 , R ^B2 , R ^B3 , R ^B4 , R ^B5 , R ^B6 and/or R ^B7 together form a divalent -C _2-4 -alkylene radical, wherein one of the alkylene carbon units is forms a carbonyl unit (which may be replaced by -C(=O)-), or a divalent -OC _1-3 -alkylene radical or a divalent -OC _1-3 -alkylene-O- radical;
R ^b1 represents unsubstituted or substituted C _1-8 -aliphatic;
R ^b2 , R ^b3 independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or
together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is a nitrogen atom, 0 or 1 additional ring atoms are heteroatoms selected from N, O or S and the others are carbon atoms;
R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 independently of each other represent halogen, unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, Ar ^Y ; and/or
two of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same carbon atom of said carbocycle or said heterocycle form a divalent oxo (=0) group; and/or
2 of R ^B8 , R ^B9 , R ^B10 , R ^B11 , R ^B12 , ^{R B13} or 4 of R ^B8 , R B9 , R ^B10 , R ^B11 , R ^B12 , R ^B13 attached to the same sulfur atom of the heterocycle Dog forms a divalent oxo (=O) group to form a -S(=O)- or -S(=O) ₂ - moiety;
Ar ² is a mono- or bicyclic aryl having 5, 6, 7, 8, 9 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 ;
Hetar ² is a mono- or bicyclic heteroaryl having 5, 6, 7, 8, 9, 10 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are N, O and/or or heteroatom(s) selected from S, the remainder being carbon atoms, and the heteroaryl may be unsubstituted or substituted by substituents R ^D1 , R ^D2 , R ^D3 , R ^D4 and/or R ^D5 which may be identical or different. there is;
Cyc ² is a saturated or partially unsaturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 ; wherein the carbocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused carbocycle may further be unsubstituted or R ^C1 which may be identical or different. , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;
Hetcyc ² is a saturated or partially unsaturated, monocyclic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein 1 or 2 of said ring atoms are selected from N, O and/or S and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 which may be the same or different; wherein the heterocycle may optionally be fused to Ar ^Z or Hetar ^Z via two adjacent ring atoms of said Ar ^Z or Hetar ^Z , and the fused heterocycle may further be unsubstituted or may be the same or different R ^C1 , R may be substituted with ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 ;
Ar ^X and Ar ^Z are each independently an unsubstituted or substituted benzo ring;
Ar ^Y is unsubstituted or mono- or di-substituted phenyl;
Hetar ^Y1 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH;
Hetar ^Z is a beach selected from the group consisting of pyrrole, furan, thiophene, pyrazole, imidazole, oxazole, isoxazole, thiazole, oxadiazole, triazole, tetrazole, pyridine, pyrimidine, pyrazine, and pyran a cyclic or substituted 5 or 6-membered heteroaryl ring;
Cyc ^Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by halogen, OH, C _1-4 -alkyl there is;
Hetcyc ^X 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 said ring atoms are N, O and/or heteroatom(s) selected from S, the remainder being carbon atoms, wherein the heterocycles may be unsubstituted or the same or different, R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , may be substituted with R ^X7 and/or R ^X8 , wherein the heterocycle is optionally a carboxylic acid bioisoster;
Hetcyc ^Y is a saturated, partially unsaturated or aromatic, monocyclic heterocycle having 3, 4, 5, 6 or 7 ring atoms, wherein 1, 2, 3 or 4 of said ring atoms are N, O and/or heteroatom(s) selected from S and the others being carbon atoms;
Hetcyc ^Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom;
R ^C1 , R ^C2 , R ^C3 , R ^C4 , R ^C5 , R ^C6 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;
R ^D1 , R ^D2 , R ^D3 , R ^D4 , R ^D5 independently of each other represent unsubstituted or substituted C _1-6 -aliphatic;
R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 independently of each other are unsubstituted or substituted C _1-6 -aliphatic, unsubstituted or substituted C _1-6 -alifatoxy, halogen, hydroxy ; Hetar ^Y1 , CH ₂ -Hetar ^Y1 , Cyc ^Y1 , Hetcyc ^Y1 , -CH ₂ -Hetcyc ^Y1 ; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to the same ring atom of said carbocycle or heterocycle may form a divalent C _2-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of the alkylene radical may optionally independently of each other be replaced by O, NH, or NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _1-4 -alkyl; and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to different ring atoms of said carbocycle or heterocycle may form a divalent C _1-6 -alkylene radical; , 1 or 2 non-adjacent carbon units of said alkylene radical may optionally, independently of each other be replaced by O, NH, or NC _1-4 -alkyl;
R ^X1 , R ^X2 , R ^X3 , R ^X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 are independently of each other unsubstituted or substituted C _1-6 -aliphatic, C _1-6 -alifatoxy, halogen , -OH, -NR ^2d -S(=0) ₂ -R ^2g , Hetcyc ^Y , O-Hetcyc ^Y ; and/or
two of R ^X1 , R ^X2 , R ^X3 , R ^X4 , R X5 , R ^X6 , ^{R X7 ,} R ^X8 attached to the same carbon atom of the heterocycle form a divalent oxo (=0) group; and/or two of R ^X1 , R ^X2 , R ^X3 , R X4 , R ^X5 , R ^X6 , R ^X7 , R ^X8 attached to ^the same sulfur atom of said heterocycle or R ^X1 , R ^X2 , R ^X3 , R ^{four of X4} , R ^X5 , R ^X6 , R ^X7 , R ^X8 form a divalent oxo (=0) group to form an -S(=0)- or -S(=0) ₂ - moiety;
halogen is F, Cl, Br, I;
v is 1 or 2;
w is 1 or 2;
x is 0, 1 or 2;
y is 0, 1 or 2;
z is 0, 1 or 2;
or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to claim 3,
Z ¹ is CR ^Z1 ;
Z ² is CR ^Z2 ;
R ^Z1 is H or F; is preferably H;
R ^Z2 is H or F; or together with R ² forms a divalent radical -S(=0) ₂ -N(H)-C(=0)-; preferably H,
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to any one of claims 1 to 4,
Ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties as defined in claim 1 or 3:
A-1, A-4, A-5, A-6, A-7, A-9, A-10, A-11, A-12, A-13, A-15, A-17, A- 19, A-20, A-21, A-23, A-24; preferably A-1, A-4, A-7, A-9, A-10, A-12, A-13, A-15, A-17, A-23, A-24;
R ^A1 is C _1-6 -aliphatic, -CH ₂ -Ar ^A1 ; preferably represents C _1-3 -alkyl, -CH ₂ -CN, -C _2-4 -alkynyl, -CH ₂ -Ar ^A1 :
R ^A2 represents H, C _1-6 -aliphatic;
R ^A3 is H, C _1-6 -aliphatic; preferably represents H;
Ar ^A1 represents phenyl which may be unsubstituted or monosubstituted with R ^A11 ;
R ^A11 is halogen; preferably representing F,
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to any one of claims 1 to 5,
R ¹ is Ar ¹ , Hetar ¹ , Cyc ¹ , Hetcyc ¹ , L ¹ -Ar ¹ , L ¹ -Hetar ¹ , L ² -Cyc ¹ , L ² -Hetcyc ¹ , unsubstituted or substituted, straight chain or branched C _1-6 -alkyl, C _2-6 -alkenyl or C _2-6 -alkynyl, said C _1-6 -alkyl, C _2-6 -alkenyl or C _2-6 -alkynyl being preferred preferably straight-chain or branched, unsubstituted or substituted with 1, 2 or 3 halogens;
Ar ¹ is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryl is unsubstituted or may be the same or different substituents R ^B1 , may be substituted with R ^B2 and/or R ^B3 ; preferably phenyl or naphthalenyl, especially phenyl, which may be unsubstituted or substituted by substituents R ^B1 and or R ^B2 which may be the same or different;
Hetar ¹ is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2 or 3 of the ring atoms are N, O and/or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being unsubstituted or substituents which may be the same or different R ^B1 , may be substituted with R ^B2 and/or R ^B3 ; Preferably heteroaryl may be unsubstituted or substituted with substituents R ^B1 and/or R ^B2 which may be the same or different;
Cyc ¹ is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^B8 and/or R ^B9 ; wherein a carbocycle may optionally be fused to Ar ^X through two adjacent ring atoms of said Ar ^X , and the fused carbocycle may be further unsubstituted by R ^C1 and/or R ^C2 which may be identical or different. can be substituted;
Hetcyc ¹ is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N, O and/or S and the remainder are carbon atoms, the heterocycle may be unsubstituted or substituted with R ^B8 and/or R ^B9 , which may be the same or different, and if one of the heteroatoms is S, the heterocycle may also be R ^B8 , R ^B9 , may be substituted with R ^B10 and R ^B11 ; It is preferably a saturated monocyclic heterocycle having 5 or 6 ring atoms, wherein one of said ring atoms is a heteroatom selected from O and S and the others are carbon atoms, and the heterocycle is unsubstituted or the same as or R ^B8 and/or R ^B9 , which may be different, and when one of the heteroatoms is S the heterocycle may also be substituted with R ^B8 , R ^B9 , R ^B10 and R ^B11 ;
L ¹ is a divalent radical selected from the group consisting of -S(=0) ₂ -, unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene; In both, one of the carbon units of the alkylene or alkenylene chain may be replaced by -O-; Preferably -S(=0) ₂ -, -CH ₂ -, -CH ₂ -CH ₂ -, -CH ₂ -CH ₂ -C(CH ₃ )H-, -CH ₂ -CH ₂ -C(CH ₃ ) is a divalent radical selected from the group consisting of ₂ -, -CH ₂ -CH ₂ -O-CH ₂ -, -CH ₂ -CH=CH-;
L ² is a divalent radical selected from the group consisting of unsubstituted or substituted, straight-chain or branched C _1-6 -alkylene or C _2-6 -alkenylene, in both of which an alkylene or alkenylene chain One of the carbon units of may be replaced by -O-; is a divalent radical preferably selected from the group consisting of -CH ₂ -, -CH ₂ -CH ₂ -;
R ^B1 , R ^B2 , R ^B3 are independently of each other straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl is unsubstituted or mono-substituted with —CN or substituted with 1, 2 or 3 halogens. may be), straight-chain or branched C _1-4 -alkoxy (the C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens), -O-CH ₂ -C≡CH, straight-chain or branched -SC _1-4 -alkyl, said -SC _1-4 -alkyl 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 , -CH ₂ -Ar ² , Hetar ² , represents Cyc ² , Hetcyc ² ;
or two adjacent R ^B1 , R ^B2 and/or R ^B3 together represent a divalent -C _3-4 -alkylene radical wherein one of the alkylene carbon units is replaced by a carbonyl unit (-C(=O)-) can be), or 2 forms an -OC _2-3 -alkylene radical;
Ar ² is phenyl;
Hetar ² is a monocyclic heteroaryl having 5 or 6 ring atoms, wherein 1, 2, 3, 4, 5 of the ring atoms are heteroatom(s) selected from N, O and/or S; the rest are carbon atoms; It is preferably a monocyclic heteroaryl having 5 ring atoms, wherein one of said ring atoms is N and the others are carbon atoms, or one of said ring atoms is N and one of said ring atoms is S and the remainder are carbon atoms;
Cyc ² is cyclopropyl, cyclobutyl, cyclopentyl, each of which may be unsubstituted or monosubstituted with R ^D6 or disubstituted with R ^D6 and R ^D7 independently of each other;
Hetcyc ² is pyrrolidinyl, piperidinyl, each of which may be unsubstituted or monosubstituted with R ^D6 or disubstituted with R ^D6 and R ^D7 independently of each other;
R ^B8 , R ^B9 are independently of each other F, C _1-2 -alkyl (the C _1-2 -alkyl may be unsubstituted or substituted with 1, 2 or 3 F ), C _1-2 -alkoxy, represents Ar ^Y ; or
R ^B8 and R ^B9 are attached to the same carbon atom of the carbocycle Cyc ¹ or the heterocycle Hetcyc ¹ and form a divalent oxo (=0) group; or
R ^B8 and R ^B9 and R ^B10 and R ^B11 are attached to the same sulfur atom of the heterocycle and form two divalent oxo (=0) groups to form an -S(=0) ₂ - moiety;
Ar ^X is an unsubstituted benzo ring;
Ar ^Y is phenyl;
R ^C1 and R ^C2 independently of each other represent C _1-6 -alkyl, which may be independently substituted with 1, 2 or 3 F atoms;
R ^D6 , R ^D7 are independently of each other C _1-6 -alkyl which may be substituted with 1, 2, or 3 F atoms or 1 hydroxy group; or hydroxy;
Halogen is F, Cl, Br,
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to any one of claims 1 to 6,
R ² is -C(=0)-OR ^2a or Hetcyc ^X ; preferably represents -C(=0)-OR ^2a ;
R ^2a is H, straight-chain or branched, unsubstituted or substituted C _1-4 -alkyl or Cat; preferably represents H, methyl, ethyl or Cat;
Cat is a monovalent cation selected from the group consisting of lithium (Li), sodium (Na) and potassium (K); preferably represents sodium;
Hetcyc ^X is 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-on-3-yl), 3-bromo-4,5-dihydro-1,2-oxazol-5-yl, 3-chloro-4,5-dihydro-1,2-oxazol-5-yl, 3-(1H- 1,2,3-triazol-1-yl)-4,5-dihydro-1,2-oxazol-5-yl, 3-(2H-1,2,3-triazol-2-yl) -4,5-dihydro-1,2-oxazol-5-yl, 3-(pyrimidin-5-yloxy)-4,5-dihydro-1,2-oxazol-5-yl, 3 -Hydroxy-oxetan-3-yl, 5-hydroxy-4H-pyran-4-one-2-yl, 3,3-difluoropyrrolidin-2-one-4-yl, 3,3 -Difluoropyrrolidin-2-one-5-yl, 3,3-difluoro-2,3-dihydro-1H-pyrrol-2-one-4-yl, 3,3-difluoro represents -2,3-dihydro-1H-pyrrol-2-one-5-yl;
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to any one of claims 1 to 6,
R ² represents -C(=0)-NR ^2b R ^2c ;
R ^2b and R ^2c independently of each other represent H or straight-chain or branched C _1-8 -aliphatic which may be unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents which may be the same or different ;
or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms; wherein said heterocycle may optionally be fused with Hetar ^Z as defined in any one of claims 1 to 7;
or one of R ^2b and R ^2c represents H and the other represents Cyc ² or Hetcyc ² (both as defined in any one of claims 1 to 7);
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to claim 8,
(a)
R ^2b represents hydrogen,
R ^2c is hydrogen; represents straight-chain or branched C _1-8 -alkyl, Cyc 2 or Hetcyc ² which may be unsubstituted or substituted ^by R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 , which may be the same or different, wherein ,
R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 are independently of each other halogen, in particular F; -NR ^Ea R ^Eb , -OH, OR ^Ec , Ar ^E , Hetar ^E , Cyc ^E , Hetcyc ^E ;
Ar ^E is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; preferably phenyl or naphthalenyl, especially phenyl;
Hetar ^E is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are N, O and / or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being an unsubstituted substituent which may be the same or different R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; In particular heteroaryl is unsubstituted or may be the same or different substituents R ^F1 and / or monocyclic heteroaryl having 5 or 6 ring atoms which may be substituted by R ^F2 ; Preferably heteroaryl is imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, each of which is unsubstituted or monosubstituted with C _1-4 -alkyl; pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, each of which is 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, pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl; It is selected from the group consisting of oxadiazolyl, triazolyl, thiazolyl, and isothiazolyl;
Cyc ^E is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^G1 and/or R ^G2 ; In particular a saturated monocyclic carbocycle having 3, 4, 5, or 6 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by R ^G1 and/or R ^G2 which may be the same or different. there is; preferably cyclopropyl, cyclobutyl, cyclohexenyl;
Hetcyc ^E 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 ( s) and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^G1 and/or R ^G2 which may be the same or different; especially saturated monocyclic heterocycles having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N and/or O and the others are carbon atoms, wherein heteroatoms the cycle may be unsubstituted or substituted with R ^G1 and/or R ^G2 ; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); Piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, each of which may be unsubstituted or monosubstituted with -OH ); morpholinyl, morpholin-1-yl, morpholin-2-yl, each of which may be unsubstituted or monosubstituted with methyl; 1,4-dioxanil; dihydropyranyl, tetrahydropyranyl, tetrahydropyran-3-yl;
R ^{E a} , R ^Eb independently of each other represents H, C _1-4 -alkyl, -C(=O)-OC _1-4 -alkyl; in particular both represent H or one represents H and the other represents C(=0)-O-tert.-butyl;
R ^Ec represents H or C _1-4 -alkyl, in particular H or methyl;
R ^F1 , R ^F2 and/or R ^F3 are, independently of each other, straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl is unsubstituted or monosubstituted by -CN, OH, -OC _1-4 -alkyl or 1 , may be substituted with 2 or 3 halogens); straight-chain or branched C _1-4 -alkoxy, which C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens; straight-chain or branched -SC _1-4 -alkyl, which -SC _1-4 -alkyl may be unsubstituted or substituted with 1, 2 or 3 halogens; C _3-7 -cyclopropyl optionally substituted by halogen, OH and/or C _1-4 -alkyl; F, Cl, Br, -CN, -S(=O)-C _1-3 -alkyl, S(=O) ₂ -C _1-3 -alkyl, -NH ₂ , -NH(C _1-3 -alkyl ) -N(C _1-3 -alkyl) ₂ , -OH; especially methyl, hydroxymethyl, methoxymethyl, F, cyclopropyl, cyclobutyl; Preferably R ^F1 , only one of R ^F2 and R ^F3 is present and represents methyl or F;
and/or two of R ^F1 , R ^F2 , R ^F3 attached to two different ring atoms of the aryl or heteroaryl form a divalent C _1-6 -alkylene radical, optionally 1 or 2 of the alkylene radical two non-adjacent carbon units independently of each other may be replaced by O, NH, NC _1-4 -alkyl, in particular -(CH ₂ ) ₄ -, -CH ₂ -O-(CH ₂ ) ₂ -;
R ^G1 and/or R ^G2 are independently of each other halogen, hydroxy, unsubstituted or substituted C _1-6 -aliphatic, in particular C _1-4 -alkyl optionally substituted by OH, C _1-6 -alifatoxy , in particular -OC _1-4 -alkyl, -C(=O)-OC _1-4 -alkyl, Hetar ^Y2 , -CH ₂ -Hetar ^Y2 , Hetcyc ^Y2 ; preferably only one of R ^G1 and R ^G2 is present and represents hydroxy;
and/or R ^G1 and R ^G2 attached to the same ring atom of the carbocycle or heterocycle form a divalent C _2-6 -alkylene radical, wherein optionally 1 or 2 non-adjacent carbon units of the alkylene radical may independently of one another be replaced by O, NH, NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _1-4 -alkyl, in particular -(CH ₂ ) ₂ -O-CH ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -;
and/or R ^G1 and R ^G2 attached to two different ring atoms of the carbocycle or heterocycle form a divalent C _1-6 -alkylene radical, optionally on one or two non-adjacent carbon atoms of the alkylene radical. The units may independently of one another be replaced by O, NH, NC _1-4 -alkyl, in particular by -CH ₂ -;
Cyc ² is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycles are unsubstituted or independently of each other R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 , wherein the carbocycles may optionally be fused to Ar ^Z or Hetar ^Z through two adjacent ring atoms and the fused carbocycles are optionally independently of each other R ^C1 , R ^C2 and / or may be further substituted with R ^C3 ;
Hetcyc ² is a saturated monocyclic heterocycle having 4, 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N, O and/or S and the others are carbon atom, and the heterocycle may be unsubstituted or substituted independently of each other by R ^D6 , R ^D7 , R ^D8 , R ^D9 and/or R ^D10 , wherein the heterocycle may optionally be fused to Ar ^Z or Hetar ^Z and The fused heterocycles may optionally be further substituted independently of each other with R ^C1 , R ^C2 and/or R ^C3 ;
R ^C1 , R ^C2 , R ^C3 represent C _1-4 -alkyl;
R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 are independently of each other halogen, in particular F; hydroxy; -C _1-4 -alkyl optionally substituted by OH and/or halogen, in particular methyl, hydroxymethyl, 2-fluoroethyl; -OC _1-4 -alkyl, in particular methoxy, ethoxy; Hetar ^Y1 , -CH ₂ -Hetar ^Y1 , Cyc ^Y1 , Hetcyc ^Y1 , -CH ₂ -Hetcyc ^Y1 ;
and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to the same ring atom of the carbocycle or heterocycle form a divalent C _2-6 -alkylene radical, wherein optionally 1 or 2 non-adjacent carbon units of an alkylene radical can independently of each other be replaced by O, NH, NC _1-4 -alkyl, wherein the alkylene radical is optionally OH, C _1-4 -alkyl or -OC _{1 -4} -alkyl, in particular -(CH ₂ ) ₃ -, -CH ₂ -CH(OC ₂ H ₅ )-CH ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -; ;
and/or two of R ^D6 , R ^D7 , R ^D8 , R ^D9 , R ^D10 attached to two different ring atoms of the carbocycle or heterocycle form a divalent C _1-6 -alkylene radical; Optionally 1 or 2 non-adjacent carbon units of the alkylene radical are, independently of each other, O, NH, NC _1-4 -alkyl, in particular -CH ₂ -, -(CH ₂ ) ₃ -, -O-(CH ₂ ) ₂ -, -O-(CH ₂ ) ₃ -;
Ar ^Z is benzo;
Hetar ^Y1 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is C _1-4 -alkyl which is unsubstituted or optionally substituted with F, OH; In particular, pyrrolyl, thiophenyl, pyrazolyl, methylpyrazolyl, imidazolyl, methylimidazolyl, triazolyl, oxadiazolyl, methyloxadiazolyl, pyridinyl, fluoropyridinyl, methylpyridinyl, pyrimidinyl , methylpyrimidinyl;
Hetar ^Y2 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH; in particular pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl;
Hetar ^Z is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole;
Cyc ^Y1 is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by halogen, OH, C _1-4 -alkyl and, in particular, cyclopropyl;
Hetcyc ^Y1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom; in particular tetrahydrofuranyl;
Hetcyc ^Y2 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom; in particular tetrahydrofuranyl, morpholinyl, tetrahydropyranyl;
or
(b)
R ^2b and R ^2c together with the nitrogen atom to which they are attached form, independently of each other, a saturated or partially unsaturated heterocycle optionally substituted with R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 and/or R ^Y5 ; wherein the heterocycle may optionally be fused to Hetar ^Z ; the heterocycle is selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine, and morpholine;
R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 , R ^Y5 are independently of each other halogen, in particular F; -NH ₂ , -N(H)-C _1-4 -alkyl, -N(H)-C(=O)-OC _1-4 -alkyl, -N(C _1-4 -alkyl) ₂ ; -OH; C _1-4 -alkyl optionally substituted with -OH, -OC _1-4 -alkyl, -OC _3-7 -cycloalkyl, -O-CH ₂ -C _3-7 -cycloalkyl, in particular methyl, -CH ₂ OH, -(CH ₂ ) ₂ OH, -(CH ₂ ) ₃ OH, -CH ₂ OCH ₃ , -(CH ₂ ) ₂ OCH ₃ , cyclopropylmethoxy; -OC _1-4 -alkyl, in particular methoxy; Hetar ^Y2 ; -CH ₂ -Hetar ^Y2 ; represents Hetcyc ^Y2 ;
and/or two of R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 , R ^Y5 attached to the same ring atom of the heterocycle form a divalent C _2-6 -alkylene radical, optionally 1 of an alkylene radical. or two non-adjacent carbon units independently of each other are O, NH, NC _1-4 -alkyl, in particular -(CH ₂ ) ₄ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₂ -, -(CH ₂ ) ₂ -O-(CH ₂ ) ₃ -;
and/or two of R ^Y1 , R ^Y2 , R ^Y3 , R ^Y4 , R ^Y5 attached to two different ring atoms of the heterocycle form a divalent C _1-6 -alkylene radical, optionally an alkylene radical 1 or 2 non-adjacent carbon units of may independently of each other be replaced by O, NH, NC _1-4 -alkyl, in particular -(CH ₂ ) ₄ -;
Hetar ^Y2 is a 5 or 6-membered monocyclic heteroaryl, wherein 1, 2, 3, 4 ring atoms are heteroatoms selected from N, O and/or S and the remainder are carbon atoms, wherein heteroaryl is unsubstituted or substituted with C _1-4 -alkyl which may optionally be substituted with halogen, OH; in particular pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, hydroxymethyloxazolyl, pyrimidinyl;
Hetar ^Z is pyrrole, N-methyl-pyrrole, pyrazole, imidazole, triazole;
Hetcyc ^Y2 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatoms selected from N, O and/or S and the others are carbon is an atom; in particular tetrahydrofuranyl, morpholinyl, tetrahydropyranyl;
or
(c)
R ^2b is a straight chain of branched C _1-4 -alkyl optionally substituted with OH; especially methyl, 2-hydroxyethyl;
R ^2c is straight-chain or branched C _1-8 which may be independently of each other substituted with Cyc ² , Hetcyc ² or R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 which may be unsubstituted or identical or different -represents an alkyl;
Phosphorus, a compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to claim 9,
(a)
R ^2b represents hydrogen;
R ^2c is hydrogen; represents straight-chain or branched C _1-8 -alkyl, Cyc 2 or Hetcyc ² which may be unsubstituted ^or substituted by R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 , which may be the same or different, wherein ,
R ^E1 , R ^E2 , R ^E3 , R ^E4 and/or R ^E5 are independently of each other halogen, in particular F; -NR ^Ea R ^Eb , -OH, OR ^Ec , Ar ^E , Hetar ^E , Cyc ^E , Hetcyc ^E ;
Ar ^E is a mono- or bicyclic aryl having 6 or 10 ring carbon atoms, wherein the aryls are unsubstituted or may be identical or different substituents R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; preferably phenyl or naphthalenyl, especially phenyl;
Hetar ^E is a monocyclic heteroaryl having 5 or 6 ring atoms or a bicyclic heteroaryl having 9 or 10 ring atoms, wherein 1, 2, 3 or 4 of the ring atoms are N, O and / or heteroatom(s) selected from S and the remainder being carbon atoms, the heteroaryl being an unsubstituted substituent which may be the same or different R ^F1 , may be substituted with R ^F2 and/or R ^F3 ; In particular heteroaryl is unsubstituted or may be the same or different substituents R ^F1 and / or monocyclic heteroaryl having 5 or 6 ring atoms which may be substituted by R ^F2 ; Preferably heteroaryl is imidazolyl, 1H-imidazol-1-yl, 1H-imidazol-2-yl, each of which is unsubstituted or monosubstituted with C _1-4 -alkyl; pyridyl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl, each of which is unsubstituted or monosubstituted with -F; pyrimidinyl, pyrimidin-2-yl, pyrimidin-3-yl, pyrimidin-4-yl, pyrimidin-5-yl; It is selected from the group consisting of pyrazinyl and pyrazin-2-yl;
Cyc ^E is a saturated or partially unsaturated, mono- or bicyclic carbocycle having 3, 4, 5, 6, 7 or 8 ring carbon atoms, wherein the carbocycles may be unsubstituted or the same or different. may be substituted with R ^G1 and/or R ^G2 ; In particular a saturated monocyclic carbocycle having 3, 4, 5, or 6 ring carbon atoms, wherein the carbocycle may be unsubstituted or substituted by R ^G1 and/or R ^G2 which may be the same or different. there is; preferably cyclobutyl;
Hetcyc ^E is a saturated or partially unsaturated, monocyclic heterocycle having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N, O and/or S and the remainder being carbon atoms, wherein the heterocycle may be unsubstituted or substituted with R ^G1 and/or R ^G2 which may be the same or different; especially saturated monocyclic heterocycles having 5 or 6 ring atoms, wherein 1 or 2 of said ring atoms are heteroatom(s) selected from N and/or O and the others are carbon atoms, wherein heteroatoms the cycle may be unsubstituted or monosubstituted with R ^G1 ; preferably tetrahydrofuranyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl (each of which may be unsubstituted or monosubstituted with -OH); pyrrolindinyl, pyrrolindin-1-yl, pyrrolindin-2-yl, pyrrolindin-3-yl (each of which may be unsubstituted or monosubstituted with -OH); Piperidinyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4-yl, each of which may be unsubstituted or monosubstituted with -OH ); morpholinyl, morpholin-1-yl, morpholin-2-yl;
R ^{E a} , R ^Eb independently of each other represents H, C _1-4 -alkyl, -C(=O)-OC _1-4 -alkyl; in particular both represent H or one represents H and the other represents C(=0)-O-tert.-butyl;
R ^Ec represents H or C _1-4 -alkyl, in particular H or methyl;
R ^F1 , R ^F2 and/or R ^F3 are, independently of each other, straight-chain or branched C _1-6 -alkyl, which C _1-6 -alkyl is unsubstituted or monosubstituted by -CN, OH, -OC _1-4 -alkyl or 1 , which may be substituted with 2 or 3 halogens), straight-chain or branched C _1-4 -alkoxy (the C _1-4 -alkoxy may be unsubstituted or substituted with 1, 2 or 3 halogens), straight-chain or by branched -SC _1-4 -alkyl, wherein -SC _1-4 -alkyl may be unsubstituted or substituted with 1, 2 or 3 halogens, halogen, OH and/or C _1-4 -alkyl optionally substituted C _3-7 -cyclopropyl, F, Cl, Br, -CN, -S(=O)-C _1-3 -alkyl, S(=O) ₂ -C _1-3 -alkyl, -NH ₂ , -NH(C _1-3 -alkyl) -N(C _1-3 -alkyl) ₂ , -OH; especially methyl, F; Preferably R ^F1 , only one of R ^F2 and R ^F3 is present and represents methyl or F;
R ^G1 and/or R ^G2 independently of one another represent halogen, hydroxy, unsubstituted or substituted C _1-4 -alkyl, -OC _1-4 -alkyl, in particular hydroxy; preferably only one of R ^G1 and R ^G2 is present and represents hydroxy;
Cyc ² is a saturated monocyclic carbocycle having 3, 4, 5, 6 or 7 ring carbon atoms, wherein the carbocycle may be unsubstituted or monosubstituted with R ^D6 , wherein
R ^D6 is C _1-4 -alkyl unsubstituted or mono-substituted by -OH, in particular -CH ₂ OH;
in particular Cyc ² is cyclopropyl, cyclobutyl or 1-hydroxymethylcyclobutyl;
Hetcyc ² is a saturated monocyclic heterocycle having 5 or 6 ring atoms, 1 or 2 of which are heteroatom(s) selected from N, O and/or S and the others are carbon atoms; , wherein the heterocycle may be unsubstituted or monosubstituted with hydroxy; in particular tetrahydrofuranyl or hydroxytetrahydrofuranyl; preferably 4-hydroxytetrahydrofuran-3-yl;
or
(b)
R ^2b and R ^2c together with the nitrogen atom to which they are attached form a 3-hydroxypyrrolidinyl, 2-methyl-3-hydroxypyrrolidinyl or 3-hydroxypiperidinyl ring;
Phosphorus, a compound, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or a pharmaceutically acceptable salt of any of each of the foregoing, including mixtures thereof in any ratio. According to any one of claims 1 to 6,
R ² is -(CH ₂ ) _x -NR ^2d -C(=O)-R ^2e , -SR ^2f , -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S( =O) ₂ -NR ^2h R ²ⁱ , -S(=O) ₂ -OH, -S(=O)(=NR ^2j )-OH, -S(=O)(=NR ^2j )-R ^2g , - S(=0)(=NR ^2k )-NR ^2l R ^2m , -(CH ₂ ) _z -NR ^2d -S(=0) ₂ -R ^2g ; Specifically -S(=O)-R ^2f , -S(=O) ₂ -R ^2g , -S(=O) ₂ -NR ^2h R ²ⁱ , -S(=O)(=NR ^2j )-R ^2g , -S(=O)(=NR ^2k )-NR ^2l R ^2m , -(CH ₂ ) _z -NR ^2d -S(=O) ₂ -R ^2g , -C(=O)-N=S(=O )-R ^2s R ^2t , -C(=O)-N=S(=NR ^2u )-R ^2s R ^2t ; Preferably, -S-CH ₃ , -S(=O)-CH ₃ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -NH ₂ , -S(=O) ₂ - NHCH ₃ , -S(=O)(=NH)-CH ₃ , S(=O)(=NH)-N(CH ₃ ) ₂ , -NH-S(=O) ₂ -CH ₃ , -N( CH ₃ )-S(=0) ₂ -CH ₃ , -NH-S(=0) ₂ -CH=CH ₂ , -CH ₂ -NH-S(=0) ₂ -CH=CH ₂ ;
R ^2e is C _1-6 -alkyl optionally substituted with H, -OH or monocyclic 5- or 6-membered heteroaryl; C _3-7 -cycloalkyl, monocyclic 5- or 6-membered heteroaryl; In particular H, methyl, hydroxymethyl, methylpyridin-2-yl, methylpyridin-3-yl, methylpyridin-4-yl, cyclopropyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl represents;
R ^2f and R ^2g are each independently unsubstituted or substituted C _1-8 -aliphatic; in particular independently of one another C _1-4 -alkyl or C _2-4 -alkenyl _: preferably independently of one another methyl or -CH=CH ₂ denote:
R ^2h , R ²ⁱ independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, aryl, heterocyclyl, heteroaryl; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms; in particular independently of each other represents C _1-4 -alkyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl, optionally substituted by H or -OH or together with the nitrogen atom to which they are attached form a pyrrolidinyl ring, wherein the ring is optionally substituted with -OH and/or phenyl and represents pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-5-yl;
R ^2d , R ^2j , R ^2k independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic, in particular H, methyl;
R ^2l , R ^2m independently of each other represent H, unsubstituted or substituted C _1-8 -aliphatic; or together with the nitrogen atom to which they are attached form an unsubstituted or substituted saturated, partially unsaturated or aromatic heterocycle having 3, 4, 5, 6, 7 ring atoms, wherein one of said ring atoms is said nitrogen atom, 0 or 1 additional ring atom is a heteroatom selected from N, O or S and the others are carbon atoms; in particular C _1-4 -alkyl; preferably represents methyl;
R ^2s , R ^2t are independently of each other C _1-6 -alkyl, OC _1-4 -alkyl, NH ₂ , NHC _1-4 -alkyl, N(C _1-4 -alkyl) which may be optionally substituted with —OH ₂ , pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl; especially methyl, ethyl, 2-hydroxyethyl, 3-hydroxy propyl, 2-aminoethyl, 3-(N,N-dimethylamino)propyl; or together form a divalent C _3-4 -alkylene radical optionally substituted by -NH ₂ , -CN , or a divalent C _2-5 -alkylene radical, wherein optionally said C _2-5 -alkylene One of the carbon units of the radical may be replaced by O, NH or NC _1-4 -alkyl; In particular -(CH ₂ ) ₃ -, -CH ₂ -C(NH ₂ )H-CH ₂ -, -CH ₂ -C(CN)H-CH ₂ -, -CH ₂ -C(CH ₂ -NH-CH ₂ )-CH ₂ -, -(CH ₂ ) ₄ -;
R ^2u represents hydrogen or C _1-4 -alkyl;
x represents 0 or 1;
z represents 0 or 1;
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. The method of any one of claims 1, 2, 5 to 11,
Ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

Z ¹ is CH;
Z ² is CH;
Z ³ is CH or N;
R ¹ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoro Methylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4 -Cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl , 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl , 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2- 1, 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-methylsulfanylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl Midin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano- 6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5 ,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2- yl, quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazoline -2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]phetan-1-yl, cyclohexyl, 4-methylcyclo Hexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-difluorospiro[3.3]heptane-2 -yl, 1H-inden-2-yl; Benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidine- 1-yl) phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)phenylmethyl, 3-tert-butylphenylmethyl, 3-(difluoromethoxy ) Phenylmethyl, 2- (difluoromethyl) phenylmethyl, 3- (difluoromethyl) phenylmethyl, 3- (trifluoromethyl) phenylmethyl, 4- (trifluoromethyl) phenyl] methyl, 2 -(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3-methane Sulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrol-1-yl)phenylmethyl, 2-methyl-3-methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl, 2 -Methyl-3-(trifluoromethyl)phenylmethyl, 3-trifluoromethyl-4-fluorophenylmethyl, 2-fluoro-5-(trifluoromethoxy)phenylmethyl, 2-methoxy-3 -trifluoromethoxyphenylmethyl, 2-fluoro-3-methoxyphenylmethyl, 2-fluoro-3-(trifluoromethyl)phenyl]methyl, 2-fluoro-3-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, naphthalin-1-ylmethyl, 5,6,7,8-tetrahydronaphthalen-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-dihydro-2H-1-benzopyran-8- Ilmethyl, 2-phenylethyl, 2-(2-methylphenyl)-ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl , 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2- (4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2-(2,4-difluorophenyl)ethyl, 2-( difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl-3-phenylbutyl, 2-(benzyloxy)ethyl; 5-ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazol-2-ylmethyl, 2-methyl -1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2-propyl) Pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazol-2-ylmethyl, 1-benzimidazole -2-yl)methyl, 1-(2-methylpropyl)-1H-imidazol-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridin- 2-ylmethyl, 2-methylpyridin-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-(thiophen-3-yl)ethyl, 5-trifluoromethylthio Ofen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H-pyrrolo [1,2-b] pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imidazo[ 1,2-a] pyridin-3-ylmethyl, 6-methylimidazo [1,2-a] pyridin-3-ylmethyl, imidazo [1,2-a] pyridin-5-ylmethyl, imi polyzo[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]phetan-1-ylmethyl, bicyclo[2.2.1]heptane- 2-ylmethyl, bicyclo[2.2.2]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept -2-en-2-yl] methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4 ,4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl;
R ² is -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH ₃ , -C(=O)-NH ₂ , -C(=O)-NHCH ₃ , -C(=O)-NHCH ₂ CH ₃ , -C(=O)-NH(CH ₂ ) ₂ CH ₃ , -C(=O)-N(H)-cyclopropyl, -C(=O) -N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH ₂ CH ₂ -OH, -C(=O)-N(H) -CH ₂ CH ₂ -OCH ₃ , -C(=O)-N(H)-CH ₂ -C(H)(OH)-CH ₃ , -C(=O)-N(H)-CH ₂ C (CH ₃ ) ₂ OH, -C(=0)-N(H)-C(H)(CH ₃ )-CH ₂ OH, -C(=0)-N(H)-C(H)(CH ₂ CH ₃ )-CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-CH ₂ CH ₂ -O-CH ₃ , -C(=O)-N( H)-C(CH ₃ ) ₂ CH ₂ CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-phenyl, -C(=O)-N(H) -C(CH ₃ )(CH ₂ OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH ₃ )-phenyl, -C(=O)-N( H)-CH ₂ -1H-1-methylimidazol-2-yl, -C(=O)-N(H)-(CH ₂ ) ₂ -1H-imidazol-1-yl, -C(= O)-N(H)-CH ₂ -pyridin-2-yl, -C(=O)-N(H)-CH ₂ -pyridin-3-yl, -C(=O)-N(H)- CH ₂ -pyridin-4-yl, -C(=O)-N(H)-C(H)(CH ₂ OH)-pyridin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-4-yl, -C(=O)-N(H) -CH ₂ -pyridazin-2-yl, -C(=O)-NH-C(CH ₂ OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -NH-C(=O)-CH=CH ₂ , -NH-C(=O)-CF=CH ₂ , -NH-C(=O)-CH ₂ Cl, -NH-C(=O)- C≡CH, -CH ₂ -NH-C(=O)-CH=CH ₂ , -CH ₂ -NH-C(=O)-CH ₂ Cl, -CH ₂ -NH-C(=O)-C≡CH, -S(=O)-CH ₃ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -OH, -S(=O) ₂ -NH ₂ , -S(=O) ₂ -NHCH ₃ , -S(=O)(=NH)-N(CH ₃ ) ₂ , -S(=O)(=N- CH ₃ )-N(CH ₃ ) ₂ , -S(=O)(=N-CH ₃ )-OH, -S(=O)(=NH)-CH ₃ , -P(=O)(OH) ₂ , F, -CN; preferably represents -C(=O)-OH, -C(=O)-ONa,
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. According to any one of claims 3 to 11,
Ring A represents a 5-membered heteroaromatic ring selected from the group consisting of the following ring moieties:

Z ¹ is CH;
Z ² is CH;
R ¹ is phenyl, 3-fluorophenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methylphenyl, 4-ethylphenyl, 4-difluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoro Methylphenyl, 4-(1,1-difluoroethyl)phenyl, 4-(2,2,2-trifluoroethyl)phenyl, 4-(1-trifluoromethylcyclopropyl)-phen-1-yl, 4 -Cyclopentylphenyl, 4-ethoxyphenyl, 4-difluoromethoxyphenyl, 4-trifluoromethoxyphenyl, 3-(trifluoromethyl)sulfanylphenyl, 4-(trifluoromethyl)sulfanylphenyl , 3-trifluoromethyl-4-methylphenyl, 2-fluoro-4-trifluoromethylphenyl, 2-fluoro-4-trifluoromethoxyphenyl, 3-fluoro-4-(n-propyl)phenyl , 2,3-dimethyl-4-methoxyphenyl, 6-fluoronaphth-2-yl; 5-trifluoromethylfuran-2-yl; 5-trifluoromethylthiophen-2-yl, 2-trifluoromethyl-1,3-thiazol-4-yl, 3-fluoropyridin-2-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl, 3-ethylpyridin-2-yl, 6-ethylpyridin-3-yl, 4-difluoromethylpyridin-2-yl, 4-trifluoromethylpyridin-2- 1, 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-methylsulfanylpyrimidin-2-yl, 5-cyclopropylpyrimidin-2-yl, 5-ethylpyrimidin-2-yl, 5-difluoromethylpyrimidin-2-yl Midin-2-yl, 5-trifluoromethylpyrimidin-2-yl, 5-cyanopyrimidin-2-yl, 5-cyano-3-fluoropyridin-2-yl, 5-cyano- 6-methylpyridin-2-yl, 3-fluoro-5-(trifluoromethyl)pyridin-2-yl, 5-oxo-5H,6H,7H-cyclopenta[b]pyridin-2-yl, 5 ,6,7,8-tetrahydroquinolin-2-yl, 5-oxo-5,6,7,8-tetrahydroquinolin-2-yl, 5H,6H,7H-cyclopenta[b]pyridin-2- yl, quinolin-2-yl, isoquinolin-3-yl, 6-methylquinolin-2-yl, 8-methoxyquinolin-4-yl, furo[3,2-b]pyridin-5-yl, quinazoline -2-yl, 6-fluoroquinazolin-2-yl, 1,5-naphthyridin-2-yl; 3-methylcyclobutyl, cyclopentyl, 3-methylcyclopentyl, 3,3-dimethylcyclopentyl, 3-trifluoromethyl-bicyclo[1.1.1]phetan-1-yl, cyclohexyl, 4-methylcyclo Hexyl, 4-(trifluoromethyl)cyclohexyl, 4,4-difluorocyclohexyl, cyclohex-1-enyl, 2-oxocycloheptyl, 6,6-difluorospiro[3.3]heptane-2 -yl, 1H-inden-2-yl; Benzenesulfonyl (phenylsulfonyl), 3-methylphenylsulfonyl, benzyl, 2-ethoxyphenylmethyl, 3-chlorophenylmethyl, 3-fluorophenylmethyl, 4-chlorophenylmethyl, 3-(pyrrolidine- 1-yl) phenylmethyl, 3-methylphenylmethyl, 4-methylphenylmethyl, 3-ethylphenylmethyl, 3-(propan-2-yl)phenylmethyl, 3-tert-butylphenylmethyl, 3-(difluoromethoxy ) Phenylmethyl, 2- (difluoromethyl) phenylmethyl, 3- (difluoromethyl) phenylmethyl, 3- (trifluoromethyl) phenylmethyl, 4- (trifluoromethyl) phenyl] methyl, 2 -(prop-2-yn-1-yloxy)phenylmethyl, 3-(1,3-thiazol-2-yl)phenylmethyl, 3-(trifluoromethyl)sulfanylphenylmethyl, 3-methane Sulfonylphenylmethyl, 3-(dimethylamino)phenylmethyl, 3-(pyrrol-1-yl)phenylmethyl, 2-methyl-3-methoxyphenylmethyl, 3-trifluoromethyl-5-methylphenylmethyl, 2 -Methyl-3-(trifluoromethyl)phenylmethyl, 3-trifluoromethyl-4-fluorophenylmethyl, 2-fluoro-5-(trifluoromethoxy)phenylmethyl, 2-methoxy-3 -trifluoromethoxyphenylmethyl, 2-fluoro-3-methoxyphenylmethyl, 2-fluoro-3-(trifluoromethyl)phenyl]methyl, 2-fluoro-3-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, naphthalin-1-ylmethyl, 5,6,7,8-tetrahydronaphthalen-1-ylmethyl, 2,3-dihydro-1-benzofuran-7-ylmethyl, 3,4-dihydro-2H-1-benzopyran-8- Ilmethyl, 2-phenylethyl, 2-(2-methylphenyl)-ethyl, 2-(2-methoxyphenyl)ethyl, 2-(3-methoxyphenyl)ethyl, 2-(4-methoxyphenyl)ethyl , 2-(2-fluorophenyl)-ethyl, 2-(3-fluorophenyl)-ethyl, 2-(4-fluorophenyl)-ethyl, 2-(2-chlorophenyl)-ethyl, 2- (4-chlorophenyl)-ethyl, 2-(4-bromophenyl)-ethyl, 2-[4-(trifluoromethyl)phenyl]ethyl, 2-(2,4-difluorophenyl)ethyl, 2-( difluoromethoxy)-5-fluorophenylmethyl, 2-phenylpropyl, 3-phenylpropyl, 3-methyl-3-phenylbutyl, 2-(benzyloxy)ethyl; 5-ethylfuran-2-ylmethyl, 5-(trifluoromethyl)furan-2-ylmethyl, 4-(propan-2-yl)-1,3-thiazol-2-ylmethyl, 2-methyl -1,3-thiazol-4-ylmethyl, 2-trifluoromethyl-1,3-thiazol-4-ylmethyl, 1-ethylpyrazol-5-ylmethyl, 1-(2-propyl) Pyrazol-5-ylmethyl, 1-ethylimidazol-5-ylmethyl, 1-ethylimidazol-2-ylmethyl, 1-propylimidazol-2-ylmethyl, 1-benzimidazole -2-yl)methyl, 1-(2-methylpropyl)-1H-imidazol-5-ylmethyl, 5-tert-butyl-1,3-oxazol-2-ylmethyl, 3-fluoropyridin- 2-ylmethyl, 2-methylpyridin-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-(thiophen-3-yl)ethyl, 5-trifluoromethylthio Ofen-2-ylmethyl, 1-methyl-1H-indol-6-yl)methyl, 1-benzofuran-3-ylmethyl, 1-benzothiophen-3-ylmethyl, 4H,5H,6H-pyrrolo [1,2-b] pyrazol-3-ylmethyl, pyrazolo[1,5-a]pyridin-7-ylmethyl, pyrazolo[1,5-a]pyridin-3-ylmethyl, imidazo[ 1,2-a] pyridin-3-ylmethyl, 6-methylimidazo [1,2-a] pyridin-3-ylmethyl, imidazo [1,2-a] pyridin-5-ylmethyl, imi polyzo[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]phetan-1-ylmethyl, bicyclo[2.2.1]heptane- 2-ylmethyl, bicyclo[2.2.2]octan-2-ylmethyl, bicyclo[2.2.1]hept-5-en-2-ylmethyl, 6,6-dimethylbicyclo[3.1.1]hept -2-en-2-yl] methyl; 3,3-dimethyltetrahydrofuran-2-ylmethyl, 1,1-dioxothian-4-ylmethyl, 2-(thian-4-yl)ethyl; 2,2-dimethyl-4,4,4-trifluoropentyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-methylbutyl, 3,3-dimethyl-4 ,4,4-trifluorobutyl, 3,3,3-trifluoroprop-1-yn-1-yl;
R ² is -C(=O)-OH, -C(=O)-ONa, -C(=O)-OCH ₃ , -C(=O)-NH ₂ , -C(=O)-NHCH ₃ , -C(=O)-NHCH ₂ CH ₃ , -C(=O)-NH(CH ₂ ) ₂ CH ₃ , -C(=O)-N(H)-cyclopropyl, -C(=O) -N(H)-(1-hydroxymethyl)cyclobutan-1-yl, -C(=O)-N(H)-CH ₂ CH ₂ -OH, -C(=O)-N(H) -CH ₂ CH ₂ -OCH ₃ , -C(=O)-N(H)-CH ₂ -C(H)(OH)-CH ₃ , -C(=O)-N(H)-CH ₂ C (CH ₃ ) ₂ OH, -C(=0)-N(H)-C(H)(CH ₃ )-CH ₂ OH, -C(=0)-N(H)-C(H)(CH ₂ CH ₃ )-CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-CH ₂ CH ₂ -O-CH ₃ , -C(=O)-N( H)-C(CH ₃ ) ₂ CH ₂ CH ₂ OH, -C(=O)-N(H)-C(H)(CH ₂ OH)-phenyl, -C(=O)-N(H) -C(CH ₃ )(CH ₂ OH)-phenyl, -C(=O)-N(H)-C(H)(CH(OH)CH ₃ )-phenyl, -C(=O)-N( H)-CH ₂ -1H-1-methylimidazol-2-yl, -C(=O)-N(H)-(CH ₂ ) ₂ -1H-imidazol-1-yl, -C(= O)-N(H)-CH ₂ -pyridin-2-yl, -C(=O)-N(H)-CH ₂ -pyridin-3-yl, -C(=O)-N(H)- CH ₂ -pyridin-4-yl, -C(=O)-N(H)-C(H)(CH ₂ OH)-pyridin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-2-yl, -C(=O)-N(H)-CH ₂ -1,3-pyrimidin-4-yl, -C(=O)-N(H) -CH ₂ -pyridazin-2-yl, -C(=O)-NH-C(CH ₂ OH)-cyclobutyl, -C(=O)-3-hydroxy-pyrrolidin-1-yl, -NH-C(=O)-CH=CH ₂ , -NH-C(=O)-CF=CH ₂ , -NH-C(=O)-CH ₂ Cl, -NH-C(=O)- C≡CH, -CH ₂ -NH-C(=O)-CH=CH ₂ , -CH ₂ -NH-C(=O)-CH ₂ Cl, -CH ₂ -NH-C(=O)-C≡CH, -S(=O)-CH ₃ , -S(=O) ₂ -CH ₃ , -S(=O) ₂ -OH, -S(=O) ₂ -NH ₂ , -S(=O) ₂ -NHCH ₃ , -S(=O)(=NH)-N(CH ₃ ) ₂ , -S(=O)(=N- CH ₃ )-N(CH ₃ ) ₂ , -S(=O)(=N-CH ₃ )-OH, -S(=O)(=NH)-CH ₃ , -P(=O)(OH) ₂ , F, -CN; preferably represents -C(=O)-OH, -C(=O)-ONa,
A compound, or a pharmaceutically acceptable salt of any of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. A compound selected from Table 1 and Table 1b, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in all ratios, acceptable salts. 15. The compound according to any one of claims 1 to 14 for use as a medicament, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in any ratio. Including, pharmaceutically acceptable salts of each of the above. 15. A compound according to any one of claims 1 to 14 for use in the prevention and/or treatment of a medical condition or disease which is affected by inhibiting the YAP-TEAD and/or TAZ-TEAD interaction, or a compound thereof A pharmaceutically acceptable salt of each of the foregoing, including any N-oxide, solvate, tautomer or stereoisomer and/or mixtures thereof in any ratio. 15. The method according to any one of claims 1 to 14, characterized by cancer, in particular tumors including solid tumors, breast cancer, lung cancer, liver cancer, ovarian cancer, squamous cell carcinoma, renal cancer, gastric cancer, medulloblastoma, colorectal cancer, pancreatic cancer; A compound for use in the prevention and/or treatment of a medical condition or disease selected from the group consisting of cardiovascular disease and fibrosis, in particular liver fibrosis, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or or a pharmaceutically acceptable salt of each of the foregoing, including mixtures thereof in any ratio. comprising as active ingredient at least one compound according to any one of claims 1 to 14, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in all proportions. Thus, a pharmaceutical composition comprising each of the above pharmaceutically acceptable salts together with a pharmaceutically acceptable carrier. 19. The pharmaceutical composition according to claim 18, comprising the second active ingredient, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in all proportions, 15. A pharmaceutical composition further comprising an acceptable salt, wherein the second active ingredient is not a compound of formula I and formula I-A as defined in any one of claims 1 to 14. A set (kit) containing the following individual packs:
a) an effective amount of a compound of formula I or formula IA according to any one of claims 1 to 14, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or in any ratio pharmaceutically acceptable salts of each of the above, including mixtures thereof; and
b) a further active ingredient in an effective amount, which is not a compound of formula I and formula IA as defined in any one of claims 1 to 14. A compound according to any one of claims 1 to 14, or any N-oxide, solvate, tautomer or stereoisomer thereof and/or mixtures thereof in all proportions, comprising A process for the preparation of a pharmaceutically acceptable salt, characterized by:
(a) a compound of Formula II-a or II-Aa

wherein Z ¹ , Z ² , Z ³ , rings A and R ² are as defined for compounds of formula I or IA in any one of claims 1 to 14, and R ² is -C(= not O)-OH or -C(=O)-OCat;
(a) (1) reacting with a compound of Formula III in a CN cross-coupling reaction under suitable reaction conditions;
R ¹ -Hal
III,
wherein R ¹ is as defined for compounds of formula I or IA in any one of claims 1 to 14 and Hal represents Cl, Br or I;
or
(a) (2) in a CN cross-coupling reaction under suitable reaction conditions, first converting to a tricyclic compound of formula IV or IV-A;

;
Then in another CN cross-coupling reaction under suitable reaction conditions, by reacting with a compound of formula III
R ¹ -Hal
III;
(a) (3) providing a compound of formula I or IA as defined in any one of claims 1 to 14; and
optionally
(a) (4) In the compound of formula I or IA, when R ² is -C(=O)-OR ^2a , wherein R ^2a is unsubstituted or substituted C _1-8 -aliphatic, this formula subjecting a compound of I or IA to saponification under suitable conditions to give a compound of the respective formula I or IA, wherein R ² is -C(=0)-OH or -C(=0)-OCat ;
or
(b) a compound of Formula II-b or II-Ab

wherein Z ¹ , Z ² , Z ³ , rings A and R ² are as defined for compounds of formula I or IA in any one of claims 1 to 14, and R ² is -C(= not O)-OH or -C(=O)-OCat;
(b) (1) by reacting with a compound of Formula V in a CN cross-coupling reaction under suitable reaction conditions;
R ¹ -NH ₂
V,
wherein R ¹ is as defined for the compounds of formula I or IA in any one of claims 1 to 14;
providing a compound of formula I or IA as defined in any one of claims 1 to 14; and
optionally
(b) (2) In the compound of formula I or IA, when R ² is -C(=O)-OR ^2a , wherein R ^2a is unsubstituted or substituted C _1-8 -aliphatic, this formula subjecting a compound of I or IA to saponification under suitable conditions to give a compound of the respective formula I or IA, wherein R ² is -C(=0)-OH or -C(=0)-OCat .

Images