EA043276B1 - SUBSTITUTED TRIAZOLOQUINOXALINE DERIVATIVES - Google Patents

Description

The present invention relates to compounds corresponding to the general formula (II) or (III)

which act as glucocorticoid receptor modulators and can be used to treat and/or prevent diseases that are at least partially mediated by the glucocorticoid receptor.

Glucocorticoids (GCs) exert potent anti-inflammatory, immunosuppressive, and disease-modifying therapeutic effects mediated by the glucocorticoid receptor (GR). They have been widely used for decades to treat inflammatory and immune diseases and are still the most effective therapy for these conditions. However, chronic treatment of inflammatory diseases with HA is hampered by the side effects associated with HA. Such unwanted side effects include insulin resistance, diabetes, hypertension, glaucoma, depression, osteoporosis, adrenal suppression, and muscle wasting, with osteoporosis and diabetes being the most medically severe (Hapgood JP. et al., Pharmacol Ther. 2016 Sep;165: 93-113; Buttgereit F. el al., Clin Exp Rheumatol. 2015 Jul-Aug; 33 (4 Suppl 92):S29-33; Hartmann K. et al., Physiol Rev. 2016 Apr; 96( 2):409-47).

One example of an oral glucocorticoid is prednisone, which is often prescribed to treat several inflammatory diseases (De Bosscher K et al., Trends Pharmacol Sci. 2016 Jan; 37(1):4-16; Buttgereit F. et al., JAMA. 2016; 315(22):2442-2458). Because glucocorticoids cause adrenal suppression, prednisolone withdrawal can be severe if the drug is abruptly stopped when all signs of the disease disappear. Therefore, a gradual reduction in the dose of HA to physiological is often part of treatment protocols to reduce the risk of relapse and the development of other withdrawal symptoms (Liu D. et al., Allergy Asthma Clin Immunol. 2013 Aug 15; 9(1):30). Thus, there is a high medical need for new effective anti-inflammatory drugs with fewer side effects.

Recent research has focused on the development of partial agonists or selective glucocorticoid receptor modulators that activate pathways to inhibit inflammation but avoid targeting pathways that lead to GC-related side effects. It has been demonstrated that most of these effects are mediated by various GH-dependent genomic mechanisms called transactivation and transrepression. The anti-inflammatory effect of HA is mainly due to transrepression of inflammatory genes, while certain side effects are predominantly mediated by transactivation of several genes. According to the nature of the ligand, GH can be selectively modulated into a specific conformation that favors transrepression over transactivation, resulting in an improved therapeutic effect (De Bosscher K et al., Trends Pharmacol Sci. 2016 Jan; 37(1):4- 16). The concept of such dissociated ligands was defined about two decades ago, and several compounds have been identified and evaluated in preclinical and clinical trials, but none of them has yet been approved for clinical use.

Compounds that are active glucocorticoid receptor modulators are also known from WO 2009/035067 and WO 2017/034006.

The aim of the present invention was to provide new compounds that are glucocorticoid receptor modulators and that preferably have advantages over prior art compounds. The novel compounds, in particular, should be suitable for use in the treatment and/or prevention of disorders or diseases that are at least partially mediated by the glucocorticoid receptor.

This goal has been achieved in accordance with the subject matter of the claims.

Surprisingly, the compounds of the present invention have been found to be highly effective glucocorticoid receptor modulators.

The present invention relates to a compound corresponding to the general formula (II) or (III)

where R ¹ represents C ₁ _ ₁₀ alkyl; C ₃ _ ₁₀ cycloalkyl; phenyl or pyridyl;

- 1 043276 where Cz. ₁₀ cycloalkyl, phenyl and pyridyl may optionally be connected through a ^^ alkylene bridge;

R ² is F; Cl; Br; I; C _1-10 alkyl; _C3 . ₁₀ cycloalkyl or O-C _1-10 alkyl;

R ³ is H; F; Cl; Br; I; C _1-10 alkyl or O-C _1-10 alkyl;

R ⁵ and R ⁶ are unsubstituted C _1-4 alkyl;

X is N or NR ⁷ ;

Z is N, NR ⁷ or CR ⁹ ;

provided that where X is NR ⁷ , Z is N or CR ⁹ ;

when X is N, Z is NR ⁷ ;

R ⁷ is H or LR ⁸ ; where L is a bond; S(O); S(O) ₂ ; C _1-6 alkylene; C(O); C _1-6 αkylene-C(O); C(O)-O; C _1-6 alkylene-C(O)-O; or C _1-6 alkylene-N(H)-C(O)-O;

R ⁸ is C _1-10 alkyl; C _3-10 cycloalkyl or 3-7 membered heterocycloalkyl;

where C ₃ .l ₀ cycloalkyl and 3-7-membered heterocycloalkyl may optionally be connected through a C _1-6 alkylene bridge;

R ⁹ and R ¹⁰ are independently H; F; Cl; Br; I; CN; C1_10alkyl; C3.10 cycloalkyl or 3-7 membered heterocycloalkyl; R ¹¹ is F; Cl; Br; I; CN; _{C1_10} alkyl or O- _{C1_10} alkyl _;

n is 0, 1 or 2;

where _C1 . ₁₀ alkyl, C ₁ . ₄ alkyl and C ₁ _ ₆ alkylene are in each case independently of one another linear or branched, saturated or unsaturated;

where 3-7-membered heterocycloalkyl means heterocycloaliphatic saturated residues having from 3 to 7 ring members, in each case at least one carbon atom is replaced by O;

where Cl.l ₀ alkyl, and C ₁ . ₄ alkyl, in each occurrence independently of one another, are unsubstituted, mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; _CF3 ; _CF2H ; CFH ₂ ; HE; O-C ₁ . ₆ alkyl; _NH2 ; N(H)(C ₁ _ ₆ alkyl); and N(C ₁ _ ₆ alkyl) ₂ ;

where phenyl and pyridyl in each case are unsubstituted; in the form of the free compound or its physiologically acceptable salt.

In a preferred embodiment, the compound of the present invention is in the form of a free compound. For specification purposes, free compound preferably means that the compound of the present invention is not present in salt form. Methods for determining whether a chemical is present in free compound or salt form are known to those skilled in the art, such as ¹⁴ N or ¹⁵ N solid state NMR spectroscopy, X-ray diffraction, X-ray powder diffractometry (XRPD), IR, Raman , XPS. You can also use the ¹ H-NMR spectrum recorded in solution to take into account the presence of protonation.

In another preferred embodiment, the compound of the present invention is present in the form of a physiologically acceptable salt. For the purposes of this specification, the term physiologically acceptable salt preferably refers to a salt derived from a compound of the present invention and a physiologically acceptable acid or base.

In accordance with the present invention, the compound in accordance with the present invention may be present in any possible form, including solvates, co-crystals and polymorphs. For the purposes of this specification, the term solvate preferably refers to the adduct of (i) a compound of the present invention and/or a physiologically acceptable salt thereof with (ii) separate molecular equivalents of one or more solvents.

Furthermore, the compound of the present invention may be present in the form of a racemate, enantiomers, diastereomers, tautomers, or any mixtures thereof.

The present invention also includes isotopic isomers of a compound of this invention, wherein at least one atom of the compound is replaced by an isotope of the corresponding atom that is different from the predominantly natural isotope, as well as any mixtures of isotopic isomers of such a compound. Preferred isotopes are ² H (deuterium), ³ H (tritium), ¹³ C and ¹⁴ C. Isotopic isomers of a compound of the invention can generally be prepared using conventional procedures known to those skilled in the art.

In accordance with the present invention, the terms C ₁ _ ₁₀ αkyl, C ₁ . ₈ alkyl, C ₁ . ₆ αkyl and C ₁ . ₄ alkyl preferably means acyclic saturated or unsaturated aliphatic (i.e., non-aromatic) hydrocarbon residues, which may be linear (i.e., straight-chain) or branched, which may be unsubstituted or mono- or polysubstituted (e.g., di- or tri-substituted) and which contain 1 to 10 (i.e. 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10), 1 to 8 (i.e. 1, 2, 3, 4, 5, 6, 7 or 8), 1 to 6 (i.e. 1, 2, 3, 4, 5 or 6) and 1 to 4 (i.e. 1, 2, 3 or 4) carbon atoms , respectively. In a preferred embodiment, C ₁ . ₁₀ αkyl, C ₁ . ₈ alkyl, C ₁ . ₆ alkyl and C _{1 4} alkyl are saturated. In another preferred embodiment, C ₁ _ ₁₀ alkyl, C ₁ . ₈ αkyl, C ₁ . ₆ alkyl and C ₁ _ ₄ alkyl are unsaturated. In accordance with this variant

- 2 043276 entities C _1-10 alkyl, _C1-8 alkyl, _C1-6 alkyl and C1_ ₄ alkyl contain at least one C-C double bond (C=C-bond) or at least one C-C triple bond (C^C bond). In another preferred embodiment, C _1-10 alkyl, C1. ₈ alkyl, C _1-6 alkyl and C1_ ₄ alkyl are (i) saturated or (ii) unsaturated, wherein _C1-10 alkyl, _C1-8 alkyl, _C1-6 alkyl and _C1-4 alkyl contain at least one, preferably one, triple C-C bond (C^C-bond). Preferred C _1-10 alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH ₂ CH=CH ₂ , -CH=CH-CH _H , -C (=CH ₂ )-CH ₃ ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2- pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3- dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, npropyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2CH=CH2, -CH=CH-CH ₃ , -C(=CH ₂ )-CH ₃ ), n- butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, npentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n- octyl, n-nonyl and n-decyl. Preferred _{C1_8} alkyl groups are selected from methyl, ethyl, ethenyl(vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2CH=CH2, -CH=CH- _CH3 , -C( =CH2) _-CH3 ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl, 2pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2- yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2propynyl, propenyl (-CH2CH=CH2, -CH=CH- _CH3 , -C(=CH2) _-CH3 ), n-butyl , 1-butynyl, 2-butynyl, 1butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1pentenyl, 2-pentenyl, 1-pentynyl, 2-pentynyl , 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2methylbut-2-yl, 3-methylbut-1-ynyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl and n-octyl. Preferred _C1-6 alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2 -methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpentyl -2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2CH=CH2, -CH=CH- _CH3 , -C(=CH2) _-CH3 ), n -butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1-pentynyl , 2-pentynyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 3-methylbut-1-ynyl, 2,2dimethylpropyl, n-hexyl. Particularly preferred _C1-6 alkyl groups are selected from _{C1_4} alkyl groups. Preferred _{C1_4} alkyl groups are selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH2CH=CH2, -CH=CH- _CH3 , -C( =CH2) _CH3 ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and 3-methylbut-1-ynyl.

In addition, in accordance with the present invention, the terms _C1-6 alkylene; _C1-4 alkylene and _C1-2 alkylene refer to linear or branched, preferably linear, and preferably saturated aliphatic residues, which are preferably selected from the group consisting of methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2 - or -C (CH ₃ ) 2-), butylene (-CH ₂ CH ₂ CH ₂ CH ₂ -), pentylene (-CH ₂ CH 2 CH ₂ CH _{2 CH 2} -) and hexylene (-CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ CH ₂ -); more preferably from methylene (-CH2-) and ethylene (-CH2CH2-) and most preferably from methylene (-CH2-). Preferably the _C1-6 alkylene is selected from _C1-4 alkylene, more preferably _C1-2 alkylene.

Moreover, in accordance with the present invention, the terms _C3-10 cycloalkyl and _C3-6 cycloalkyl preferably mean cyclic aliphatic hydrocarbons containing 3, 4, 5 _, 6, 7, 8, 9 or 10 carbon atoms and 3, 4, 5 or 6 carbon atoms, respectively, and hydrocarbons in each case may be saturated or unsaturated (but not aromatic), unsubstituted or mono - or polysubstituted. Preferably, _C3-10 cycloalkyl and _C3-6 cycloalkyl are saturated _. C ₃ - ₁₀ cycloalkyl and C ₃ - ₆ cycloalkyl can be associated with the corresponding general higher order structure through any desired and possible ring member of the cycloalkyl group. _C3-10 cycloalkyl and _C3-6 cycloalkyl groups can also be fused with additional _saturated , (partially) unsaturated, (hetero)cyclic, aromatic, or heteroaromatic ring systems _, i. with cycloalkyl, heterocyclyl, aryl or heteroaryl residues, which in each case may in turn be unsubstituted or mono- or polysubstituted. In addition, _C3-10 cycloalkyl and _C3-6 cycloalkyl may _contain one

- 3 043276 or a plurality of bridging links, such as in the case of adamantyl, bicyclo[2.2.1]heptyl or bicyclo[2.2.2]octyl. However, preferably, C ₃ - ₁₀ cycloalkyl and C ₃ - ₆ cycloalkyl are neither fused with additional ring systems nor bridged. More preferably, C ₃ _ ₁₀ cycloalkyl and C ₃ - ₆ cycloalkyl are neither fused with additional ring systems nor bridged, and are saturated. Preferred C ₃ . ₁ ocycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, adamantyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]heptyl and bicyclo[2.2 .2]octyl. Particularly preferred C ₃ . ₁ ocycloalkyl groups are selected from C ₃ _ ₆ alkyl groups. Preferred C ₃ . _{The 6} cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl. Particularly preferred C ₃ - ₆ cycloalkyl groups are selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, most preferably cyclopropyl.

In accordance with the present invention, the terms 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl preferably mean heterocycloaliphatic saturated or unsaturated (but not aromatic) residues having from 3 to 7, i.e. 3, 4, 5, 6 or 7 ring members and 3 to 6, i.e. 3, 4, 5 or 6 ring members, respectively, in each case at least one, and if appropriate also two or three carbon atoms are substituted by a heteroatom or a heteroatomic group which are independently selected from the group consisting of O, S, S(=O), S(=O) ₂ , N, NH and NH(C _{1 .4} αkyl) such as N(CH ₃ ), the carbon atoms in the ring being unsubstituted or mono- or polysubstituted. Preferably, 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl are saturated. 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl groups can also be fused with additional saturated or (partially) unsaturated cycloalkyl or heterocyclyl, aromatic or heteroaromatic ring systems. More preferably, however, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl are not fused with additional ring systems. Even more preferably, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl are not fused with additional ring systems and are saturated. The 3-7 membered heterocycloalkyl and 3-6 membered heterocycloalkyl groups may be linked to the overall higher order structure via any desired and possible ring member of the heterocycloaliphatic residue, unless otherwise indicated. In a preferred embodiment, the 3-7 membered heterocycloalkyl and the 3-6 membered heterocycloalkyl are linked to a common higher order structure via a carbon atom.

Preferred 3-7 membered heterocycloalkyl groups are selected from the group consisting of azepanyl, dioxepanyl, oxazepanyl, diazepanyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl, tetrahydropyranyl, oxetanyl, oxiranyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl; tetrahydropyrrolyl, dihydroquinolinyl, dihydroisoquinolinyl, dihydroindolinyl, dihydroisoindolyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and tetrahydroindolinyl. Particularly preferred 3-7 membered heterocycloalkyl groups are selected from 3-6 membered heterocycloalkyl groups. Preferred 3-6 membered heterocycloalkyl groups are selected from the group consisting of tetrahydropyranyl, oxetanyl, oxiranyl, tetrahydrofuranyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolane silt, dihydropyrrolyl, dioxanyl, dioxolanyl, dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, dihydroindolinyl, dihydroisoindolyl and tetrahydroindolinyl. Particularly preferred 3-6 membered heterocycloalkyl groups are selected from the group consisting of tetrahydropyranyl, oxetanyl, oxiranyl and tetrahydrofuranyl.

In accordance with the present invention, the term aryl preferably means aromatic hydrocarbons containing from 6 to 14, i.e. 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring members, preferably containing 6 to 10, i.e. 6, 7, 8, 9 or 10 ring members including phenyls and naphthyls. Each aryl residue may be unsubstituted or mono- or polysubstituted. The aryl may be linked to the overall higher order structure through any desired and possible ring member of the aryl residue. Aryl residues may also be fused with additional saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring systems, which in turn may be unsubstituted or mono- or polysubstituted. In a preferred embodiment, the aryl is fused with an additional ring system. Examples of fused aryl residues are: 2H-benzo[b][1,4]oxazin-3(4H)-onyl, 1H-benzo[d]imidazolyl, 2,3-dihydro-1H-indenyl, tetra

- 4 043276 hydronaphthalenyl, isochromane, 1,3-dihydroisobenzofuranyl, benzodioxolanyl and benzodioxanyl. Preferably, aryl is selected from the group consisting of phenyl, 1H-benzo[d]imidazolyl, 2Hbenzo[b][1,4]oxazin-3(4H)-onyl, 2,3-dihydro-1H-indenyl, tetrahydronaphthalenyl, isochroman , 1,3dihydroisobenzofuranyl, 1-naphthyl, 2-naphthyl, fluorenyl and anthracenyl, each of which may be respectively unsubstituted or mono- or polysubstituted. In another preferred embodiment, the aryl is not fused to any additional ring system. A particularly preferred aryl is phenyl, unsubstituted or mono- or polysubstituted.

In accordance with the present invention, the term 5- or 6-membered heteroaryl preferably means a 5- or 6-membered cyclic aromatic residue containing at least 1, and if appropriate 2, 3, 4 or 5 heteroatoms, each heteroatom independently of each other the groups S, N and O are selected, and the heteroaryl residue may be unsubstituted or mono- or polysubstituted, unless otherwise indicated. In the case of heteroaryl substitution, the substituents may be the same or different and may be in any desired and possible position of the heteroaryl. Linkage to the overall higher order structure can be via any desired and possible ring member of the heteroaryl residue, unless otherwise indicated. Preferably the 5- or 6-membered heteroaryl is linked to the overall higher order structure via a carbon atom of the heterocycle. Heteroaryl may also be part of a bi- or polycyclic system having no more than 14 ring members, wherein the ring system may be formed by additional saturated or (partially) unsaturated cycloalkyl or heterocycloalkyl, aromatic or heteroaromatic ring systems, which in turn may be unsubstituted either mono- or polysubstituted. In a preferred embodiment, the 5- or 6-membered heteroaryl is part of a bior polycyclic, preferably bicyclic, system. In another preferred embodiment, the 5- or 6-membered heteroaryl is not part of a bi- or polycyclic system. Preferably, the 5- or 6-membered heteroaryl is selected from the group consisting of pyridyl (i.e., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, benzofuranyl, benzimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl , benzotriazolyl, benzoxazolyl, benzoxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indazolyl, indolizinyl, indolyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl , phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl. A particularly preferred 5- or 6-membered heteroaryl is selected from the group consisting of pyridyl (ie 2-pyridyl, 3-pyridyl, 4-pyridyl).

Compounds according to the invention are defined by substituents, for example R ¹ , R ² and R ³ ( ^1st generation substituents), which may themselves be substituted if desired ( ^2nd generation substituents). Depending on the definition, these substituent substituents may in turn optionally be substituted ( ^3rd generation substituents). If, for example, R ¹ = C1.1oalkyl ( ^1st generation substituent), then C1. _{The 10} αalkyl may in turn be substituted, for example, by N(H)(C _{1 .6} alkyl) ( ^2nd generation substituent). This makes it possible to obtain the functional group R ¹ = (C1.10αkyl-NH-C1.6alkyl). NH-C1.6αkyl in turn can then be substituted, for example, by Cl ( ^3rd generation substituent). In general, this makes it possible to obtain the functional group R ¹ = C1. ₁₀ alkyl-NH-C ₁ . ₆ alkyl, where C ₁ . ₆ alkyl from NH-C ₁ . ₆ αlkyl is substituted by Cl. However, in a preferred embodiment, the ^3rd generation substituents will not be substituted, i. e. deputies of the ^4th generation will be absent. More preferably, ^2nd generation substituents will not be substituted, ie. ^3rd generation deputies will be absent.

If a residue occurs multiple times in a molecule, then that residue can respectively have different meanings for different substituents: if, for example, R ² and R ³ are C ₁ . ₆ alkyl, then C ₁ . ₆ αkyl may, for example, be ethyl for R ² and may be methyl for R ³ .

In connection with the terms C ₁ . ₁₀ alkyl, C ₁ . ₆ αkyl, C ₁ .4 alkyl, C ₃ . ₁₀ cycloalkyl, C ₃ . ₆ cycloalkyl, 37-membered heterocycloalkyl, 3-6-membered heterocycloalkyl, C ₁ . ₆ αkylene, ^^alkylene and C ₁ . ₂ alkylene is the term substituted in the sense of the present invention and, with respect to the corresponding residues or groups, refers to a single substitution (mono-substitution) or multiple substitution (poly-substitution), for example, di-substitution or tri-substitution; more preferably mono-substitution or di-substitution; one or more hydrogen atoms independently of each other by at least one substituent. In the case of multiple substitution, i.e. in the case of polysubstituted residues, such as di- or trisubstituted residues, such residues may be polysubstituted on different or identical atoms, for example, trisubstituted on one carbon atom, as in the case of CF3, CH2CF3, or disubstituted, as in the case of 1,1-difluorocyclohexyl , or in different places, as in the case of CH(OH)-CH=CH-CHC1 ₂ or 1-chloro-3-fluorocyclohexyl. Multiple substitution can be carried out with one or with different substituents.

With respect to the terms aryl, phenyl, heteroaryl, and 5- or 6-membered heteroaryl, the term substituted in the sense of the present invention refers to a single substitution (mono-substitution) or multiple substitution (poly-substitution), for example, a di- or tri-substitution, of one or more hydrogen atoms independently of each other by at least one substituent.

Multiple substitution can be carried out with one or with different substituents.

In accordance with the present invention preferably C ₁ . ₁₀ alkyl, C ₁ . ₆ alkyl, C ₁ . ₄ alkyl, C ₃ . ₁₀ cycloalkyl, C ₃ . ₆ cycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, C ₁ . ₆ alkylene, C ₁ . ₄ alkylene and C ₁ . ₂ alkylene are in each case independently of one another unsubstituted, mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CN; C1.6αkyl; CF3; CF2H; CFH2; _CF2Cl ; CFCL; C(O)-C1.6αkyl; C(O)-OH; C(O)-OC1.6 alkyl; C(O)-NH2; C(O)-N(H)(C1.6 alkyl); C(O)-N( _C1.6 αkylα)2; HE; =O; OCF3; OCF2H; OCFH2; OCF2Q; OCFCL; _OC1 . ₆ alkyl; О-С(О)-C ₁ . ₆ alkyl; O-C(O)-O-C ₁ . ₆ alkyl; O-(CO)-N(H)(C _{1 .6} alkyl); О-С(О)-N(C ₁ . ₆ αkyl) ₂ ; OS(O)2-NH2; O-S(o) ₂ -N(H)(C _{1 .6} alkyl); OS(O) ₂ -](C ₁ . ₆ alkyl) ₂ ; NH2; N(H)(C _{1 .6} alkyl); N(C ₁ . ₆ αkyl) ₂ ; N(H)-C(O)-C1.6 alkyl; N(H)-C(O)-O-C1.6αkylα; N(H)-C(O)-NH2; N(H)-C(O)-N(H)( _C1.6 alkyl); N(H)-C(O)N(C _{1 .6} alkyl) ₂ ; N(C _1-6 alkyl)-C(O)-C _1-6 alkyl; N(C _1-6 alkyl)-C(O)-O-C _1-6 αkyl; N(C _1-6 alkyl)-C(O)-NH ₂ ; N(c _1-6 αkyl)-C(O)-N(H)(C _1-6 αkyl); N(C _1-6 alkyl)-C(O)-N(C _1-6 alkyl) ₂ ; N(H)-S(O) ₂ OH; N(H)-S(O) ₂ -C ₁ . ₆ alkyl; N(H)-S(O) ₂ -OC _1-6 alkyl; N(H)-S(O) ₂ -NH ₂ ; N(H)-S(O) ₂ -N(H)(C _1-6 αkyl); N(H)-S(o) ₂ N(C _1-6 alkyl) ₂ ; N(C _1-6 αkyl)-S(O) ₂ -OH; N(C _1-6 alkyl)-S(O) ₂ -C _1-6 alkyl; N(C _1-6 alkyl)-S(O) ₂ -O-C _1-6 alkyl; N(C _1-6 alkyl) S(O) ₂ -NH ₂ ; N(C _1-6 alkyl)-S(O) ₂ -N(H)(C _1-6 αkyl); N(C _1-6 αkyl)-S(O) ₂ -N(C _1-6 alkyl) ₂ ; SCF ₃ ; SCF2H; SCFH2; SC _1-6 αkyl; S(O)-C _1-6 αkyl; S(O) ₂ -C _1-6 alkyl; S(O) ₂ -0h; S(O) ₂ -OC _1-6 alkyl; S(O) ₂ -NH ₂ ; S(O) ₂ -N(H)(C _1-6 alkyl); S(O) ₂ -N(C ₁ . ₆ alkyl) ₂ ; _C3 . ₆ cycloalkyl; 3-6 membered heterocycloalkyl; phenyl; 5 or 6 membered heteroaryl; O-C ₃ . ₆ cycloalkyl; O-(3-6 membered heterocycloalkyl); O-phenyl; O-(5 or 6-membered heteroaryl); C(O)-C ₃ . ₆ cycloalkyl; C(O)-(3-6 membered heterocycloalkyl); C(O)phenyl; C(O)-(5 or 6-membered heteroaryl); S(O) ₂ -(C _{3 .6} cycloalkyl); S(O) ₂ -(3-6 membered heterocycloalkyl); S(O) ₂ -phenyl and S(O) ₂ -(5 or 6-membered heteroaryl).

Preferred substituents from C ₁ . ₁ oαkyla, C ₁ . ₆ alkyl, C ₁ . ₄ αkyl, C ₃ . ₁ ocycloalkyl, C ₃ . ₆ cycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl, C ₁ . ₆ alkylene and C ₁ . ₄ αkylenes are selected from the group consisting of F; Cl; Br; I; CN; _C1 . ₆ alkyl; _CF3 ; CF2H; CFH2; C(O)-NH ₂ ; C(O)-N(H)(C _{1 .6} alkyl); C(O)-N(C _{1 .6} alkyl) ₂ ; OH; OCF ₃ ; OCF2H; OCFH2; O-C ₁ . ₆ alkyl; NH2; N(H)(C _{1 .6} αlkylα); N(C ₁ . ₆ alkyl) ₂ ; SCF ₃ ; SCF2H; SCFH2; _SC1 . ₆ alkyl; S(O)-C ₁ . ₆ alkyl; S(O) ₂ -C ₁ . ₆ alkyl; _C3 . ₆ cycloalkyl; 3-6 membered heterocycloalkyl; phenyl and 5 or 6-membered heteroaryl; and particularly preferably F, CN, CH3, CH2CH3, CF3; CF2H; CFH2; C(O)-NH2; C(O)-N(H)(CH3); C(O)-N(CH3)2; OH, NH2, OCH ₃ , SCH ₃ , S(O) ₂ (CH ₃ ), S(O)(CH ₃ ), N(CH ₃ ) ₂ , cyclopropyl and oxetanyl. According to this embodiment, C ₁ . ₁ oαkyl, C ₁ . ₆ alkyl, C ₁ . ₄ alkyl, C ₃ . ₁ ocycloalkyl, C ₃ . ₆ cycloalkyl, 3-7 membered heterocycloalkyl, 3-6 membered heterocycloalkyl are preferably each independently unsubstituted, mono- or tri-substituted, more preferably unsubstituted or mono-substituted, or di-substituted with a substituent selected from the group consisting of F; Cl; Br; I; CN; _C1 . ₆ alkyl; _CF3 ; CF2H; CFH2; C(O)-NH2; C(O)-N(H)(C1.6alkyl); C(O)-N( _C1.6 αkylα)2; HE; OCF3; OCF2H; OCFH2; O-C1.6 alkyl; NH2; N(H)(C ₁ . ₆ αlkulα); N(C ₁ . ₆ alkyl) ₂ ; SCF ₃ ; _sCf2H ; SCfH ₂ ; _SC1 . ₆ alkyl; S(O)-C ₁ . ₆ alkyl; S (O) ₂ -C ₁ . ₆ alkyl; _C3 . ₆ cycloalkyl; 3-6 membered heterocycloalkyl; phenyl and 5 or 6 membered heteroaryl. Preferably C ₁ . ₆ α-kylene groups and C ₁ . ₄ alkylene groups are unsubstituted.

According to the present invention, preferably aryl, phenyl and 5- or 6-membered heteroaryl are each independently unsubstituted or mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CN; _C1 . ₆ alkyl; _CF3 ; CF2H; CFH2; _CF2Cl ; CFCl ₂ ; _C1 . ₄ αkylene-CF ₃ ; _C1 . ₄ alkylene-CF ₂ H; From ₁ . ₄ αkylene-CFH ₂ ; C(O)-C ₁ . ₆ alkyl; C(O)-OH; C(O)OC1.6 alkyl; C(O)-N(H)(OH); C(O)-NH2; C(O)-N(H)( _C1.6 alkyl); C(O)-N( _C1.6 alkyl)2; HE; OCF3; OCF2H; OCFH2; _OCF2Cl ; OCFCl ₂ ; _OC1 . ₆ alkyl; O-C _3-6 cycloalkyl; O-(3-6 membered heterocycloalkyl); NH2; N(H)(C _{1 .6} alkyl); N(C ₁ . ₆ alkyl) ₂ ; N(H)-C(O)-C ₁ . ₆ alkyl; N(C ₁ . ₆ alkyl)-C(O)-C ₁ . ₆ alkyl; N(H)-C(O)-NH ₂ ; N(n)-C(O)-N(H)(C _{1 .6} alkyl); N(H)-C(O)-N(C _{1 .6} alkyl) ₂ ; N(c _{1 .6} alkyl)-C(o)-N(H)(C _{1 .6} αkyl); N(C _{1 .6} alkyl)-C(O)-N(C _{1 .6} alkyl) ₂ ; N (H) -S (O) ₂ -C ₁ . ₆ alkyl; SCF ₃ ; _SC1 . ₆ alkyl; S(O)-C ₁ . ₆ alkyl; S(O) ₂ -C ₁ . ₆ alkyl; S(O) ₂ -NH ₂ ; S(O) ₂ -N(H)(C _{1 .6} αkyl); S (O) ₂ -N (C _{1. 6} αkyl) ₂ ; C ₃ _ ₆ cycloalkyl; _{C1_4} alkylene- _{C3_6} cycloalkyl _; 3-6 membered heterocycloalkyl; _{C1_4} alkylene-(3-6 membered heterocycloalkyl); phenyl or 5 or 6 membered heteroaryl. Preferred aryl, phenyl and 5- or 6-membered heteroaryl substituents are selected from the group consisting of F; Cl; Br; I; CN; _C1 . ₆ alkyl; _CF3 ; CF2H; CFH2; C1_ ₄ alkylene-CF ₃ ; From ₁ . ₄ αkylene-CF ₂ H; From ₁ . ₄ alkylene-CFH ₂ ; HE; OCF ₃ ; OCF2H; OCFH2; O- _{C1_6} alkyl; O-C ₃ _ ₆ cycloalkyl and C _3-6 cycloalkyl; and particularly preferably F; Cl; Br; CN; _CH3 ; CH ₂ CH ₃ ; _CF3 ; CF2H; CFH2; CH2-CF3; OH; OCF ₃ ; OCF2H; OCFH2; O-CH ₃ ; O-cyclopropyl and cyclopropyl. In accordance with the present embodiment, each of the aryl, phenyl and 5- or 6-membered heteroaryl independently of each other is preferably unsubstituted, mono-, di- or tri-substituted, more preferably unsubstituted, mono-substituted or disubstituted substituent selected from the group consisting of F; Cl; Br; I; CN; _C1 . ₆ alkyl; _CF3 ; CF2H; CFH2; From ₁ . ₄ alkylene-CF ₃ ; _C1 . ₄ alkylene-CF ₂ H; _C1 . ₄ alkylene-CFH ₂ ; HE; OCF ₃ ; OCF2H; OCFH2; O-C ₁ . ₆ alkyl; O-C ₃ _ ₆ cycloalkyl and C ₃ _ ₆ cycloalkyl.

In a preferred embodiment, the compound of the present invention has

- 6 043276 general formula (II) or (III)

In a preferred embodiment, X is NR ⁷ and Z is N or CR ⁹ . More preferably X is NR ⁷ and Z is CR ⁹ . In another preferred embodiment, X is N and Z is NR ⁷ .

More preferably, the compound of the present invention has the general formula (II) or (III) wherein X is NR ⁷ and Z is N or CR ⁹ , more preferably CR ⁹ .

In yet another preferred embodiment, R ¹ is CH3, CF3, CF2H; CFH2; ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl; tert-butyl; (CH ₂ ) _1-2 OCH ₃ ; (CH ₂ ) _1-2 OH; (CH ₂ ) _0-2 C(H)(OH)-(CH ₂ ) _0-2 CH ₃ ; (CH ₂ ) _1-2 N(CH ₃ ) ₂ ; ((CH ₂ ) _0-2 -cyclopropyl, (CH ₂ ) _0-2 -cyclobutyl, (CH ₂ ) _0-2 cyclopentyl and (CH ₂ ) _0-2 -cyclohexyl; (CH ₂ ) _0-2 -phenyl; (CH ₂ ) _0-2 -pyridyl.

In a specific preferred embodiment, R ² is F; Cl; Br; CN; methyl; ethyl; n-propyl; 2-propyl; n-butyl; isobutyl; sec-butyl; tert-butyl; _CF3 ; _{CH2CF3 ;} CHF ₂ ; CH ₂ CHF ₂ ; CH2F; CH2CH2F; OCH3; OCH2CH3; OC(H)(CH3)2; OCH2CH2CH3; OC(CH3)3; OCF3; OCH2CF3; OCHF2; OCH2CHF2; OCH2F; OCH2CH2F; CH2OH; CH2CH2OH; CH2C(H)(OH)CH3; CH2CH2CH2OH; CH ₂ CH ₂ CH ₂ CH ₂ OH; C(CH ₃ ) ₂ CH ₂ OH; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl.

In a specific preferred embodiment, R ³ is H; F; Cl; Br; methyl; ethyl; n-propyl; 2-propyl; n-butyl; isobutyl; sec-butyl; tert-butyl; _CF3 ; _{CH2CF3 ;} CHF ₂ ; CH ₂ CHF ₂ ; CH2F; CH2CH2F; OCH3; OCH2CH3; OC(H)(CH3)2; OCH2CH2CH3;OC(CH3)3; OCF3; OCH2CF3; OCHF2; OCH2CHF2; OCH2F; OCH2CH2F; CH2OH; CH2CH2OH; CH2C(H)(OH)CH3; CH2CH2CH2OH; CH2CH2CH2CH2OH; C(CH3)2CH2OH.

In accordance with the present invention, R ⁵ and R ⁶ is independently unsubstituted C _1-4 alkyl. Preferably R ⁵ and R ⁶ are independently H, CH3, CH2CH3; CH2CH2CH3, CH(CH3)2 or CH2CH2CH2CH3, more preferably H, CH3, CH2CH3 or CH2CH2CH3; even more preferably H, CH3 or CH2CH3; most preferably H or CH3. In a particular preferred embodiment, R ⁵ and R ⁶ are both CH3.

In a particular preferred embodiment, the compound of the present invention has the general formula (II) or (III) wherein X is NR ⁷ and Z is N or CR ⁹ , more preferably CR ⁹ , and wherein R ⁵ and R ⁶ are both CH3.

In a preferred embodiment, at least one of R ¹ , R ² , R ³ , R ⁵ and R ⁶ is not H. More preferably, both R ⁵ and R ⁶ are not H and at least one of R ¹ , R ² and R ³ is not H. In a preferred embodiment, both R ⁵ and R ⁶ are not H and one of R ¹ , R ² and R ³ is not H. In another preferred embodiment, both R ⁵ and R ⁶ are not H, and two of R ¹ , R ² and R ³ are not H. In yet another preferred embodiment, R ¹ , R ² , R ³ , R ⁵ and R ⁶ are not H.

In a particularly preferred embodiment, the compound of the present invention has the general formula (II) or (III); and/or

X is NR ⁷ and Z is N or CR ⁹ ; and/or

R ⁵ and R ⁶ are both methyl; and/or at least one of R ¹ , R ² and R ³ is not H.

In accordance with the present invention, R ⁷ is H or LR ⁸ .

In a preferred embodiment, R ⁷ is H. According to this embodiment, preferably X is NH and Z is N or CR ⁹ ; or X is N and Z is NH. More preferably X is NH and Z is CR ⁹ .

Still further according to this embodiment, preferably the compound of the present invention has the general formula (II) or (III) wherein X is NH and Z is N or CR ⁹ , more preferably CR ⁹ .

In another preferred embodiment, R ⁷ is not H. In this preferred embodiment, R ⁷ is LR ⁸ .

More preferably L is a bond; S(O); S(O) ₂ ; C _1-4 alkylene; C(O); C _1-4 alkylene C(O); C(O)-O; C _1-4 alkylene-C(O)-O; C _1-4 alkylene-N(H)-C(O) or C _1-4 alkylene-N(H)-C(O)-O; even more preferably an S(O) bond; S(O) ₂ ; CH ₂ ; CH2CH2; C(CH ₃ ) ₂ ; CH ₂ CH ₂ CH ₂ ; C(O); CH ₂ -C(O); CH ₂ CH ₂ -C(O); CH2CH2CH2-CO; C(CH3)2-C(O); C(O)-O; CH2-C(O)-O; CH2CH2-CO-O; CH2CH2CH2-C(O)-O; C(CH3)2C(O)-O; CH ₂ -N(H)-C(O); CH ₂ CH ₂ -N(H)-C(O); C(CH ₃ ) ₂ -N(H)-C(O); CH ₂ CH ₂ CH ₂ -N(H)-C(O); CH ₂ -N(H)- 7 043276

C(O)-O; CH2CH2-N(H)-C(O)-O; C(CH ₃ ) ₂ -N(H)-C(O)-O or CH2CH2CH2-N(H)-C(O)-O; most preferably a bond; S(O) ₂ ; CH2; C(O); C(O)-O; CH2-C(O)-O; CH2CH2-C(O)-O; CH2CH2-N(H)-C(O) or CH2CH2N(H)-C(O)-O.

More preferably R ⁸ is

_C1 . ₆ alkyl is selected from the group consisting of methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2 -methylbutyl, 3methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpentyl -2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; preferably from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH ₂ CH=CH ₂ , CH=CH-CH ₃ , -C(=CH ₂ )-CH ₃ ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl and tert-butyl;

^^cycloalkyl which is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl; preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; or

3-6 membered heterocycloalkyl groups are selected from the group consisting of tetrahydropyranyl, oxetanyl, oxiranyl, tetrahydrofuranyl, thiazolidinyl, tetrahydrothiophenyl, tetrahydropyridinyl, thiomorpholinyl, morpholinyl, pyrrolidinyl, 4-methylpiperazinyl, morpholinonyl, azetidinyl, aziridinyl, dithiolanyl, dihydropyrrolyl, dioxanyl, dioxolanyl , dihydropyridinyl, dihydrofuranyl, dihydroisoxazolyl, dihydrooxazolyl, imidazolidinyl, isoxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyranyl, tetrahydropyrrolyl, dihydroindolinyl, dihydroisoindolyl and tetrahydroindolinyl; preferably tetrahydropyranyl, oxetanyl, oxiranyl and tetrahydrofuranyl;

where C ₃ . ₆ cycloalkyl and 3-6 membered heterocycloalkyl may optionally be connected via C ₁ . ₄ α-kylene bridge; and where C ₁ . ₆ alkyl, C ₃ . ₆ cycloalkyl and 3-6 membered heterocycloalkyl are each independently unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F, CN, CH ₃ , CH ₂ CH ₃ , CF ₃ ; CF2H; CFH2; C(O)-NH ₂ ; C(O)-N(H)(CH ₃ ); C(O)-N(CH ₃ ) ₂ ; OH, NH2, OCH ₃ , SCH ₃ , S(O) ₂ (CH ₃ ), S(O)(CH ₃ ), N(CH ₃ ) ₂ , cyclopropyl and oxetanyl.

Most preferably R ⁸ is methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, CF3, CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F, CHFCH3, CHFCH2F, CHFCHF2, CHFCF3 CF2CH3 CF2CH2F CF2CHF2 CF2CF3 CH2CH2CF3 CH2CH2CHF2 CH2CH2CH2F CH2CHFCH3 CH2CHFCH2F CH2CHFCHF2 CH2CHFCF3 CH2CF2CH3 CH2CF2CH2F CH2CF2CHF2 CH2CF2CF3 CH2OH CH2CH2OH , C(H)(OH)CH3, CH2CH2CH2OH, C(CH3 )2OH, C(H)(OH)CH2CH3, C(H)(CH3)-CH2OH, CH2C(H)(OH)-CH3, CH2CH2CH2CH2OH, CH2CH2C(H)(OH)CH3, CH2C(H)(OH) CH2CH3, C(H)(OH)CH2CH2CH3, CH2-C(CH3)2-OH, C(CH3)2CH2OH, C(H)(OH)CH2CF3, C(H)(OH)CH2CHF2, C(H)( OH)CH2CH2F, CH2C(H)(OH)-CF3, CH2C(H)(OH)-CHF2, CH2C(H)(OH)-CH2F, CH2OCH3, CH2CH2OCH3, C(H)(CH3)-OCH3, CH2CH2CH2OCH3, C(CH3)2OCH3, C(H)(OCH3)CH2CH3, C(H)(CH3)CH2OCH3, CH2C(H)(OCH3)-CH3, CH2CH2CH2CH2OCH3, CH2CH2C(H)(OCH3)CH3, CH2C(H)( OCH3)CH2CH3, C(H)(OCH3)CH2CH2CH3, CH2-C(CH3)2-OCH3, C(CH3)2CH2OCH3, CH2NH2, CH2CH2NH2, CH2CH2CH2NH2, C(CH3)2NH2, C(H)(NH2)CH2CH3, C(H)(CH3)-CH2NH2, CH2C(H)(NH2)-CH3, CH2CH2CH2CH2NH2, CH2CH2C(H)(NH2)CH3, CH2C(H)(NH2)CH2CH3, C(H)(NH2)CH2CH2CH3, CH2 -C(CH3)2-NH2,

C(CH3)2CH2NH2, CH2N(CH3)2, CH2CH2N(CH3)2, CH2CH2CH2N(CH3)2, C(CH3)2N(CH3)2,

C(H)(N(CH3)2)CH2CH3, C(H)(CH3)-CH2N(CH3)2, CH2C(H)(N(CH3)2)-CH3, CH2CH2CH2CH2N(CH3)2, CH2CH2C(H )(N(CH3)2)CH3, CH2C(H)(N(CH3)2)CH2CH3, C(H)(N(CH3)2)CH2CH2CH3, CH2-C(CH3)2-N(CH3)2, C(CH3)2CH2N(CH3)2, CH2-C(O)N(CH3)2, CH2CH2-C(O)N(CH3)2, CH2CH2CH2-C(O)N(CH3)2, C(CH3) 2C(O)N(CH3)2, C(H)(C(O)N(CH3)2)CH2CH3, C(H)(CH3)-CH2-C(O)N(CH3)2, CH2C(H )(C(O)N(CH3)2)-CH3, CH2CH2CH2CH2-C(O)N(CH3)2, CH2CH2C(H)(C(O)N(CH3)2)CH3, CH2C(H)(C (O)N(CH3)2)CH2CH3,

C(H)(C(O)N(CH3)2)CH2CH2CH3, CH2-C(CH3)2-C(O)N(CH3)2, C(CH3)2CH2-C(O)N(CH3)2 , (CH2) o-2-cyclopropyl, (CH ₂ ) ₀ _ ₂ -cyclobutyl, (CH ₂ ) ₀ _ ₂ -cyclopentyl, (CH ₂ ) ₀ _ ₂ -cyclohexyl, (CH ₂ ) ₀ . ₂ tetrahydropyranyl, (CH ₂ ) ₀ _ ₂ -oxetanyl, (CH ₂ ) ₀ _ ₂ -oxiranyl, or (CH ₂ ) ₀ _ ₂ -tetrahydrofuranyl.

Preferred implementation options (from E1 to E45) cover those in which L and R ⁸ have the meaning indicated in the table below.

- 8 043276

L ^R8 L ^R8 E1 CONNECTION (CH ₂ )o-b-C1.u-alkyl E24 C1-b-alkylene-C(0)-0 (CH ₂ )o-b-3-7-membered heterocycloalkyl E2 connection (CH ₂ )o.b-Sz.u-Cycloalkyl E25 C1.b-alkylene-K(H)C(0) (CH ₂ )o-b-C1.u-alkyl E3 connection (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E26 C1. _b -alkylene-K(H)C(0) (CH ₂ ) ₀ . ₆ -Sz.u-Cycloalkyl E4 S(O) (CH ₂ ) ₀ . ₆ -C1.yu-azhil E27 C1. ₆ -alkylene-M (H) - C (0) (CH ₂ )o- _6-3-7 -membered heterocycloalkyl E5 S(O) (CH ₂ ) ₀ . ₆ -Sz.u-Cycloalkyl E28 C1. ₆ -alkylene-M(C1.ualkyl)-C(O) (CH ₂ )o. _b -C1.1o-alkyl E6 S(O) (CH ₂ ) ₀ . _6-3-7 membered heterocycloalkyl E29 C1. ₆ -alkylene-M(C1.ualkyl)-C(O) (CH ₂ ) ₀ . ₆ -Sz.u-Cycloalkyl E7 S(O) ₂ (CH ₂ ) ₀ . ₆ -C1.u-alkyl EZO C1. ₆ -alkylene-M(C1.ualkyl)-C(O) (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E8 S(O) ₂ (CH ₂ ) ₀ . ₆ -Sz.u-Cycloalkyl E31 C1. _b -alkylene-1Ch(H)0(0)-0 (CH ₂ )o. _b -C1.1o-alkyl E9 S(O) ₂ (CH ₂ )o-6-3-7-membered heterocycloalkyl E32 C1. ₆ -alkylene-M(H)0(0)-0 (CH ₂ )o.b-C3.u-cycloalkyl EY Ο _μ6 - (CH ₂ ) ₀ . ₆ -C1.u-alkyl E3Z C1. ₆ -alkylene-K(H)- (CH ₂ ) ₀ . _6-3-7 -membered alkylene 0(0)-0 heterocycloalkyl E11 Ο _μ6 alkylene (CH ₂ ) ₀ _ ₆ -Сз_ю ^_ Cycloalkyl E34 C1. ₆ -alkylene-M(C1.ualkyl)-C(0)-0 (CH ₂ ) ₀ . ₆ -C1.u-alkyl E12 Ο _μ6 alkylene (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E35 C1. ₆ -alkylene-M(C1.ualkyl)-C(0)-0 (CH ₂ ) ₀ . ₆ -C3.1o-Cycloalkyl E13 C(O) (CH ₂ )o. _b -C1.1o-alkyl E36 C1. ₆ -alkylene-M(C1.ualkyl)-C(0)-0 (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E14 C(O) (CH ₂ ) ₀ _ ₆ -C3_u-Cycloalkyl E37 0 (CH ₂ ) ₀ . ₆ -C1.u-alkyl E15 C(O) (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E38 0 (CH ₂ ) ₀ . ₆ -C3.1o-Cycloalkyl E16 Ο _μ6 alkylene- C(O) (CH ₂ )o. _b -C1.1o-alkyl E39 0 (CH ₂ )o_ ₆ -3-7-membered heterocycloalkyl E17 Ο _μ6 alkylene- C(O) (CH ₂ )o-b-Cs-u-Cycloalkyl E40 NH (CH ₂ )o-b-C1.u-alkyl E18 Ο _μ6 alkylene- C(O) (CH ₂ )o-b-3-7-membered heterocycloalkyl E41 NH (CH ₂ )o.b-Sz.u-Cycloalkyl E19 0(0)-0 (CH ₂ )o. _b -C1.1o-alkyl E42 NH (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E20 0(0)-0 (CH ₂ ) ₀ _ ₆ -C3_u-Cycloalkyl E43 K(C1.u-alkyl) (CH ₂ ) ₀ . ₆ -C1.u-alkyl E21 0(0)-0 (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E44 K(C1.u-alkyl) (CH ₂ ) ₀ . ₆ -C3.1o-Cycloalkyl E22 ο _μ6 alkylene- 0(0)-0 (CH ₂ )o. _b -C1.1o-alkyl E45 K(C1.u-alkyl) (CH ₂ ) ₀ _ ₆ -3-7-membered heterocycloalkyl E23 ο _μ6 alkylene- 0(0)-0 (CH ₂ ) ₀ _ ₆ -C3_u-Cycloalkyl

In a particularly preferred embodiment

L is a bond; S(O); S(O) ₂ ; C _1-4 alkylene; C(O); C _1-4 alkylene-C(O); C(O)-O; C _1-4 alkyleneC(O)-O; C _1-4 alkylene-N(H)-C(O) or C _1-4 alkylene-N(H)-C(O)-O;

R ⁸ is C _1-6 alkyl; C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

where C _3-6 cycloalkyl and 3-6 membered heterocycloalkyl may optionally be connected via a C _1-4 alkylene bridge.

More preferably

L is a bond; S(O); S(O) ₂ ; C _1-4 alkylene; C(O); C _1-4 alkylene-C(O); C(O)-O; C _1-4 alkyleneC(O)-O; C _1-4 alkylene-N(H)-C(O) or C _1-4 alkylene-N(H)-C(O)-O; even more preferably a bond; S(O); S(O)2; CH2; CH2CH2; C(CH3)2; CH2CH2CH2; C(O); CH2-C(O); CH2CH2-CO; CH2CH2CH2-CO; C(CH3)2C(O); C(O)-O; CH ₂ -C(O)-O; SCCH2-C(O)-O; CH2CH2CH2-CO-O; C(CH3b-C(O)-O; CH2-N(H)-C(O); CH2CH2-N(H)-C(O); C(CH3)2-N(H)-C(O) ;CH2CH2CH2-N(H)-C(O);CH2-N(H)-C(O)-O;CH2CH2-N(H)-C(O)O;C(CH3)2-N(H) -C(O)-O or CH2CH2CH2-N(H)-C(O)-O; most preferably a bond; S(O)2; CH2; C(O); C(O)-O; CH2-C( O)-O; CH2CH2-C(O)-O; CH2CH2-N(H)-C(O) or CH2CH2-N(H)-C(O)-O; and

R ⁸ is C _1-6 alkyl; C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl;

where C3-6 cycloalkyl and 3-6 membered heterocycloalkyl may optionally be connected via a C _1-4 alkylene bridge; and preferably where C _1-6 alkyl; C _3-6 cycloalkyl and 3-6 membered heterocyclo-9 043276 alkyl are each independently unsubstituted or mono- or poly-substituted with one or more substituents selected from the group consisting of F; Cl; Br; I; CN; From ₁ . ₆ alkyl; _CF3 ; CF2H; CFH2;

C(O)-NH ₂ ; C(O)-N(H)(C _1-6 alkyl); C(O)-N(C _1-6 alkyl) ₂ ; HE; OCF ₃ ; OCF2H; OCFH2; O-C _1-6 alkyl; NH2;

N(H)(C _{1 .6} αkyl); N(C ₁ . ₆ alkyl) ₂ ; SCF ₃ ; _sCf2H ; SCFH2; _SC1 . ₆ alkyl; S(O)-C ₁ . ₆ alkyl; S(O) ₂ -C ₁ . ₆ alkyl;

C _3-6 cycloalkyl; 3-6 membered heterocycloalkyl; phenyl and 5 or 6 membered heteroaryl.

More preferably R ⁹ is H; F; Cl; Br; I; CN; methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CF ₃ , CHF ₂ , CH ₂ F, CH ₂ CF ₃ , CH ₂ CHF ₂ , CH ₂ CH ₂ F, cyclopropyl, cyclobutyl, tetrahydropyranyl, oxetanyl, oxiranyl, tetrahydrofuranyl.

In a specific preferred embodiment, R ⁹ is H; F; CN; methyl; ethyl; n-propyl; 2-propyl; CF3; CH2CF3; CHF2; CH2CHF2; CH2F; CH2CH2F.

More preferably R ¹⁰ is H; F; Cl; Br; I; CN; methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2-propynyl, propenyl (-CH ₂ CH=CH ₂ , -CH=CH-CH ₃ , -C(=CH ₂ )-CH ₃ ), n-butyl, 1-butynyl, 2butynyl, 1-butenyl, 2-butenyl, 3-methyl-1-butynyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CF ₃ , CHF2, CH2F, CH2CF3, CH2CHF2 , C (H)(CH3)-CH2OH, CH2C(H)(OH)-CH3, CH2CH2CH2CH2OH, CH2CH2C(H)(OH)CH3, CH2C(H)(OH)CH2CH3, C(H)(OH)CH2CH2CH3, CH2- C(CH3)2-OH, C(CH3)2CH2OH, C(H)(OH)CH2CF3, C(H)(OH)CH2CHF2, C(H)(OH)CH2CH2F, CH2C(H)(OH)-CF3 , CH2C(H)(OH)-CHF2, CH2C(H)(OH)-CH2F, CH2OCH3, CH2CH2OCH3, C(H)(CH3)-OCH3, CH2CH2CH2OCH3, C(CH2)2OCH3, C(H)(OCH3) CH2CHz, C(H)(CHz)-SchOSCHz, SchS(H)(OCHz)-CH3, CH2CH2CH2CH2OSH3,

CH2CH2C(H)(OCH3)CH3, CH2C(H)(OCH3)CH2CH3, C(H)(OCH3)CH2CH2CH3, CH2-C(CH3)2-OCH3, C(CH3)2CH2OCH3, CH2NH2, CH2CH2NH2, CH2CH2CH2NH2, C (CH3)2NH2, C(H)(NH2)CH2CH3, C(H)(CH3)CH2NH2, CH2C(H)(NH2)-CH3, CH2CH2CH2CH2NH2, CH2CH2C(H)(NH2)CH3, H)(NH2)CH2CH2CH3, CH2-C(CH3)2-NH2, QCHjbCH^, CH^CH3b, CHSHCH^CH3^, CH2CH2CHN(CH3)2, C(CH3CHCH3)2, CHCHCHCH3CHCHCH3, C(H)(CH3) -CHN(CH3)2, SCHSHCHSNzb)CH3, CH2CH2CH2CH2N(CH3)2,

C(H)Sch(CH3)2)CH2CHSCH3, CH2-C(CH3)2-N(CH3)2, CSN3^CHS^CH3E

In a preferred embodiment, at least one of R ⁹ and R ¹⁰ is H.

In a preferred embodiment, n is 0. In another preferred embodiment, n is 1. In yet another preferred embodiment, n is 2. More preferably, n is 1 or 2, most preferably 1.

In a specific preferred embodiment, R ¹¹ is F; C1; Br; I; CN; C _1-6 alkyl or O-C _1-6 alkyl;

preferably wherein C _1-6 alkyl is at each occurrence independently unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F and CF3.

More preferably R ¹¹ is F; Cl; Br; I; CN; CH ₃ , CH ₂ CH ₃ , O-CH ₃ or OCH ₂ CH ₃ .

In a specific preferred embodiment, R ¹¹ is F; Cl; Br; I; CN; C _1-6 alkyl or O-C ₁ _ ₆ alkyl; and/or n is 0, 1 or 2.

In a preferred embodiment, the compound according to the present invention is selected from the group consisting of:

- 10 043276

7,9-Difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3а]quinoxaline

8-(1-Cyclopropyl-6-fluoro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a] quinoxaline

7,9-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a] quinoxaline

1 -[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6fluoro-1 H-indole -1 -yl] -ethanone

7,9-Difluoro-8-(6-fluoro-2-methyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a] quinoxaline

4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro 1H-indole-2 -carbonitrile

7,9-Difluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

7,9-Difluoro-1,4,4-trimethyl-8-[3-(trifluoromethyl)-1H-indol-7-yl]-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

1-Ethyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

7-(1-Ethyl-7,9-difluoro-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)lH-indole-3-carbonitrile

1-Ethyl-7,9-difluoro-4,4-dimethyl-8-(3-prop-1-ynyl-1H-indol-7-yl)-5H[1,2,4]triazolo[4,3- a] quinoxaline

1 -Ethyl-7,9-difluoro-8-(5-fluoro-1H-indol-7-yl)-4,4-dimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

- 11 043276

7-(1-Ethyl-7,9-difluoro-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-5fluoro-1 H-indol- 3-carbonitrile

1-Ethyl-7,9-difluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-4,4-dimethyl-5H[ 1,2,4]triazolo[ 4,3-a]quinoxaline

7-(1-Ethyl-7,9-difluoro-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-5methyl-1 H-indol- 3-carbonitrile

8-[1-(Ethylsulfonyl)-b-fluoro-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3- a] quinoxaline

8-[1-(Cyclopropylsulfonyl)-6-fluoro-1H-indol-4-yl]-7,9-difluoro-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3-a ]quinoxaline

1 -[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 1Nind ol-1-yl ]-ethanone

7,9-Difluoro-8-[6-fluoro-1-(2,2,2-trifluoro-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7,9-Difluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-[5-fluoro-3-(2,2,2-trifluoro-ethyl)-1H-indol-7-yl]-1,4,4,9-tetramethyl-5H[1,2, 4]triazolo[4,3-a]quinoxaline

7-Fluoro-1,4,4,9-tetramethyl-8- [3 - (2,2,2-trifluoro-ethyl) -1 H-indol-7-yl] -5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-(1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

7-Fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3а]quinoxaline

8-(1-Cyclopropyl-1 H-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-1,4,4,9-tetramethyl-8-(3-prop-1-ynyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

7-Fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-9-(trifluoromethyl)-5H- 12 043276

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

9-Chloro-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-(5-fluoro-3-methyl-1 H-indol-7-yl)-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

8-(3-Cyclopropyl-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a] quinoxaline

1-Ethyl-7-fluoro-8-(6-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3а]quinoxaline

8-[1-(Cyclopropyl-methyl)-6-fluoro-1H-indol-4-yl]-1-ethyl-7-fluoro-4,4,9-trimethyl5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

1 -Ethyl-7-fluoro-8- [6-fluoro-1 - (2-methoxy-ethyl) -1 H-indol-4-yl] -4,4,9-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo [4,3-a]quinoxaline

4-[7-(7-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nind ol-3-yl ]-2-methyl-but-3-in-2-ol

[3-[7-(7-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nind ol-3 - yl]-1,1-d imethyl-prop-2-ynyl]-amine

9-Chloro-8-(3-cyclobutyl-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

7-Fluoro-1,4,4,9-tetramethyl-8-(3-tetrahydro-furan-3 -yl-1 H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

8-(3-Ethyl-5-fluoro-1H-indol-7-yl)-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

2-[4-(9-Ethyl-7-fluoro-1,4,4-trimethyl-5Н-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)-6fluoro-1Н -ind ol-1 -yl]-ethanol

- 13 043276

2-[4-(9-Ethyl-7-fluoro-1,4,4-trimethyl-5Н-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)-6fluoro-1Н -indazol-1 -yl]-ethanol

9-Ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

9-Ethyl-7-fluoro-8-(5-fluoro-3-methyl-1 H-indol-7-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

9-Ethyl-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

9-Ethyl-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

9-Ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3-a ]quinoxaline

1-Benzyl-7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

1-Benzyl-7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

1-But-2-ynyl-7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

1-But-2-ynyl-7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7,9-Difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-1-(pyridin-4-ylmethyl)-5H-[ 1,2,4 ]triazolo[4,3-a]quinoxaline

7,9-Difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-1-(pyridin-4-yl-methyl)-5H[1,2,4]triazolo[ 4,3-a]quinoxaline

7,9-Difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-1-(pyridin-3-ylmethyl)-5H-[ 1,2,4 ]triazolo[4,3-a]quinoxaline

7,9-Difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-1-(pyridin-2-ylmethyl)-5H-[ 1,2,4 ]triazolo[4,3-a]quinoxaline

7,9-Difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-1-(pyridin-2-yl-methyl)-5H- 14 043276

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-(5-fluoro-3-prop-1-ynyl-1 H-indol-7-yl)-1-(methoxymethyl)-4,4,9trimethyl-5H-[ 1,2,4 ]triazolo[4,3-a]quinoxaline

[7-Fluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxalin-1-yl]-MeOH

1-[7-Fluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxalin-1-yl]-ethanol

7-Fluoro-8-(5-fluoro-3-prop-1-ynyl-1 H-indol-7-yl)-1-(2-methoxy-ethyl)-4,4,9trimethyl-5H-[1 ,2,4]triazolo[4,3-a]quinoxaline

1-(Cyclopropyl-methyl)-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

1-Cyclopropyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

8-(3-Cyclopropyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

8-(6-Fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-7(trifluoromethyl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline

1,4,4,9-Tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-7-(trifluoromethyl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

9-Chloro-8-(3-cyclopropyl-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

7-Fluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

8-(3-Cyclopropyl-5-fluoro-1 H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

8-(1-Cyclopropyl-6-fluoro-1 H-indol-4-yl)-7-fluoro-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

7-[7-Fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 a]quinoxalin-8-yl]-1H-indol-3- carbonitrile

- 15 043276

200 7,9-Difluoro-8-[ 1 -(isopropylsulfonyl)- 1H-indol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

201 8-[1-(Cyclopentylsulfonyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

202 8-[ 1 -(Cyclopropyl-methyl)- 1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

203 7,9-Difluoro-1,4,4-trimethyl-8-[1-(tetrahydro-pyran-4-ylsulfonyl)-1H-indol-4yl]-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

204 7,9-Difluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

205 8-[1-(Cyclopropylsulfonyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

207 7,9-Difluoro-1,4,4-trimethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

208 7,9-Difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

210 8-[1-(Cyclopropylmethylsulfonyl)-1H-indol-4-yl]-7,9-d iftoro-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3 -a]quinoxaline

212 2-[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)-1Nindol-1-yl ]-M,M-d imethyl-acetamide

213 1 -[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 1Nind ol-1 - yl]-2-methoxy-ethanone

214 7,9-Difluoro-8-(5-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

219 3-[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)-1Nindol-1-yl ]-propionic acid methyl ester

221 7,9-Difluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

222 7,9-Difluoro-1,4,4-trimethyl-8-(2-methyl-2H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3 - 16 043276

a] quinoxaline

223 1 -[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 1Nind ol-1 - yl]-2-dimethylamino-ethanone

224 7,9-Difluoro-8-(5-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

225 7,9-Difluoro-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl]-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

228 T4-[2-[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)1H-indole -1-yl]-ethyl]-carbamic acid tert-butyl ester

229 Т4-[2-[4-(7,9-Difluoro-1,4,4-trimethyl-5Н-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)1 Н- indol-1-yl]-ethyl]-2,2-d iftoro-propionamide

230 2-[4-(7,9-Difluoro-1,4,4-trimethyl-5Н-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)-1Nind ol-1 - yl]-ethylamine

232 7,9-Difluoro-8-(1H-indazol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

233 7,9-Difluoro-8-[1-(2-methoxy-ethyl)-1H-indazol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

234 8-[1-(Cyclopropylsulfonyl)-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

235 8-[1-(Cyclopropyl-methyl)-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

236 8-(1-Ethyl-1H-indazol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

237 8-(2-Ethyl-2Н-indazol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5Н-[1,2,4]triazolo[4,3a]quinoxaline

- 17 043276

240 1-Ethyl-7-fluoro-4,4,9-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

241 1-Ethyl-7-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

242 8-(1-Cyclopropyl-1H-indazol-4-yl)-1-ethyl-7-fluoro-4,4,9-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

243 8-(1-Cyclopropyl-1H-indazol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

244 1-Ethyl-7-fluoro-8-(5-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

247 1-Ethyl-7-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

248 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

249 7-Fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-9-methoxy-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

250 7-Fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-9-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4, 3-a]quinoxaline

251 9-Fluoro-8-(5-fluoro-3-methyl-1 H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

252 7-(Difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl] 5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

253 8-[1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

254 7-Chloro-9-fluoro-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl]-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

255 9-Fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-7-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4, 3-a]quinoxaline

256 9-Fluoro-8-(1H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- 18 043276

a] quinoxaline

257 9-Fluoro-7-methoxy-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl]-5H[1,2,4]triazolo[4,3-a ]quinoxaline

258 2-[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nindazol-1-yl ]-ethanol

259 7-(Difluoro-methoxy)-9-fluoro-8-[1-(2-methoxy-ethyl)-2-(trifluoromethyl)-1H-indol-4yl]-1,4,4-trimethyl-5H-[ 1,2,4]triazolo[4,3-a]quinoxaline

260 4-(7-Fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)1H-indole-1-carboxylic acid tert-butyl ester

263 9-Fluoro-7-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

264 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

266 9-Fluoro-7-methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

267 7-(Difluoro-methoxy)-9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

268 7-(Difluoro-methoxy)-9-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

269 9-Fluoro-7-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

270 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

271 7,9-Difluoro-1,4,4-trimethyl-8-[1-methylsulfonyl-2-(trifluoromethyl)-1H-indol-4yl]-5H-[1,2,4]triazolo[4,3 - a] quinoxaline

272 7-Chloro-9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

273 7-(Difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

- 19 043276

275 7-(Difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4yl)-5H-[1,2,4]triazolo[4,3 - a] quinoxaline

276 7,9-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a ]quinoxaline

277 7-Chloro-9-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

278 7-Fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

279 7-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

280 7-Chloro-9-fluoro-8-[1-(2-methoxy-ethyl)-1 H-indol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

281 7-Fluoro-9-methoxy-8-[1-(2-methoxy-ethyl)-1 H-indol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

282 7-(Difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

283 9-Fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

284 7-Chloro-9-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

285 7-Chloro-9-fluoro-1,4,4-trimethyl-8-(1-methyl-1 H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

286 7-Fluoro-8-(1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

287 7-(Difluoro-methoxy)-9-fluoro-8-[ 1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-1,4,4trimethyl-5H-[ 1.2, 4]triazolo[4,3-a]quinoxaline

288 9-Fluoro-7-methoxy-8-[1-(2-methoxy-ethyl)-1 H-indol-4-yl]-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

289 7,9-Difluoro-8-[ 1 -(2-methoxy-ethyl)-2-(trifluoromethyl)-1 H-indol-4-yl]-1,4,4- 20 043276 trimethyl-5H- [ 1,2,4]triazolo[4,3-a]quinoxaline

290 7-Chloro-9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

292 9-(Difluoro-methyl)-7-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl5H-[1,2,4] triazolo[4,3-a]quinoxaline

293 7-Chloro-9-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

294 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

295 7-(Difluoro-methyl)-9-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl5H-[1,2,4] triazolo[4,3-a]quinoxaline

296 7-(Difluoro-methyl)-9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo [4,3-a]quinoxaline

297 7-(Difluoro-methoxy)-9-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

298 7-(Difluoro-methyl)-9-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

299 1-Ethyl-7-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-4,4,9-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

302 9-(Difluoro-methyl)-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo [4,3-a]quinoxaline

306 7-(Difluoro-methyl)-9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

309 1,4,4,7,9-Pentamethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

310 7 -Methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-9(trifluoromethyl)-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

312 8-[1-Cyclopropyl-2-(trifluoromethyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3 - a] quinoxaline

- 21 043276

313 7-Chloro-8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-9-fluoro-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

314 8-[1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-9-fluoro-7-methoxy-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

315 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

317 7-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

318 7-(Difluoro-methoxy)-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)5H-[1,2,4]triazolo[4, 3-a]quinoxaline

319 9-(Difluoro-methyl)-7-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

320 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

321 9-Fluoro-1,4,4,7-tetramethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

324 8-[1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-1,4,4,7,9-pentamethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

325 7-(Difluoro-methyl)-9-fluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

327 7-Chloro-8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

328 8-(6-Fluoro-1-methylsulfonyl-1 H-indol-4-yl)-1,4,4,7,9-pentamethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

329 8-(6-Fluoro-1-methylsulfonyl-1 H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo [4,3-a]quinoxaline

330 8-[1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

331 8-[1 -(2-Methoxy-ethyl)- 1H-indol-4-yl]-1,4,4,7,9-pentamethyl-5H- 22 043276

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

332 9-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,7-tetramethyl-5H[1,2,4]triazolo[4,3 - a] quinoxaline

333 7-Chloro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a ]quinoxaline

334 7-Methoxy-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo [4,3-a]quinoxaline

335 7-(Difluoro-methoxy)-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

336 7-(Difluoro-methoxy)-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

337 9-Fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,7-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

338 7-Chloro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

339 7-Fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indazol-4-yl)-9-methoxy-1,4,4trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

341 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-1,4,4,7,9-pentamethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

342 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

343 7-(Difluoro-methyl)-9-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

344 7-Methoxy-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

345 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-7-methoxy-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

346 9-(Difluoro-methyl)-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

- 23 043276

347 7-Chloro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a ]quinoxaline

348 1 -Ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-4,4,9-trimethyl5H-[1,2,4]triazolo[4,3 - a] quinoxaline

351 7-Fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1 H-indol-4-yl]-9-methoxy-1,4,4-trimethyl5H-[1,2, 4]triazolo[4,3-a]quinoxaline

353 9-Fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1 H-indol-4-yl]-7-methoxy-1,4,4-trimethyl5H-[1,2, 4]triazolo[4,3-a]quinoxaline

354 7,9-Difluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

356 1,4,4,7,9-Pentamethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

357 7-Methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

358 7-Chloro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

359 9-Fluoro-1,4,4,7-tetramethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

360 7-(Difluoro-methoxy)-1,4,4,9-tetramethyl-8-(3-methyl-1 H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

361 7-Fluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

362 8-[1-(Ethylsulfonyl)-6-fluoro-1H-indol-4-yl]-7-fluoro-9-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4, 3-a]quinoxaline

363 7-Chloro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

364 9-Fluoro-8-(5-fluoro-3-methyl-1 H-indol-7-yl)-1,4,4,7-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

365 7-(Difluoro-methoxy)-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H- 24 043276

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

367 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

368 7-Chloro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

369 8-[1-(Ethylsulfonyl)-6-fluoro-1H-indol-4-yl]-7-methoxy-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo [4,3-a]quinoxaline

370 8-[1-(Ethylsulfonyl)-6-fluoro-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

371 8-[1-(Ethylsulfonyl)-1H-indol-4-yl]-7-methoxy-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

372 8-[1 -(Ethylsulfonyl)-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

373 8-(6-Fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,7,9-pentamethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

376 8-(6-Fluoro-1-methylsulfonyl-1H-indazol-4-yl)-7-methoxy-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

377 7-Fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

379 2-[6-Fluoro-4-(9-fluoro-7-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl)-1 N-ind ol-1-yl]-ethanol

380 2-[6-Fluoro-4-(7-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3 a]quinoxalin-8-yl)- 1 H-ind ol-1-yl]-ethanol

381 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

382 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4yl)-5H-[1,2,4]triazolo[4,3 - a] quinoxaline

383 [2-[4-(7,9-Difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nindol-1 - yl]-ethyl]-dimethylamine

- 25 043276

384 8-(1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-7-(difluoro-methoxy)-1,4,4,9-tetramethyl5H-[1,2,4] triazolo[4,3-a]quinoxaline

385 2-[4-(7-(Difluoro-methyl)-9-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3а]quinoxalin-8-yl]-6 -fluoro-1H-indol-1-yl]-ethanol

386 7-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

387 7-Methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indazol-4-yl)-9(trifluoromethyl)-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

388 1,4,4,7,9-Pentamethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

390 9-(Difluoro-methyl)-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

392 8-(1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-9-fluoro-1,4,4,7-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

393 8-(1-(2,2-Difluoro-ethyl)-1 H-indol-4-yl]-7-(difluoro-methoxy)-9-fluoro-1,4,4trimethyl-5H-[1, 2,4]triazolo(4,3-a]quinoxaline

394 7-(Difluoro-methoxy)-9-fluoro-8-[6-fluoro-1 -(2-methoxy-ethyl)- 1H-indol-4-yl]-1,4,4trimethyl-5H-[ 1, 2,4]triazolo(4,3-a]quinoxaline

395 2-[4-(7-(Difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-5H-(1,2,4]triazolo[4,3а]quinoxalin-8-yl]-6 -fluoro-1H-indol-1-yl]-ethanol

396 7-(Difluoro-methyl)-9-fluoro-8-[6-fluoro-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-1,4,4trimethyl-5H-[ 1,2,4]triazolo(4,3-a]quinoxaline

397 8-(1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-7-fluoro-9-methoxy-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

398 8-[1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl 5H-[ 1, 2,4]triazolo[4,3-a]quinoxaline

399 7-Fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

400 9-(Difluoro-methyl)-7-fluoro-8-[1-(isopropylsulfonyl)-1H-indol-4-yl]-1,4,4- 26 043276 trimethyl-5H-[ 1,2,4] triazolo[4,3-a]quinoxaline

401 8-[1-(Cyclopropylsulfonyl)-1H-indol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

402 9-(Difluoro-methyl)-7-fluoro-8-[6-fluoro-1 -(2-methoxy-ethyl)-1 H-indol-4-yl]-1,4,4trimethyl-5H-[ 1,2,4]triazolo[4,3-a]quinoxaline

403 8-(6-Fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-7(trifluoromethyloxy)-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

404 7-Chloro-9-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H[ 1,2,4 ]triazolo[4,3-a]quinoxaline

405 1,4,4,9-Tetramethyl-8-(3-methyl-1H-indol-7-yl)-7-(trifluoromethyloxy)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

406 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H[1,2,4]triazolo[4,3 -a]quinoxaline

407 8-(5-Fluoro-3-methyl-1Н-indol-7-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)5Н-[1,2,4]triazolo[4 ,3-a]quinoxaline

445 7,9-Difluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3а]quinoxaline

446 7-Fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-9(trifluoromethyl)-5H-[1,2,4]triazolo[4,3-a ]quinoxaline

447 2-[6-Fluoro-4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl ]-1 H-ind ol-1 -yl]-ethanol

448 8-[1-(Ethylsulfonyl)-b-fluoro-1 H-indazol-4-yl]-7-fluoro-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4 ]triazolo[4,3-a]quinoxaline

449 2-[6-Fluoro-4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl ]-1 H-ind azol-1 -yl]-ethanol

450 1,4,4,9-Tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

451 2-[6-Fluoro-4-(1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-а]quinoxalin-8-yl)-1Nind ol-1 - yl]-ethanol

- 27 043276

452 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

453 8-(6-Fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

454 7-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

455 8-[1-(Ethylsulfonyl)-1H-indol-4-yl]-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3 -a]quinoxaline

456 2-[4-[7-Fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl] -1 H- indol-1-yl]-ethanol

457 1,4,4,9-Tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

458 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H[1,2,4]triazolo[4,3 -a]quinoxaline

459 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

460 8-[1-(2-Methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

461 9-(Difluoro-methyl)-8-[1-(ethylsulfonyl)-1 H-indol-4-yl]-7-fluoro-1,4,4-trimethyl5H-[1,2,4]triazolo [4,3-a]quinoxaline

462 9-Cyclopropyl-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

463 9-Cyclopropyl-7-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

464 7-Fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

465 1,4,4,9-Tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-7-(trifluoromethyloxy)5H-[1,2,4]triazolo[4,3-a]quinoxaline

466 9-(Difluoro-methyl)-7-fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H- 28 043276

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

467 7-Fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

468 7-Fluoro-8-(6-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

469 8-[1-(2,2-Difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-1,4,4,9-tetramethyl-7(trifluoromethyloxy)-5H- [ 1.2 ,4]triazolo[4,3-a]quinoxaline

470 7-Fluoro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H[1,2,4]triazolo[4,3-a]quinoxaline

471 2-[6-Fluoro-4-[1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H-[1,2,4]triazolo[4,3а]quinoxalin-8-yl] -1 N-ind ol-1-yl]-ethanol

472 8-[1-(2,2-Difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4trimethyl-5H-[ 1,2,4]triazolo[4,3-a]quinoxaline

473 7-Fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-8-[6-(trifluoromethyl)-1H-indol-4-yl]5H-[1,2,4]triazolo[4,3 -a]quinoxaline

474 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

475 7-Chloro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H[1,2,4]triazolo[4,3-a]quinoxaline

476 7-Fluoro-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1 H-indol-4-yl)-9(trifluoromethyl)-5H- [1,2,4] triazolo[4,3-a]quinoxaline

477 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)5H-[1,2,4]triazolo[4,3 -a]quinoxaline

478 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1Nindol-4-yl)-5H-[1,2,4] triazolo[4,3-a]quinoxaline

479 4-[7-Fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 a]quinoxalin-8-yl]-1H-indol-6 -carbonitrile

480 8-[6-Fluoro-1 -(2-methoxy-ethyl)- 1H-indazol-4-yl]-1,4,4,9-tetramethyl-7(trifluoromethyloxy)-5H- [ 1.2, 4]triazolo[4,3-a]quinoxaline

- 29 043276

481 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methyl-1 H-indol-4-yl)-5H[1,2,4]triazolo[4, 3-a]quinoxaline

482 8-(3-Cyclopropyl-5-fluoro-1 H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

483 8-(3-Cyclopropyl-5-fluoro-1 H-indol-7-yl)-7-fluoro-9-methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3-a]quinoxaline

484 7-Fluoro-8-(7-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

485 7-Chloro-8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a ]quinoxaline

486 7-Fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

487 7-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

488 7-Chloro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

489 8-[1-(2,2-Difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H[ 1,2,4 ]triazolo[4,3-a]quinoxaline

490 7-Fluoro-8-(1H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

491 7-Chloro-1,4,4,9-tetramethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a ]quinoxaline

492 7,9-Difluoro-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

493 7-Fluoro-1,4,4,9-tetramethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a ]quinoxaline

494 4-(7-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nindole-6-carbonitrile

495 8-[1-(Cyclopropylmethylsulfonyl)-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl- 30 043276

5H-[1,2,4]triazolo[4,3-a]quinoxaline

496 9-(Difluoro-methyl)-7-fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

497 7,9-Difluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-

a) quinoxaline

498 1,4,4-Trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

499 8-(6-Fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3-a ]quinoxaline

500 8-[1-(2,2-Difluoro-ethyl)-1H-indol-4-yl]-7-methoxy-1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4 ]triazolo[4,3-a]quinoxaline

501 7,9-Difluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

502 8-[1-(Cyclopropylmethylsulfonyl)-1H-indol-4-yl]-9-(difluoro-methyl)-7-fluoro1,4,4-trimethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

503 1,4,4-Trimethyl-8-(3-methyl-1H-indol-7-yl)-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

504 7-Fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

505 7-Fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

506 7-Chloro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

507 8-(5-Fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

508 7-Chloro-8-[1-(2,2-difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-9-fluoro-1,4,4-trimethyl5H-[1,2, 4]triazolo[4,3-a]quinoxaline

509 7-Methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3-a]quinoxaline

- 31 043276

510 7-Fluoro-8-(1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

511 8-(6-Chloro-1H-indol-4-yl)-7,9-d iftoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

512 9-(Difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(7-methyl-1-methylsulfonyl-1Nindol-4-yl)-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

513 8-(6-Chloro-1H-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

514 8-(1-Cyclopropyl-1H-indol-4-yl)-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

515 9-(Difluoro-methyl)-7-fluoro-8-(5-fluoro-1 H-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4 ,3-a]quinoxaline

516 7-Fluoro-8-(5-fluoro-1 H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3 -a]quinoxaline

517 8-(6-Fluoro-1-methyl-1 H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo [4,3-a]quinoxaline

518 7-Fluoro-8-(6-fluoro-1-methyl-1 H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

519 7-Chloro-8-(6-fluoro-1-methyl-1 H-indol-4-yl)-1,4,4,9-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

520 9-Fluoro-8-(6-fluoro-1-methyl-1 H-indol-4-yl)-1,4,4,7-tetramethyl-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

521 9-(Difluoro-methyl)-7-fluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo [4,3-a]quinoxaline

522 8-(6-Fluoro-1-methyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

[ 1,2,4]tr iazolo[4,3 -a]quinoxaline

523 8-(1-Cyclopropyl-1 H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3 -a]quinoxaline

524 7-Fluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-32 043276

a] quinoxaline

525 8-(7-Chloro-1-methylsulfonyl-1H-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a ]quinoxaline

526 9-(Difluoro-methyl)-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3 - a] quinoxaline

527 9-(Difluoromethyl)-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

528 9-(Difluoromethyl)-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

529 8-(7-Chloro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

530 8-(7-Chloro-1H-indol-4-yl)-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3-a ]quinoxaline

531 4-[7-Fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 a]quinoxalin-8-yl]-1 H-indol -7-carbonitr yl

532 7-Fluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[4 ,3-a]quinoxaline

533 7-Chloro-8-(1-cyclopropyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

534 4-(7-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nindole-7-carbonitrile

535 7-Fluoro-8-(7-fluoro-1 H-indazol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3- a] quinoxaline

536 7-Fluoro-8-(6-methoxy-1-methylsulfonyl-1 H-indol-4-yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H-[1,2,4] triazolo[4,3-a]quinoxaline

537 7-Fluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a ]quinoxaline in the form of a free compound or a physiologically acceptable salt thereof.

The compounds of the present invention may be synthesized by standard organic chemistry reactions known to those skilled in the art, or by the method described herein (cf. Reaction Scheme 1 below), or similar. The reaction conditions of the synthesis routes described herein are known to the person skilled in the art and for some cases are shown in the examples described herein.

- 33 043276

Reaction Scheme 1

The substituted indole/indazole moiety in compounds of formula (VII) can be introduced by subjecting the compound of formula (IV) to a metal-catalyzed C-C cross-coupling reaction. Metal-catalyzed C-C cross-coupling reactions are known in the art (cf. Metal Catalyzed CrossCoupling Reactions and More, Volume 3 Set Wiley, 2014; Angew. Chem. Int. Ed., 2012, 51, 5062-5085). Favorable C-C cross-coupling reactions are palladium-catalyzed cross-coupling reactions (cf. Angew. Chem., 2005, 117, 4516-4563). Triazole cyclization of compound (II) gives compounds of general formula (III). The formation of triazole on quinoxalines is known in the art (cf. Heterocycles, 1992, 34, 771-780; Biological and Pharmaceutical Bulletin, 2005, 28, 1216-1220). Electrophilic aromatic bromination of compound (III) gives compound (IV). Aromatic bromination reactions are well known (cf. Science of Synthesis, Compounds with One Saturated CarbonHeteroatom Bond, Volume 35, Houben-Weyl, 2007). If desired, the compound of formula (II) may be brominated to compound (V), which may undergo a metal-catalyzed cross-coupling reaction to give compound (VI). The formation of the triazole leads to an alternative route for the preparation of compounds of general formula (VII). Copper-mediated quinoxaline cyclization of compound (I) to compound (II) is known in the art (cf. Adv. Synth. Catal., 2010, 352, 2531-2537). Compounds of formula (I) are commercially available or can be prepared by methods known in the art.

Compounds in accordance with the present invention can be obtained by the method described in this document, or in a similar manner.

In a preferred embodiment, the compounds of the present invention are glucocorticoid receptor modulators. In the sense of the present invention, the term selective glucocorticoid receptor modulator preferably means that the respective compound in a cell-target binding assay for glucocorticoid receptor agonistic or antagonistic activity exhibits an EC50 or IC50 value for the glucocorticoid receptor of not more than 15 μM (10-10 ^-6 mol /l) or not more than 10 µM; more preferably not more than 1 μm; even more preferably not more than 500 nm (10 ^-9 mol/l); even more preferably not more than 300 nm; even more preferably not more than 100 nM; most preferably not more than 10 nM; and in particular not more than 1 nM.

One skilled in the art will know how to test compounds for modulation (agonistic or antagonistic) activity of the glucocorticoid receptor. Preferred target binding assays for testing compounds for their agonist or antagonist activity (EC ₅₀ , IC ₅₀ ) at the glucocorticoid receptor are described herein below:

Cellular glucocorticoid receptor assays.

Potential selective glucocorticoid receptor modulators of the present invention can be tested for modulation of glucocorticoid receptor activity using cellular assays. These assays use the Chinese Hamster Ovary (CHO) cell line, which contains fragments of the glucocorticoid receptor as well as fusion proteins. The glucocorticoid receptor fragments used are capable of binding to a ligand (eg, beclomethasone) to identify molecules that compete for binding to glucocorticoid ligands.

- 34 043276th receptor. More specifically, the glucocorticoid receptor ligand-binding domain is fused to the DNA-binding domain (DBD) of the GAL4 transcription factor (GAL4 DBD-GR) and stably integrated into a CHO cell line containing the GAL4-UAS-luciferase reporter construct. To identify selective glucocorticoid receptor modulators, the reporter cell line is incubated with the molecules using an 8-point semi-log compound dilution curve for several hours. After cell lysis, the luminescence generated by luciferase after addition of the substrate is detected and EC ₅₀ or IC ₅₀ values can be calculated. The involvement of molecules that induce gene expression through binding of the glucocortoid receptor to DNA leads to the expression of the luciferase gene under the control of the GAL4 DBD-GR fusion protein and, consequently, to a dose-dependent increase in the luminescence signal. Binding of molecules that suppress beclomethasone-induced luciferase gene expression under the control of the GAL4 DBDGR fusion protein results in a dose-dependent decrease in the luminescence signal.

In a preferred embodiment, a compound of the present invention in a cell target binding assay for glucocorticoid receptor agonist or antagonist activity exhibits an EC ₅₀ or IC ₅₀ value for the glucocorticoid receptor of not more than 1 μM (10 ^-6 mol/l); more preferably not more than 500 nm (10 ^-9 mol/l); even more preferably not more than 300 nm; even more preferably not more than 100 nM; most preferably not more than 50 nM; and in particular not more than 10 nM or not more than 1 nM.

In a preferred embodiment, a compound of the present invention in a cell target binding assay for glucocorticoid receptor agonist or antagonist activity exhibits a glucocorticoid receptor EC50 or IC50 value ranging from 0.1 nM (10 ^-9 mol/l) to 1000 nM; more preferably 1 to 800 nM; even more preferably 1 to 500 nM; even more preferably 1 to 300 nM; most preferably 1 to 100 nM; and in particular from 1 to 80 nM.

Preferably, the compounds of the present invention are useful as selective glucocorticoid receptor modulators.

Thus, the compounds according to the present invention are preferably useful in the treatment or prevention in vivo of diseases associated with the involvement of the glucocorticoid receptor.

Thus, the present invention also relates to a compound according to the present invention for use in modulating glucocorticoid receptor activity.

Thus, another aspect of the present invention relates to a compound according to the present invention for use in the treatment and/or prevention of a disorder mediated at least in part by a glucocorticoid receptor. Another aspect of the present invention relates to a method of treating a disorder mediated at least in part by a glucocorticoid receptor, the method comprising administering a therapeutically effective amount of a compound of the present invention to a subject in need thereof, preferably a human.

An additional aspect of the invention relates to the use of the compounds in accordance with the present invention as a medicine.

Another aspect of the present invention relates to a dosage form containing a compound in accordance with the present invention. Preferably the dosage form contains a compound in accordance with the present invention and one or more pharmaceutical excipients, such as physiologically acceptable carriers, additives and/or excipients; and optionally one or more additional pharmacologically active ingredients. Examples of suitable physiologically acceptable carriers, additives and/or excipients are fillers, solvents, diluents, colorants and/or binders. Such substances are known to the person skilled in the art (see H. P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, Editio Cantor Aulendoff).

The dosage form according to the present invention is preferably for systemic, topical or local administration, preferably for oral administration. Thus, the dosage form may be in liquid, semi-solid or solid form, for example, in the form of injections, drops, juices, syrups, sprays, suspensions, tablets, patches, films, capsules, patches, suppositories, ointments, creams, lotions. , gels, emulsions, aerosols, or in a form consisting of a plurality of solid particles, for example, in the form of pellets or granules, if appropriate compressed into tablets, decanted into capsules or suspended in a liquid, and can also be administered as such.

Dosage form in accordance with the present invention is preferably obtained using conventional methods, devices, methods and processes known in the art. The amount of a compound of the present invention to be administered to a patient may vary and depends, for example, on the weight or age of the patient, as well as the route of administration, the indication and the severity of the disease. Preferably from 0.001 to 100 mg/kg, more preferably from

- 35 043276

0.05 to 75 mg/kg, most preferably 0.05 to 50 mg of a compound of the present invention is administered per kg of the patient's body weight.

It is believed that the glucocorticoid receptor has the potential to modify various diseases or disorders in mammals such as humans. These include, in particular, inflammatory diseases.

Another aspect of the present invention relates to a compound according to the present invention for use in the treatment and/or prevention of pain and/or inflammation; more preferably inflammatory pain.

An additional aspect of the present invention relates to a method for the treatment of pain and/or inflammation; more preferably inflammatory pain.

Examples

The following abbreviations are used in descriptions of experiments:

AcOH = acetic acid;

Ac = acetyl group;

Attaphos=bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(I);

Ar = argon;

BISPIN (or Bis-Pin) = bis(pinacolato)diboron;

dba=dibenzylideneacetone;

DCM = dichloromethane;

DIPEA=N,N-diisopropylethylamine;

DMADMF = N,N-dimethylformamide dimethyl acetal;

DMAP=4-(dimethylamino)pyridine;

DMF = N,N-dimethylformamide;

DMSO = dimethyl sulfoxide;

dppf = 1,1'-bis-(diphenylphosphanyl)ferrocene;

EtOAc = ethyl acetate;

EtOH = ethanol;

h = hour;

LDA = lithium diisopropylamide;

LiHMDS=lithium bis(trimethylsilyl)amide;

MeOH = methanol;

min = minute;

n-BuLi = n-butyllithium;

room pace. = room temperature;

Rt = retention time;

tert = tertiary;

TEA = triethylamine;

THF = tetrahydrofuran;

p-TSA = p-toluenesulfonic acid;

TMSCl = trimethylsilyl chloride;

X-Phos = 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-1)

i) DMADMF/dioxai>'bp. with reverse, cold. F shtrrshptshgn '' NO.- AcOH / powder Fe / bp. with * turn, cold.

Stage-1

+-° O -./ । c-c' g r-o b-r

KOAS/

Pd ₂ dba ₃ in

'O „Przhoettashe junction A-1

Stage- 2:

Step 1 To a stirred solution of 2-bromo-4-fluoro-6-nitrotoluene (4.69 g, 20 mmol, 1 eq.) in 1,4-dioxane (25 mL) was slowly added N,N-dimethylformamide dimethyl acetal (13 .3 ml, 100 mmol, 5 eq.), pyrrolidine (1.47 ml, 20 mmol, 1 eq.). The reaction mixture was then stirred for 18 h at 100°C. The reaction mixture was concentrated to give a dark residue. To this residue was added AcOH (30 ml), iron powder (11 g, 200 mmol, 10 eq.), and then the reaction mixture was refluxed for 1 h. The reaction mixture was then cooled to room. temp., and then filtered through a layer of celite. The filtrate was neutralized with 50% sodium hydroxide solution and then extracted with EtOAc (2x100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude material, which was purified by column chromatography to give 4-bromo-6-fluoro-1H-indole (1 .3 g

- 36 043276

30%) as a brown liquid.

Step 2: To a stirred suspension of 4-bromo-6-fluoro-1H-indole (1.1 g, 5.1 mmol, 1 eq.), bis(pinacolato)diboron (2.6 g, 10.2 mmol, 2 eq.), potassium acetate (2.0 g, 20.4 mmol, 4 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. Pd ₂ (dba) ₃ (0.07 g, 0.07 mmol. 0.015 eq.), tricyclohexylphosphine (0.102 g, 0.36 mmol, 0.07 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was then stirred for 14 h at 110°C. The reaction mixture was then cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Hindole (1, 1 g, 82%) as a light yellow solid.

Synthesis of 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-2)

Step 1 Sodium hydride (60%, 0.07 g, 1 .68 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 min at room temperature. pace. Methanesulfonyl chloride (0.114 ml, 1.26 mmol, 1.5 eq.) was then added to the reaction mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature. pace. The reaction mixture was diluted with EtOAc (50 ml). The combined organic layers were washed with water (5x10 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indole (0.1 g, 41%) as a white solid with a metallic tint.

Step 2. To a stirred suspension of 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indole (1.2 g, 3.53 mmol, 1 eq.) in 1,4-dioxane (20 ml) was added bis -pinacolatedibor (1.79 g, 7.06 mmol, 2 eq.), potassium acetate (1.39 g, 10.62 mmol, 4 eq.), and the mixture was deoxygenated with Ar for 10 minutes. Pd ₂ (dba) ₃ (0.048 g, 0.052 mmol, 0.015 eq.), tricyclohexylphosphine (0.071 g, 0.25 mmol, 0.07 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was stirred for 14 h at 110°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude product, which was purified by column chromatography to give 6-fluoro-1-(methylsulfonyl)-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (1.0 g, 80%) as a light yellow solid.

Synthesis of 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolαn-2-yl)-1H-indole (intermediate A-3)

8g

SOiPh

PhSOjCI

Steel-t B' .GF

Mi!

Verse-2

pen n/axn

60°C

Sydney-w

KSAs/

1-: ¹¹ :

Stage-4

Step 1 To a stirred solution of 4-bromo-6-fluoroindole (3.4 g, 15.88 mmol, 1 eq.) in THF (80 mL) was added sodium hydride (60% suspension) (0.95 g, 23 .8 mmol, 1.5 equiv.) at 0°C. The reaction mixture was stirred for 30 min at room temperature. pace. p-Toluenesulfonyl chloride (3.36 g, 19.06 mmol, 1.2 eq.) was then added to the reaction mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature. pace. The reaction mixture was quenched with ice (20 g). Separated the organic layer, and

- 37 043276 the aqueous layer was extracted with EtOAc (2x30 ml). The combined organic layer was washed with brine (50 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give 4-bromo-6-fluoro-1(phenylsulfonyl)-1H-indole ( 2.1 g, 38%) as a white solid.

Step 2 To a stirred solution of 4-bromo-6-fluoro-1-(phenylsulfonyl)-1H-indole (2.0 g, 5.43 mmol, 1 eq.) in THF (26 mL) was added LDA (11 .96 ml, 11.96 mmol, 2.2 eq.) at 0°C. The reaction mixture was then stirred for 20 min at 0°C. Methyl iodide (1.96 g, 11.96 mmol, 2.2 eq.) was then added to the reaction mixture and stirred for 16 hours at room temperature. pace. The reaction mixture was quenched by adding saturated ammonium chloride solution (30 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (2x50 ml). The combined organic layer was washed with brine (50 ml), dried over Na2SO4, concentrated under reduced pressure to give the crude product, which was purified by column chromatography to give 4-bromo-6-fluoro-2methyl-1-(phenylsulfonyl)-1H-indole ( 1.8 g, 90%) as a white solid.

Step 3 To a stirred solution of 4-bromo-6-fluoro-2-methyl-1-(phenylsulfonyl)-1H-indole (0.2 g, 0.53 mmol, 1 eq.) in THF, MeOH, and water ( 2 ml, 1 ml, 0.5 ml) was added sodium hydroxide (0.08 g, 2.11 mmol, 4 eq.). The reaction mixture was then stirred for 4 hours at room temperature. pace. The solvents were evaporated and water was added to the residue and a precipitate formed which was collected by filtration and dried in vacuo to give a solution of 4-bromo-6-fluoro-2-methyl-1H-indole (0.1 g, 83%) as a white solid.

Step 4 Into a stirred suspension of 4-bromo-6-fluoro-2-methyl-1H-indole (0.5 g, 2.19 mmol, 1 eq.), bis(pinacolato)diboron (0.67 g, 4. 39 mmol, 2 eq.), potassium acetate (0.86 g, 8.8 mmol, 4 eq.) in 1,4dioxane (20 ml) was deoxygenated with Ar for 10 min. Pd ₂ (dba) ₃ (0.11 g, 1.09 mmol. 0.05 eq.), tricyclohexylphosphine (0.05 g, 0.17 mmol, 0.08 eq.) was then added to the reaction mixture and again deoxygenated Ar for 10 min. The reaction mixture was then stirred for 14 h at 110°C. The reaction mixture was then cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography to give 6-fluoro-2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H- indole (0.4 g, 66%) as a light yellow solid.

Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carbonitrile (intermediate A-4)

Vg.

O

".ABOUT

MOM Xylene?

I>d ₂ ;dba I'PiCyj;

dizhsash' kip. with reverse hippod.

Stjia-Z

Step 1 To a stirred solution of 2-bromo-4-fluoro-benzaldehyde (0.6 g, 2.95 mmol, 1 eq.) in MeOH (5 mL) was added methyl azidoacetate (1.35 g, 11.22 mmol, 4 equiv.), cooled to -15°C. Then 25% NaOMe (2.7 ml, 11.82 mmol, 4 eq.) was added and the mixture was stirred for 4 h at this temperature. Then the reaction mixture was poured onto ice, the resulting solid was filtered and dried. Xylene was added to this solid and heated to reflux for 16 hours. The reaction mass was then evaporated and the crude product taken up in EtOAc (20 ml), washed with brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography to give methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate (0.35 g, 41%) as a white solid.

Step 2 To a stirred solution of methyl 4-bromo-6-fluoro-1H-indole-2-carboxylate (3 g, 11.03 mmol, 1 eq) were added THF (8 ml), MeOH (4 ml), H ₂ O (4 ml) followed by the addition of LiOH (1.3 g, 33.08 mmol, 3 equiv.) and stirred for 16 h at room. pace. The reaction mass was then evaporated and the crude material was taken up in H ₂ O and acidified with 2N HCl and extracted with EtOAc (2x50 ml), washed with H ₂ O (20 ml), brine (20 ml), dried over Na ₂ SO ₄ and concentrated with obtaining 4-bromo-6-fluoro-1H-indole-2-carboxylic acid (1.2 g, 43%) as a white solid with a metallic tint.

Step 3. To a stirred solution of 4-bromo-6-fluoro-III-indole-2-carboxylic acid (1 g, 3.87

- 38 043276 mmol, 1 eq.) in DCM (20 ml) was added oxalyl chloride (0.6 ml, 7.75 mmol, 2 eq.) at 0°C and stirred for 2 h. The solvent was then evaporated under N2 atmosphere, the crude material was cooled to 0°C, and then added aq. NH ₃ solution, and the mixture was stirred for 20 minutes. Then the reaction mass was extracted with EtOAc (2x30 ml), washed with saline (20 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography to give 4-bromo-6-fluoro-1H-indole-2-carboxamide (0.5 g, 50%) as a white solid.

Step 4 POCl ₃ (0.27 ml , 2.91 mmol, 5 eq.), heated to boiling for 3 h. The solvent was then evaporated and the crude product was cooled and basified with sat. NaHCO ₃ solution and extracted with EtOAc (2x15 ml), washed with H2O (10 ml), brine (10 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography to give 4-bromo-6-fluoro-1H-indole-2-carbonitrile (0.08 g, 58%) as a sticky mass.

Step 5 To a stirred solution of 4-bromo-6-fluoro-1H-indole-2-carbonitrile (0.08 g, 0.33 mmol, 1 eq.) in 1,4-dioxane was added KOAc (0.07 g, 0.67 mmol, 2 eq.), bispinacolate diboron (0.17 g, 0.67 mmol, 2 eq.), degassed with Ar for 10 min. Then Pd ₂ (dba) ₃ (0.03 g, 0.03 mmol, 0.1 eq.), P(Cy) ₃ (0.01 g, 0.03 mmol, 0.1 eq.), mixture heated to boiling for 16 h. Then the reaction mass was filtered through a pad of celite, washed with EtOAc, the filtrate was washed with H ₂ O (10 ml), brine (10 ml), dried over Na ₂ SO ₄ and concentrated to obtain crude 6-fluoro -4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carbonitrile (0.08 g) which was used in the next step without further purification.

Synthesis of 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-7)

Step 1 To a solution of 2-bromo-4-methyl-1-nitrobenzene (1.0 g, 4.63 mmol, 1 eq.) in THF (30 ml) was added vinylmagnesium bromide (18.5 ml, 18.5 mmol, 4 eq., 1.0 M solution in THF) at -60° C. under nitrogen. The reaction mixture was then stirred at the same temperature for 4 hours. The reaction mixture was quenched with sat. ammonium chloride solution -60°C Then the resulting mixture was extracted

EtOAc (2x50 ml), washed with brine and concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 7bromo-5-methyl-1H-indoleα (0.5 g, 52%) as a thick yellow liquid .

Step 2 To a solution of 7-bromo-5-methyl-1H-indole (0.5 g, 2.38 mmol, 1 eq.) in 1,4-dioxane (10 ml) was added KOAc (0.932 g, 9.52 mmol, 4 eq.), bis-pinacolatodiboron (1.2 g, 4.76 mmol, 2 eq.), the reaction mixture was deoxygenated with Ar for 15 min.

Then Pd ₂ dba ₃ (0.032 g, 0.0375 mmol, 0.015 eq.), tricyclohexylphosphine (0.48 g, 0.171 mmol, 0.072 eq.) was added and the mixture was deoxygenated with Ar for 10 min. The reaction mixture was refluxed for 16 hours Then the reaction mixture was cooled to room. pace. and filtered through celite and concentrated under reduced pressure. The concentrated mass was purified by flash column chromatography to give 5-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indole (0.5 g, 81.7 %) as a yellow solid.

Synthesis of 1-(ethylsulfonyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-8)

F (J EtSO^OI || g ,g l THF

J ’ Sydney-1

Vg 'U- ^: s

.. Γξ __________________________

..J' KOAe/ ” l=H-| dh. Stritsitogezhsilfzhfsh

Stattia-T Intermediate A-8

Step 1: Sodium hydride (60%, 0.224 g, 9 .34 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 min at room temperature. pace. Ethansulfonyl chloride (0.604 ml, 7 mmol, 1.5 eq.) was then added to the reaction mixture at 0°C. The reaction mixture was then stirred for 2 h at room temperature. pace. The reaction mixture was diluted with EtOAc (200 ml). The combined organic layers were washed with water (5x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-1-(ethylsulfonyl)-6-fluoro-1H-indole (0.513 g, 36%) as a white solid with a metallic tint.

Step 2: A stirred suspension of 4-bromo-1-(ethylsulfonyl)-6-fluoro-1H-indole (0.51 g, 1.6 mmol, 1 eq), bis(pinacolato)diboron (0.843 g, 3.2 mmol, 2 eq.), potassium acetate (0.653 g, 6.4 mmol, 4 eq.) in 1,4-dioxane (15 ml) was deoxygenated with Ar for 10 min. Pd ₂ (dba) ₃ (0.023 g, 0.025 mmol, 0.015 eq.), tricyclohexylphosphine (0.036 g, 0.12 mmol, 0.072 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was then stirred for 14 h at 110°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-(ethylsulfonyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)- 1H-indole (0.212 g, 38%) as a white solid with a metallic tint.

Synthesis of 1-(cyclopropylsulfonyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindole (intermediate A-9)

Stage-1 Stage-2

Step 1 To a stirred solution of 4-bromo-6-fluoro-1H-indole (1.0 g, 4.67 mmol, 1 eq.) in DMF (24 ml) was added sodium hydride (60%) (0.467 g, 11 .68 mmol, 2.5 eq.) at 0°C, and the mixture was stirred at room temperature. pace. within 30 min. Cyclopropanesulfonyl chloride (1.3 g, 9.34 mmol. 2.0 eq.) was then added to the reaction mixture and stirred again for an additional 2 hours. After completion of the reaction, the reaction mixture was quenched with water and extracted with EtOAc (2x100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 4-bromo-1-(cyclopropylsulfonyl)-6 -fluoro-1H-indole (0.6 g, 40%) as a white solid.

Step 2 To a stirred solution of 4-bromo-1-(cyclopropylsulfonyl)-6-fluoro-1H-indole (0.5 g, 1.57 mmol, 1 eq) was added bis(pinacolato)diboron (0.790 g, 3. 14 mmol, 2 eq.), potassium acetate (0.46 g, 4.71 mmol, 3 eq.) in 1,4-dioxane (20 ml), and the mixture was deoxygenated with Ar for 10 min. PdCl ₂ (dppf) DCM (0.128 g, 0.157 mmol, 0.1 eq.) was then added and the mixture was stirred at 90° C. for an additional 16 h. After completion of the reaction, the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-(cyclopropylsulfonyl)-6-fluoro-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-indole (0.600 g, 76%) as a light yellow solid.

Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanone (intermediate A-10)

lo n /

I, + AcCI,

\._ /NH ______._______► ' _ ^-’1 porridge. pace.

Stage-1.

Intermediate connection Λ 10

Step 1 To a stirred solution of 4-bromo-1H-indole (0.5 g, 2.55 mmol, 1 eq.) in THF (25 ml) was added sodium hydride (60%) (0.122 g, 3.06 mmol, 1.2 equiv.) at 0°C and continued stirring at room. pace. within 30 min. Acetyl chloride (0.02 ml, 3.06 mmol, 1.2 eq.) was then added to the reaction mixture and stirred again for an additional 2 hours. The reaction mixture was quenched with water and extracted with EtOAc (2x100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 1-(4-bromo-1Nindole-1- yl)ethanone (0.55 g, 91%) as a brown liquid.

Step 2 To a stirred solution of 1-(4-bromo-1H-indol-1-yl)ethanone (0.55 g, 2.31 mmol, 1 eq), bis(pinacolato)diboron (0.707 g, 4.62 mmol, 2 eq.), potassium acetate (0.680 g, 6.93 mmol, 3 eq.) in 1.4/O O

KOAciCyjP.·

P^idnar··

Dshzhsan/v^s

- 40 043276 dioxane (20 ml) was deoxygenated with Ar for 10 min. Pd ₂ (dba) ₃ (0.106 g, 0.1155 mmol, 0.08 eq.), Cy ₃ R (0.052 g, 0.1848 mmol. 0.08 eq.) was then added to the reaction mixture and refluxed at 90°C for an additional 16 hours the Reaction mixture was cooled to room. pace. and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-(4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl )ethanone (0.600 g, 92%) as a brown liquid.

Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1H-indole (intermediate A -eleven)

Step 1 To a solution of 4-bromo-6-fluoro-1H-indole (2.0 g, 9.345 mmol, 1 eq.) in DMF (25 ml) was added Cs ₂ CO ₃ (15.18 g, 46.72 mmol , 5 eq.), 1,1,1-trifluoro-2-iodoethane (5.8 g, 28.037 mmol, 3.0 eq.) in a sealed vial. The reaction mixture was refluxed at 50° C. for 24 hours. The reaction mixture was filtered through a sintered glass filter and the filtrate was diluted with EtOAc (100 ml). The organic layer was washed with cold water (3x50 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give a crude product which was purified by flash column chromatography to give a mixture which was further purified by preparative HPLC to give 4-bromo-6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indoleα (0.400 g, 14%) as a white solid with a metallic tint.

Step 2: A stirred solution of 4-bromo-6-fluoro-1-(2,2,2-trifluoroethyl)-III-indole (0.450 g, 1.52 mmol, 1 eq.), bis(pinacolato)diboron (0.461 g , 1.824 mmol, 1.2 eq.), potassium acetate (0.446 g, 4.56 mmol, 3 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. PdCl ₂ (dppf)·DCM (0.124 g, 0.152 mmol. 0.1 eq.) was then added to the reaction mixture and stirred at 90° C. for an additional 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give crude 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1-(2,2,2-trifluoroethyl)-1H- indole, which was used in the next step without further purification.

Synthesis of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-12)

Step 1 To a stirred solution of 4-bromo-1H-indole (1.0 g, 5.1 mmol, 1 eq.) in DMF (20 mL) was added sodium hydride (60%, 0.245 g, 10.2 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 min at room temperature. pace. Methanesulfonyl chloride (0.584 ml, 7.6 mmol, 1.5 eq.) was then added to the reaction mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature. pace. The reaction mixture was diluted with EtOAc (100 ml). The combined organic layers were washed with water (5x20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-1-(methylsulfonyl)-1H-indole (0.532 g, 38%) as a white solid with a metallic tint.

Step 2. To a stirred suspension of 4-bromo-1-(methylsulfonyl)-1H-indole (0.36 g, 1.31 mmol, 1 eq.), bis(pinacolato)diboron (0.66 g, 2.62 mmol , 2 eq.), potassium acetate (0.57 g, 5.25 mmol, 4 eq.) in 1,4-dioxane (10 L) was deoxygenated with Ar for 10 min. Pd2(dba)3 (0.018 g, 0.019 mmol, 0.015 eq.), tricyclohexylphosphine (0.027 g, 0.094 mmol, 0.072 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was then stirred for 14 hours at 110° C. The reaction mixture was then cooled to room temperature. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole ( 0.31 g, 73%) as a white solid with a metallic tint

- 41 043276 com.

Synthesis of 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethyl)-1H-indole (intermediate A -13)

F„ ₽ ₃ С

.1 c/ · -.. C ί*Έ. :I - ‘Stage-!

KOAe.· = .. . ¹

DshzhsavTE^S

Stage-2 ^C ₃ C

Intermediate knowledgeable A-13

Step 1 To a solution of 7-bromo-5-fluoro-1H-indole (0.5 g, 2.336 mmol, 1 eq.) in DCM (25 mL) was added 2,6-di-tert-butylpyridine (0.893 g, 4.672 mmol, 2 equiv.), the mixture was stirred for 10 min at room temperature. pace. 2,2,2-Trifluoroethyl(2,4,6-trimethylphenyl)iodonium trifluoromethanesulfonate (1.45 g, 3.063 mmol, 1.3 eq) was added and the mixture was stirred for 2 hours at room temperature. pace. The solvent was evaporated to give the crude product which was purified by flash column chromatography to give 7-bromo-5-fluoro-3-(2,2,2-trifluoroethyl)-1H-indole (0.300 g, 43%) as a white solid with a metallic tint.

Step 2. A stirred solution of 7-bromo-5-fluoro-3-(2,2,2-trifluoroethyl)-1H-indole (0.9 g, 3.04 mmol, 1 eq), bis(pinacolato)diboron ( 1.53 g, 6.081 mmol, 2 eq.), potassium acetate (0.893 g, 9.121 mmol, 3 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. PdCl ₂ (dppf)·DCM (0.215 g, 0.304 mmol. 0.1 eq.) was then added to the reaction mixture and the mixture was stirred at 90° C. for an additional 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give the crude product, which was purified by flash column chromatography to give 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2 ,2,2trifluoroethyl)-1H-indole (0.600 g, 58%) as a tarry liquid.

Synthesis of 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethyl)-III-indole (intermediate A-14)

F ₃ C, ι _g

CF-Ch; hbto.-SI ,---_

G P ShVRg; 2eve'sn-O- G G]

B» a ' ⁿ

Stage-!

I.Omu FoChidppf!.· Dioyuei/EeYaS

Stage-2

Crvmvmchive information AL4

Step 1 To a solution of 7-bromo-1H-indole (0.264 g, 1.346 mmol, 1 eq.) in DCM (25 ml) was added 2,6-di-tert-butylpyridine (0.515 g, 2.694 mmol, 2 eq.) , the mixture was stirred for 10 min at room temperature. pace. 2,2,2-trifluoroethyl(2,4,6-trimethylphenyl)iodonium trifluoromethanesulfonate (1.4 g, 1.7509 mmol, 1.3 eq.) was added and stirring was continued for 2 hours at room temperature. pace. The solvent was evaporated to give a crude product which was purified by flash column chromatography to give 7-bromo-3-(2,2,2-trifluoroethyl)-1H-indole (0.300 g, 81%) as a white metallic solid.

Step 2. A stirred solution of 7-bromo-3-(2,2,2-trifluoroethyl)-1H-indole (0.15 g, 0.539 mmol, 1 eq), bis(pinacolato)diboron (273 g, 1.079 mmol, 2 eq.), potassium acetate (0.158 g, 1.617 mmol, 3 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. PdCl2(dppf) DCM (0.044 g, 0.054 mmol 0.1 eq.) was then added to the reaction mixture and stirred at 90° C. for an additional 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude product which was purified by flash column chromatography to give 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2 ,2-trifluoroethyl)-1H-indole (0.100 g, 57%) as a tarry liquid.

Synthesis of 5-fluoro-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-15)

MO ₂

F,.. ..

1-0 about /

4->- ⁱⁿ '%

7-0 pg

Vg

THF

Stage-1

-G;

n

KCAc.-Fd^uaiy

Su .R/Dpskgan ^c ?0 ^J <:

Stage-2

IN.

ABOUT' '

Przeyagunminve information D-15

Stage 1. To a solution of 2-bromo-4-fluoro-1-nitrobenzene (0.5 g, 2.27 mmol, 1 eq.) in THF (20 ml) was added (E)-prop-1-en-1- ylmagnesium bromide (0.5 M in THF) (13.6 ml, 6.818 mmol, 3 equiv.) at -60°C under nitrogen atmosphere. The reaction mixture was then stirred at the same temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution at -60°C. flash chromatography to give 7-bromo-5-fluoro-3-methyl-1H-indole (0.3 g, 58%) as a thick yellow liquid.

Step 2 To a solution of 7-bromo-5-fluoro-3-methyl-1H-indoleα (0.8 g, 3.669 mmol, 1 eq.) in 1,4-dioxane (15.0 ml) was added KOAC (1, 43 g, 14.67 mmol, 4 eq.), bispinacolatodibor (1.12 g, 7.33 mmol, 2 eq.). The solution was degassed with Ar for 20 min followed by the addition of Pd ₂ (dba) ₃ (0.16 g, 0.183 mmol, 0.05 eq.), Cy ₃ P (0.082 g, 0.293 mmol, 0.08 eq.). The reaction mixture was stirred for 16 hours. After completion of the reaction (the progress of the reaction was monitored by TLC), the solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give 5-fluoro-3-methyl-7-(4, 4,5,5-tetramethyl-1,3,2-dioxαborolαn-2-yl)-1H-indolα (0.7 g, 70%) as a brown solid.

Synthesis of 3-cyclopropyl-5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-16)

CONL _g

---eleven

DMF Ύ' Ή i Jr

Stage-1

LHMOS/ = urine

TTF

5g

Stzdnya-2 g> .. ^?n p. ... G ^an , Il J ............----......-......—* h, Karshryshchaf ] ·,

Xantphos Br ~O 1,4-Diyazhsan'

Stage-3

Oxalic acid F.

GivSNNS*

Stage-4

KOAe/ 1.4-Dioian g with 'ό

G-,

Pvmeitvchive yedasheshi

A-16

Step 1 To a stirred solution of 7-bromo-5-fluoroindole (7.0 g, 32.7 mmol, 1 eq.) in DMF (175 mL) was added potassium hydroxide powder (4.56 g, 81.77 mmol, 2 .5 equiv.). The reaction mixture was then stirred for 30 min at room temperature. pace. Iodine (12.46 g, 49.06 mmol, 1.5 eq.) was then added to the reaction mixture and finally stirred for 2 hours at room temperature. pace. The reaction mixture was diluted with EtOAc (1000 ml) and washed with water (5x100 ml) followed by brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 7-bromo-5-fluoro-3-iodo-1H-indole (6.2, 56%) as a brown solid.

Step 2 To a stirred solution of 7-bromo-5-fluoro-3-iodo-1H-indole (6.2 g, 18.23 mmol, 1 eq.) in THF (109 ml) was added dropwise LiHMDS (1 M) (91.15 ml, 91.15 mmol, 5 equiv.) at -78°C under an inert atmosphere. The reaction mixture was stirred for 30 minutes under these conditions. MOMCl (5.83 g, 72.94 mmol, 4 eq.) was then added to the reaction mixture at -78°C. The reaction mixture was allowed to warm up to room temperature. temp., and then stirred for 16 hours, the Reaction mixture was quenched by adding a saturated solution of ammonium chloride (100 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 7-bromo-5-fluoro-3-iodo-1(methoxymethyl)-1H-indole (5.4 g, 57%) as a white solid with a metallic tint.

Step 3: A stirred suspension of 7-bromo-5-fluoro-3-iodo-1-(methoxymethyl)-1H-indole (2.7 g, 7.03 mmol, 1 eq), cyclopropylboronic acid (1.84 g, 2.03 mmol, 3 eq.), K ₃ PO ₄ (4.5 g, 21.05 mmol, 3 eq.) in 1,4-dioxane (45 ml) was deoxygenated with Ar for 10 min. Pd(OAc)2 (0.08 g, 0.3525 mmol, 0.05 eq.), xantphos (0.407 g, 0.713 mmol, 0.1 eq.) was then added to the reaction mixture and again deoxygenated for 10 min. At the end, the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 7-bromo-3-cyclopropyl-5-fluoro-1-(methoxymethyl)-1H-indole (0.65 g, 31%) as a white solid substances with a metallic tint.

Step 4 To a stirred solution of 7-bromo-3-cyclopropyl-5-fluoro-1-(methoxymethyl)-1Hindole (1.25 g, 4.19 mmol, 1 eq) in MeOH/water (3:1) (66 ml) oxalic acid (1.13 g, 12.58 mmol, 3 eq.) was added. The reaction mixture was then stirred at 90°C for 18 h. The reaction mixture was cooled to room temperature. pace. and concentrated under reduced pressure to give a residue. The residue was diluted with EtOAc (100 ml) and washed with water (2x40 ml) and brine (40 ml). The organic layer was dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude

- 43 043276 product, which was purified by column chromatography to obtain 7-bromo-3-cyclopropyl-5-fluoro1H-indole (0.57 g, 54%) as a colorless liquid.

Step 5: Stirring suspension of 7-bromo-3-cyclopropyl-5-fluoro-1H-indole (0.57 g, 2.24 mmol, 1 eq.), bis-pinacolatodiboron (1.7 g, 6.73 mmol, 3 eq.), potassium acetate (0.66 g, 6.73 mmol, 3 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. Pd ₂ (dba) ₃ (0.031 g, 0.033 mmol, 0.015 eq.), tricyclohexylphosphine (0.047 g, 0.168 mmol, 0.075 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was then stirred for 14 h at 110°C. The reaction mixture was then cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 3-cyclopropyl-5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H- indole (0.35 g, 52%) as a white solid with a metallic tint.

Synthesis of 3-cyclobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-17)

P] "mvyal ™ chyaye mvdgpmiie A-G7

Step 1 To a stirred solution of 2,2,2-trichloroacetic acid (9.97 g, 61.22 mmol, 1.5 eq.), triethylsilane (19.7 ml, 122.4 mmol, 3.0 eq.) in toluene (20 ml) was added 7-bromo-1H-indole (8.0 g, 40.81 mmol), cyclobutanone (3.37 ml, 44.89 mmol, 1.1 eq.) in toluene (20 ml) , the mixture was stirred at 70°C for 16 hours After completion of the reaction (the reaction was followed by TLC), the reaction mixture was cooled to 10°C, quenched sat. aqueous NaHCO ₃ solution, extracted with EtOAc (2x300 ml), the organic layer was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered, and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified on combiflash columns to obtain 7-bromo-3-cyclobutyl-1H-indole (5.0 g, 49%) as a white solid.

Step 2 KOAC (1.17 g, 12 .0 mmol, 3.0 eq.), bis-pinocolate diboron (2.03 g, 8.0 mmol, 2 eq.) The solution was degassed with Ar for 20 min followed by the addition of PdCl ₂ (dppf) DCM (0.16 g, 0.2 mmol, 0.05 eq.). The reaction mixture was stirred at 90° C. for 16 hours. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give 3-cyclobutyl-7-(4.4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.1 g, 93%), as a white metallic solid.

Synthesis of 3-(tetrahydrofuran-3-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-18)

Step 1 To a stirred solution of 2,2,2-trichloroacetic acid (7.48 g, 45.91 mmol, 1.5 eq.), triethylsilane (14.8 ml, 91.83 mmol, 3.0 eq.) in toluene (15 ml) was added 7-bromoindole (6.0 g, 30.611 mmol), dihydrofuran-3-one (2.58 ml, 33.67 mmol, 1.1 eq.) in toluene (15 ml) at 70 °C and stirred for 24 h. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was cooled to 10°C, quenched sat. aq. NaHCO ₃ solution, extracted with EtOAc (2x300 ml), the organic layer was washed with brine (50 ml), dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure to give a crude product which was purified by a combi-flash column to give 7-bromo- 3-(tetrahydrofuran-3-yl)-1H-indole (1.1 g, 14%) as a sticky solid.

Step 2 To a solution of 7-bromo-3-(tetrahydrofuran-3-yl)-1H-indole (1.0 g, 3.75 mmol, 1 eq.) in 1,4-dioxane (30 ml) was added KOAC (1, 1 g, 11.27 mmol, 3.0 eq.), bis-pinacolate diboron (1.9 g, 7.51 mmol,

- 44 043276 eq.). The solution was degassed with Ar for 20 min followed by the addition of PdCl ₂ (dppf) DCM (0.15 g, 0.18 mmol, 0.05 eq.). The reaction mixture was stirred at 90° C. for 16 hours. After completion of the reaction (reaction progress was monitored by TLC), the solvent was evaporated under reduced pressure to give a crude product, which was purified by column chromatography to give 3-(tetrahydrofuran-3-yl) -7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.0 g, 85%) as a white metallic solid.

Synthesis of 3-ethyl-5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-19)

Prvmvzhutv’shvv

-z

Ητ-Ηφρΐ:, DMFayaLz

Stage-4

Step 1 In DMF (10 ml) POCl ₃ (0.22 ml, 2.412 mmol, 1.1 eq) was added at 0°C. To this solution of 7-bromo-5-fluoro-1H-indole (0.5 g, 2.192 mmol, 1 eq.) was added dropwise, and the mixture was stirred at 0° C. for 1 hour. monitored by TLC), the reaction mixture was basified with NaOH and acidified again with HCl. A solid precipitated which was filtered, washed with water and dried under reduced pressure to give 7-bromo-5fluoro-1H-indole-3-carbaldehyde (0.23 g, 43%) as a white solid.

Step 2 To a solution of 7-bromo-5-fluoro-1H-indole-3-carbaldehyde (0.23 g, 0.95 mmol, 1 eq.) in THF (10 ml) was added methylmagnesium bpromide (3.0 M in THF ) (1.1 ml, 3.33 mmol, 3.5 eq.) at -78° C. under nitrogen. The reaction mixture was then stirred at the same temperature for 4 hours. The reaction mixture was quenched with saturated ammonium chloride solution at -78°C. -bromo-5-fluoro-1H-indol-3-yl)ethanol (0.12 g, 50%) as a thick yellow liquid which was used for the next step without further purification.

Step 3 To a solution of 1-(7-bromo-5-fluoro-1H-indol-3-yl)ethanol (0.12 g, 0.465 mmol, 1 eq.) in THF (5 mL) was added LAH (0.045 g, 1.162 mmol, 2.5 eq.) at 0°C under nitrogen. The reaction mixture was stirred at rt. pace. within 1 h. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was quenched using the Fischer work-up technique. The resulting mixture was then filtered through a sintered and the filtrate was evaporated under reduced pressure to give a crude product, which was purified by column chromatography to give 7-bromo-3-ethyl-5fluoro-1H-indole (0.07 g, 63%) as a brown gum .

Step 4 Stirring suspension of 7-bromo-3-ethyl-5-fluoro-1H-indole (0.4 g, 1.652 mmol, 1 eq.), bis(pinacolato)diboron (0.46 g, 1.818 mmol, 1, 1 eq.), potassium acetate (0.485 g, 4.956 mmol, 3 eq.) in 1,4-dioxane (25 ml) was deoxygenated with Ar for 10 min. PdCl ₂ (dppf)·DCM (0.13 g, 0.165 mmol. 0.1 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was then stirred for 16 h at 110°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 3-ethyl-5fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indole (0.36 g, 75%) as a light yellow gum.

Synthesis of 2-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanol (intermediate A-20)

Projesitochlve connection D-20

- 45 043276

Step 1 To a solution of 4-bromo-6-fluoro-1H-indole (0.5 g, 2.34 mmol, 1 eq.) in DMF (5 ml) was added sodium hydride (0.130 g, 2.80 mmol, 1 .2 equiv.) at 0°C. The solution was stirred at rt. pace. for 30 min followed by the addition of (2-bromoethoxy)(tert-butyl)dimethylsilane (1.17 g, 4.67 mmol, 2.0 eq.), the reaction mixture was stirred at room. pace. within 2 h. After completion of the reaction (the reaction was followed by LC-MS), the reaction mixture was diluted with EtOAc (20 ml) and the organic layer was washed with cold water (5x10 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro-1Nindole (0.85 g, 98%) as a brown liquid containing (2- bromoethoxy)(tert-butyl)dimethylsilane as an impurity.

Step 2 To a stirred solution of 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoro1H-indole (1.3 g, 3.49 mmol, 1 eq.) in THF (15 ml) was added TBAF (3.49 ml) (1M) at room. temp., and the mixture was stirred for 16 h. After completion of the reaction (the reaction was followed by LC-MS and TLC), the reaction mixture was diluted with EtOAc (20 ml) and the organic layer was washed with cold water (5x10 ml), saline solution (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give 2-(4-bromo-6-fluoro-1H-indol-1-yl)ethanol (0.55 g, 61%) as a brown liquid.

Step 3. A stirred solution of 2-(4-bromo-6-fluoro-1H-indol-1-yl)ethanol (0.55 g, 2.13 mmol, 1 eq.), bis(pinacolato)diboron (0.647 g, 2.55 mmol, 1.2 eq.), potassium acetate (0.626 g, 6.393 mmol, 3 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. PdCl ₂ (dppf)DCM (0.173 g, 0.213 mmol. 0.1 eq.) was then added to the reaction mixture and the mixture was stirred at 90° C. for 16 h. After the reaction was completed (reaction progress was monitored by TLC), the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude product which was used in the next step without further purification.

Synthesis of 2-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethanol (intermediate A-21)

Step 1 K ₂ CO ₃ (0.38 g, 2 .79 mmol, 3.0 equiv.) at room. temp., and the mixture was stirred for 20 minutes. Then 2-bromo-ethanol (0.07 ml, 0.93 mmol, 1 eq.) was added and the mixture was stirred for 16 h at 50°C. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mass was quenched with ice water and extracted with EtOAc (3x20 ml), washed with H2O (3x20 ml), brine (25 ml), dried over Na2SO4 and concentrated. The crude product was purified by column chromatography to give 2-(4-bromo-6-fluoro-1H-indazol-1-yl)ethanol (0.12 g, 50%) as a white solid.

Step 2 To a solution of 2-(4-bromo-6-fluoro-1H-indazol-1-yl)ethanol (0.9 g, 3.473 mmol, 1 eq.) in 1,4-dioxane (60.0 ml) was added KOAc (1.02 g, 10.419 mmol, 3 eq.), bispinacolatodibor (1.76 g, 6.947 mmol, 2.0 eq.). The solution was degassed with Ar for 20 min followed by the addition of Pd ₂ (dba) ₃ (0.17 g, 0.173 mmol, 0.05 eq.), Cy ₃ P (0.077 g, 0.277 mmol, 0.08 eq.). The reaction mixture was stirred for 16 hours. After the completion of the reaction (the progress of the reaction was monitored by TLC), the solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give (6-fluoro-4-(4.4, 5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1yl)ethanol (0.95 g, 89%) as a brown solid.

Synthesis of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (intermediate A-22)

MeSOjCI .........NaN......................

DMF

In SP m

CODES 1D1“Dvdksan

Stage-!

Step 1. To a stirred solution of 4-bromo-1H-indazole (1.0 g, 5.07 mmol, 1 eq.) in DMF (25

- 46 043276 ml) sodium hydride (60%, 0.406 g, 10.152 mmol, 2 eq.) was added in portions at 0°C. The reaction mixture was stirred for 30 min at room temperature. pace. Methanesulfonyl chloride (0.59 ml, 7.6 mmol, 1.5 eq.) was added to the reaction mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature. pace. The reaction mixture was diluted with EtOAc (150 ml). The combined organic layers were washed with water (5x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh 10% EtOAc/hexane; R _g value -0.5) to give 4-bromo-1-(methylsulfonyl)-1H-indazole (0.95 g, 69%) in as a light yellow solid.

Step 2: Stirring suspension of 4-bromo-1-(methylsulfonyl)-1H-indazole (0.95, 3.45 mmol, 1 eq.), bis(pinacolato)diboron (1.75 g, 6.91 mmol, 2 eq.), potassium acetate (1.01 g, 10.36 mmol, 3 eq.) in 1,4-dioxane (35 ml) was deoxygenated with Ar for 10 min. Pd(dppf)Cl ₂ .DCM (0.141 g, 0.1727 mmol 0.05 eq.) was added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was stirred for 14 h at 110°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give crude material which was purified by column chromatography (silica gel 230400 mesh, 10% EtOAc/hexane; R _f -value -0.45) to give 1-(methylsulfonyl)-4-(4.4.5 ,5-Tetramethyl 1,3,2-dioxaborolan-2-yl)-1H-indazole (0.9 g, 85.4%) as a white metallic solid.

Synthesis of 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (intermediate A-23)

0¾ Jl /

G ,. _X H M ₅ SO ₂ Cl _c su _V,.

D»A ---A' -- ⁷ rilapgkz.DX? .: v θΓ YG KOAc. 1.4-Diskgan β

Oh '0

Stage-1 Stage-! './

Prome ^ 'tochzhve "edniie A-23

Step 1 Sodium hydride (60%, 0.446 g, 11 .16 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 min at room temperature. pace. Methanesulfonyl chloride (0.65 ml, 8.37 mmol, 1.5 eq) was added to the reaction mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature. pace. The reaction mixture was diluted with EtOAc (150 ml). The combined organic layers were washed with water (5x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh 10% EtOAc/hexane; R _g value -0.5) to give 4-bromo-6-fluoro-1-(methylsulfonyl)1H-indazole (1.3 g, 80 %) as a light yellow solid.

Step 2. To a stirred suspension of 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indazole (1.3, 4.43 mmol, 1 eq.), bis(pinacolato)diboron (2.25 g, 8 .87 mmol, 2 eq.), potassium acetate (1.3 g, 13.3 mmol, 3 eq.) in 1,4-dioxane (45 ml) was deoxygenated with Ar for 10 min. Pd(dppf)Cl ₂ .DCM (0.18 g, 0.22 mmol 0.05 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was stirred for 14 h at 110°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography (silica gel 230-400 mesh, 10% EtOAc/hexane; _Rg value -0.45) to give 6-fluoro-1-(methylsulfonyl)-4-( 4,4,5,5-tetramethyl 1,3,2-dioxaborolan-2-yl)-1H-indazole (1.1 g, 73%) as a white solid with a metallic tint.

Synthesis of 6-fluoro-1-(2-methoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-24)

Step 1: Sodium hydride (0.112 g, 2.8 mmol , 1.2 equiv.) at 0°C. The reaction mixture was then stirred for 30 min at room temperature. temp. 1-Bromo-2-methoxyethane (0.812 ml, 5.84 mmol, 2.5 eq.) was then added to the reaction mixture at 0°C. The reaction mixture was stirred for 2 h at room temperature. pace. The reaction mixture was diluted with EtOAc (50 ml). The combined organic layers were washed with water (5x10 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (230400 mesh silica gel 20% EtOAc/hexane; Rd-O.6) to give 4-bromo-6-fluoro-1-(2-methoxyethyl)N-indole (0.63 g, 99%) brown resin.

Step 2. To a stirred suspension of 4-bromo-6-fluoro-1-(2-methoxyethyl)-III-indole (0.8 g, 2.94 mmol, 1 eq.), bis-pinacolatodiboron (1.2 g, 4.4 mmol, 1.5 eq.), potassium acetate (0.865 g, 8.823 mmol, 3 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. Then PdCl ₂ (dppf)·DCM (0.239 g, 0.29 mmol. 0.01 eq.) was added and the reaction mixture was stirred for 14 h at 90°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography (silica gel 230-400 mesh 5% EtOAc/hexane; I _g value -0.6) to give 6-fluoro-1-(2-methoxyethyl)-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.93 g, 99%) as light brown tarry solid.

Synthesis of 1 -(2,2-difluoroethyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-25 )

"l. SCH

TsO at F

Cs-COjOii

DMFALO'S

Receiving method

Boronag

Stage-1

Interim information AL!

Step 1 To a stirred solution of 4-bromo-6-fluoro-1H-indole (0.1 g, 0.469 mmol, 1 eq.) in DMF (25 ml) was added Cs ₂ CO ₃ (0.457 g, 1.407 mmol, 3 eq. .) followed by the addition of LiBr (86.84 g, 0.469 mmol, 1 eq.), the mixture was stirred at room temperature. pace. within 10 min. Then 2,2 difluoroethyl 4-methylbenzenesulfonate (0.133 g, 0.563 mmol, 1.2 eq.) was added to the reaction mixture and heated at 80° C. for 3 h (TLC). The reaction mixture was then diluted with water (10 ml), EtOAc (15 ml). The organic layer was washed with cold water (3x10 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; TLC system: EtOAc/ hexane (3:7), _Rf- value-0.5) to give 4-bromo-1-(2,2-difluoroethyl)-6-fluoro-1H-indole (0.75 g, 58%).

Step 2: Suspension of 4-bromo-1-(2,2-difluoroethyl)-6-fluoro-1H-indole (0.2 g, 0.722 mmol, 1 eq), bis(pinacolato)diboron (0.275 g, 1.083 mmol , 1.5 eq.), potassium acetate (0.212 g, 2.166 mmol, 3 eq.) in 1,4dioxane (10 ml) was deoxygenated with Ar for 10 min. A complex of 1,1'-bis-(diphenylphosphino)ferrocene palladium(II) dichloride and DCM (0.03 g, 0.0361 mmol, 0.05 eq) was then added to the reaction mixture and the reaction mixture was heated at 100°C within 16 h (LC-MS). The reaction mixture was then cooled to room. temp., filtered through a Celite pad, and the filtrate was concentrated under reduced pressure to give crude 1-(2,2-difluoroethyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolane -2-yl)-1H-indole, which was used in the next step without further purification (~49% yield in LC-MS).

Synthesis of 3-cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-26)

KOI

DMF

I HMDS '

HE

Stage-1

THF

Flock-2

Er

K;P0;rPdiCAc:7

Xantphee

J _s 4-Jzhsan

Stage-3

Shaya acid

MeON/SHO

Stage-4

G.

I am ⁰ lilSPK-J

Pu-LPi

ΚΚΟΛύ. ¹ 1.4-Drive: en

Shvmiatvchvve d-26

Starting from 7-bromo-1H-indole, Intermediate A-26 was synthesized similarly to the synthesis described for Intermediate A-16.

Synthesis of 1-cyclopropyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-27)

- 48 043276

NM-/

CSOAC Pyridine W * C% - G ³ Λ

Η / 0 В-в ^τ -Ν /'° Cj- I . -j-- smi i s'dcljdppiy d'o ^bl dmfaygs

Proieiutochive "ediiii-e A-27

stages

Step 1 To a stirred solution of 4-bromo-6-fluoro-1H-indole (5.4 g, 25.23 mmol, 1 eq.) in toluene (45 mL) was added cyclopropylboronic acid (4.33 g, 50.46 mmol, 2 eq.), Cu(OAc) ₂ (0.46 g, 2.52 mmol, 0.1 eq.), 2-(4,5-dihydro-1H-imidazol-2-yl)phenol (0 .41 g, 2.52 mmol, 0.1 eq.), pyridine (6.0 g, 75.7 mmol, 3 eq.). The reaction mixture was stirred for 24 h at 65°C. The solvent was removed under reduced pressure and azeotropically distilled twice with MeOH. The residue was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane; Rd-O.6) to give 4-bromo-1-cyclopropyl-6-fluoro-1H-indole (0.85 g, 13%) in brown liquid.

Step 2: A stirred suspension of 4-bromo-1-cyclopropyl-6-fluoro-1H-indole (0.85 g, 3.35 mmol, 1 eq), bis(pinacolato)diboron (1.7 g, 6.7 mmol, 2 eq.), potassium acetate (1.31 g, 13.38 mmol, 4 eq.) in 1,4-dioxane (20 ml) was deoxygenated with Ar for 10 min. Pd ₂ (dba) ₃ (0.046 g, 0.05 mmol, 0.015 eq.), tricyclohexylphosphine (0.067 g, 0.24 mmol, 0.072 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. The reaction mixture was stirred for 14 h at 110°C. The reaction mixture was cooled to room. temp., and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to give a crude material which was purified by column chromatography (silica gel 230-400 mesh, 20% EtOAc/hexane; R _f -value -0.6) to give 1-cyclopropyl-6-fluoro-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.61 g, 61%) as a light yellow solid.

¹ H NMR (400 MHz; DMSOL ₆ , 20°C): δ 7.45 (dd, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 6.67 (d, 1H ), 3.41(m, 1H), 1.32(12H), 1.03-1.08(2H), 0.82-0.92(2H).

Synthesis of 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1Н-indole (intermediate A-71) '7 Βχ 'у I .С Ac /^dCl. ,dppf v. g' Oh

I 1,4-Dioxane ®&°C

Remember to “eat A-T1

A mixture of 7-bromo-5-fluoro-III-indole (1 g, 4.7 mmol, 1 eq.), bis(pinacolato)diboron (2.02 g, 7.9 mmol, 1.7 eq.), acetate potassium (917 mg, 9.4 mmol, 2 eq.), a complex of 1,1'-bis-(diphenylphosphino)ferrocene palladium(II) dichloride and DCM (382 mg, 0.467 mmol, 0.1 eq.) in 1, 4-dioxane (13 ml) was degassed with nitrogen and the reaction mixture was stirred at 60°C. After completion of the reaction (the progress of the reaction was followed by LC-MS) sat. sodium bicarbonate solution was added to the reaction mixture, which was then extracted with EtOAc (2x). The combined organic layers were washed with brine, dried over anhydrous MgSO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel; EtOAc/cyclohexane as eluent) to give 5-fluoro7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (940 mg, 77%).

Intermediates in the table. 1 was synthesized similarly to Intermediate A-1 - Intermediate A-27.

- 49 043276

Table 1

intermediate connection Synthesized similarly Structure Intermediate, connection A-30 Intermediate conn.-A-2 ABOUT \ Z / KZ That Intermediate, junction A-31 Intermediate conn.-A-2 Oh from Intermediate, junction A-32 Intermediate conn.-A-N O-sh Z ^ζ^ Intermedia, junction A-33 Intermediate conn.-A-10 O-sp Ζ | K _O Intermedia, junction A-34 Intermediate conn.-A-N τζ^° Z / KZ ω-Ο Intermediate, junction A-35 Intermediate conn.-A-2 О-ш li/D ¹ ω' о Intermediate, junction A-36 Intermediate conn.-A-N o ^z Z'Z cn-O Intermedia, junction A-37 Intermediate conn.-A-N /^z to-O Intermedia, junction A-38 Intermediate conn.-A-N X° ^ ^N ' Intermedia, junction A-39 Intermediate conn.-A-N

- 50 043276

Intermediate, connection A-40 Intermediate conn.-A-2 θ-® CQ-o Intermediate, junction A-41 Intermediate conn.-A-27 O'-ni ^z z Intermedia, junction A-42 Intermediate conn.-A-N O-sh ^Z^^ Intermediate, junction A-43 Intermediate conn.-A-N OSH r>=/ ^ζ ABOUT Intermedia, junction A-44 Intermediate conn.-A-27 Oot ^ζ Intermediate, junction A-45 Intermediate conn.-A-2 OT \ , ^ω Γ> -Π^/\\ Ο Ο Intermedia, junction A-46 Intermediate conn.-A-N Ύ'ό Intermedia, junction A-47 Intermediate conn.-A-2 Oot\Ο Ο Intermedia, junction A-48 Intermediate conn.-A-2 ο Ο \ ζ c0O Intermedia, junction A-49 Intermediate conn.-A-N OR ϊ \ Intermediate, connection A-50 Intermediate conn.-A-22 o >-__/ ^Ζ 'Ζ ^w ~( ⁼ / co-O

- 51 043276

Intermediate, conn.- A-51 Intermediate conn.-A-20 zV^p Ο-αί Z About t Intermedia, junction A-54 Intermediate conn.-A-22 O Z lKZ w-O _o y< Intermediate, junction A-56 Intermediate conn.-A-N Ο-αί 1Gu \u003d / ή ^ζ^ Intermedia, junction A-57 Intermediate conn.-A-22 About Z /=< J CQ-O Intermediate, junction A-58 Intermediate conn.-A-22 Ο-αί ^ζ 'ζ^ Ο Intermedia, junction A-59 Intermediate conn.-A-21 Ο-αί \ Intermedia, connection A-60 Intermediate conn.-A-22 Γ II ο _ \ 'λ·>θ Λ Intermedia, junction A-63 Intermediate conn.-A-22 Ο-αί \ ^ο Intermediate, junction A-66 Intermediate conn.-A-22 Ο-αί

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Intermedia, junction A-68 Intermediate conn.-A-22 O-from Ή Z 1 ,O s/g Intermedia, junction A-72 Intermediate conn.-A-22 R/\ CQ-O Intermediate, junction A-73 Intermediate conn.-A-21 ^FAY- Intermediate, junction A-75 Intermediate conn.-A-71 Ο-αί rw Z\ Z Intermediate, junction A-76 Intermediate conn.-A-22 o_o'l o z co-o Intermedia, junction A-77 Intermediate conn.-A-22 O Z / KZ “-o

Intermediates in the table. 2 are commercially available.

table 2

Name Structure 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-6(trifluoromethyl)-1H-indole I Z \ /=<J 5-fluoro-Sh-indole-4-boronic acid pinacol ester to ll m-o 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-2H-indole -Δ/ ⁰ '?// N x ° H

- 53 043276

1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan2-yl)- 1H-indazole X 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-2(trifluoromethyl)-1H-indole A Eh ( νη \-F F F 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H indazole CQ-O ex NH tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indazole-1-carboxylate /L K U \u003d N ^x But. in' ^he indole-4-boronic acid n-A n J 1,1-dimethylethy l-4 - (4,4,5,5 -tetramethyl-1,3,2dioxaborolan-2 -yl) - 1H-indo l-1 -carboxylate A Eh /? od 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-1H-indole I' ex HN^ (7-chloro-1H-indazol-4-yl)boronic acid “But but ''ξ'ΝΗ 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboro Daniel) 1H-indazole /er Ο-αί F π ^=N 7-methoxy-4 - (4,4,5,5 -tetramethyl-1,3,2dioxaborolan-2 -yl) - 1H-indazo l A 1 /4/° ex ( ⁴ nh 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-7(trifluoromethyl)-1H-indazole O-co XNH _CF3 (6-(trifluoromethyl)-1H-indazol-4-yl)boronic acid BUT. _B ^ / but 'Y'nh

-54043276

F (6-Fluoro-1H-indazol-4-yl)boronic acid ^N °R NO T L Ζ mm 7 -chloro -6 -fluoro-4 - (4,4,5,5 -tetramethyl-1,3,2dioxaborolan-2 -yl) - 1H-indazo l A ° F ί T NH "Ν 7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan2-yl)-III-indo l A ° F t ^<ΉΗ 7-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-Sh-indole A ° GM z \ I ^o 6-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)- N-indole _v°y A ° NH (1H-indol-7-yl)boronic acid BUT, " BUT jP) HN-/ 3-Methyl-1H-indazole-7-boronic acid D but P HNN N ¹¹ 4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindole-6-carbonitrile O-ED T z /=<J Pm ^F 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indazole % G T NH^=N 7-fluoro-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)- 1Nindole and about G T NH F 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indazole cd-o ml NH Cl 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indole % jOi NH 7-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indole % £JT NH

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Synthesis of 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-1):

Step 1: Suspension of 2-bromo-4,6-difluoroaniline (25 g, 120.19 mmol, 1 eq.), 2-amino-2-methylpropanoic acid (24.75 g, 240.38 mmol, 2 eq.), K3PO4 (50.96 g, 240.38 mmol, 2 equiv.), CuI (2.29 g, 12.02 mmol, 0.1 equiv.) in dry DMSO (375 ml) in a hermetically sealed vessel Ar was deoxygenated for 20 min. The reaction mixture was then stirred at 125° C. for 16 hours. After completion of the reaction, it was filtered through a pad of celite and washed with EtOAc (100 ml). The filtrate was diluted with EtOAc (500 ml) and washed with water (3x150 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography to give 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (34.0 g, 67%) as a brown solid.

Stage 2. To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (34.0 g, 160 mmol, 1 eq.) in toluene (650 ml) was added the reagent Lausson (97.3 g, 240 mmol, 1.5 eq.) at room. temp., and the reaction mixture was refluxed at 120°C for 40 min. After completion of the reaction, the reaction mixture was quenched with sat. NaHCO ₃ (250 ml) followed by extraction with EtOAc (3x150 ml). The combined organic layers were washed with water (300 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography to give 6,8-difluoro-3,3-dimethyl-3 ,4-dihydroquinoxaline-2(1H)-thione (26 g, 66%) as a yellow solid.

Step 3 To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (5.0 g, 21.9 mmol, 1 eq.) in n-BuOH (60 ml) was added acetohydrazide (5.35 g, 72.3 mmol, 3.3 eq.) followed by the addition of AcOH (6 ml), and then the reaction mixture was stirred at 140°C for 16 hours. After completion of the reaction, the reaction mixture was concentrated , and the residue was diluted with EtOAc (150 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography to give 7,9-difluoro-1,4,4-trimethyl -4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (4.5 g, 82%) as a white solid with a metallic tint.

Step 4 To a stirred solution of 7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (4.5 g, 18 mmol, 1 eq. .) in DMF (40 ml) N-bromosuccinimide (3.5 g, 19.8 mmol, 1.1 eq.) was added in portions. The reaction mixture was allowed to warm up to room temperature. pace. and stirred for 2 hours. The reaction mixture was diluted with EtOAc (300 ml). The combined organic layers were washed with water (5x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography to give 8-bromo-7,9difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (4.0 g, 61%) as a brown solid.

Synthesis of 8-bromo-1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-а]quinoxaline (intermediate B-2):

Acceptable information B2

Step 1. To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (7.0 g, 30.7 mmol, 1 eq.) in n-BuOH (84 ml) was added propionohydrazide (8.92 g, 101.3 mmol, 3.3 eq.) followed by the addition of acetic acid (8.4 ml), and then the reaction mixture was stirred at 140°C for 16 hours. After completion of the reaction the reaction mixture was concentrated and the residue was diluted with EtOAc (150 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and evaporated to give the crude product which was purified by column chromatography to give 1-ethyl-7,9-difluoro-4, 4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (6.0 g, 74%) as a white metallic solid.

Step 2: A stirred solution of 1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (5.5 g, 20.8 mmol , 1 eq.) in DMF (50 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (3.89 g, 21.8 mmol, 1.05 eq.). The reaction mixture was allowed to warm up to room temperature. pace. and stirred for 1.5 h. After completion of the reaction, the reaction mixture was diluted with EtOAc (300 ml), the organic layers were washed with water (5x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give 8-bromo-1-ethyl-7,9-difluoro-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (4.4 g, 62%) as a white solid with a metallic tint.

Synthesis of 8-bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-а]quinoxaline (intermediate B-3):

DMSO, "a ° c

Stage-1 Lausson's reagent

Toluene, 120¾. p Stage-2

Stage-3

POCI/TEA

Herds-4 nib; SCKA VA:

Stage-5

J ' mn _a mn _g n _g o S-1.04 TEZHTGF

Proprietary connection B-3

Stage 1. Suspension of 2-bromo-4-fluoro-6-methylaniline (5 g, 24.5 mmol, 1 eq.), 2-aminoisobutyric acid (5.05 g, 49 mmol, 2 eq.), Cs ₂ CO ₃ (15.92 g, 49 mmol, 2 equiv.), copper iodide (0.466 g, 2.45 mmol, 0.1 equiv.) in dry DMSO (75 ml) in a sealed vessel was deoxygenated with Ar for 20 min. The reaction mixture was then stirred at 125° C. for 16 hours. The reaction mixture was filtered through a pad of celite and washed with EtOAc (100 ml). The filtrate was diluted with EtOAc (200 ml) and washed with water (3x100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give 6-fluoro-3 ,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (3.0 g, 59%) as a brown solid.

Step 2 To a solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (3.66 g, 17.6 mmol, 1 eq.) in toluene (75 ml) added Lausson's reagent (10.67 g, 26.2 mmol, 1.5 eq.) at room. temp., and the reaction mixture was stirred at 120°C for 40 min. The reaction mixture was quenched with sat. NaHCO ₃ solution (100 ml) followed by extraction with EtOAc (2x100 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 6-fluoro-3,3,8-trimethyl -3,4-dihydroquinoxaline-2(1H)-thione (2.8 g, 71%) as a yellow solid.

Step 3 To a stirred solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (5.50 g, 24.55 mmol, 1 eq.) in THF (30 mL ) was added dropwise hydrazine hydrate (5.17 ml, 122.76 mmol, 5 eq.) at 0°C. The reaction mixture was then stirred for 16 hours at room temperature. pace. TEA (16.7 ml, 122.76 mmol, 5 eq.) was added to the reaction mixture and stirred for an additional 10 minutes. Acetyl chloride (5.78 g, 73.65 mmol, 3 eq.) was added very slowly to the reaction mixture at 0° C. and then stirred for 2 h at room temperature. pace. The reaction mixture was quenched with water (50 ml) and extracted with DCM (5x100 ml). The combined organic layers were washed with brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was washed with diethyl ether to give Na-(6-fluoro-3,3,8trimethyl-3,4-dihydroquinoxalin-2(1H)-ylidene) acetohydrazide (5.5 g, 85%) as a white solid.

Step 4 N'-(6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-ylidene)acetohydrazide (5.5 g, 20.8 mmol, 1 eq) was taken up in round bottom flask (50 ml), then cooled to -10°C. Phosphorus oxychloride (18.4 ml, 197.6 mmol, 9.5 eq) was then added dropwise to the compound followed by TEA (2.9 ml, 20.8 mmol, 1 eq) dropwise. After that, the reaction mixture was stirred at -10°C for 10 min, and then 10 min at room. pace. and finally heated to boiling for 4 hours. The reaction mixture was cooled to 0°C, and then crushed ice was added dropwise with constant stirring. Cold ammonia solution (100 ml) was then slowly added to this aqueous portion. The aqueous layer was extracted with DCM (2x 100 ml). The combined organic layers were washed with saline

- 57 043276

solution (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to obtain a crude material. The crude product was purified by column chromatography to give 7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3.0 g, 59% ) as a yellow solid.

Step 5. A stirred solution of 7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (4.0 g, 16.2 mmol, 1 eq.) in DMF (40 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (3.1 g, 17.1 mmol, 1.05 eq.). The reaction mixture was allowed to warm up to room temperature. pace. and stirred for 1.5 h. The reaction mixture was diluted with EtOAc (300 ml) and the organic layers were washed with water (5x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to give 8-bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (3.3 g, 63%) as a white solid with a metallic tint.

Synthesis of 8-bromo-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B-4):

CF, CI, ..X

BrgmnrsEanke NH I

Π'-/y- ¹ -Steel-i ^F'C -.'-J'

DMSO, Iv°С

Stage-2

ABOUT

X g -l ^eF ' n A ij

[IJ 1 I ¹ I DM

I.4,. ' F η | _Ct ^h Stage- 5

Intermediate B-4

Step 1 To a solution of 4-fluoro-2-trifluoromethyl-phenylamine (50 g, 0.279 mol) in DCM (550 ml) was added a solution of Br ₂ (15.1 ml, 0.29 mol) in DCM (100 ml) dropwise at 0°C and the resulting reaction mixture was stirred at 0°C for 2 h. The reaction mixture was diluted with water (1000 ml) and extracted with EtOAc (2x500 ml). The combined organic layers were washed with water (2x500 ml) followed by brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product, which was purified by column chromatography to give 2-bromo-4fluoro-6-trifluoromethyl-phenylamine (50 g, 69.4%) as a brown liquid.

Step 2 To a stirred suspension of 2-bromo-4-fluoro-6-trifluoromethyl-phenylamine (25 g, 0.097 mol) in dry DMSO (375 ml) was added 2-amino-2-methyl-propionic acid (20 g, 0.194 mol ) followed by the addition of K ₃ PO ₄ (41.1 g, 0.194 mol) at room. pace. The resulting reaction mixture was degassed with nitrogen for 30 min, then CuCl (0.96 g, 0.0097 mol) was added and the reaction mixture was stirred at 140°C for 16 h. The reaction mixture was cooled to room. pace. and filtered through celite. The Celite layer was washed with EtOAc (500 ml). The resulting filtrate was poured into ice water (1000 ml). The resulting aqueous layer was extracted with EtOAc (2x250 ml). All organics were washed with water (2x500 ml), brine (250 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to give a crude product which was purified by column chromatography to give 6-fluoro-3,3- dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin2-one (16 g, 63%) as a brown solid.

Step 3 To a solution of 6-fluoro-3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one (26 g, 0.0992 mol) in toluene (390 ml) was added Lausson's reagent (60.14 g, 0.1488 mol) at rt. temp., and the reaction mixture was refluxed at 120°C for 2 hours, the Reaction mixture was concentrated. The resulting solid residue was quenched with sat. NaHCO ₃ solution (1500 ml) and the resulting aqueous layer was extracted with EtOAc (3x500 ml). The combined organic layers were washed with water (1000 ml), brine (1000 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product. The resulting crude product was purified by column chromatography to give 6-fluoro-3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxaline-2-thione (26 g, 94.3%) as a yellow solid.

Step 4 To a stirred solution of 6-fluoro-3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1Hquinoxaline-2-thione (29.5 g, 0.106 mol) in THF (750 ml) was added hydrazine dropwise -hydrate (15.91 g, 0.318 mol) at 0°C. The reaction mixture was stirred at rt. pace. over 16 h. TEA (101.19 ml, 0.742 mol), acetyl chloride (30.14 ml, 0.424 mol) were added successively to the reaction mixture dropwise at 0°C, and the mixture was stirred for 2 h at room. pace. The reaction mixture was quenched with water (500 ml) and extracted with 10% MeOH-DCM (5x500 ml). The combined organics were washed with brine (250 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give (6-fluoro-3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxaline-2 -ylidene)-hydrazide acetic acid (30 g, 88.9%) as a white solid with a metallic tint.

Stage 5. (6-Fluoro-3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1 H-quinoxalin-2-ylidene)-hydrazide

- 58 043276 acetic acid (17 g, 0.053 mol) was transferred into a round bottom flask and then cooled to -10°C. Phosphorus oxalyl chloride (24.7 ml, 0.265 mol) was then added dropwise to the compound followed by TEA (7.36 ml, 0.053 mol) dropwise. After that, the reaction mixture was stirred at 10°C for 10 min, and then for 10 min at room. temp., and at the end the mixture was heated to boiling for 4 hours, the Reaction mixture was cooled to 0°C and quenched with crushed ice in water (250 ml). The aqueous portion was then made alkaline by dropwise addition of cold ammonia solution (250 ml). The resulting alkaline aqueous layer was then extracted with EtOAc (3x500 ml). All organics were washed with brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude product. The resulting crude product was purified by solvent trituration using MTBE to give 7-fluoro-1,4,4-trimethyl-9-trifluoromethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (8 .5 g, 53%) as a yellow solid.

Step 6 To a solution of 7-fluoro-1,4,4-trimethyl-9-trifluoromethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (5.9 g, 19.64 mmol ) in DMF (177 ml) was added NBS (3.84 g, 21.61 mol) in portions at -10°C. The resulting reaction mixture was stirred at room temperature. pace. within 16 hours the Reaction mixture was diluted with water (500 ml) and was extracted with EtOAc (2x750 ml). The combined organic layers were washed with water (750 ml) followed by brine (400 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude product. The resulting crude product was purified by column chromatography to give 8-bromo-7-fluoro-1,4,4-trimethyl-9trifluoromethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3 g , 40%) as a white solid with a metallic tint.

Synthesis of 8-bromo-9-chloro-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-5):

С ,7--¼ ¹ J , ^g , RmgentLtgssen _ή Ύ · A' _GF । । “ - I s , ' ΐ Toluene h * - h - -- I j

Stage-2 Stage-J

Stage-1, g ^p .-U. - ¹ - 1 _Ί '= ^; , < ι

KSh. ΐ CfpaiH. COLD,

I''Ai

Stage- =·· ^? ·

Intermediate Swedashein® V-5

Step 1 To a stirred suspension of 2-bromo-6-chloro-4-fluoro-phenylamine (75 g, 0.334 mol) in dry DMSO (1125 ml) was added 2-amino-2-methyl-propionic acid (68.8 g, 0.668 mol) followed by the addition of K ₃ PO ₄ (141.8 g, 0.668 mol) at room. pace. The resulting reaction mixture was degassed with nitrogen for 30 min, then CuCl (6.36 g, 0.0334 mol) was added and the reaction mixture was heated at 140°C for 6 h. The reaction mixture was cooled to room. pace. and filtered through celite. The Celite layer was washed with EtOAc (1500 ml). The resulting filtrate was poured into ice water (2000 ml). The resulting aqueous phase was extracted with EtOAc (2x750 ml). All organics were washed with water (2x1500 ml) followed by brine (750 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the crude product. The crude product was purified by column chromatography to give 8-chloro-6-fluoro-3,3-dimethyl-3,4-dihydro-1Hquinoxalin-2-one (40 g, 52.4%) as a brown solid.

Step 2 To a solution of 8-chloro-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (25 g, 0.109 mol) in toluene (375 ml) was added Lausson's reagent (66 .26 g, 0.1639 mol) at room temperature temp., and the reaction mixture was refluxed at 120°C for 2 hours, the Reaction mixture was concentrated. The resulting solid residue was quenched with sat. NaHCO ₃ solution (1500 ml) and the resulting aqueous layer was extracted with EtOAc (3x500 ml). The combined organic layers were washed with water (750 ml), brine (750 ml), dried over anhydrous Na2SO4, and evaporated to give the crude product. The resulting crude product was purified by column chromatography to give 8-chloro-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxaline-2-thione (24 g, 89.7%) as a yellow solid.

Step 3 To a stirred solution of 8-chloro-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxaline-2thione (28.8 g, 0.118 mol) in THF (750 ml) was added hydrazine dropwise -hydrate (17.7 g, 0.354 mol) at 0°C. The reaction mixture was stirred at rt. pace. over 16 h. TEA (82.4 ml, 0.59 mol) was added followed by the addition of acetyl chloride (25.16 ml, 0.354 mol) to the reaction mixture dropwise at 0° C. and stirred for 2 h at room temperature. pace. After consumption of starting material (reaction progress monitored by LC-MS) the reaction mixture was diluted with water (500 ml), extracted with 10% MeOH-DCM (5x500 ml). The combined organics were washed with brine (250 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give (8-chloro-6fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-ylidene )-acetic acid hydrazide (30 g, 90%) as a white solid.

- 59 043276

Step 4. (8-Chloro-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxαlin-2-ylidene)-acetic acid hydrazide (15 g, 0.052 mol) was transferred to a round bottom flask (500 ml ), then cooled to -10°C. Phosphorus oxalyl chloride (24.23 ml, 0.26 mol) was then added dropwise to the compound followed by TEA (7.22 ml, 0.052 mol) dropwise. After that, the reaction mixture was stirred at 10°C for 10 min, and then 10 min at room. pace. and finally at reflux for 1.5 h. After consumption of the starting material (the reaction was followed by LC-MS), the reaction mixture was cooled to 0°C and quenched with crushed ice in water (250 ml). The aqueous portion was then made alkaline by dropwise addition of cold ammonia solution (250 ml). The resulting alkaline aqueous layer was then extracted with EtOAc (3x500 ml). All organics were washed with brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound. The resulting crude product was purified by solvent trituration using MTBE to give 9-chloro-7-fluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (8 .6 g, 61%) as a white solid with a metallic tint.

Step 5. To a solution of 9-chloro-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (15 g, 0.056 mol) in DMF (450 ml) was added NBS (10.9 g, 0.0616 mol) in portions at -10°C. The resulting reaction mixture was stirred at room temperature. pace. within 16 hours After consumption of the starting material (the reaction was followed by LC-MS), the reaction mixture was diluted with water (800 ml), was extracted with EtOAc (2x750 ml). The combined organic layers were washed with water (2x750 ml) followed by brine (400 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude compound. The resulting crude product was purified by column chromatography to give 8-bromo-9-chloro-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (12, 1 g, 62%) as a white solid with a metallic tint.

Synthesis of 8-bromo-1-ethyl-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-6):

Stage-1

Intermediate connection

Step 1. Hydrazine was added dropwise to a stirred solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxαlin-2-thione (10 g, 0.0445 mol) in THF (250 ml) -hydrate (6.69 g, 0.1337 mol) at 0°C. The reaction mixture was stirred at rt. pace. over 16 h. TEA (30.98 ml, 0.2229 mol) was added followed by dropwise addition of propionyl chloride (11.67 ml, 0.1337 mol) at 0° C. and the mixture was stirred for 2 h at room temperature. pace. After consumption of starting material (reaction progress monitored by LC-MS) the reaction mixture was diluted with water (250 ml), extracted with 10% MeOH-DCM (5x250 ml). The combined organics were washed with brine (250 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give (6-fluoro-3,3,8-trimethyl 3,4-dihydro-1H-quinoxalin-2-ylidene)- propionic acid hydrazide (12 g, 96.7%) as a white solid with a metallic tint.

Step 2. Propionic acid (6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-ylidene)-hydrazide (12 g, 0.0431 mol) was transferred to a round bottom flask and then cooled to -10°C. Phosphorus oxalyl chloride (20.1 ml, 0.2158 mol) was then added dropwise to the compound followed by TEA (6 ml, 0.0431 mol) dropwise. After that, the reaction mixture was stirred at -10°C for 10 min, and then 10 min at room. pace. and finally at reflux for 4 hours. After consumption of the starting material (the reaction was followed by LC-MS), the reaction mixture was cooled to 0°C and quenched with crushed ice in water (250 ml). The aqueous portion was then made alkaline by dropwise addition of cold ammonia solution (250 ml). The resulting alkaline aqueous layer was then extracted with EtOAc (3x500 ml). All organics were washed with brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound. The resulting crude product was purified by solvent trituration using MTBE to give 1-ethyl-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (6, 5 g, 58%) as a white solid with a metallic tint.

Step 3. To a solution of 1-ethyl-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (7.5 g, 0. 0288 mol) in DMF (180 ml) was added NBS (5.3 g, 0.0302 mol) in portions at -10°C. The resulting reaction mixture was stirred at room temperature. pace. within 4 hours After consumption of the source material (the reaction was followed by LC-MS), the reaction mixture was diluted with water (500 ml), was extracted with EtOAc (2x250 ml). The combined organic layers were washed with water (500 ml) followed by brine (400 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to give the crude compound. The resulting crude product was purified by column chromatography to give 8-bromo-1-ethyl-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a] quinoxaline (3.8 g, 38%) as a white solid with a metallic tint.

Synthesis of 8-bromo-9-ethyl-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-а]quinoxaline (intermediate B-8):

^£ with -F'L

Il t * ¹ . · = : Р=1 I, ί Staia-1. Reagent '· A' Lachtgen ' Stage-!

·: '

D?SFA

Strzshchiya-8

P|name:^toshjs»food™mp1:e V-8

Step 1 A stirred solution of 2-bromo-4-fluoro-1-nitrobenzene (5.0 g, 22.52 mmol, 1 eq.) in toluene (110 mL) was degassed with Ar for 20 minutes. To the above solution of tert-butylvinyltin (7.8 g, 24.77 mmol, 1.1 eq.) was added Pd(PPh ₃ ) ₄ (0.832 ml, 0.72 mmol, 0.05 eq.), then stirred in for 48 hours at 90°C and 24 hours at room. pace. The solvent was evaporated and the residue was dissolved in EtOAc (500 ml). The organic layer was washed with water and then with brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography (silica gel 230-400 mesh; 5% EtOAc/hexane; R _r value -0.4) to give 4-fluoro-1 -nitro-2-vinylbenzene (3.5 g, 93%) as a brown solid which still includes some organotin reagents and starting material (not completely removed).

Step 2 A stirred solution of 4-fluoro-1-nitro-2-vinylbenzene (6.0 g) in EtOH (400 ml) was degassed with Ar for 20 minutes. Pd/C (50% moisture) (1.0 g, 20%) was added to the above solution and purged with hydrogen in a Parr mixing flask at 60 psi. inch for 1 h. The solvent was evaporated and the residue was dissolved in EtOAc (500 ml). The organic layer was washed with water many times and then with brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane; R _f -value -0.4) to give 2-ethyl- 4fluoroaniline (2.0 g, 99%) as a light brown solid which still includes some starting material.

Step 3 A stirred solution of 2-ethyl-4-fluoroaniline (0.6 g, 4.314 mmol, 1 eq.) in DCM (40 mL) at -10°C was treated portionwise with solid N-bromosuccinimide (0.844 g, 4.745 mmol, 1 .1 equiv.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 1.5 h. The reaction mixture was diluted with DCM (100 ml) and the organic layer was washed with water (2x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (5% EtOAc/hexane; Rf-0.4)) to give 2-bromo-6-ethyl-4-fluoroaniline (0.875 g, 93%) as some red liquids.

Step 4: Suspension of 2-bromo-6-ethyl-4-fluoroaniline (0.2 g, 0.917 mmol, 1 eq.), 2-amino-2-methylpropanoic acid (0.19 g, 1.834 mmol, 2 eq.), K3PO4 (0.39 g, 1.834 mmol, 2 equiv.), copper chloride (0.01 g, 0.092 mmol, 0.1 equiv.) in dry DMSO (10 ml) in a hermetically sealed vessel was deoxygenated with Ar for 20 min. The reaction mixture was then stirred at 100° C. for 16 hours. The reaction mixture was filtered through a pad of celite and washed with EtOAc (50 ml). The filtrate was diluted with EtOAc (50 ml) and washed with water (3x50 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 20% EtOAc/hexane; RI-value-0.4) to give 8-ethyl-6-fluoro3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.1 g, 49%) in as a brown solid.

Step 5 To a solution of 8-ethyl-6-fluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (1.5 g, 6.76 mmol, 1 eq.) in toluene ( 25 ml) was added Lausson's reagent (2.7 g, 6.76 mmol, 1.0 eq.) at room. temp., and the reaction mixture was refluxed at 120°C for 40 min.

- 61 043276

The reaction mixture was quenched with sat. NaHCO ₃ solution (100 ml) followed by extraction with EtOAc (2x100 ml). The combined organic layer was washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography (silica gel 230-400 mesh; 20% EtOAc/hexane; Rf- value -0.4) to give 8-ethyl-6-fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (1.5 g, 93%) as a yellow solid.

Step 6 To a stirred solution of 8-ethyl-6-fluoro-3,3-dimethyl-3,4-dihydroquinoxαlin-2(1H)thione (0.5 g, 2.1 mmol, 1 eq.) in THF (30 ml) was added dropwise hydrazine hydrate (1 ml, 31.2 mmol, 14 eq.) at 0°C. The reaction mixture was then stirred for 16 hours at room temperature. pace. TEA (1.5 ml, 10.50 mmol, 5 eq.) was then added to the reaction mixture and stirred for an additional 10 minutes. Acetyl chloride (0.85 mL, 10.50 mmol, 5 eq.) was then added very slowly to the reaction mixture at 0° C., followed by stirring for 2 h at room temperature. pace. The reaction mixture was diluted with water (50 ml) and extracted with DCM (5x100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give crude material, purified by washing with diethyl ether to give N'(8-ethyl-6-fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2( 1H)-ylidene)acetohydrazide (1.55 g, 89%) as a white solid.

Step 7 To N'-(8-ethyl-6-fluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-ylidene)acetohydrazide (2.05 g, 7.37 mmol, 1 eq. ) was added POCl ₃ (7.1 ml) at 0°C. TEA (1.0 ml) was added to the mixture and it was stirred for 5 min at 0°C. The reaction mixture was gradually brought to room. temp., and then boiled under reflux overnight. After completion of the reaction, the reaction mixture was cooled to 0° C. and added portionwise to the chilled (0° C.) aqueous ammonia solution with vigorous stirring. After neutralization, it was extracted with DCM (3x100 ml). The combined organic layer was washed with water (2x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh; EtOAc; Rf-value-0.4) to give 9-ethyl-7-fluoro1,4,4-trimethyl-4,5-dihydro[1,2,4] triazolo[4,3-a]quinoxaline (1 g, 52%) as a yellow solid.

Step 8. A stirred solution of 9-ethyl-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (0.1 g, 3.84 mmol , 1 eq.) in DMF (20 ml) at -10°C was treated with portions of solid N-bromosuccinimide (0.684 g, 0.47 mmol, 1 eq.) for more than 10 min. The reaction mixture was allowed to warm to room temperature. pace. And stirred for 1 h. After completion of the reaction (the reaction was monitored by TLC), the reaction mixture was diluted with EtOAc (50 ml) and the organic layer was washed with water (5x10 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 230-400 mesh; 5% MeOH/DCM; R _f -value -0.3) to give 8-bromo-9-ethyl-7-fluoro-1,4,4-trimethyl-4 ,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g, 93%) as a white metallic solid.

¹ H NMR (400 MHz; DMSO-06, 20°C): δ 6.93 (s, 1H), 6.78-6.81 (1H), 2.80-2.93 (2H), 2, 38 (s, 3H), 1.43 (br s, 6H), 0.95-0.98 (3H).

Synthesis of 1-benzyl-8-bromo-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-13):

Step 1. To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (1.5 g, 6.571 mmol, 1 eq.) in n-BuOH (25 ml) 2-phenylacetohydrazide (3.25 g, 21.685 mmol, 3.3 eq.) was added followed by the addition of acetic acid (2.5 ml) and then the reaction mixture was stirred at 140° C. for 16 h. the progress of the reaction was monitored by TLC), the reaction mixture was diluted with water (50 ml), was extracted with EtOAc (2x50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by combi-flash column chromatography (7% MeOH/DCM; R _f -value- 0.3) to give 1-benzyl-7,9-difluoro-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1 g, 47%) as white solid with a metallic tint.

- 62 043276

Step 2: A stirred solution of 1-benzyl-7,9-difluoro-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g, 3.067 mmol, 1 eq.) in DMF (8 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (0.573 g, 3.22 mmol, 1.05 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (the reaction progress was monitored by TLC), the reaction mixture was diluted with EtOAc (100 ml), the organic layers were washed with water (5x20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by combi-flash column chromatography (5% MeOH/DCM; _Rf -value-0.3) to give 1-benzyl-8-bromo 7,9-difluoro-4,4-dimethyl-4,5-dihydro[1, 2,4]triazolo[4,3-a]quinoxaline (0.8 g, 64.5%) as a white metallic solid.

1H NMR (400 MHz; DMSO-d6, 20°C): δ 7.15-7.26 (4H), 7.03-7.06 (2H), 6.72 (d, 1H), 4.36 (d, 2H), 1.48 (s, 6H).

Synthesis of 8-bromo-7,9-difluoro-4,4-dimethyl-1-(pyridin-4-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (intermediate B -14):

P|me^t "chno" mixing B-14

Step 1. To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (1.5 g, 6.5 mmol, 1 eq.) in n-BuOH (50 ml) was added pyridin-4-yl-acetic acid hydrazide (3.27 g, 21 mmol, 3.3 eq.) followed by the addition of acetic acid (5 ml), and then the reaction mixture was stirred at 140°C for 16 h After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was diluted with water (100 ml), extracted with EtOAc (2x100 ml), the combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH/DCM; R _f -value -0.5) to give 7,9-difluoro-4,4dimethyl -1-(pyridin-4-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1 g, 47%) as a white metallic solid.

Step 2. A stirred solution of 7,9-difluoro-4,4-dimethyl-1-(pyridin-4-ylmethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1 g, 3.05 mmol, 1 eq.) in DMF (30 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (0.598 g, 3.36 mmol, 1.1 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 16 h. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was diluted with water (100 ml), was extracted with EtOAc (3x50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH/DCM; Rf-0.4) to give 8-bromo-7,9-difluoro-4,4-dimethyl-1-(pyridin-4-ylmethyl )-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.48 g, 39%) as a brown solid.

1H NMR (400 MHz; DMSO-d6, 20°C): δ 8.38-8.41 (2H), 7.55 (d, 1H), 7.55 (d, 1H), 7.29 (dd , 1H), 7.24 (s, 1H), 6.77 (d, 1H), 4.34-4.36 (2H), 1.49 (s, 6H).

Synthesis of 8-bromo-7,9-difluoro-4,4-dimethyl-1-(pyridin-3-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B -15):

Step 1. To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (1.5 g, 6.5 mmol, 1 eq.) in n-BuOH (50 mL) pyridin-3-yl-acetic acid hydrazide compound (3.27 g, 21 mmol, 3.3 eq.) was added followed by addition of acetic acid (5 mL) and then the reaction mixture was stirred at 140° C. for 16 h. After completion of the reaction (the reaction progress was monitored by TLC), the reaction mixture was diluted with water (100 ml), extracted with EtOAc (2x100 ml), the combined organic layer was washed with water (100 ml), brine (100 ml), dried over anhydrous

- 63 043276

Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH/DCM; R _f -value -0.5) to give 7,9-difluoro-4,4-dimethyl1 -(pyridin-3-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.3 g, 47%) as a white metallic solid.

Step 2. A stirred solution of 7,9-difluoro-4,4-dimethyl-1-(pyridin-3-ylmethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1 g, 3.05 mmol, 1 eq.) in DMF (30 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (0.598 g, 3.36 mmol, 1.1 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 16 h. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was diluted with water (100 ml), was extracted with EtOAc (3x50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH/DCM; _Rf -value-0.4) to give 8-bromo-7,9-difluoro-4,4-dimethyl-1-(pyridine- 3-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (0.8 g, 65%) as a brown solid.

¹ H NMR (400 MHz; DMSO-d ₆ , 20°C): δ 8.44 (d, 1H), 7.25 (s, 1H), 7.14 (d, 2H), 6.76 (d , 1H), 4.37-4.39 (2H), 1.49 (s, 6H), 1.123 (s, 3H).

Synthesis of 8-bromo-7,9-difluoro-4,4-dimethyl-1-(pyridin-2-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B -16):

Stage-! Prozheyaetochnove evedinenie V-I

Step 1. To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thioneα (1.5 g, 6.5 mmol, 1 eq.) in n-BuOH (50 mL) pyridin-2-yl-acetic acid hydrazide compound (3.27 g, 21 mmol, 3.3 eq.) was added followed by addition of acetic acid (5 mL) and then the reaction mixture was stirred at 140° C. for 16 h. After completion of the reaction (the reaction was monitored by TLC), the reaction mixture was diluted with water (100 ml), extracted with EtOAc (2x100 ml), the combined organic layer was washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH/DCM; R _f -value -0.5) to give 7.9difluoro-4,4- dimethyl-1-(pyridin-2-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.3 g, 14%) as white metallic solid .

Step 2. A stirred solution of 7,9-difluoro-4,4-dimethyl-1-(pyridin-2-ylmethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1 g, 3.05 mmol, 1 eq.) in DMF (30 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (0.598 g, 3.36 mmol, 1.1 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 16 h. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was diluted with water (100 ml), was extracted with EtOAc (3x50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh; 10% MeOH/DCM; R _r value -0.4) to give 8-bromo-7,9-difluoro-4,4-dimethyl-1-(pyridine-2 -ylmethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.3 g, 56%) as a brown solid.

Synthesis of 8-bromo-7-fluoro-1-(methoxymethyl)-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B-17):

Shch "International connection B-17

Step 1 To a stirred solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (4.5 g, 20.09 mmol, 1 eq.) in cyclohexanol (20 mL ) was added 2-methoxyacetohydrazide (2.5 g, 24.10 mmol, 1.2 eq.). The reaction mixture was then stirred at 160° C. for 6 hours. The reaction mixture was cooled to room temperature. temp., diluted with EtOAc (100 ml) and washed with water (2x50 ml) followed by washing with saline (50 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give crude material which was purified with silica gel (230-400)

- 64 043276 column chromatography (5% MeOH/DCM; _Rg value-0.4) to give 7-fluoro-1-(methoxymethyl)4,4,9-trimethyl-4,5-dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline (1.1 g, 20%) as a white solid with a metallic tint.

Step 2. A stirred solution of 7-fluoro-1-(methoxymethyl)-4,4,9-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.1 g, 3, 96 mmol, 1 eq.) in DMF (12 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (0.744 g, 4.18 mmol, 1.05 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (the reaction was monitored by LC-MS), the reaction mixture was diluted with EtOAc (100 ml), the organic layers were washed with water (5x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; _Rg value-0.3) to give 8-bromo7-fluoro-1-(methoxymethyl)-4,4,9-trimethyl-4, 5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g, 71%) as a white metallic solid.

Synthesis of (8-bromo-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-1-yl) MeOH (intermediate B- 18):

sn o ^he '

I n II, y-Ts „ with JL *'· ΗL 4 h ί| Ί Ϊ ¹¹ - π Ί Τ>”' ^: Ί Ί ' HJ Tsshlottzlgl ji ' Stzhia-2 ^Λ F' IFFl

Stage-1H

F^t^t^tam! swedineshge B-18

Step 1 To a stirred solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (See Synthesis Example 69) (7.7 g, 34.37 mmol, 1 eq.) in cyclohexanol (34.4 ml) was added 2hydroxyacetohydrazide (3.77 g, 42.25 mmol, 1.2 eq.). The reaction mixture was stirred at 160° C. for 6 hours. The reaction mixture was cooled to room temperature. temp., diluted with EtOAc (34.4 ml) and washed with water (2x50 ml) followed by washing with saline (50 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material, which was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; R _g value -0.3) to obtain (7-fluoro- 4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-1-yl) MeOH (0.95 g, 11%) as a white solid with metallic tint.

Step 2: A stirred solution of (7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-1-yl) MeOH (1.745 g, 6.66 mmol, 1 eq.) in DMF (25 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (1.24 g, 6.99 mmol, 1.05 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (the reaction was monitored by LC-MS), the reaction mixture was diluted with EtOAc (150 ml), the organic layers were washed with water (5x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel (230400) column chromatography (5% MeOH/DCM; Rd-O.3) to give (8-bromo-7-fluoro-4,4,9trimethyl-4,5-dihydro[1,2,4 ]triazolo[4,3-a]quinoxalin-1-yl) MeOH (1.45 g, 63.8%) as a white metallic solid.

Synthesis of 1-(8-bromo-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)ethanol (intermediate compound B-19):

Step 1. To a stirred solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (6.5 g, 29 mmol, 1 eq.) in THF (36 ml) at hydrazine hydrate (7.25 ml, 145 mmol, 5 eq.) was added dropwise at 0°C. The reaction mixture was stirred for 16 hours at room temperature. pace. TEA (19.73 ml, 145 mmol, 5 eq.) was added to the reaction mixture and stirred for an additional 10 minutes. 2(Benzyloxy)propanoyl chloride (7.5 ml, 72.5 mmol, 2.5 eq.) was added very slowly to the reaction mixture at 0° C. and then stirred for 2 h at room temperature. pace. The reaction mixture was quenched with water

- 65 043276 (50 ml) and extracted with DCM (3x100 ml). The combined organic layers were washed with brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by washing with diethyl ether to give

2-(benzyloxy)-N'-(6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1 H)-ylidene) propanehydrazide (7.5 g,

67%) as a white solid with a metallic tint.

Step 2 2-(benzyloxy)-N'-(6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)ylidene)propanehydrazide (2.5g, 6.51mmol, 1 eq.) was transferred to a round bottom flask (50 ml), then cooled to -10°C. Phosphorus oxychloride (6.23 ml, 65.1 mmol, 10 eq) was then added dropwise to the compound followed by TEA (0.903 ml, 6.51 mmol, 1 eq) dropwise. After that, the reaction mixture was stirred at -10°C for 10 min, and then 10 min at room. pace. and finally at reflux for 4 hours. The reaction mixture was cooled to 0°C and then added dropwise to crushed ice with constant stirring. Cold ammonia solution (100 ml) was slowly added to this aqueous portion. The aqueous part was extracted with DCM (2x100 ml). The combined organic layers were washed with brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography (silica gel 230-400 mesh; 5% MeOH/DCM; Rf-value 0.4) to give 1-(1-( benzyloxy)ethyl)-7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (1.0 g, 42%) as a yellow solid .

Step 3. Stirring solution of 1-(1-(benzyloxy)ethyl)-7-fluoro-4,4,9-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2, 5 g, 6.83 mmol, 1 eq.) in MeOH (250 ml) was well deoxygenated with Ar for 10 min. Pd/C (0.5 g) was added to the reaction mixture and the mixture was again deoxygenated for 10 minutes. Finally, the reaction mixture was placed in a Parr apparatus. The reaction mixture was shaken at rt. pace. for 24 hours under a hydrogen atmosphere at 50 psi. inch. The reaction mixture was filtered through a pad of celite and washed with MeOH (100 ml), the filtrate was concentrated under reduced pressure to give pure 1-(7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo [4,3a]quinoxalin-1-yl)ethanol (1.0 g, 53%) as a white solid.

Step 4 Stirred solution of 1-(7-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-1-yl)ethanol (1.0 g , 3.8 mmol, 1 eq.) in DMF (15 ml) at -10°C was treated in portions over 10 min with solid N-bromosuccinimide (0.71 g, 3.99 mmol, 1.05 eq.). The reaction mixture was allowed to warm to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (the reaction was monitored by LC-MS), the reaction mixture was diluted with EtOAc (100 ml), the organic layers were washed with water (5x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; R _g value -0.3) to give 1-(8-bromo-7-fluoro-4,4,9trimethyl-4,5-dihydro [1,2,4]triazolo[4,3-a]quinoxalin-1-yl)ethanol (0.95 g, 70%) as a white metallic solid.

Synthesis of 8-bromo-7-fluoro-1-(2-methoxyethyl)-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B-20 ):

„ . B-MI Interconnection

Stiya-1 ‘

Step 1. To a stirred solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (3.0 g, 13.5 mmol, 1 eq.) in THF (18 ml ) was added dropwise hydrazine hydrate (3 ml, 67.56 mmol, 5 eq.) at 0°C. The reaction mixture was then stirred for 16 hours at room temperature. pace. TEA (15 ml, 94.57 mmol, 7 eq.) was added to the reaction mixture and stirred for an additional 10 minutes. 3-Methoxypropanoyl chloride (4.9 g, 40.5 mmol, 3 eq.) was added very slowly at 0° C. and then stirred for 2 h at room temperature. pace. The reaction mixture was quenched with water (50 ml) and extracted with DCM (3x100 ml). The combined organic layers were washed with brine (100 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give crude material, purified by washing with diethyl ether to give N'-(6-fluoro-3,3,8-trimethyl-3,4dihydroquinoxaline-2(1H)-ylidene )-3-methoxypropanehydrazide (2.5 g, 60%) as a white solid with a metallic tint.

Step 2 and Step 3 N'-(6-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-ylidene)-3methoxypropanehydrazide was converted to intermediate B-20 following the general synthetic route, described for intermediate B-12 (step 2 and step 3).

¹ H NMR (400 MHz; DMSO-de, 20°C): δ 6.81-6.87 (2H), 3.60 (m, 2H), 3.15 (s, 3H), 2.37 ( s, 3H), 1.20-1.65 (8H).

- 66 043276

Synthesis of 8-bromo-1-(cyclopropylmethyl)-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B-21):

Important information B-21

Step 1. To a solution of 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (4 g, 13.79 mmol, 1 eq.) in toluene (50 ml) added Lausson's reagent (8.36 g, 20.69 mmol, 1.5 eq.) at room. temp., and the reaction mixture was refluxed at 120°C for 40 min. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ (50 ml) followed by extraction with EtOAc (3x75 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 15% EtOAc/hexane; R _f -value-0.3) to give 7-bromo-6,8-difluoro-3,3-dimethyl3,4-dihydroquinoxaline-2(1H)-thione (3.1 g, 73%) as a yellow solid substances.

Step 2. To a solution of 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (0.5 g, 1.63 mmol, 1 eq.) in n -BuOH (10 ml) was added 2-cyclopropylacetohydrazide (0.614 g, 5.39 mmol, 3.3 eq.) followed by the addition of acetic acid (1 ml), and then the reaction mixture was stirred at 140°C for 16 h. After reaction was completed (reaction progress was monitored by TLC), the reaction mixture was diluted with water (20 ml), extracted with EtOAc (3x30 ml). The combined organic layers were washed with water (30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; EtOAc; R _f -value -0.2) to obtain 8-bromo-1-(cyclopropylmethyl)-7,9difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0 .35 g, 79%) as a white solid.

Synthesis

a] quinoxaline (intermediate B-22):

8-bromo-1-cyclopropyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-

Starting from 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-thione and cyclopropanecarbohydrazide, intermediate B-22 was synthesized similarly to the synthesis described for intermediate B-21 (step 2).

Synthesis of 8-bromo-1,4,4,9-tetramethyl-7-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-23):

I; Reagent. , g | 11 ' v Jivczchi 1 h .i-ι . ^g '

........ , I - : .γI ___, DMF4.v5p saltier g Ί, . Toluene [ 1 tt-l..lge * * "1

Х-Р „ , ' · h ¹ 12 « ΡΛ - '

- ^F - Stage-1 >·

Stage-2

E-|( 'H *

Prvme "t" chzh "e connection B-23

Starting from 2-bromo-6-methyl-4-(trifluoromethyl)aniline, Intermediate B-23 was synthesized analogously to the synthesis described for Intermediate B-4 (Step 2-Step 6).

Intermediates in the table. 3 was synthesized similarly to the synthesis depicted in reaction scheme 1.

b - 'II'

And Stage-3 ^e j Σ . j Steal—

'.RS J..»A ί G ^G ' _β ____________________ * II

Stage-3 - . - 67 043276

Table 3

intermediate connection Structure NMR Intermediate, connection B-24 F Υ= ^Ν » Η ¹ 'H NMR (DMSO-d _b ) δ: 6.94 (d, 1H), 6.58 (d, 1H), 3.85 (s, 3H), 2.49 (d, 3H), 1.47 (s, 6H) Intermediate, connection B-25 ^Χ Ο \== ^β \1κ Υ Υ Η N r ^N 'H NMR (DMSO-d ₆ ) δ: 7.00 (s, br), 6.77 (d, 1H), 3.61 (s, 3H), 2.47 (s, 3H), 1.47 (s, 6H) Intermediate, connection B-26 F Λ ΒαΑα Υ γ Η N 'H NMR (DMSO-d ₆ ) δ: 7.15 (s, SH), 7.04 (s, 1H), 2.52 (s, 3H), 1.48 (s, 6H). Intermediate, connection B-27 ^f Υ=ν Br-x Υ. \ η ъ Η 'H NMR (DMSO-d ₆ ) δ: 7.29 (t, W), 7.19 (d, 1H), 6.81 (s, 1H), 2.52 (d, 3H), 1.48 (s, 6H) Intermediate, connection B-29 ^f V* YL F ^H L NMR (DMSO-%) δ: 7.24 (d, 1H), 7.14 (d, 1H), 7.12 (t, 1H), 2.54 (d, 3H), 1.49 (s , 6H) Intermediate, connection B-31 ι X ^N > ΛΑ Η 'H NMR (DMSO-d ₆ ) δ: 6.85 (s, SH), 6.48 (s, 1H), 2.39 (s, 3H), 2.35 (s, 3H), 2.33 (s, 3N), 1.42 (s, 6H) Intermediate, connection B-32 ^F 4 ^F yN ^βγ \Υ^ ^ν Υ ^ν ^lxx Η 'H NMR (DMSO-d ₆ ) δ: 7.24 (s, SH), 6.94 (s, 1H), 3.87 (s, 3H), 2.32 (s, 3H), 1.69 (s, ZN), 1.23 (s, ZN). Intermediate, connection B-33 1 ^βγ ^^ ^ν ^ ^ν XX X Υ 'H NMR (DMSO-Db) δ: 7.07 (s, br), 6.82 (s, 1H), 2.39 (s, 6H), 1.43 (br, 6H). Intermediate, connection B-34 FROM ΙΖ L NMR (CDC1 ₃ ) δ: 6.60 (s, 1H), 4.06 (br, 1H), 2.62 (d, 3H), 2.37 (s, 3H), 1.59 (s, 6H). Intermediate, connection B-35 1 Br^ -Ν Υ ^Ν χ XX χ L NMR (DMSO-d ₆ ) δ: 7.22 (t, SH), 6.84 (s, 1H), 6.83 (s, 1H), 2.40 (s, 3H), 2.39 ( s, 3N), 1.44 (s, 6H) Intermediate, connection B-36 1 εγχι,μυ f 1 ^{n 3} H NMR (DMSO-Db) δ: 6.61 (s, 1H), 6.59 (s, 1H), 3.81 (s, 3H), 2.33 (s, 3H), 2.32 ( s, 3N), 1.41 (br, 6H). Intermediate, connection B-37 1 Χ ^Ν ' _ΒΓ χΐ _Ν ХЦ- 4f ^Η L NMR (DMSO-d ₆ ) δ: 7.01 (s, 1H), 6.95 (s, 1H), 2.40 (s, 6H), 1.43 (br, 6H).

- 68 043276

Synthesis

8-bromo-9-(difluoromethyl)-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B-28):

BUT;

F

F,

Eb#, ladies,

Article-.!

OsN

Sgadia-2

7--1 HCl

^CHFj DXM id

CHF _Z ,Υ "he kjpo _4< c"ei. dmso

Stage-4

Luoshn's reagent

Stage-5 F' ' } AcCi, TEA

Stage-6

Strgshpya-3

PQCh. TEA

Stage-7

F _{4 X} F

Step 1 To a stirred solution of 5-fluoro-2-nitro-benzaldehyde (20.0 g, 118.27 mmol) in DCM (600 ml) was added DAST (23.3 ml, 177.51 mmol) at 0°C. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, the reaction mixture was quenched to sat. NaHCO ₃ solution and extracted with DCM (2x500 ml). The combined organic layers were washed with water (500 ml) followed by brine (500 ml), then dried over anhydrous Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography using 23% EtOAc/hexane to give 2-difluoromethyl-4-fluoro-1-nitrobenzene (22.0 g, 88%) as a yellow liquid.

Step 2 To a stirred solution of 2-difluoromethyl-4-fluoro-1-nitrobenzene (22.0 g, 115.16 mmol) in ethanol (372 ml) was added SnCl ₂ -2H ₂ O (103.7 g, 460 .46 mmol) followed by the addition of conc. HCl (76 ml) at 0°C. The reaction mixture was stirred at ambient temperature for 2 hours. After completion of the reaction, the reaction mixture was concentrated, the residue was made basic with 5N NaOH solution and extracted with MTBE (2x500 ml). The combined organic layers were washed with water (500 ml) followed by brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude material was purified by column chromatography using 23% EtOAc/hexane to give 2-difluoromethyl-4-fluoro-phenylamine (12.5 g, 41%) as a yellow gum.

Step 3 To a solution of 2-difluoromethyl-4-fluoro-phenylamine (8.0 g, 49.64 mmol) in DCM (150 ml) was added a solution of bromine (3.84 ml, 74.47 mmol) in DCM (100 ml ) dropwise at 0°C. The resulting reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction (the progress of the reaction was followed by TLC in 10% EA-hexane, Rf=0.7), the reaction mixture was quenched with saturated NaHCO ₃ solution. The two layers were separated, the aqueous layer was then extracted with DCM (2x200 ml). The combined organic layers were washed with water (2x500 ml) and brine (250 ml), then dried over anhydrous Na2SO4 and concentrated under reduced pressure. In parallel, three batches were prepared from this reaction, which were then combined to give the crude compound. This crude material was purified by column chromatography (silica gel 100-200 mesh and 5% EtOAc/hexane as eluent) to give 2-bromo-6-difluoromethyl-4-fluorophenylamine (18.0 g, 51%) as a white solid substances.

Step 4 To a stirred suspension of 2-bromo-6-difluoromethyl-4-fluoro-phenylamine (18.0 g, 73.77 mmol) in dry DMSO (270 ml) was added 2-amino-2-methyl-propionic acid (15 .2 g, 147.54 mmol) followed by addition of K3PO4 (31.31 g, 147.54 mmol) at ambient temperature. The resulting reaction mixture was degassed with nitrogen for 30 min, then copper chloride (730 mg, 7.37 mmol) was added and the reaction mixture was heated at 125° C. for 16 h. % EA-hexane, R _f 0.4), the reaction mixture was cooled to ambient temperature and filtered through celite. The Celite layer was washed with EtOAc (2x200 ml). The resulting filtrate was poured into ice-cold water (500 ml). The resulting aqueous layer was extracted with EtOAc (2x250 ml). The combined organic layers were washed with water (3x200 ml) and brine (400 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain a crude mixture. The crude mixture was purified by column chromatography (silica gel 100-200 mesh and 15% EtOAc/hexane as eluent) to give 8-difluoromethyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxαlin-2-one (9 .0 g, 50%) as a brown solid.

Step 5 To a stirred solution of 8-difluoromethyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H

- 69 043276 quinoxalin-2-one (9.0 g, 36.88 mmol) in toluene (300 ml) Lausson's reagent (22.39 g, 55.32 mmol) was added at ambient temperature and the reaction mixture was then heated to 120°C for 3 hours After completion of the reaction (the reaction was followed by TLC in 20% EA-hexane, Rf 0.6), the reaction mixture was cooled to ambient temperature and then concentrated under reduced pressure. The resulting residue was quenched with sat. NaHCO ₃ solution (500 ml), the resulting aqueous layer was extracted with EtOAc (3x250 ml). The combined organic layers were washed with water (500 ml) and brine (250 ml), dried over anhydrous Na ₂ SO ₄ and then evaporated to dryness under reduced pressure. The crude material was purified by column chromatography (silica gel 100-200 mesh and 20% EtOAc/hexane as eluent) to give 8-difluoromethyl-6-fluoro-3,3-dimethyl-3,4dihydro-1H-quinoxaline-2-thione (9 .0 g, 94%) as a yellow solid.

Step 6 To a stirred solution of 8-difluoromethyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1Hquinoxaline-2-thione (9.0 g, 34.57 mmol) in THF (60 ml) was added drops of hydrazine hydrate (5.19 g, 103.73 mmol) at 0°C. The reaction mixture was stirred at room temperature for 16 hours. TEA (24.2 ml, 172.89 mmol) followed by the addition of acetyl chloride (7.4 ml, 103.73 mmol) to the reaction mixture dropwise at 0°C, and the resulting reaction mixture was then stirred for 2 h at ambient temperature environment. After completion of the reaction (the progress of the reaction was followed by LC-MS), the reaction mixture was diluted with water and extracted with 10% MeOH-DCM (5x100 ml). The combined organic layers were washed with brine, dried over Na ₂ SO ₄ and concentrated under reduced pressure to give (8-difluoromethyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1Hquinoxalin-2-ylidene)-acetic hydrazide acid (9.0 g, 87%, crude) as a pale yellow solid.

Step 7. Acetic acid (8-difluoromethyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-ylidene)-hydrazide (9.0 g, 30 mmol) in a round bottom flask was cooled to -10°C. Phosphorus oxalyl chloride (13.98 mL, 150 mmol) was added dropwise followed by triethylamine (4.2 mL, 30 mmol) dropwise. The reaction mixture was stirred at -10°C for 10 min, and then 10 min at room temperature. pace. and finally at reflux for 2 hours. After completion of the reaction (the progress of the reaction was followed by LC-MS), the reaction mixture was cooled to 0°C and quenched with crushed ice in water (200 ml). The aqueous portion was then made alkaline by dropwise addition of cold aqueous ammonia (500 ml). The resulting alkaline aqueous layer was then extracted with EtOAc (3x250 ml). The combined organic layers were washed with saturated aqueous sodium chloride, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give the crude product. The resulting crude material was co-distilled twice with MTBE, then triturated with hexane and dried to give 9-difluoromethyl-7-fluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxaline (4.5 g, 53%) as a pale yellow solid.

Step 8 To a solution of 9-difluoromethyl-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (11.0 g, 39.0 mmol ) in DMF (180 ml) was added NBS (7.2 g, 40.2 mmol) in portions at 0°C. The resulting reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction (reaction progress was monitored by LC-MS), the reaction mixture was diluted with water (400 ml), extracted with EtOAc (2x400 ml). The combined organic layers were washed with water (2x200 ml) and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by column chromatography (silica gel 100-200 mesh and 5% MeOH/DCM as eluent) to give 8-bromo-9-difluoromethyl-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1 ,2,4]triazolo[4,3a]quinoxaline (7.2 g, 65%) as a white metallic solid.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 6.91-6.64 (m, 2H), 4.58 (s, 1H), 2.56 (s, 3H), 1.58 (br s, 3H), 1.24 (br. s, 3H).

Synthesis of 8-bromo-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-40):

Step 1: Suspension of 2-bromo-6-methylaniline (1.0 g, 54.0 mmol, 1.0 eq.), 2-aminobutyric acid (1.1 g, 10.8 mmol, 2.0 eq.) Ar was deoxygenated in DMSO (10 ml) in a hermetically sealed vessel for 20 min. K ₃ PO ₄ (2.3 g, 10.8 mmol, 2.0 eq.), CuCl (53.0 mg, 5.4 mmol, 0.1 eq.) was then added. The reaction mixture was then stirred at 140° C. for 16 hours. After completion of the reaction, the reaction mixture was filtered through a pad of celite and the pad of celite was washed with EtOAc (100 mL). The filtrate was diluted with EtOAc (100 ml), washed with water (3x150 ml) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and then evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc/hexane; Rf-value-0.4) to give 3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.6 g, 60%).

Step 2 To a solution of 3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (7.0 g, 36.0 mmol, 1.0 eq.) in toluene (75 ml) was added the reagent Lausson (22.0 g, 55 mmol, 1.5 eq.) at ambient temperature and the reaction mixture was then refluxed at 120° C. for 40 minutes. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ solution (100 ml) followed by extraction with EtOAc (2x100 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give the crude compound, which was purified by column chromatography (230-400 mesh silica gel; 20% EtOAc/hexane ; R _f -value -0.4) to give 3,3,8trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (5.0 g, 66%) as a yellow solid.

Step 3 To a stirred solution of 3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)thione compound (5.0 g, 62.4 mmol, 1 eq.) in THF (30 ml) was added dropwise hydrazine hydrate (6.0 ml, 121.0 mmol, 5 eq.) at 0°C. The reaction mixture was then stirred for 16 hours at ambient temperature. TEA (16.5 ml, 122.7 mmol, 5 eq.) was then added to the reaction mixture and the reaction mixture was stirred for an additional 10 minutes. Acetyl chloride (5.65 g, 73.65 mmol, 3 eq.) was then added to the reaction mixture very slowly at 0° C. and the resulting reaction mixture was then stirred for 2 hours at ambient temperature. The reaction mixture was then diluted with water (50 ml) and extracted with DCM (5x100 ml). The combined organic layers were washed with brine (100 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give the crude material, purified by washing with diethyl ether to give N'-(3,3,8trimethyl-3,4-dihydroquinoxaline-2 (1H)-ylidene)acetohydrazide (2.0 g, 34%) as a white solid.

Step 4. N'-(3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-ylidene)acetohydrazide (6.0 g, 24 mmol, 1 eq) was transferred to a round bottom flask (50 ml) , then cooled to -10°C. Phosphorus oxychloride (23.0 ml, 243 mmol, 10 eq) was then added dropwise to the compound followed by TEA (3.5 ml, 24 mmol, 1 eq) dropwise. Thereafter, the reaction mixture was stirred at -10°C for 10 min and then 10 minutes at ambient temperature and finally at reflux for 4 h. The reaction mixture was then cooled to 0°C and then added dropwise into crushed ice in water with constant stirring. Then cold ammonia solution (100 ml) was slowly added thereto. The aqueous portion was then extracted with DCM (2x100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound, which was purified by column chromatography (silica gel 230-400 mesh; 5% MeOH/DCM; R _f -value- 0.4) to give 1,4,4,9tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3.2 g, 58.6%) as a yellow solid substances.

Step 5. A stirred solution of 1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (3.2 g, 14 mmol, 1.00 eq) in DMF (40 ml) at -10° C. was treated with solid N-bromosuccinimide (2.7 g, 15 mmol, 1.05 eq.) in batches over 10 min. The reaction mixture was allowed to warm to ambient temperature and then stirred for 1.5 h. After completion of the reaction (the reaction was monitored by LC-MS), the reaction mixture was diluted with EtOAc (300 ml), washed with water (5x50 ml) and saline solution (50 ml), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give the crude compound, which was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; R _f -value-0.3) to give 8- bromo1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2.0 g, 48%) as a white metallic solid.

Synthesis of 8-bromo-9-cyclopropyl-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-а]quinoxaline (intermediate B-44):

- 71 043276

Step 1: 2-Bromo-4-fluoro-phenylamine (20.0 g, 0.105 mol) was dissolved in acetic anhydride (10 ml) at 10° C. and stirred at ambient temperature for 3 hours. reaction was monitored by TLC, 10% ethyl acetate/hexane) the thick reaction mass was diluted with n-hexane and filtered. The solid was washed with n-hexane and then dried under vacuum to give N-(2-bromo-4-fluorophenyl)acetamide (20.0 g, 82%) as a white solid with a metallic tint.

Step 2 To a stirred solution of N-(2-bromo-4-fluoro-phenyl)acetamide (65.0 g, 0.28 mol) in toluene-water (1:1, 1.3 L) was added tricyclohexylphosphine (7 .85 g, 0.03 mol) followed by the addition of K ₃ PO ₄ (208.2 g, 0.98 mol) at ambient temperature. This mixture was then degassed with Ar for 30 minutes. Cyclopropylboronic acid (31.2 g, 0.37 mol) was added followed by Pd(OAc)2 (3.2 g, 0.01 mol) and the reaction mixture was heated to 100°C for 16 h. material (reaction followed by TLC, 20% EAhexane, R _f 0.4) the reaction mixture was cooled to ambient temperature, diluted with EtOAc (1 L), washed with water (2x500 ml) followed by washing with brine (500 ml) , then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude compound. The resulting crude compound was purified by column chromatography (silica gel 100-200 mesh and 15-20% EtOAc/hexane as eluent) to give N-(2-cyclopropyl-4-fluorophenyl)acetamide (51.5 g, 95%) as a brownish solid.

Step 3 A stirred suspension of N-(2-cyclopropyl-4-fluorophenyl)acetamide (4) (52.0 g, 0.269 mol) in HCl (2.1 L, 2 M) was heated to 90° C. for 16 hours After completion of the reaction (the progress of the reaction was followed by TLC, 20% EA-hexane, R _f 0.6), it was cooled to ambient temperature and basified to pH ~13-14 with NaOH solution (2 M). The mixture was extracted with EtOAc (1 L). The organic layer was then washed with water (2x500 ml) and brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 2-cyclopropyl-4-fluorophenylamine (40.0 g, crude) as dark brown liquid.

Step 4 To a stirred solution of 2-cyclopropyl-4-fluoro-phenylamine (20.0 g, 0.132 mol) in DMF (350 ml) was added NBS (85.0 g, 0.477 mol) portionwise at -10°C. The resulting reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction (the reaction progress was monitored by TLC, 20% EtOAc/hexane), the reaction mixture was diluted with water (1 l), extracted with MTBE (2x750 ml). The combined organic layers were washed with cold brine (3x500 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel 100-200 mesh and 5-10% EtOAc/hexane as eluent) to give 2-bromo-6-cyclopropyl-4-fluoro-phenylamine (20.2 g, 65% over two steps). ) as a brownish liquid.

Step 5 To a stirred suspension of 2-bromo-6-cyclopropyl-4-fluoro-phenylamine (20.0 g, 86.88 mmol) in dry DMSO (300 ml) was added 2-amino-2-methylpropionic acid (17.9 g, 173.94 mmol) followed by the addition of K ₃ PO ₄ (36.9 g, 173.94 mmol) at ambient temperature. The resulting reaction mixture was degassed with Ar for 30 min. CuCl (860 mg, 8.69 mmol) was then added and the _reaction mixture was heated to 140° C. for 16 h. ) the reaction mixture was cooled to ambient temperature and filtered through a pad of celite. The Celite layer was washed with EtOAc (500 ml). The organic layer s was washed with water (2x750 ml) and brine (500 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain a crude material. The resulting crude material was purified by column chromatography using 15-72 043276

20% EtOAc-hexane to give 8-cyclopropyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (10.1 g, 50%) as a brown solid.

Step 6 To a solution of 8-cyclopropyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (10.0 g, 42.7 mmol) in toluene (200 ml) was added Lausson's reagent (25.9 g, 64.1 mmol) at ambient temperature, and the reaction mixture was refluxed at 120°C for 1 h. hexane, Rf 0.7) the reaction mass was cooled to ambient temperature and extinguished with a saturated solution of NaHCO ₃ (35 ml). The resulting aqueous layer was extracted with EtOAc (3x500 ml). The combined organic layers were washed with water (500 ml) followed by brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude material. The resulting crude material was purified by column chromatography (using silica gel 100-200 mesh and 5-10% EtOAc/hexane) to give 8-cyclopropyl-6-fluoro-3,3-dimethyl-3,4-dihydro-III-quinoxaline-2- thione (9.5 g, 89%) as a yellow solid.

Step 7 To a stirred solution of 8-cyclopropyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1Hquinoxaline-2-thione (9.0 g, 36.0 mmol) in THF (216 ml) was added drops of hydrazine hydrate (5.3 ml, 108 mmol) at 0°C. The reaction mixture was then stirred at ambient temperature for 16 hours. TEA (30.2 ml, 216.0 mmol) followed by the addition of acetyl chloride (10.3 ml, 144.0 mmol) was then added dropwise to the reaction mixture at 0° C, and the reaction mixture was stirred for 2 h at ambient temperature. After completion of the reaction (the progress of the reaction was followed by LC-MS) the reaction mixture was diluted with water (300 ml), was extracted with EtOAc (2x500 ml). The combined organic layers were washed with brine (300 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give [8-cyclopropyl-6-fluoro-3,3-dimethyl-3,4dihydro-1H-quinoxaline-(2E) -ylidene]-hydrazide acetic acid (9.0 g, crude) as a pale yellow solid.

Step 8. [8-Cyclopropyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxaline-(2E)-ylidene]-acetic acid hydrazide (6.0 g, 20.66 mmol) transferred to a round bottom flask and cooled to -10°C. Phosphorus oxalyl chloride (9.7 ml, 103.32 mmol) was added thereto and the mixture was stirred at -10° C. for 15 minutes. TEA (2.9 ml, 20.66 mmol) was slowly added to the reaction mixture at -10° C. and the mixture was stirred for 15 minutes. The reaction mixture was then stirred at ambient temperature for 15 min followed by heating to 120° C. for 1.5 h. crushed ice in water and alkalized (pH ~ 8-9) using an aqueous solution of ammonia. The resulting alkaline aqueous layer was extracted with EtOAc (2x500 ml). The combined organic layers were washed with water (500 ml) followed by brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The residue was triturated with 50% MTBE-hexane (50 ml x 2) to give 9-cyclopropyl-7-fluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (5.0 g, crude) as a pale yellow solid.

Step 9: To a stirred solution of 9-cyclopropyl-7-fluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (5.0 g, 18.36 mmol) in DMF (80 ml) was added NBS (3.4 g, 18.91 mol) in portions at -10°C. The resulting reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction (reaction progress was monitored by LC-MS), the reaction mixture was diluted with water (250 ml), extracted with EtOAc (2x250 ml). The combined organic layers were washed with cold brine (3x250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (silica gel 100-200 mesh and 30-35% acetone/hexane as eluent) to give 8-bromo-9-cyclopropyl-7fluoro-1,4,4-trimethyl-4,5-dihydro[ 1,2,4]triazolo[4,3-a]quinoxaline (1.2 g, 17% over three steps) as a white solid with a metallic tint.

¹ H NMR (400 MHz, DMSO-d6): δ 6.89 (s, 1H), 6.81-6.79 (t, 1H), 2.50-2.47 (d, 3H), 2, 08 (t, 1H), 1.67 (s, 3H), 1.37 (br, 1H), 1.10 (s, 3H), 0.92 (b, 1H) 0.82 (br, 1H) , 0.01 (br, 1H).

- 73 043276

Synthesis of 8-bromo-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-48):

Pr * Meldt "Chiv®" Unity B-48

Step 1 To a stirred suspension of 2-bromo-6-trifluoromethyl-phenylamine (25.0 g, 0.104 mol) in dry DMSO (375 ml) was added 2-amino-2-methyl-propionic acid (21.5 g, 0.208 mol ) followed by addition of K ₃ PO ₄ (44.2 g, 0.208 mol) at ambient temperature. The resulting reaction mixture was degassed with nitrogen for 30 min, then copper chloride (1.03 g, 0.010 mol) was added and the reaction mixture was heated to 140°C for 6 h. After consumption of the starting material (the reaction was monitored by TLC, 20% EA-hexane, Rf 0.4), the reaction mixture was cooled to ambient temperature and filtered through celite. The Celite layer was washed with EtOAc (2x250 ml). The resulting filtrate was poured into ice-cold water (800 ml). The resulting aqueous layer was extracted with EtOAc (2x500 ml). The combined organic layers were washed with water (2x650 ml) and brine (650 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain a crude material. The resulting crude material was triturated with MTBE-hexane to give 3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one (17.0 g, 66%) as a brown solid.

Step 2 To a solution of 3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-one (17.0 g, 0.07 mol) in toluene (300 ml) was added Lausson's reagent (42 .6 g, 0.105 mol) at ambient temperature and the _reaction mixture was then refluxed at 120° C. for 2 h. 6), the reaction mixture was quenched with sat. NaHCO ₃ solution (450 ml), the resulting aqueous layer was extracted with EtOAc (2x300 ml). The combined organic layers were washed with water (400 ml) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude compound. The resulting crude material was purified by column chromatography (silica gel 100-200 mesh and 10% EtOAc/hexane as eluent) to give 3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1Hquinoxaline-2-thione (17.0 g , 94%) as a yellow solid.

Step 3 To a stirred solution of 3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxaline2-thione (17.0 g, 0.065 mol) in THF (500 ml) was added hydrazine hydrate (9.8 g, 0.195 mol) dropwise at 0°C. The reaction mixture was then stirred at ambient temperature for 4 hours. TEA (63.7 ml, 0.455 mol) followed by the addition of acetyl chloride (20.4 g, 0.260 mol) was then added to the reaction mixture dropwise at 0°C and the resulting mixture stirred for 16 h at ambient temperature. After completion of the reaction (the progress of the reaction was followed by LC-MS), the reaction mixture was diluted with water (300 ml), extracted with 10% MeOH-DCM (2x300 ml). The combined organic layers were washed with brine (350 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to give (3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1Hquinoxalin-2-ylidene)-acetic hydrazide acid (16.0 g, crude) as a white solid with a metallic tint.

Step 4. Acetic acid (3,3-dimethyl-8-trifluoromethyl-3,4-dihydro-1H-quinoxalin-2-ylidene)-hydrazide (16.0 g, 0.053 mol) was transferred to a round bottom flask and then cooled to -10°C. Phosphorus oxalyl chloride (24.7 ml, 0.265 mol) was then added dropwise, followed by triethylamine (7.34 ml, 0.053 mol) added dropwise. After that, the reaction mixture was stirred at -10°C for 10 min, then left to warm at ambient temperature for 10 min, then heated to boiling for 4 h. After completion of the reaction (the reaction was followed by LC-MS) the reaction mixture was cooled to 0° C. and then quenched with crushed ice in water (300 ml). The aqueous portion was then made basic by adding cold aqueous ammonia (150 ml) dropwise. The resulting alkaline aqueous layer was then extracted with EtOAc (3x150 ml). United Organic

- 74 043276 the layers were washed with saline (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude compound. The resulting material was purified by column chromatography (silica gel 230-400 mesh and 5% MeOH/DCM as eluent) to obtain

1,4,4-trimethyl-9-trifluoromethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (5.0 g, 27% over two steps) as white solid with a metallic tint.

Step 5. To a solution of 1,4,4-trimethyl-9-trifluoromethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (4.8 g, 0.017 mol) in DMF ( 120 ml) was added NBS (3.3 g, 0.019 mol) in portions at 0°C. The resulting reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction (reaction progress was monitored by LC-MS), the reaction mixture was diluted with water (250 ml), extracted with EtOAc (2x150 ml). The combined organic layers were washed with water (2x180 ml) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound. The resulting crude compound was combined with another batch of the same reaction (using 5.0 g of 1,4,4-trimethyl-9-trifluoromethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline), then purified by column chromatography (silica gel 230-400 mesh and 5% MeOH/DCM as eluent) to give 8-bromo-1,4,4-trimethyl-9trifluoromethyl-4,5-dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline (5.3 g, 42% overall yield) as a white solid with a metallic tint.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.66-7.64 (d, 1H), 7.31 (s, 1H), 7.14-7.12 (d, 1H), 2 .34 (s, 3H), 1.70 (s,

3H), 1.21 (s, 3H).

Synthesis of 8-bromo-9-(difluoromethyl)-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-52):

L η

L

H(I

E..

Stage-1

Reagent

Yaausysha

Mon

Mp theft

ABOUT

K ₃ ROD, CII dmso Stage-2

P]»W»TVCH*e Details B-S1

Step 1 To a stirred solution of 2-amino-3-bromo-benzoic acid (100.0 g, 0.465 mol) in MeOH (1 L) was added conc. H2SO4 (100 ml) at 0°C and the mixture was heated to 80°C for 48 h. After completion of the reaction (the reaction was monitored by TLC, 5% EA-hexane, Rf 0.4), the reaction mixture was cooled to ambient temperature. The reaction mixture was then concentrated under reduced pressure, the resulting residue was made basic with sat. NaHCO ₃ solution (up to pH~8-9), then extracted with EtOAc (2x500 ml). The combined organic layers were washed with water (250 ml) and brine (250 ml), then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give 2-amino-3-bromo-benzoic acid methyl ester (80.0 g, 75%) as a brownish solid.

Step 2 To a stirred suspension of 2-amino-3-bromo-benzoic acid methyl ester (30.0 g, 0.131 mol) in dry DMSO (450 ml) was added 2-amino-2-methyl-propionic acid (27.1 g , 0.262 mol) followed by the addition of K ₃ PO ₄ (55.6 g, 0.262 mol) at ambient temperature. The resulting reaction mixture was degassed with nitrogen for 30 min, then copper chloride (1.29 g, 0.01 mol) was added and the reaction mixture was heated to 140°C for 4-5 h. using TLC, 20% EA-hexane, R _f 0.4) the reaction mixture was cooled to ambient temperature and filtered through celite. The Celite layer was washed with EtOAc (2x250 ml). The resulting filtrate was poured into ice-cold water (800 ml). The aqueous layer was extracted with EtOAc (2x500 ml). The combined organic layers were washed with water (2x650 ml) and brine

- 75 043276 solution (650 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain methyl 2,2-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylate (3 .0 g, crude). The aqueous layer was acidified with conc. HCl (pH~2-3) then extracted with EtOAc (2x500 ml). The combined organic layers were washed with brine (500 mL), dried over anhydrous Na2SO4 and evaporated under reduced pressure to give 2,2-dimethyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-5-carboxylic acid (15.0 G). This material was dissolved in MeOH (150 ml) followed by slow addition of conc. H ₂ SO ₄ (15 ml) at 0°C. The resulting reaction mixture was then stirred at 90° C. for 50 hours. The reaction mixture was concentrated and the resulting residue was basified with sat. NaHCO ₃ solution (pH~8-9) then extracted with EtOAc (2x250 ml). The combined organic layers were washed with water (150 ml) and brine (150 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to give methyl-2,2-dimethyl-3-oxo-1,2,3,4 -tetrahydroquinoxaline-5carboxylate (-13 g, crude). Combined batches of methyl 2,2-dimethyl-3-oxo-1,2,3,4tetrahydroquinoxaline-5-carboxylate were triturated with hexane to give 2,2-dimethyl-3-oxo-1,2,3,4tetrahydro-quinoxaline- 5-carboxylic acid methyl ester (13.1 g, 43%) as a brownish solid.

Step 3 To a stirred solution of 2,2-dimethyl-3-oxo-1,2,3,4-tetrahydro-quinoxaline-5carboxylic acid methyl ester (20.0 g, 85.47 mmol) in toluene (430 ml) was added Lausson's reagent (51.9 g, 128.21 mmol) at ambient temperature, and the reaction mixture was then heated to 120° C. for 2 h. Rf 0.6), the reaction mixture was quenched with sat. NaHCO ₃ solution (500 ml), the resulting aqueous layer was extracted with EtOAc (2x400 ml). The combined organic layers were washed with water (500 ml) and brine (300 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to give the crude compound. The resulting crude material was purified by column chromatography (silica gel 100-200 mesh, 7-8% EtOAc in hexane as eluent) to give 2,2-dimethyl-3-thioxo-1,2,3,4-tetrahydro-quinoxaline-5- carboxylic acid methyl ester (16.0 g, 75%) as a yellow solid.

Step 4 To a stirred solution of 2,2-dimethyl-3-thioxo-1,2,3,4-tetrahydro-quinoxaline-5carboxylic acid methyl ester (30.0 g, 0.12 mol) in THF (800 ml) was added hydrazine hydrate (10.6 ml, 0.22 mol) was added dropwise at 0°C, and the mixture was then stirred at ambient temperature for 10 h. TEA (60.3 ml, 0.43 mol) was then added to the reaction mixture. ) dropwise at 0°C followed by the addition of acetyl chloride (23.1 ml, 0.32 mol) and the resulting mixture was stirred for 4 h at ambient temperature. After completion of the reaction (the progress of the reaction was followed by LC-MS), the reaction mixture was diluted with water (500 ml), extracted with 10% MeOH-DCM (2x300 ml). The combined organic layers were then washed with brine (350 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting compound was then purified by column chromatography (silica gel 100-200 mesh and 1.5-2% MeOH in DCM as eluent) to give 3-(acetyl-hydrazono)-2,2-dimethyl-1,2,3,4- tetrahydro-quinoxaline-5-carboxylic acid methyl ester (20.1 g, 58%) as a white solid with a metallic tint.

Step 5. To 3-(acetyl-hydrazono)-2,2-dimethyl-1,2,3,4-tetrahydro-quinoxaline-5-carboxylic acid methyl ester (12.0 g, 41.35 mmol) was added acetic anhydride (200 ml), the resulting mixture was heated to 140°C for 8 hours After completion of the reaction (the reaction was followed by LCMS), the reaction mixture was concentrated under reduced pressure. The residue was diluted with EtOAc, washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude material was purified by column chromatography (100-200 mesh silica gel and 1.5-2% MeOH in DCM as eluent) to give 5-acetyl-1,4,4trimethyl-4,5-dihydro[1,2,4] methyl ester triazolo[4,3-a]quinoxaline-9-carboxylic acid (5.5 g, 42%) as a white solid with a metallic tint.

Step 6. Stirring solution of 5-acetyl-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline-9-carboxylic acid methyl ester (5.4 g, 0 ,12 mol) in 6N HCl (200 ml) was heated to 80°C for 6 hours. After completion of the reaction (the reaction was monitored by LC-MS), the reaction mixture was concentrated, the residue was subjected to azeotropic distillation with toluene (four times) followed by trituration with pentane ether to give 1,4,4-trimethyl4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-carboxylic acid methyl ester dihydrochloride salt (5.2 g , crude) as a greenish solid.

Step 7. To a stirred solution of 1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-carboxylic acid methyl ester dihydrochloride salt (2.5 g, 7. 25 mmol) in THF (70 ml) was slowly added lithium aluminum hydride (18.12 ml, 18.12 mmol, 2 M in THF) at 0°C, and the resulting reaction mixture was stirred at ambient temperature for 16 hours. After completion of the reaction (the progress of the reaction was followed by LC-MS) the reaction mixture was quenched with a saturated solution of Na ₂ SO ₄ and then filtered through a pad of celite. The Celite layer was then washed with hot THF (3x50 ml). The combined filtrates were concentrated under reduced pressure and

- 76 043276 then subjected to azeotropic distillation with toluene (3x50 ml) to obtain (1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-yl)methanol ( 1.9 g, crude) as a brownish solid.

Step 8. (1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-yl)methanol (2.2 g, 9.01 mmol) dissolved in THF-DCE (1:1, 65 ml). Manganese dioxide (4.7 g, 54.06 mmol) was added, the resulting reaction mixture was stirred at 80-90° C. for 48 h. and the Celite layer was washed with THF-DCE (1:1, 25 ml). The combined filtrate was concentrated under reduced pressure and the resulting crude material was purified by column chromatography (silica gel 100-200 mesh, 2-2.5% MeOH-DCM as eluent) to give 1,4,4-trimethyl-4,5-dihydro[ 1,2,4]triazolo[4,3a]quinoxaline-9-carbaldehyde (1.74 g, 80%) as a white metallic solid.

Step 9 To a stirred solution of 1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline-9-carbaldehyde (2.0 g, 8.25 mmol) in DMF (30 ml) was added NBS (1.5 g, 8.50 mmol) in portions at 0°C, and the resulting reaction mixture was then stirred at this temperature for 1 h. After completion of the reaction (the reaction was followed by LC-MS ), the reaction mixture was diluted with water (250 ml), was extracted with EtOAc (2x150 ml). The combined organic layers were washed with water (2x180 ml), dried over anhydrous Na ₂ SO ₄ then concentrated under reduced pressure. The resulting crude material was purified by column chromatography (230-400 mesh silica gel, 2-3% MeOH in DCM as eluent) to give 8-bromo-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[ 4,3-a]quinoxaline-9-carbaldehyde (1.1 g, 42%) as a brownish solid.

Step 10 8-Bromo-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-carbaldehyde (1.0 g, 3.12 mmol ) was dissolved in DCM (10 ml), cooled to 0°C. DAST (0.61 ml, 1.5 eq.) was added and the reaction mixture was stirred at 10-15° C. for 6 h. The reaction mixture was then kept at 20° C. for 16 h. The reaction mixture was then heated to 0° C. DAST (0.61 ml, 1.5 eq.) was added and the reaction mixture was stirred for 3 hours. DAST (0.61 ml, 1.5 eq.) was then added and the reaction mixture was stirred for an additional three hours. The reaction mixture was then quenched with a sat. NaHCO ₃ solution (pH~8-9) at 0°C and extracted with DCM (50 ml x 2). The combined organic layers were washed with cold water (30 ml) and brine (30 ml), dried over sodium sulfate, then concentrated under reduced pressure to give the crude compound. The described reaction was carried out in parallel in four batches, using 1.0 g (3.12 mmol) of 8-bromo-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3 -a]quinoxaline-9-carbaldehyde. The pooled batches of crude compounds were purified by column chromatography (silica gel 230-400 mesh, 3035% acetone in hexane as eluent) to give 8-bromo-9-difluoromethyl-1,4,4-trimethyl-4,5dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline (1.4 g, 33%) as a white solid with a metallic tint.

¹ H NMR (400 MHz, DMSO-d6): δ 7.57-7.54 (d, 1H), 7.27-7.06 (t, 1H), 7.04-7.03 (m, 2H ), 2.41 (s, 3H), 1.68 (br. s, 3H), 1.19 (br. s, 3H).

Any of the intermediates-A can be associated with any of the intermediates-B in standard chemical reactions that are known to the person skilled in the art, such as those described herein below.

Example 1: 7,9-difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a ]quinoxaline

To a solution of 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-1) (0 .5 g, 1.52 mmol, 1 eq.) in toluene:EtOH (2:1) (9 ml) was added 10% solution of Na ₂ CO ₃ (1.5 ml) and 6-fluoro-4-(4, 4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Intermediate A-1) (0.40 g, 1.52 mmol, 1 eq) in a sealed vial . The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.09 g, 0.08 mmol, 0.05 eq.). The reaction mixture was refluxed at 130°C for 16 h. After completion of the reaction, the reaction mixture was evaporated to dryness and the residue was diluted with EtOAc (50 ml) and washed with water (2x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by flash column chromatography to give 7,9-difluoro-8-(6-fluoro-1Nindol-4-yl)-1,4,4-trimethyl-4,5- dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.35 g, 60%) as a light yellow solid.

1H NMR (400 MHz; DMSO-06, 20°C): δ 11.3 (s, 1H), 7.39-7.41 (1H), 7.25-7.29 (1H), 7.18 (s, 1H), 6.967.00 (1H), 6.78-6.81 (1H), 5.75 (s, 1H), 2.48 (s, 3H), 1.16-1.57 ( 6H). LC-MS: found [M+H]+: 384.

- 77 043276

Example 2: 8-(1-cyclopropyl-6-fluoro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline

F

Stirring solution of 7,9-difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (Example 1) (0.2 g, 0.52 mmol, 1 eq.), cyclopropylboronic acid (0.09 g, 1.05 mmol, 2 eq.), Na ₂ CO ₃ (0.11 g, 1 04 mmol, 2 equiv.) in DCM (4 ml) was well deoxygenated with Ar. A hot suspension of Cu(OAc) (0.95 g, 0.52 mmol, 1 eq.), bipyridine (0.71 g, 0.522 mmol, 1 eq.) in DCM (4 ml) was added to the reaction mixture. The reaction mixture was then stirred for 16 h at 70°C. The reaction mixture was filtered through a pad of celite and washed with DCM (30 ml).

The organic layer was washed with water (2x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by flash column chromatography to give compound 8-(1-cyclopropyl-6-Fluoro-1H- indol-4-yl)-7,9-diFluoro-1,4,4trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.045 g, 20%) as white a solid with a metallic tint.

¹ H NMR (400 MHz; DMSO-d ₆ , 20°C): δ 7.43 (d, 1H, J=9.2 Hz), 7.38 (d, 1H, J=2.8 Hz), 7.19 (s, 1H), 7.04 (d, 1H, J=9.6 Hz), 6.78 (d, 1H, J=10.8 Hz), 6.25 (s, 1H), 3.45 (m, 1H), 2.5 (s, 3H), 1.56 (s, 3H), 1.48 (s, 3H), 1.05-0.98 (m, 4H). LC-MS: found [M+H]+: 424.

Example 3: 7,9-difluoro-8-(6-fluoro-1-(methylsulfonyl)-1 H-indol-4-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4] triazolo[4,3-a]quinoxaline

F

To a solution of 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-1) (0 .8 g, 2.43 mmol, 1 eq.) in toluene: EtOH (2:1) (15 ml) was added 10% solution of Na ₂ CO ₃ (2 ml) and 6-fluoro-1-(methylsulfonyl)-4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindole (Intermediate A-2) (0.99 g, 2.92 mmol, 1.2 eq.) in a hermetically sealed container. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.14 g, 0.12 mmol, 0.05 eq.). The reaction mixture was refluxed at 130°C for 16 h. After completion of the reaction, the solvent was removed under reduced pressure, and the residue was diluted with EtOAc (50 ml) and washed with water (2x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and the solvent were evaporated to give the crude product, which was purified by flash column chromatography to give the compound 7,9-difluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)1,4, 4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.12 g, 12%) as a white solid.

1H NMR (400 MHz; DMSO-d ₆ , 20°C): δ 7.71 (d, 1H, J=9.2 Hz), 7.66 (d, 1H, J=3.2 Hz), 7 .35 (d, 1H, J=9.6 Hz), 7.27 (s, 1H), 6.81 (d, 1H, J=10.8 Hz), 6.72 (s, 1H), 3 .58 (s, 3H), 2.74 (s, 3H), 1.56 (s, 3H), 1.50 (s, 3H).

LC-MS: found [M+H] ⁺ : 461.8.

Example 4: 1-(4-(7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 6fluoro-1 H-indol-1 -yl)ethanone

F

To a stirred solution of 7,9-difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a ]quinoxaline (Example 1) (0.4 g, 1.044 mmol, 1 eq.) was added sodium hydroxide powder (0.105 g, 2.61 mmol, 2.5 eq.), tetrabutylammonium hydrogen sulfate (0.071 g, 0.21 mmol, 0.02 eq.) in DCM (8 ml). A solution of acetyl chloride (0.123 g, 1.55 mmol, 1.5 eq.) in DCM (4 ml) was added to the reaction mixture. The reaction mixture was then stirred for 4 hours at room temperature. pace. The reaction mixture was diluted with DCM (50 ml) and washed with water (2x20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude which was purified by flash column chromatography to give 1-(4-(7, 9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxalin-8-yl)-6-fluoro-1H-indol-1-yl)ethanone (0.065 g, 15%) as a white solid.

1H NMR (400 MHz; DMSO-d ₆ , 20°C): δ 8.17 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=3.6 Hz), 7 .30 (d, 1H, J=9.6 Hz), 7.26 (s, 1H), 6.81 (d, 1H, J=10.4 Hz), 6.64 (s, 1H), 2 .67 (s, 3H), 2.5 (s, 3H), 1.57 (s, 3H), 1.49 (s, 3H). LC-MS: found [M+H] ⁺ : 426.1.

- 78 043276

Example 5: 7,9-difluoro-8-(6-fluoro-2-methyl-1 H-indol-4-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[ 4,3-a]quinoxaline

F

Example 5 was synthesized in analogy to the procedure described for Example 1 using 6-fluoro-2methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole ( intermediate A-3) and intermediate B-1.

¹ H NMR (400 MHz; DMSO-H, 20°C): δ 11.17 (s, 1H), 7.16-7.12 (m, 2H), 6.89 (d, 1H, J=9 .92 Hz), 6.78 (d, 1H, J=10.56 Hz), 5.95 (s, 1H), 2.50 (s, 3H), 2.34 (s, 3H), 1, 52 (s, 6H).

Example 6 4-(7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro1 H-indole-2-carbonitrile

Example 6 was synthesized in analogy to the procedure described for Example 1 using 6-fluoro-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-2-carbonitrile (Intermediate A4) and Intermediate B-1.

1H NMR (400 MHz, DMSO-b ₆ ): δ 12.66 (s, 1H), 7.39 (dd, J=8.16 Hz, 1H), 7.32 (s, 1H), 7.25 (s, 1H), 7.22 (dd, J=10.56 Hz, 1H), 6.81 (dd, J=10.64 Hz, 1H), 2.49 (s. 3H), 1.54 (s, 6H).

LC-MS: found [M+H]+: 409.1

Example 9: 7,9-difluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline ^N γN 1XA

Η

Example 9 was synthesized in analogy to the procedure described for Example 5 using 7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and Intermediate B-1.

1H NMR (400 MHz, DMSO-b ₆ ): δ 11.01 (s, 1H), 7.60-7.64 (1H), 7.34 (s, 1H), 7.06-7.14 ( 3H), 6.79-6.82(1H), 6.51(s, 1H), 2.43(s, 3H), 1.54-1.56(6H).

Example 10 7,9-difluoro-1,4,4-trimethyl-8-(3-(trifluoromethyl)-1H-indol-7-yl)-4,5dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline

Step 1. To a stirred solution of 7,9-difluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (Example 9) (1.4 g, 3.83 mmol, 1 eq.) in DMF (4 ml) was added potassium hydroxide powder (0.537 g, 9.5 mmol, 2.5 eq.). The reaction mixture was then stirred for 30 min at room temperature. pace. Iodine (0.487 g, 3.83 mmol, 1 eq.) was then added and the reaction mixture was stirred for 4 hours. The reaction mixture was then poured into ice water and a precipitate formed. The precipitate was then collected by filtration and dried to give 7,9-difluoro-8-(3-iodo-III-indol-7-yl)-1,4,4trimethyl-4,5-dihydro[1,2,4]triazolo[ 4,3-a]quinoxaline (0.5 g, 27%) as a brown solid.

Step 2. To a suspension of 7,9-difluoro-8-(3-iodo-1H-indol-7-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3 -a]quinoxaline (1.0 g, 2.04 mmol, 1 eq.), diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate (1.645 g, 4.07 mmol, 2 eq.) in DMF (20 ml) were deoxygenated with Ar for 10 min. Copper powder (0.388 mg, 6.11 mmol, 3 eq.) was then added to the reaction mixture. The reaction mixture was then stirred at 100° C. for 24 hours. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with EtOAc (150 ml). The organic layer was then washed with water (5x30 ml) and brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by flash column chromatography to give 7,9-difluoro-1,4,4trimethyl -8-(3-(trifluoromethyl)-1H-indol-7-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.12 g, 14%) in form of a white solid.

- 79 043276

1H NMR (400 MHz; DMSO^, 20°C): δ 11.86 (s, 1H), 7.99 (s, 1H), 7.68 (m, 1H), 7.3 (d, 2H, J=4.04 Hz),

7.2 (s, 1H), 6.81 (d, 1H, J=10.28 Hz), 2.5 (s, 3H), 1.55 (d, 6H, J=4.72 Hz). LC-MS: found [M+H]+: 434.2.

Example 11: 1-ethyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline

To a solution of 8-bromo-1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-2) (1.0 g, 2.91 mmol, 1 eq.) in toluene:EtOH (2:1) (10 ml) was added 10% solution of Na ₂ CO ₃ (2 ml) and (1H-indol-7-yl) 6oronic acid (1.06 g, 4.37 mmol, 1.5 eq.) in a sealed vial. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.168 g, 0.145 mmol, 0.05 eq.). The reaction mixture was refluxed at 110° C. for 16 hours. After completion of the reaction, the solvent was evaporated and the residue was diluted with EtOAc (150 ml). The organic layer was washed with water (2x50 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography to give 1-ethyl-7,9-difluoro-8-(1H -indol-7-yl)-4,4-dimethyl-4,5-dihydro[1,2,4]triαzolo[4,3a]quinoxaline (0.93 g, 84%) as white metallic solid .

1H NMR (400 MHz; DMSO-d ₆ , 20°C): δ 10.99 (s, 1H), 7.61-7.63 (1H), 7.35 (s, 1H), 7.08- 7.12(3H), 6.796.82(1H, 6.52(s, 1H), 2.80-2.92(2H), 1.55(s, 6H), 1.17-1.23( 3H) LC-MS: found [M+H]+: 380.2.

Example 12 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)1 H -indole-3 -carbonitrile

Step 1. To a stirred solution of 1-ethyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxaline (Example 11) (0.50 g, 1.32 mmol, 1 eq.) in DMF (10 ml) was added potassium hydroxide powder (0.185 g, 3.3 mmol, 2.5 eq.). The reaction mixture was then stirred for 30 min at room temperature. pace. Iodine (0.402 g, 1.58 mmol, 1.2 eq.) was then added to the reaction mixture and stirred for 4 hours. The reaction mixture was then diluted with EtOAc (80 ml) and washed with water (5x20 ml) and saturated aqueous sodium chloride solution (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-ethyl-7,9-difluoro-8-(3-iodo-Shindol-7-yl)-4 ,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.25 g, 38%) as a light brown solid.

Step 2 Stirring suspension of 1-ethyl-7,9-difluoro-8-(3-iodo-1H-indol-7-yl)-4,4-dimethyl4,5-dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline (0.25 g, 0.495 mmol, 1 eq.), CuCN (0.088 g, 0.99 mmol, 2 eq.), tetraethylammonium cyanide (0.038 g, 0.247 mmol, 0.5 eq.) in DMF and THF (1:1) (8 ml) Ar was well deoxygenated for 10 min. Pd ₂ dba ₃ (0.022 g, 0.0247 mmol, 0.05 eq.), dppf (0.041 g, 0.0742 mmol, 0.15 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. At the end the reaction mixture was stirred for 18 h at 110°C. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with EtOAc (30 ml). The organic layer was washed with water (5x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 7-(7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1, 2,4]triazolo[4,3-a]quinoxalin-8-yl)1H-indole-3-carbonitrile (0.08 g, 40%) as a white metallic solid.

Example 13: 1-ethyl-7,9-difluoro-4,4-dimethyl-8-(3-(prop-1-yn-1-yl)-1H-indol-7-yl)-4,5dihydro[1 ,2,4]triazolo[4,3-a]quinoxaline

1-Ethyl-7,9-difluoro-8-(3-iodo-1H-indol-7-yl)-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3a] solution ]quinoxaline (0.5 g, 0.99 mmol, 1 equiv.) in THF and TEA (1:1) (8 ml) was deoxygenated with Ar for 10 min

- 80 043276 in a hermetically sealed vessel. Pd(PPh ₃ ) ₂ Cl ₂ (0.035 g, 0.0455 mmol, 0.05 eq.), CuI (0.038 g, 0.198 mmol, 0.2 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min at 78°C. In the test tube, prop-1-yne gas condensed into TEA (4 ml) at -78°C. The volume increased to 5 ml. The condensed prop-1-yne gas was then immediately poured into the reaction mixture at -78°C. The reaction mixture was then stirred for 2 h at -78°C and 14 h at room. pace. The reaction mixture was diluted with DCM (50 ml). The organic layer was washed with water (2x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-ethyl7,9-difluoro-4,4-dimethyl-8-(3-(prop-1-yne -1-yl)-III-indol-7-yl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (0.09 g, 22%) as a white solid with metallic shade.

1H NMR (400 MHz, DMSO-d ₆ ): δ 11.27 (s, 1H), 7.62-7.60 (m, 1H), 7.56 (d, J=2.48 Hz, 1H) , 7.20-7.13 (m, 3H), 6.80 (d, J=10.24 Hz, 1H), 2.90-2.81 (m, 2H), 2.10 (s, 3H), 1.56 (s, 3H), 1.53 (s, 3H), 1.21 (t, J=7.44 Hz, 3H).

Example 14 1-ethyl-7,9-difluoro-8-(5-fluoro-1H-indol-7-yl)-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline

NH ( Ar ϊ A

1J A n'

Example 14 was synthesized in analogy to the procedure described for Example 11 using 5-fluoro7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and Intermediate B- 2.

1H NMR (400 MHz, DMSO-d ₆ ): δ 11.2 (s, 1H), 7.40-7.44 (2H), 7.19 (s, 1H), 7.00-7.03 ( 1H), 6.80-6.83 (1H), 6.51 (s, 1H), 2.85-2.90 (2H), 1.55 (s, 6H), 1.20-1.24 (3H).

Example 15 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-5fluoro -1 H-indole-3-carbonitrile

Step 1. To a stirred solution of 1-ethyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxaline (Example 14) (1.2 g, 3.0 mmol, 1 eq.) in DMF (25 ml) was added potassium hydroxide powder (0.425 g, 7.5 mmol, 2.5 eq.). The reaction mixture was then stirred for 30 min at room temperature. pace. Iodine (1.14 g, 4.5 mmol, 1.5 eq.) was then added to the reaction mixture and stirred for 4 hours. The reaction mixture was then diluted with EtOAc (200 ml) and washed with water (5 x 20 ml) and saturated aqueous sodium chloride solution (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-ethyl-7,9-difluoro-8-(5-fluoro-3-iodo-1Nindole-7- yl)-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.0 g, 64%) as a light brown solid.

Step 2 Stirring suspension of 1-ethyl-7,9-difluoro-8-(5-fluoro-3-iodo-1H-indol-7-yl)-4,4dimethyl-4,5-dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline (0.4 g, 0.764 mmol, 1 eq.), CuCN (0.137 g, 1.53 mmol, 2 eq.), tetraethylammonium cyanide (0.06 g, 0.382 mmol, 0.5 equiv.) in DMF and THF (1:1) (14 ml) were well deoxygenated with Ar for 10 min. Pd ₂ dba ₃ (0.035 g, 0.038 mmol, 0.05 eq.), dppf (0.063 g, 0.114 mmol, 0.15 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. At the end the reaction mixture was stirred for 18 h at 110°C. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with EtOAc (30 ml). The organic layer was washed with water (5x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[ 1,2,4]triazolo[4,3a]quinoxalin-8-yl)-5-fluoro-1H-indole-3-carbonitrile (0.110 g, 34%) as a white metallic solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 12.28 (s, 1H), 8.37 (s, 1H), 7.56-7.53 (m, 1H), 7.30-7, 26 (m, 2H), 6.82 (d, J=10.36 Hz, 1H), 2.89-2.82 (m, 2H), 1.57 (s, 3H), 1.53 (s , 3H), 1.22 (t, J=7.32 Hz, 3H).

- 81 043276

Example 16: 1-ethyl-7,9-difluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1H-indol-7-yl)-4,4-dimethyl-4 ,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline

Example 16 was synthesized by analogy with the procedure described for example 13, starting from 1-ethyl-7,9difluoro-8-(5-fluoro-3-iodo-1H-indol-7-yl)-4,4-dimethyl-4 ,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.37 (s, 1H), 7.65 (d, J=1.96 Hz, 1H), 7.33 (t, J=1.68 Hz, 1H), 7.20 (s, 1H), 7.10 (d, J=8.76 Hz, 1H), 6.80 (d, J=10.4 Hz, 1H), 2.88- 2.84 (m, 2H), 2.09 (s, 3H), 1.56 (s, 3H), 1.53 (s, 3H), 1.21 (t, J=7.28 Hz, 3H ).

Example 17 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-5methyl -1 H-indole-3-carbonitrile

Step 1 To a solution of intermediate B-2 (0.65 g, 1.77 mmol, 1 eq.) in toluene:EtOH (2:1) (9 ml) was added 10% Na ₂ CO ₃ solution (1.0 ml) and Intermediate A-7 (0.548 g, 2.13 mmol, 1.2 eq.) in a sealed vial. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.102 g, 0.0885 mmol, 0.05 eq.). The reaction mixture was refluxed at 110° C. for 16 hours. After completion of the reaction, the reaction mixture was evaporated to dryness and the residue was diluted with EtOAc (50 ml). The organic layer was washed with water (2 x 30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography to give 1-ethyl-7,9-difluoro-4,4 -dimethyl-8-(5-methyl1H-indol-7-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.61 g, 88%) as white solid with a metallic tint.

Step 2 To a stirred solution of 1-ethyl-7,9-difluoro-4,4-dimethyl-8-(5-methyl-1H-indol-7-yl)4,5-dihydro[1,2,4]triazolo [4,3-a]quinoxaline (0.6 g, 1.52 mmol, 1 eq.) in DMF (10 ml) was added potassium hydroxide powder (0.213 g, 3.816 mmol, 2.5 eq.). The reaction mixture was then stirred for 30 min at room temperature. pace. Iodine (0.387 g, 3.052 mmol, 2 eq.) was then added to the reaction mixture and stirred for 4 hours. The reaction mixture was then diluted with EtOAc (100 ml) and washed with water (5 x 20 ml) and brine (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 1-ethyl-7,9-difluoro-8-(3-iodo-5-methyl-1H-indole- 7-yl)-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.35 g, 44%) as a light brown solid.

Step 3 Stirring suspension of 1-ethyl-7,9-difluoro-8-(3-iodo-5-methyl-1H-indol-7-yl)-4,4dimethyl-4,5-dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline (0.15 g, 0.308 mmol, 1 eq.), Zn(CN) ₂ (0.036 g, 0.308 mmol, 1 eq.), TMEDA (0.014 ml, 0.0929 mmol , 0.3 eq.) in DMA (3 ml) was well deoxygenated with Ar for 10 min. Pd ₂ dba ₃ (0.028 g, 0.0308 mmol, 0.1 eq.), xantphos (0.018 g, 0.0308 mmol, 0.1 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min. At the end the reaction mixture was stirred for 14 h at 90°C. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with EtOAc (30 ml). The organic layer was washed with water (5x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-4,5-dihydro[ 1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-5-methyl1H-indole-3-carbonitrile (0.08 g, 63%) as a white metallic solid.

- 82 043276 ¹ H NMR (400 MHz, DMSO-d6): δ 12.04 (s, 1H), 8.22 (s, 1H), 7.51 (s, 1H), 7.22 (s, 1H ), 7.14 (s, 1H), 6.82 (d, J=9.48 Hz, 1H), 2.94-2.82 (m, 2H), 2.47 (s, 3H), 1 .56 (s, 3H), 1.53 (s, 3H), 1.21 (t, J=7.4 Hz, 3H).

Example 18 8-(1-(ethylsulfonyl)-6-fluoro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo [4,3-a]quinoxaline

Example 18 was synthesized in analogy to the procedure described for Example 3 using 1(ethylsulfonyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III -indole (Intermediate A-8) and Intermediate B-1.

1H NMR (400 MHz, DMSO-d6): δ 7.72-7.67 (m, 2H), 7.36 (d, J=9.92 Hz, 1H), 7.27 (s, 1H), 6.81 (d, J=10.64 Hz, 1H), 6.72 (s, 1H), 3.74 (q, J=7.28 Hz, 2H), 2.25 (s, 3H), 1.56 (s, 3H), 1.5 (s, 3H), 1.12 (t, J=7.28 Hz, 3H).

Example 19 8-(1-(cyclopropylsulfonyl)-6-fluoro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo [4,3-a]quinoxaline

Example 19 was synthesized in analogy to the procedure described for Example 3 using 1(cyclopropylsulfonyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -indole (Intermediate A-9) and Intermediate B-1.

1H NMR (400 MHz, DMSOCH): δ 7.75 (d, J=9.2 Hz, 1H), 7.69 (s, 1H), 7.36 (d, J=8.4 Hz, 1H) , 7.28 (s, 1H), 6.81 (d, J=10.0 Hz, 1H), 3.33 (s, 3H), 1.50-1.57 (m, 6H), 1, 31 (s, 2H), 1.13 (s, 2H).

Example 20: 1-(4-(7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 1Nindol-1-yl)ethanone

10CFC/'io h

P ^ mea ^ exact seeshsheshge B-1

To a solution of 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-1) (0 .5 g, 1.57 mmol, 1 eq.) in dioxane:isoamyl alcohol (2:1) (9 ml) was added a solution of K2CO3 (0.725 g, 5.25 mmol, 3 eq.) and 1-(4-( 4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indol-1-yl)ethanone (Intermediate A-10) (0.634 g, 1.929 mmol, 1.1 eq. ). The solution was degassed with Ar for 20 min followed by the addition of Attaphos (0.061 g, 0.087 mmol, 0.05 eq.). The reaction mixture was refluxed at 100° C. for 16 h. The solvent was evaporated to dryness and the residue was diluted with EtOAc (50 ml) and washed with water (2x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ , and the solvent was evaporated to give a crude product which was purified by preparative HPLC to give 1-(4-(7,9-difluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a ]quinoxalin-8-yl)-1H-indol-1-yl)ethanone (0.160 g, 22%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 8.41 (d, J=8 Hz, 1H), 7.92 (d, J=3.6 Hz, 1H), 7.43 (t, J =8.0 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.19 (s, 1H), 6.81 (d, J=10.4 Hz, 1H), 6.62 (br, 1H), 2.67 (s, 3H), 1.57 (s, 3H), 1.49 (s, 3H).

Example 21: 7,9-difluoro-8-(6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indol-4-yl)-1,4,4-trimethyl-4,5dihydro[ 1 ,2,4]triazolo[4,3-a]quinoxaline

To a solution of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(2,2,2-trifluoroethyl)-1Nindole (intermediate A- 11) (0.4 g, 1.166 mmol, 1 eq.) in toluene:EtOH (2:1) (9 ml) 10% Na ₂ CO ₃ solution (0.4 ml) and intermediate B-1 (0.307 g, 0.932 mmol, 0.8 eq.) c

- 83 043276 hermetically sealed vessel. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.067 g, 0.058 mmol, 0.05 eq.). The reaction mixture was refluxed at 90° C. for 16 hours. The reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude product which was purified by preparative HPLC to give compound 7,9-difluoro-8-(6-fluoro-1-(2,2,2-trifluoroethyl)-III-indol-4-yl) -1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.055 g, 10%) as a white metallic solid.

1H NMR (400 MHz, DMSO-J6): δ 7.65 (d, J=10 Hz, 1H), 7.46 (d, J=3.2 Hz, 1H), 7.21 (s, 1H) , 7.09 (d, J=9.6 Hz, 1H), 6.80 (d, J=10.4 Hz, 1H), 6.43 (s, 1H), 6.81 (d, J= 10.0 Hz, 1H), 5.24 (k, J=8.8 Hz, 2H), 5.86 (br, 6H).

Example 22 7,9-difluoro-1,4,4-trimethyl-8-(1-(methylsulfonyl)-1 H-indol-4-yl)-4,5dihydro[1,2,4]triazolo[4, 3-a]quinoxaline

Example 22 was synthesized in analogy to the procedure described for example 3 using 1(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate compound A-12) and intermediate compound B-1.

¹ H NMR (400 MHz, DMSO-d ₆ ): 7.93 (d, J=8.28 Hz, 1H), 7.64 (d, J=3.64 Hz, 1H), 7.49 (t , J=7.68 Hz, 1H), 7.38 (d, J=7.24 Hz, 1H), 7.21 (s, 1H), 6.81 (d, J=10.16 Hz, 1H ), 6.71 (s, 1H), 3.52 (s, 3H), 1.57 (s, 3H), 1.5 (s, 3H).

Example 23 7-fluoro-8-(5-fluoro-3-(2,2,2-trifluoroethyl)-1H-indol-7-yl)-1,4,4,9-tetraαmethyl-4,5dihydro[1 ,2,4]triazolo[4,3-a]quinoxaline

F

To a solution of 5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethyl)-1Hindole (intermediate A- 13) (0.600 g, 1.749 mmol, 1.0 eq.) in dioxane:isoamyl alcohol (2:1) (25 ml) was added a solution of K2CO3 (0.724 g, 5.247 mmol, 3 eq.) and 8-bromo-7- fluoro-1,4,4,9-tetramethyl4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-3) (0.284 g, 0.874 mmol, 0.5 eq. ). The solution was degassed with Ar for 20 min followed by the addition of Attaphos (0.062 g, 0.087 mmol, 0.05 eq.). The reaction mixture was stirred at 100° C. for 16 hours. The solvent was evaporated to give the crude product, which was purified by flash column chromatography and preparative HPLC to give 7-fluoro-8-(5-fluoro-3-(2,2,2- trifluoroethyl)-1H-indol-7-yl)-1,4,4,9-tetramethyl4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.200 g, 25%) as white solid.

1H NMR (400 MHz, DMSO-d6): δ 11.10 (s, 1H), 7.45-7.40 (m, 2H), 6.97 (d, J=8.8, 1H), 6 .80 (s, 2H), 3.76 (k, J=10.8 Hz, 2H), 2.50 (s, 3H), 1.96 (s, 3H), 1.53 (s, 3H) , 1.44 (s, 3H).

Example 24 7-fluoro-1,4,4,9-tetramethyl-8-(3-(2,2,2-trifluoroethyl)-1H-indol-7-yl)-4,5dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline

Example 24 was synthesized in analogy to the procedure described for example 3 using 7-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(2,2,2-trifluoroethyl)- 1 H-indole (Intermediate A14) and Intermediate C.

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.97 (s, 1H), 7.64 (d, J=7.2 Hz, 1H), 7.32 (s, 1H), 7.13 (d, J=6.8, 1H), 7.04 (d, J=6.4, 1H), 6.80 (d, J=10, 1H), 6.74 (s, 1H), 3 .76 (q, J=12 Hz, 2H), 2.49 (s, 3H), 1.93 (s, 3H), 1.55 (s, 3H), 1.43 (s, 3H).

Example 25 7-fluoro-8-(1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline

P ^ v medutochive veishviie OT

To a solution of Intermediate B-3 (1.2 g, 3.69 mmol, 1 eq.) in toluene:EtOH (2:1) (15 mL)

- 84 043276 was added 10% solution of Na ₂ CO ₃ (2 ml) and (1H-indol-7-yl)boronic acid (1.07 g, 4.43 mmol, 1.2 eq.) in a sealed vessel. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.213 g, 0.1845 mmol, 0.05 eq.). The reaction mixture was stirred at 110° C. for 16 hours. The solvent was evaporated to dryness and the residue was diluted with EtOAc (150 ml). The organic layer was washed with water (2x50 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 7-fluoro-8-(1H-indole-7 -yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.85 g, 64%) as a white solid with metallic tint.

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.88 (s, 1H), 7.58-7.60 (1H), 7.30 (s, 1H), 7.06-7.11 ( 1H), 6.98-7.00(1H), 6.78-6.81(1H), 6.73(s, 1H), 6.50(s, 1H), 2.47(s, 3H ), 1.94 (s, 3H), 1.56 (s, 3H), 1.43 (s, 3H).

Example 26 7-fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline

Example 26 was synthesized in analogy to the procedure described for Example 1 using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and Intermediate B-3.

1H NMR (400 MHz, DMSOCH): δ 11.21 (s, 1H), 7.44-7.46 (1H), 7.37 (s, 1H), 7.17-7.20 (1H), 6.96-6.98(1H), 6.77-6.79(1H), 6.69(s, 1H), 6.09(s, 1H), 2.44(s, 3H), 1 .98 (s, 3H), 1.54 (s, 3H), 1.44 (s, 3H).

Example 27 8-(1-cyclopropyl-1H-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a ]quinoxaline

Stirring solution of 7-fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (Example 26 ) (0.2 g, 0.554 mmol, 1 eq.), cyclopropylboronic acid (0.095 g, 1.1 mmol, 2 eq.), Na ₂ CO ₃ (0.12 g, 1.1 mmol, 2 eq.) in DCM (4 ml) Ar was deoxygenated. A hot suspension of Cu(OAc) (0.1 g, 0.554 mmol, 1 eq.), bipyridine (0.86 g, 0.554 mmol, 1 eq.) in DCM (4 ml) was added to the reaction mixture. The reaction mixture was then stirred for 16 h at 70°C. The reaction mixture was filtered through a pad of celite and washed with DCM (30 ml). The organic layer was washed with water (2x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by flash column chromatography to give 8-(1-cyclopropyl-1H-indole-4 -yl)-7-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.07 g, 32%) as a white solid substances with a metallic tint.

1H NMR (400 MHz, DMSO-d ₆ ): δ 7.60 (d, J=8.16 Hz, 1H), 7.35 (d, J=2.96 Hz, 1H), 7.26 (t , J=7.56 Hz, 1H), 7.02 (d, J=7.08 Hz, 1H), 6.76 (d, J=10.12 Hz, 1H), 6.71 (s, 1H ), 6.05 (s, 1H), 3.49-3.48 (m, 1H), 2.42 (s, 3H), 1.98 (s, 3H), 1.52 (s, 3H) , 1.42 (s, 3H), 1.08-0.99 (m, 4H).

Example 28 7-fluoro-1,4,4,9-tetramethyl-8-(3-(prop-1-yn-1-yl)-1H-indol-7-yl)-4,5dihydro[1,2 ,4]triazolo[4,3-a]quinoxaline

Step 1. To a stirred solution of 7-fluoro-8-(1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (Example 25) (0.85 g, 2.35 mmol, 1 eq.) in DMF (20 ml) was added potassium hydroxide powder (0.329 g, 5.87 mmol, 2.5 eq.). The reaction mixture was then stirred for 30 min at room temperature. pace. Iodine (0.897 g, 3.53 mmol, 1.5 eq.) was then added to the reaction mixture and stirred for 4 hours. The reaction mixture was then diluted with EtOAc (100 ml) and washed with water (5 x 20 ml) and saturated aqueous chloride solution sodium (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 7-fluoro-8-(3-iodo-1H-indol-7yl)-1,4,4,9 -tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.27 g, 24%) as a light brown solid.

- 85 043276

Step 2. A solution of 7-fluoro-8-(3-iodo-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxaline (0.48 g, 0.98 mmol, 1 eq.) in THF and TEA (1:1) (8 ml) was deoxygenated with Ar for 10 min in a sealed vessel. Pd(PPh ₃ ) ₂ Cl ₂ (0.035 g, 0.049 mmol, 0.05 eq.), CuI (0.038 g, 0.197 mmol, 0.2 eq.) was then added to the reaction mixture and again deoxygenated with Ar for 10 min at -78°C. In the test tube, prop-1-yne gas condensed into TEA (3 ml) at -78°C. The volume increased to 5 ml. The condensed prop-1-yne gas was immediately poured into the reaction mixture at -78°C. The reaction mixture was then stirred for 2 h at -78°C and for 14 h at room. pace. The reaction mixture was diluted with DCM (50 ml). The organic layer was washed with water (2x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by column chromatography to give 7-fluoro-1,4,4,9-tetramethyl-8-(3-(prop-1-yne -1-yl)-1H-indol-7-yl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.08 g, 20%) as a white solid with metallic sky tint.

1H NMR (400 MHz, DMSO-d ₆ ): δ 11.12 (s, 1H), 7.58 (d, J=7.56 Hz, 1H), 7.50 (s, 1H), 7.17 (t, J=7.56 Hz, 1H), 7.07 (d, J=7.32 Hz, 1H), 6.79 (d, J=10.16 Hz, 1H), 6.74 (s , 1H), 2.10 (s, 3H), 2.07 (s, 3H), 1.92 (s, 3H), 1.53 (s, 3H), 1.43 (s, 3H).

Example 29 7-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo [4 ,3-a]quinoxaline

To a solution of 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.25 g, 0.579 mmol, 1 eq.) in toluene :EtOH (2:1) (10 ml) was added at room temperature. temp. ) (0.223 g, 0.254 mmol, 1.5 eq.), 10% Na ₂ CO ₃ (0.5 ml). After degassing, the reaction mixture Pd(PPh ₃ ) ₄ (0.038 g, 0.028 mmol, 0.05 eq.) was added at room temperature. temp., and the reaction mixture was stirred at 90°C for an additional 16 hours, the Reaction mixture was filtered through a filter of sintered glass and diluted with water (20 ml). The aqueous layer was extracted with EtOAc (3x50 ml). The combined organic layers were washed with water (50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography to give 7-fluoro-1,4,4-trimethyl -8-(3-methyl-1H-indol-7-yl)-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.042 g, 17% ) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ , t=100°C): δ 10.29 (s, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.13-7, 04 (m, 4H), 2.45 (s, 3H), 2.28 (s, 3H), 1.75 (s, 3H), 1.31 (br, 3H).

Example 30 9-chloro-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo [4,3-a]quinoxaline

NH \ Cl \ \u003d N X ± A

Example 30 was synthesized in analogy to the procedure described for Example 29 using 5-fluoro3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole ( intermediate A-15) and intermediate B-5.

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.71 (s, 1H), 7.29 (d, J=9.6 Hz, 1H), 7.15 (s, 1H), 7.1 (s, 1H), 6.90 (d, J=10.0 Hz, 2H), 2.54 (s, 3H), 2.23 (s, 3H), 1.52 (s, 3H), 1 .45 (s, 3H).

Example 31 7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo [4,3-a]quinoxaline

Example 31 was synthesized in analogy to the procedure described for example 29 using 5-fluoro3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole ( intermediate A-15) and intermediate B-3.

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.65 (s, 1H), 7.28 (d, J=10.0 Hz, 1H), 7.15 (s, 1H), 6.90 (d, J=8.2 Hz,

- 86 043276

1H), 6.77-6.80 (m, 2H), 2.46 (s, 3H), 2.25 (s, 3H), 1.95 (s, 3H), 1.53 (s, 3H ), 1.43 (s, 3H).

Example 32 7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a ]quinoxaline

Example 32 was synthesized in analogy to the procedure described for Example 29 using 5-fluoro7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and Intermediate B- 3.

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 11.0 (s, 1H), 7.35-7.38 (2H), 6.91-6.93 (1H), 6.77-6 .81 (2H), 6.50 (s, 1H), 2.47 (s, 3H), 1.96 (s, 3H), 1.54 (s, 3H), 1.44 (s, 3H) .

Example 33 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-4,5dihydro [1,2,4]triazolo [4 ,3-a] quinoxaline

Step 1. Stirred solution of 7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3 -a]quinoxaline (Example 32) (0.7 g, 1.846 mmol, 1 eq.) in DMF (6 ml) at 10°C was added in portions over 10 min solid N-bromosuccinimide (0.338 g, 1.902 mmol, 1.03 equiv.). The reaction mixture was allowed to warm up to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (the reaction progress was monitored by LC-MS), the reaction mixture was diluted with EtOAc (30 ml), the organic layers were washed with water (5x25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure to give the crude product, which was purified by washing with ether to give 8-(3-bromo-5-fluoro-1H-indol-7-yl)-7-fluoro1,4, 4,9-Tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.8 g, 95%) as a white metallic solid.

Step 2. To a solution of 8-(3-bromo-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo [4,3-a]quinoxaline (22.0 g, 48.034 mmol, 1 eq.) in THF (400 ml) was added NaH (6.72 g, 168.11 mmol, 3.5 eq.) at room. pace. After 15 min stirring (BOC) ₂ O (15.4 ml, 75.052 mmol, 1.5 eq.) was added at room. pace. The reaction mixture was then refluxed for 16 hours. After completion of the reaction (the reaction was monitored by TLC), the reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was washed with water, brine, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to give a crude product which is. The crude product was purified by column chromatography to give tert-butyl-3-bromo-5-fluoro-7-(7-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4, 3-a]quinoxalin-8-yl)-1H-indole-1-carboxylate (17.0 g, 63%) as a brown solid.

Step 3. To a solution of tert-butyl-3-bromo-5-fluoro-7-(7-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxalin-8-yl)-1H-indole-1-carboxylate (0.35 g, 0.627 mmol, 1 eq.) in toluene: EtOH (2:1) (10.0 ml), Cs ₂ CO ₃ ( 0.611 g, 1.881 mmol, 3 eq) cyclopropylboronic acid (0.108 g, 1.254 mmol, 2 eq) was added at rt. pace. The solution was degassed with Ar for 20 min followed by the addition of Pd(OAc) ₂ (0.014 g, 0.062 mmol, 0.1 eq.), Adamantylphosphine (0.019 g, 0.062 mmol, 0.1 eq.) at room. temp., and the reaction mixture was stirred at 110°C for 16 hours After completion of the reaction (the reaction was followed by LC-MS), the solvent was evaporated, and the residue was diluted with EtOAc (150 ml). The organic layer was washed with water (2x50 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give crude tert-butyl-3-cyclopropyl-5-fluoro-7-(7-fluoro-1,4,4 ,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)1H-indole-1-carboxylate (0.15 g, 46%) as brown resin, which was used for the next

- 87 043276 stage without further purification.

Step 4. To a solution of tert-butyl-3-cyclopropyl-5-fluoro-7-(7-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxalin-8-yl)-1H-indole-1-carboxylate (0.5 g, 0.96 mmol, 1 eq.) in MeOH (12.0 ml), H ₂ O (4.0 ml), K ₂ CO ₃ (0.4 g, 2.884 mmol, 3 equiv.) was added at room. pace. The reaction mixture was then heated at 90° C. for 24 hours. After completion of the reaction (reaction progress monitored by TLC), the reaction mixture was filtered through a sintered glass filter and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC to give 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2 ,4]triazolo[4,3-a]quinoxaline (0.18 g, 45%) as a white solid.

¹ H NMR (400 MHz, DMSO-d6): δ 10.67 (s, 1H), 7.37 (d, J=9.2 Hz, 1H), 7.06 (s, 1H), 6.90 (d, J=9.6 Hz, 1H), 6.76-6.79 (m, 2H), 1.95 (s, 4H), 1.43-1.53 (m, 6H), 0, 85 (d, J=8.8 Hz, 2H), 0.61 (s, 2H); (CH ₃ - missing DMSO).

Example 34 1-ethyl-7-fluoro-8-(6-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4 ,3a]quinoxaline

Example 34 was synthesized in analogy to the procedure described for Example 29 using 6-fluoro4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole and Intermediate B- 6. LC-MS: found [M+H]+: 394.

Example 35 8-(1-(cyclopropylmethyl)-6-fluoro-1H-indol-4-yl)-1-ethyl-7-fluoro-4,4,9-trimethyl-4,5dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline

To a solution of 1-ethyl-7-fluoro-8-(6-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4, 3a]quinoxaline (Example 34) (0.1 g, 0.254 mmol, 1 eq.) in DMF (5 ml) was added sodium hydride (0.022 g, 0.508 mmol, 2 eq.) at 0°C. The solution was stirred at rt. pace. for 30 min followed by the addition of bromomethyl-cyclopropane (0.02 g, 0.152 mmol, 0.6 eq.), the reaction mixture was stirred at room. pace. within 2 h. After completion of the reaction (the reaction was followed by LCMS), the reaction mixture was diluted with EtOAc (20 ml) and the organic layer was washed with cold water (5x10 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by preparative HPLC to give 8-(1(cyclopropylmethyl)-6-fluoro-1H-indol-4-yl)-1-ethyl-7-fluoro-4,4,9-trimethyl-4,5-dihydro[ 1,2,4]triazolo[4,3-a]quinoxaline (0.03 g, 27%) as a white metallic solid.

Ή NMR (400 MHz, DMSO-d ₆ ): δ 7.47 (d, J=9.2 Hz, 2H), 6.89 (s, 1H), 6.77 (t, J=10.1 Hz , J=8.4 Hz, 1H), 6.06 (s, 1H), 4.04 (s, 2H), 2.78 (br, 2H), 1.99 (s, 3H), 1.47 (br, 6H), 1.25 (t, J=7.08 Hz, 3H), 0.53 (d, J=7.08 Hz, 2H), 0.42 (s, 2H).

Example 36: 1-ethyl-7-fluoro-8-(6-fluoro-1-(2-methoxyethyl)-1H-indol-4-yl)-4,4,9-trimethyl-4,5dihydro[1,2 ,4]triazolo[4,3-a]quinoxaline

To a solution of 1-ethyl-7-fluoro-8-(6-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4, 3a]quinoxaline (Example 34) (0.1 g, 0.254 mmol, 1 eq.) in DMF (5 ml) was added sodium hydride (0.022 g, 0.508 mmol, 2 eq.) at 0°C. The solution was stirred at rt. pace. for 30 min followed by the addition of 1-bromo-2-methoxyethane (0.022 g, 0.152 mmol, 0.6 eq.), the reaction mixture was stirred at room. pace. within 2 h. After completion of the reaction (the reaction was followed by LCMS), the reaction mixture was diluted with EtOAc (20 ml) and the organic layer was washed with cold water (5x10 ml), brine (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC to give 1-ethyl-7fluoro-8-(6-fluoro-1-(2-methoxyethyl)-1H-indol-4-yl)-4,4,9-trimethyl-4,5-dihydro [1,2,4]triazolo[4,3a]quinoxaline (0.08 g, 70%) as a white metallic solid.

¹ H NMR (400 MHz, DMSO-d6): δ 7.48 (d, J=9.4 Hz, 1H), 7.39 (s, 1H), 6.9 (br, 1H), 6.79 (d, J=8.4 Hz,

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1H), 6.05 (s, 1H), 4.34 (s, 2H), 3.68 (s, 2H), 3.24 (s, 3H), 2.67 (br, 2H), 1, 98 (s, 3H), 1.46 (br, 6H), 1.24 (t,

J=7.2 Hz, 3H).

Example 37 7-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1 H-indol-4-yl)-1,4,4-trimethyl-9(trifluoromethyl)-4,5-dihydro[1 ,2,4]triazolo[4,3-a]quinoxaline

Suspension of 8-bromo-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (intermediate B-4) ( 0.5 g, 1.32 mmol, 1 eq.), 6-fluoro-1-(methylsulfonyl)-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)- 1H-indole (Intermediate A-2) (0.536 g, 1.58 mmol, 1.2 eq.), K ₂ CO ₃ (0.55 g, 3.96 mmol, 3 eq.) in isoamyl alcohol and water (2:1) (15 ml) was degassed with Ar for 20 min followed by the addition of Attaphos (0.047 g, 0.066 mmol, 0.05 eq.). The reaction mixture was stirred at 110°C for 16 h in a sealed vessel. After completion of the reaction (the progress of the reaction was followed by LC-MS), the reaction mixture was evaporated to dryness, and the residue was diluted with EtOAc (50 ml). The organic layer was washed with water (2x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by column chromatography to give 7-fluoro-8-(6-fluoro-1-( methylsulfonyl)-1H-indol-4-yl)1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.055 g, 8%) as a white solid with a metallic tint.

¹ H NMR (400 MHz, DMSO-d ₆ , t=100°Q: δ 7.73 (d, J=9.44 Hz, 1H), 7.60 (d, J=3.64 Hz, 1H) , 7.24 (br, 2H), 7.17 (d, J=10 Hz, 1H), 6.51 (br, 1H), 3.49 (s, 3H), 2.46 (s, 3H) , 1.75 (br. 3H), 1.38 (br. 3H).

Example 38: 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-6-fluoro-1,4,4,9-tetramethyl-4,5dihydro[ 1,2,4]triazolo [4,3-a]quinoxaline

Example 38 was synthesized in analogy to the procedure described for Example 29 using 3-cyclopropyl-5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole ( intermediate A-16) and intermediate B-7.

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.64 (s, 1H), 7.36 (d, J=7.76 Hz, 1H), 7.17 (d, J=10.64 Hz , 1H), 7.08 (s, 1H), 6.9 (d, J=9.8 Hz, 1H), 6.49 (s, 1H), 2.5 (s, 3H), 1.98 (s, 3H), 1.93-1.9 (m, 1H), 1.53-1.48 (m, 6H), 0.85 (d, J=8.08 Hz, 2H), 0, 60 (d, J=3.32 Hz, 2H).

Example 39 4-(7-(7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 1Nindol-3-yl)-2-methylbut-3-yn-2-ol

Step 1. To a stirred solution of 7-fluoro-8-(1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (Example 25) (3.7 g, 10.24 mmol, 1 eq.) in DMF (25 ml), KOH (1.43 g, 25.62 mmol, 2.5 eq.) was added iodine (2, 6 g, 10.24 mmol, 1.0 eq.) in DMF (20 ml) at 0°C, and the resulting reaction mixture was stirred for 1 h at 0°C. The reaction mixture was diluted

EtOAc (800 ml), washed with aqueous sodium metabisulphite (2x300 ml), water (4x300 ml), brine (300 ml), dried (Na2SO4), filtered and concentrated under reduced pressure to give 7-fluoro-8-(3 -iodine-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (3.0 g, 61%) .

Step 2. Solution of 7-fluoro-8-(3-iodo-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4, 3-a]quinoxaline (0.3 g, 0.61 mmol, 1.0 eq.) in DMF (5 ml), TEA (5 ml) was degassed with Ar for 20 min followed by the addition of CuI (2.9 mg, 0.015 mmol, 0.025 eq.), PdCl ₂ (PPh) ₃ (21.5 g, 0.03 mmol, 0.05 eq.), 2-methylbut-3-yn-2-ol (0.077 g, 0.92 mmol, 1.5 eq.). The reaction mixture was stirred at rt. pace. within 16 h. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC to give 4-(7-(7-fluoro-1 ,4,4,9tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol-3-yl)-2-methylbut-3-yne -2-ola

- 89 043276 (0.08 g, 30%) as a white solid.

1H NMR (400 MHz, DMSO-d ₆ ): δ 11.2 (s, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.54 (s, 1H), 7.20 (t, J=7.6 Hz,

1H), 7.09 (d, J=6.8 Hz, 1H), 6.79 (d, J=10 Hz, 1H), 6.75 (s, 1H), 5.37 (s, 1H) , 2.46 (s, 3H), 1.92 (s, 3H) 1.441.51 (m, 12H).

Example 40: 4-(7-(7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)- 1Nindol-3-yl)-2-methylbut-3-in-2-amine

Solution of 7-fluoro-8-(3-iodo-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (0.3 g, 0.61 mmol, 1.0 eq.) in DMF (1.8 ml), TEA (0.17 ml, 1.23 mmol, 2.0 eq.) degassed with Ar for 20 min followed by the addition of CuI (2.9 mg, 0.015 mmol, 0.025 eq.), PdCl ₂ (PPh) ₃ (21.5 g, 0.03 mmol, 0.05 eq.), 2-methylbut-3-in- 2-amines (0.103 g, 1.23 mmol, 2.0 eq.). The reaction mixture was stirred at rt. pace. within 2 h. After the completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was filtered through a pad of celite and the filtrate was concentrated to give the crude product, which was purified by preparative HPLC to give 4-(7-(7fluoro-1,4 ,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol-3-yl)-2-methylbut3-yn-2 -amine (0.15 g, 55%) as a white solid with a metallic tint.

1H NMR (400 MHz, DMSO-de): δ 11.15 (s, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.48 (s, 1H), 7.19 ( t, J=7.4 Hz, 1H), 7.07 (d, J=6.8 Hz, 1H), 6.79 (d, J=10 Hz, 1H), 6.74 (s, 1H) , 2.46 (s, 3H), 2.05 (s, 1H), 1.92 (s, 3H) 1.421.53 (m, 12H).

Example 41 9-Chloro-8-(3-cyclobutyl-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-4,5-dihydro [1,2,4]triazolo[ 4,3-a] quinoxaline

V ί^Ίΐ

Example 41 was synthesized in analogy to the procedure described for Example 37 using 3-cyclobutyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Intermediate A17) and Intermediate B-5.

1H NMR (400 MHz, DMSO-de): δ 10.67 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.13 (s, 1H), 7.00- 7.08 (m, 3H), 6.93 (d, J=10 Hz, 1H), 3.69-3.74 (m, 1H), 2.57 (s, 3H), 2.32-2 .42 (m, 2H), 2.20-2.23 (m, 2H), 2.00-2.07 (m, 1H), 1.89-1.91 (m, 1H), 1.57 (s, 3H), 1.47 (s, 3H).

Example 42 7-fluoro-1,4,4,9-tetramethyl-8-(3-(tetrahydrofuran-3-yl)-1H-indol-7-yl)-4,5dihydro[1,2,4]triazolo [4,3-a]quinoxaline

Example 42 was synthesized in analogy to the procedure described for example 37 using 3(tetrahydrofuran-3-yl)-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H -indole (Intermediate A-18) and Intermediate B-3.

1H NMR (400 MHz, DMSO-de): δ 10.67 (s, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.15 (s, 1H), 7.08 ( t, J=7.6 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.78 (d, J=10 Hz, 1H), 6.72 (s, 1H) , 4.12-4.15 (m, 1H), 3.92-3.97 (m, 1H), 3.84 (q, J=7.6 Hz, J=15.6 Hz, 1H), 3.59-3.69 (m, 2H), 2.46 (s, 3H), 2.33-2.37 (m, 1H), 2.04-2.10 (m, 1H), 1, 93 (s, 3H), 1.55 (s, 3H), 1.42 (s, 3H).

Example 43: 8-(3-ethyl-5-fluoro-1 H-indol-7-yl)-7,9-difluoro-1,4,4-trimethyl-4,5-dihydro [ 1,2,4] triazolo[4,3-a]quinoxaline

Example 43 was synthesized in analogy to the procedure described for Example 1 using 3-ethyl-5fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole ( intermediate A-19) and intermediate B-1.

1H NMR (400 MHz, DMSO-b ₆ ): δ 10.81 (br, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.20 (s, 2H), 6.99 (d, J=7.2 Hz,

- 90 043276

1H), 6.80 (d, J=9.6 Hz, 1H), 2.69-2.71 (m, 2H), 1.54 (br, 6H), 1.27 (br, 3H); (CH ₃ -missing DMSO).

Example 44 2-(4-(9-ethyl-7-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl )6-fluoro-1 H-indol-1-yl)ethanol

gidpngnm B-8

To a stirred solution of Intermediate B-8 (0.14 g, 0.413 mmol, 1 eq.) in 1,4dioxane (10 mL) was added CsF (0.19 g, 1.24 mmol, 3 eq.), Intermediate A -20 (0.138 g, 0.45 mmol, 1.1 eq.) in a sealed vial. The solution was degassed with Ag for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.023 g, 0.021 mmol, 0.05 eq.). The reaction mixture was refluxed at 90° C. for 16 hours. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude product which was purified by column chromatography (5% MeOH/DCM, Rf-0.3) followed by preparative HPLC purification to give 2-(4-(9ethyl-7-fluoro-1,4, 4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1H-indol-1yl)ethanol (0.1 g, 56% ) as a white solid with a metallic tint.

*H NMR (400 MHz, DMSO-a ₆ ): δ 7.45-7.39 (m, 2H), 6.95 (d, J=10 Hz, br), 6.83 (s, br), 6.75 (d, J=10.1 Hz, W), 6.13 (s, W), 4.92 (s, W), 4.22 (d, J=5.6 Hz, 2H), 3.75 (d, J=4.8 Hz, 2H), 2.68-2.62 (m, W), 1.54-1.18 (m, 6H), 0.51 (s, W) .

Example 69 1-(but-2-yn-1-yl)-7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-4 ,5dihydro [1,2,4]triazolo[4,3-a]quinoxaline

Step 1. Stirred solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (3.43 g, 16.18 mmol, 1 eq.) in DMF (30 mL) at 0°C treated with portions of N-bromosuccinimide (3.02 g, 16.99 mmol, 1.05 eq.) over 10 min. The reaction mixture was stirred at 0°C for 1 h and at room temperature. pace for 30 min. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was diluted with water (100 ml), was extracted with EtOAc (3x100 ml). The combined organic layer was washed with water (4x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude product was purified by column chromatography (silica gel 100-200 mesh; 30% EtOAc/hexane; _Kg value -0.5) to give 7-bromo-6,8-difluoro-3,3dimethyl-3,4-dihydroquinoxaline-2( 1H)-one (4.0 g, 85%) as a brown solid.

Step 2 To a solution of 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (1.0 g, 3.44 mmol, 1 eq.) in toluene :EUH (2:1) (20 ml) was added 10% aqueous solution of Na ₂ CO ₃ (5.5 ml) and intermediate compound A-15 (1.42 g, 5.16 mmol, 1.5 eq.). The solution was degassed with Ag for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.199 g, 0.17 mmol, 0.05 eq.). Degassing was continued for an additional 10 minutes and the reaction mixture was heated at 110° C. for 16 hours in a sealed vessel. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was evaporated, the residue was diluted with water (25 ml), was extracted with EtOAc (3x100 ml). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and evaporated to give the crude product, which was purified by flash column chromatography (silica gel 100-200 mesh; 50% EtOAc/hexane; _Kg value-0.3) to give 6,8-difluoro-7-(5-fluoro-3methyl-1H-indol-7-yl)-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H) -one (0.510 g, 41%) as brown

-91 043276 solids.

Step 3 To a solution of 6,8-difluoro-7-(5-fluoro-3-methyl-1H-indol-7-yl)-3,3-dimethyl-3,4dihydroquinoxalin-2(1H)-one (0.500 g , 1.4 mmol, 1 eq.) in toluene (10 ml) was added Lausson's reagent (0.848 g, 2.1 mmol, 1.5 eq.) at room. temp., and the reaction mixture was refluxed at 120°C for 30 min. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was cooled, quenched with sat. NaHCO ₃ (50 ml) followed by extraction with EtOAc (3x100 ml). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 10% EtOAc/hexane; R _f -value-0.6) to give 6,8-difluoro-7-(5-fluoro-3-methyl-1H-indol-7-yl)-3,3-dimethyl-3,4-dihydroquinoxalin-2 (1 H)thione (0.480 g, 91%) as a yellow solid.

Step 4 To a solution of 6,8-difluoro-7-(5-fluoro-3-methyl-1H-indol-7-yl)-3,3-dimethyl-3,4dihydroquinoxalin-2(1H)-thione (0.240 g , 0.64 mmol, 1 eq.) in THF (6 ml) was added hydrazine hydrate (0.11 ml, 2.32 mmol, 3 eq.), the mixture was stirred overnight at room temperature. pace. The completion of the formation of 5,7-difluoro-6-(5-fluoro-3-methyl-1H-indol-7-yl)-3-hydrazono-2,2-dimethyl-1,2,3,4-tetrahydroquinoxaline was monitored with by TLC and LC-MS, (EtOAc; R _f -value -0.1). This reaction mixture was used in the next step without working up the reaction mixture and purification.

Step 5 To a solution of pent-3-ic acid (0.376 g, 3.84 mmol, 6 eq.) in benzene (8 ml) was added oxalyl chloride (0.8 ml) at 0°C and the mixture was heated at 50°C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure under nitrogen at 25°C. The residue was dissolved in THF (5 ml), the resulting solution was added dropwise to a solution of 5,7-difluoro-6-(5-fluoro-3-methyl1H-indol-7-yl)-3-hydrazono-2,2-dimethyl- 1,2,3,4-tetrahydroquinoxaline already obtained (listed above) at 0°C. TEA (0.6 ml, 3.84 mmol, 6 eq.) was added to the mixture and stirred for 1.5 h at room temperature. pace. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was quenched with water (5 ml), was extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give crude N'-(6,8-difluoro-7-(5-fluoro-3-methyl-1 H-indole -7-yl)-3,3-dimethyl-3,4-dihydroquinoxaline 2(1H)-ylidene)pent-3-ynhydrazide (0.285 g) (50% EtOAc-hexane; R _f -value -0.5), which used for the next step without further purification.

Step 6. To a solution of N'-(6,8-difluoro-7-(5-fluoro-3-methyl-1H-indol-7-yl)-3,3-dimethyl-3,4dihydroquinoxalin-2(1H)- ylidene)pent-3-inhydrazide (0.280, 0.62 mmol) in n-butanol (8 ml) glacial acetic acid (catalytic amount, 2 drops from capillary tube) was added, the mixture was heated at 140°C for 3 h. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (25 ml) and was extracted with EtOAc (3x50 ml). The combined organics were washed with brine (10 ml), dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure to a sticky mass, which was purified by preparative HPLC (5% MeOH-DCM; Rg value-0.35) to give 1-( but-2-yn-1-yl)7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-4,5-dihydro[1, 2,4]triazolo[4,3a]quinoxaline (57 mg, 10% over three steps) as a white metallic solid [another 240 mg from reaction loading, prepared from 6,8-difluoro-7-(5 -fluoro-3-methyl-1H-indol-7-yl)3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-thione and the reported yield here is the combined yield].

¹ H NMR (400 MHz, DMSO-d6): δ 10.74 (s, 1H), 7.34 (dd, 1H), 7.21 (s, 2H), 6.94 (dd, 1H), 6 .78 (d, 1H), 3.91 (s, 2H), 2.26 (s, 3H), 1.60 (s, 6H), 1.51 (br, 3H).

- 92 043276

Example 70:

1-(but-2-yn-1-yl)-7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-4,5dihydro[1,2, 4]triazolo[4,3-a]quinoxaline

Step 1. To a solution of 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (1.32 g, 4.53 mmol, 1 eq.) in toluene :EtOH (2:1) (15 ml) was added 10% aqueous solution of Na ₂ CO ₃ (7.3 ml), 3-methyl-7(4,4,5,5-tetramethyl-1,3,2-dioxaborolane -2-yl)-1H-indole (1.75 g, 6.8 mmol, 1.5 eq.). The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.262 g, 0.23 mmol, 0.05 eq.). Degassing was continued for an additional 10 minutes and the reaction mixture was heated at 110° C. for 16 hours in a sealed vessel. After completion of the reaction (the progress of the reaction was monitored by TLC), the solvent was evaporated, the residue was diluted with water (25 ml), was extracted with EtOAc (3x100 ml). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by flash column chromatography (silica gel 100-200 mesh; 50% EtOAc/ hexane; Rf value 0.3) to give 6,8-difluoro-3,3-dimethyl-7-(3-methyl-1 H-indol-7 -yl)-3,4-dihydroquinoxaline-2( 1 H) -one (0.55 g, 35%) as a brown solid.

Step 2. To a solution of 6,8-difluoro-3,3-dimethyl-7-(3-methyl-1H-indol-7-yl)-3,4-dihydroquinoxalin2(1H)-one (0.55 g, 1 .61 mmol, 1 eq.) in toluene (10 ml) was added Lausson's reagent (0.975 g, 2.41 mmol, 1.5 eq.) at room. temp., and the reaction mixture was refluxed at 120°C for 30 min. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was cooled, quenched with sat. NaHCO ₃ (50 ml) followed by extraction with EtOAc (3x100 ml). The combined organic layers were washed with water (25 ml), brine (25 ml), dried over anhydrous Na2SO4, and the solvent was evaporated to give the crude product, which was purified by column chromatography (silica gel 100-200 mesh; 10% EtOAc/hexane; R _f - value-0.7) to give 6,8difluoro-3,3-dimethyl-7-(3-methyl-1H-indol-7-yl)-3,4-dihydroquinoxalin-2(1H)-thione (0.503 g, 87%) as a yellow solid.

Step 3 To a solution of 6,8-difluoro-3,3-dimethyl-7-(3-methyl-1H-indol-7-yl)-3,4-dihydroquinoxaline2(1H)-thione (0.400 g, 1.12 mmol, 1 eq.) in THF (8 ml) was added hydrazine hydrate (0.16 ml, 3.36 mmol, 3 eq.), the mixture was stirred overnight at room temperature. pace. The completion of the formation of 5,7-difluoro-3-hydrazono-2,2-dimethyl-6-(3-methyl-1H-indol-7-yl)-1,2,3,4-tetrahydroquinoxaline was followed by TLC and LC-MS , (EtOAc; R _f -value-0.1). This reaction mixture was used in the next step without working up the reaction mixture and purification.

Step 4 To a solution of pent-3-ic acid (0.658 g, 6.72 mmol, 6 eq.) in benzene (10 ml) was added oxalyl chloride (1.4 ml) at 0°C and the mixture was heated at 50°C for 1 h under nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure under nitrogen at 25°C. The residue was dissolved in THF (5 ml), the resulting solution was added dropwise to a solution of 5,7-difluoro-3-hydrazono2,2-dimethyl-6-(3-methyl-1H-indol-7-yl)-1,2, 3,4-tetrahydroquinoxaline already obtained (mentioned above) at 0°C. TEA (1 ml, 6.72 mmol, 6 eq.) was added to the mixture and stirred for 1.5 h at room temperature. pace. After completion of the reaction (the progress of the reaction was monitored by TLC), the reaction mixture was quenched with water (5 ml), was extracted with EtOAc (3x20 ml). The combined organic layers were washed with brine (10 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give crude N'-(6,8-difluoro-3,3-dimethyl-7-(3-methyl-1 H -indol-7 -yl)-3,4-dihydroquinoxalin-2( 1H)ylidene)pent-3-ynhydrazide (0.450 g) (50% EtOAc-hexane; R _f -value -0.5), which was used for the next step without further purification.

- 93 043276

Step 5. To a solution of N'-(6,8-difluoro-3,3-dimethyl-7-(3-methyl-1H-indol-7-yl)-3,4dihydroquinoxalin-2(1H)-ylidene)pent- 3-ynhydrazide (0.450 g, 1.03 mmol) in n-butanol (8 ml) was added glacial acetic acid (catalytic amount, 2 drops with capillary tube), the mixture was heated at 140°C for 3 h. After completion of the reaction ( the progress of the reaction was monitored by TLC) the reaction mixture was concentrated under reduced pressure. The residue was diluted with water (25 ml) and was extracted with EtOAc (3x50 ml). The combined organics were washed with brine (10 ml), dried (anhydrous Na ₂ SO ₄ ) and concentrated under reduced pressure to a sticky mass, which was purified by preparative HPLC (5% MeOH-DCM; Rf-value-0.35) to give 1- (but-2-yn1-yl)-7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-4,5-dihydro[1,2,4] triazolo[4,3-a]quinoxaline (76 mg, 11% over three steps) as a white solid with a metallic tint [another 200 from reaction batch, prepared from 6,8-difluoro-3,3-dimethyl-7 -(3-methyl-1H-indol-7-yl)-3,4dihydroquinoxalin-2(1H)-thione and the reported yield here is the combined yield].

1H NMR (400 MHz, DMSO-d ₆ ): δ 10.60 (s, 1H), 7.56 (d, 1H), 7.06-7.15 (4H), 6.77 (d, 1H) , 3.90 (s, 2H), 2.29 (s, 3H), 1.60 (s, 6H), 1.51 (s, 3H).

Example 76: 7-fluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1 H-indol-7-yl)-1-(methoxymethyl)-4,4,9 -trimethyl4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline

Stage-3

Step 1 To a solution of intermediate B-17 (1.0, 2.82 mmol, 1 eq.) in toluene:ethanol (2:1) (15 ml) was added 10% Na ₂ CO ₃ solution (2 ml) and 5-fluoro-7-(tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indole (1.1 g, 4.22 mmol, 1.5 eq.) in a sealed vial. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.162 g, 0.14 mmol, 0.05 eq.). The reaction mixture was refluxed at 110° C. for 16 h. After completion of the reaction (reaction progress was monitored by LC-MS), the reaction mixture was evaporated to dryness and the residue was diluted with EtOAc (100 ml). The organic layer was washed with water (2x30 ml), brine (30 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by combi-flash column chromatography (5% MeOH/DCM; R _f -value-0 ,4) to obtain 7-fluoro-8-(5fluoro-1 H-indol-7-yl)-1 -(methoxymethyl)-4,4,9-trimethyl-4,5-dihydro[1,2,4] triazolo[4,3-a]quinoxaline (1.1 g, 96%) as a white solid with a metallic tint.

Step 2 To a stirred solution of 7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1-(methoxymethyl)-4,4,9trimethyl-4,5-dihydro[1,2,4] triazolo[4,3-a]quinoxaline (1.1 g, 2.68 mmol, 1 eq.) in DMF (20 ml) was added potassium hydroxide powder (0.39 g, 6.95 mmol, 2.5 eq. ). The reaction mixture was stirred for 30 min at room temperature. pace. Iodine (1.06 g, 4.18 mmol, 1.5 eq.) was then added to the reaction mixture and stirred for 4 hours. The reaction mixture was diluted with EtOAc (150 ml) and washed with water (5x30 ml) and saturated aqueous chloride solution sodium (30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; Rf-value-0.4) to give 7-fluoro- 8-(5-fluoro-3-iodo-1H-indol-7-yl)-1-(methoxymethyl)-4,4,9-trimethyl-4,5dihydro[1,2,4]triazolo[4,3- a]quinoxaline (0.26 g, 18%) as a light brown solid.

Step 3. Solution of 7-fluoro-8-(5-fluoro-3-iodo-1H-indol-7-yl)-1-(methoxymethyl)-4,4,9-trimethyl-4,5dihydro[1,2, 4]triazolo[4,3-a]quinoxaline (0.26 g, 0.49 mmol, 1 eq.) in THF and TEA (1:1) (6 ml) was deoxygenated with Ar for 10 min in a sealed vessel. Pd(PPh ₃ ) ₂ Cl ₂ (0.017 g, 0.024 mmol, 0.05 eq.), CuI (0.019 g, 0.097 mmol, 0.1 eq.) was added to the reaction mixture and again deoxygenated with Ar for 10 min at - 78°C. In the tube, propyne gas condensed into TEA (3 ml) at -78°C. The volume increased to 5 ml. The condensed propyne gas was instantly poured into the reaction mixture at -78°C. The reaction mixture was stirred for 2 h at -78°C and 14 h at room temperature. pace. The reaction mixture was diluted with DCM (50 ml). The organic layer was washed with water (2x20 ml) and brine (20 ml).

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The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material, which was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; R _f -value-0.4) to give 7-fluoro -8-(5-fluoro-3-(prop-1-yn-1-yl)-1H-indol-7-yl)1-(methoxymethyl)-4,4,9-trimethyl-4,5-dihydro[ 1,2,4]triazolo[4,3-a]quinoxaline (0.055 g, 25%) as a white metallic solid.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 11.21 (s, 1H), 7.59 (d, J=2.28 Hz, 1H), 7.28 (dd, J=1.96 Hz , J=6.96 Hz, 1H), 6.96 (dd, J=2.24 Hz, J=7.56 Hz, 1H), 6.83 (s, 1H), 6.78 (d, J =10.08 Hz, 1H), 4.69 (d, J=13.32 Hz, 1H), 4.61 (d, J=13.32 Hz, 1H), 3.25 (s, 3H), 2.09 (s, 3H), 1.98 (s, 3H), 1.52 (s, 3H), 1.5 (s, 3H).

Example 77: (7-fluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1 H-indol-7-yl)-4,4,9-trimethyl-4.5 dihydro[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)methanol

THF / No. A -, l ₂ o

Stage-3

I'

Example 77 was synthesized starting from Intermediate B-18 following a similar synthetic route as described for Example 76.

1 H NMR (400 MHz, DMSO-d ₆ ): δ 11.14 (s, 1H), 7.59 (s, 1H), 7.28 (d, J=7.28 Hz, 1H), 6.98 (d, J=9.6 Hz, 1H), 6.78 (t, J=6.96 Hz, 2H), 5.53 (d, J=5.48 Hz, 1H), 4.73 (d , J=5.4 Hz, 2H), 2.08 (d, J=9.28 Hz, 3H), 2.03 (s, 3H), 1.53 (s, 3H), 1.48 (s , 3H).

Example 78: 1-(7-fluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1H-indol-7-yl)-4,4,9-trimethyl-4, 5dihydro[1,2,4]triazolo[4,3-a]quinoxalin-1-yl)ethanol

vdedazheni® V-O

TFWTEA, /CHN-A

Г I ] ρ

Cui ^{JL 1} G1 ^N

G ...

Example 78 was synthesized starting from Intermediate B-19 following a similar synthetic route as described for Example 76.

1H NMR (400 MHz, DMSO-d6): δ 11.25 (s, 1H), 10.9 (br, 2H), 7.59 (t, J=2.56 Hz, 2H), 7.28 ( d, J=9.04 Hz, 2H), 7.06 (d, J=9.72 Hz, 1H), 6.96 (dd, J=2.32 Hz, J=7.6 Hz, 2H) , 6.77-6.71 (m, 4H), 5.5 (d, J=7.04 Hz, 1H), 5.36 (br, 1H), 5.03-4.95 (m, 2H ), 2.08 (t, J=6.6 Hz, 10H), 1.55 (br, 17H).

Example 79: 7-fluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1 H-indol-7-yl)-1-(2-methoxyethyl)-4.4 ,9-trimethyl4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline

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Example 79 was synthesized starting from Intermediate B-20 following a similar synthetic route as described for Example 76.

¹ H NMR (400 MHz, DMSO-d6): δ 11.29 (s, 1H), 7.59 (d, J=2.52 Hz, 1H), 7.28 (dd, J=1.6 Hz , J=6.8 Hz, 1H), 7.01 (br, 1H), 6.81 (s, 1H), 6.79 (s, 1H), 3.74 (t, J=6.56 Hz , 2H), 3.2 (s, 3H), 3.07 (br, 1H), 2.97 (br, 1H), 2.08 (d, J=9.48 Hz, 3H), 1.95 (s, 3H), 1.48 (br, 6H).

Example 87 8-(3-cyclopropyl-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo [4 ,3-a]quinoxaline

Prver E L

Starting from 7-fluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (=Example 86) Example 87 following a similar synthetic route as described for Example 33.

¹ H NMR (400 MHz, DMSO-06): δ 10.58-10.6 (1H), 7.66 (d, J=8.0 Hz, 1H), 7.36-7.40 (1H) , 7.15-6.99(m, 4H), 2.44(s, 3H), 1.94(m, 1H), 1.75(s, 3H), 1.31-1.34(3H ), 0.85 (d, J=7.96 Hz, 2H), 0.63 (m, 2H).

Example 89 7-(7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-8-yl)-1H -indole-3-carbonitrile

CF, rF··'···, -rttii.. f 1 1 Jj g-41·, thtpht [ I ||'b4 hagsd. ¹ ''. | h - G'

Example 86

Step 1. To a stirred solution of 7-fluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-9(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline (=Example 86) (0.4 g, 1.04 mmol, 1 eq.) in DMF (12 ml) was added KOH powder (0.147 g, 2.62 mmol, 2.5 eq.) . The reaction mixture was stirred for 30 min at room temperature. pace. Iodine (0.264 g, 2.08 mmol, 2 eq.) was then added to the reaction mixture and stirred for 4 hours. The reaction mixture was diluted with EtOAc (80 ml) and washed with water (5 x 20 ml) and saturated aqueous sodium chloride ( 30 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; Rj-value 0.4) to give 7-fluoro-8- (3-iodo-1H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.400 g , 66%) as a light brown solid.

Step 2 Stirring suspension of 7-fluoro-8-(3-iodo-1H-indol-7-yl)-1,4,4-trimethyl-9(trifluoromethyl)-4,5-dihydro[1,2,4] triazolo[4,3-a]quinoxaline (0.2 g, 0.369 mmol, 1 eq.), Zn(CN) ₂ (0.043 g, 0.369 mmol, 1 eq.), TMEDA (0.016 ml, 0.110 mmol, 0, 3 equiv.) in DMA (3 ml) was well deoxygenated with Ar for 10 min. Pd ₂ dba ₃ (0.033 g, 0.0369 mmol, 0.1 eq.), Xantphos (0.021 g, 0.0369 mmol, 0.1 eq.) was added to the reaction mixture and again deoxygenated with Ar for 10 min. At the end the reaction mixture was stirred for 14 h at 90°C. The reaction mixture was filtered through a pad of celite and the filtrate was diluted with EtOAc (30 ml). The organic layer was washed with water (5x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give a crude material which was purified by silica gel (230-400) column chromatography (5% MeOH/DCM; R ₁ -value-0.4) to give 7-( 7-fluoro-1,4,4-trimethyl-9(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol-3- carbonitrile (0.072 g, 44%) as a white solid with a metallic tint.

¹ H NMR (400 MHz, DMSO-d6): δ 12.10-12.19 (1H), 8.28 (d, J=2.7 Hz, 1H), 7.72 (d, J=6, 8 Hz, 1H), 7.467.51 (1H), 7.34-7.25 (m, 2H), 7.19-7.12 (m, 1H), 2.45 (s, 3H), 1, 76 (s, 3H), 1.32-1.36 (3H).

Example 446: 7-fluoro-1,4,4-trimethyl-8-(1-(methylsulfonyl)-1H-indazol-4-yl)-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo [4,3-a]quinoxaline

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To a solution of 8-bromo-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3а]quinoxaline (intermediate B-4) (0.3 g, 0.7912 mmol, 1 eq.) in t-amyl alcohol:dioxane (2:1) (15.0-7.0 ml) was added a 2 M solution of K ₂ CO ₃ (1.0 ml ) and 1-(methylsulfonyl)-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (Intermediate A-22) (0.48 g, 1 5824 mmol, 2.0 eq.). The solution was degassed with Ar for 20 min followed by the addition of Attaphos (0.028 g, 0.0395 mmol, 0.05 eq.). The reaction mixture was heated at 90° C. for 16 hours. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The combined organic layer was evaporated to give a crude product which was purified by preparative HPLC (Rf-value-0.3:5% MeOH/DCM) to give 7fluoro-1,4,4-trimethyl-8-(1-(methylsulfonyl)-1 N-indazol-4-yl)-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.065 g, 17%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 8.34 (s, 1H), 8.09 (d, 1H), 7.73 (t, 1H), 7.45 (br, 1H), 7, 27 (s, 1H), 7.19 (d, 1H), 3.50 (s, 3H), 2.49 (s, 3H), 1.66-1.78 (br, 3H), 1.23 -1.52 (br, 3H).

Example 450: 1,4.4,9-tetramethyl-8-(1-(methylsulfonyl)-1H-indol-4-yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline

To a solution of 8-bromo-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-40) (0.15 g, 0.488 mmol, 1 eq.) in dioxane:water (10:1) (22 ml) was added CsF (0.222 g, 1.464 mmol, 3 eq.), 1-(methylsulfonyl)-4-(4,4,5,5 -tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (Intermediate A-12) (0.313 g, 0.977 mmol, 2 eq.). The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.028 g, 0.024 mmol, 0.05 eq.). The reaction mixture was heated at 90° C. for 16 hours. After completion of the reaction (the progress of the reaction was followed by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The combined organic layer was evaporated to give a crude product which was purified by preparative HPLC to give 1,4,4,9-tetramethyl-8-(1-(methylsulfonyl)-1H-indol-4-yl)-4,5-dihydro[1 ,2,4]triazolo[4,3a]quinoxaline (0.085 g, 41%) as a white solid.

1H NMR (400 MHz, DMSO-d6): δ 7.88-7.85 (m, 1H), 7.62 (d, 1H), 7.48 (t, 1H), 7.28 (d, 1H ), 7.13-7.11 (m, 1H), 6.97-6.95 (m, 1H), 6.53 (s, 2H), 3.49 (s, 3H), 2.03 ( s, 3H), 1.46 (br, 6H).

In the following tables. 4, 5, 6 and 7 summarize how the remaining examples were obtained.

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Table 4

Etc. No. Intermediates Synthesis is similar yield (% mol) Ίι-nmr 45 Intermediate conn.-A21 + Intermediate conn.-B-8 Etc. 44 67% 'H NMR (400 MHz, DMSO-d ₆ , t=100 ^and C): δ 7.83 (s, 1H), 7.59 (d, 1H), 7.14 (d, 1H), 6.93 (s, 1H), 4.92-4.89 (m, 1H), 4.44 (s, 1H), 3.83 (br, 2H), 2.68-2.78 (m, 1H), 1.48 (br, 6H), 0.51 (br, 3N). 46 Intermediate conn.-A2 + Intermediate conn.-B-8 Etc. 44 48% 'H NMR (400 MHz, DMSO-Db, t=100°C): δ 7.71-7.65 (m, 2H), 7.35 (d, 1H), 6.92 (s, 1H), 6.78 (d, 1H), 6.52 (s, 1H), 3.59 (s, 3H), 2.67 (s, 1H), 1.49 (br, 6H), 0.50 (s , ZN). 47 Intermediate conn.-A15 + Intermediate conn.-B-8 Etc. 44 24% 'H NMR (400 MHz, DMSO-Db, t=100°C): δ 10.6 (s, 1H), 7.28 (dd, 1H), 7.15 (s, 1H), 6.95 ( d1H), 6.83 (s, 1H), 6.76 (d, 1H), 2.67 (c, J = 7.2 Hz, 1H), 2.25 (s, 3H), 1.50 ( br, 6H), 0.5 (br, 3N). 50 Intermediate conn.-A12 + Intermediate conn.-B-8 Etc. 44 46% 1H NMR (400 MHz, DMSO-Db, at 100°C): 7.93 (d, 1H), 7.6 (d, 1H,), 7.48 (t, 1H,), 7.32 (d , 1Hi), 6.8 (d, 1H, 1=10.32 Hz), 6.55 (s, 1H), 6.5 (d, 1Hi), 3.44 (s, 3N), 2 .76-2.67(m, 1H), 2.57-2.53 (m, ZN), 2.49 (s, ZN), 1.55 (s, ZN), 1.51 (s, ZN ), 0.53 (t, ZN). 51 Intermediate conn.-A22 + Intermediate conn.-B-8 Etc. 44 15% 1H NMR (400 MHz, DMSO-Db, at 100°C): 8.27 (s, 1H), 8.06 (d, 1H, 1=8.52 Hz), 7.73 (t, 1H, 1 =7.6 Hz), 7.45 (d, 1H, 1=7.2 Hz), 6.83 (d, 1H, 1=10.48 Hz), 6.65 (s, 1H), 3, 50 (s, ZN), 2.792.74(m, 1H), 2.57-2.53 (m, ZN), 2.51 (s, ZN), 1.55 (s, ZN), 1.53 (s, ZN), 0.54 (t, ZN). 52 Intermediate conn.-A23 + Intermediate conn.-B-8 Etc. 44 23% 1H NMR (400 MHz, DMSO-Db, at 100°C): 8.28 (s, 1H), 7.76 (d, 1H, 1=9.2 Hz), 7.41 (d, 1H, 1 \u003d 9.8 Hz), 6.83 (d, 1H, 1 \u003d 10.52 Hz), 6.72 (s, 1H), 3.54 (s, ZN), 2.83-2.76 (m , 1H), 2.60-2.54 (m, ZN), 2.52 (s, ZN), 1.55 (s, ZN), 1.53 (s, ZN), 0.57 (t, ZN). 67 Intermediate conn.-A15 + Intermediate conn.-B-13 Etc. 3 56% 'H NMR (400 MHz, DMSO-db): δ 10.73 (s, 1H), 7.32 (d, 1H), 7.16-7.25 (5H), 7.02 (d, 2H) , 6.74 (t, 2H), 4.27-4.39 (2H), 2.48 (s, 3N), 1.62 (br, 3N), 1.47 (br, 3N). 68 3-methyl-7(4,4,5,5tetramethi l-1,3,2dioxaborolan-2yl)-1H-indole + Intermediate conn.-B13 Etc. 3 60% Ή NMR (400 MHz, DMSO-db): δ 10.59 (s, 1H), 7.54 (d, 1H), 7.14-7.26 (3H), 7.06-7.12 (3H ), 7.01-7.03 (2H), 6.90 (d, 1H), 6.72 (d, 1H), 4.24-4.38 (2H), 2.28 (s, 3H) , 1.62 (s, ZN), 1.48 (s, ZN). 71 Intermediate conn.-A15 + Intermediate conn.-B-14 Etc. 3 40% Ή NMR (400 MHz, DMSO-db): δ 10.76 (s, 1H), 8.42 (d, 2H), 7.32 (dd, 1H), 7.21 (d, 2H), 7, 12 (d, 2H), 6.76-6.83 (2H), 4.344.36 (2H), 2.25 (s, 3H), 1.48-1.60 (6H). 72 3-methyl-7(4,4,5,5tetramethi l-1,3,2dioxaborolan-2yl)-1H-indole + Intermediate conn.-B14 Etc. 3 38% Ή NMR (400 MHz, DMSO-db): δ 10.62 (s, 1H), 8.42 (d, 2H), 7.54 (d, 1H), 7.06-7.15 (5H), 6.92-6.94 (1H), 6.77 (d, 1H), 4.334.38 (2H), 2.28 (s, 3N), 1.60 (s, 3N), 1.53 (s , ZN). 73 Intermediate conn.-A15 + Intermediate conn.-B-15 Etc. 3 58% Ή NMR (400 MHz, DMSO-db): δ 10.77 (s, 1H), 8.40 (d, 1H), 8.35 (s, 1H), 7.53 (d, 1H), 7, 26-7.35(2H), 7.20(s, 1H), 6.89(d, 1H), 6.78(d, 1H), 4.32.4.36(2H), 2.52 (s, 3H), 1.47-1.60 (6H). 74 Intermediate conn.-A15 + Intermediate conn.-B-16 Etc. 3 58% Ή NMR (400 MHz, DMSO-db): δ 10.82 (s, 1H), 8.30 (s, 1H), 7.67 (t, 1H), 7.30 (d, 1H), 7, 16-7.25 (4H), 6.72 (d, 1H), 6.67 (d, 1H), 4.51 (br, 2H), 2.24 (s, 3N), 1.60 (s , ZN), 1.51 (s, ZN). 75 3-methyl-7(4,4,5,5tetramethi l-1,3,2dioxaborolan-2yl)-1H-indole + Intermediate conn.-B- Etc. 3 33% Ή NMR (400 MHz, DMSO-db): δ 10.70 (s, 1H), 8.30 (d, 1H), 7.68 (t, 1H), 7.52 (d, 1H), 7, 17-7.22(2H), 7.09(s, 2H), 7.04(t, 1H), 6.81(d, 1H), 6.72(d, 1H), 4.97-4 .54 (2H), 2.27 (s, 3N), 1.60 (s, 3N), 1.51 (s, 3N).

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16 80 (1Н-indol-7yl)boronic acid + Intermediate conn.-B21 Etc. 3 29% Ή NMR (400 MHz, DMSO-d ₆ ): δ 10.97 (1H), 7.63 (dd, 1H), 7.34 (m, 1H), 7.08-7.2 (3H), 6 .80 (d, 1H), 6.51 (m, 1H), 2.78 (m, 2H), 1.57 (s, 3H), 1.54 (s, 3H), 1.59 (m, 1H), 0.42 (m, 2H), 0.12 (m, 2H). 81 (1Н-indol-7yl)boronic acid + Intermediate conn.-B22 Etc. 3 20% Ή NMR (400 MHz, DMSO-db): δ 10.98 (s, 1H), 7.62 (dd, 1H), 7.43 (m, 1H), 7.08-7.11 (3H), 6.80 (l, W), 6.50 (m, 1H), 2.09 (m, 1H), 1.60 (s, W), 1.52 (s, W), 0.88-0 .95 (4H). 82 Intermediate conn.-A26 + Intermediate conn.-B-23 Etc. 37 19% 1H NMR (400 MHz, DMSO-d ₆ ): 10.48 (s, 1H), 7.63 (d, W, 1=7.76 Hz), 7.32 (s, 1H), 7.06 ( t, 1H, J=7.44 Hz), 6.95 (d, 1H, 1=1.76 Hz), 6.9 (s, 1H), 6.87 (d, 1H, 1=7.16 Hz), 2.4 (s, ZN), 1.97-1.93 (m, 1H), 1.78 (s, ZN), 1.61 (s, ZN), 1.39 (s, ZN ), 0.88083 (m, 1H), 0.65-0.62 (m, 1H). 83 Intermediate conn.-A2 + Intermediate conn.-B-23 Etc. 37 14% 1H NMR (400 MHz, DMSO-d ₆ ): 7.69 (d, 1H, 1=10.24 Hz), 7.6 (d, 1H, 1=3.68 Hz), 7.33 (s, 1H), 7.15 (d, 1H, 1=9.12 Hz), 7.03 (s, 1H), 6.41 (s, 1H), 3.59 (s, 3H), 2.39 ( s, ZN), 1.86 (s, ZN), 1.56 (s, ZN), 1.43 (s, ZN). 84 Intermediate conn.-A12 + Intermediate conn.-B-23 Etc. 37 13% 1H NMR (400 MHz, DMSO-db): 7.9 (d, 1H, 1=8.44 Hz), 7.59 (d, 1H, 1=3.44 Hz), 7.46 (t, 1H , 1=7.84 Hz), 7.33 (s, 1H), 7.17 (d, 1H, 1=7.04 Hz), 6.99 (s, 1H), 6.41 (s, 1H ), 3.53 (s, 3N), 2.38 (s, 3N), 1.82 (s, 3N), 1.58 (s, 3N), 1.41 (s, 3N). 85 Intermediate conn.-A26 + Intermediate conn.-B-5 Etc. 3 12% 'H NMR (400 MHz, DMSO-d ₆ ): δ 10.62 (s, 1H), 7.66 (d, 1 = 8.0 Hz, 1H), 7.08 (t, 1 = 9.6 Hz, 2H), 7.00-7.02 (m, 2H), 6.92 (d, 1 = 10.0 Hz, W), 2.56 (s, ZN), 1.94 (d, 1 = 4.8 Hz, 1H), 1.56 (s, ZN), 1.46 (s, ZN), 0.83-0.88 (m, 2H), 0.61-0.64 (m, 2H). 86 (1Н-indol-7yl)boronic acid + Intermediate conn.-B4 Etc. 3 20% 'H NMR (400 MHz, DMSO-d ₆ ): δ 10.95-10.98 (1H), 7.59-7.63 (1H), 7.36-7.41 (1H), 7.31 (m, 1H), 7.02-7.16 (3H), 6.48 (s, 1H), 2.45-2.48 (3H), 1.76 (s, 3H), 1.32- 1.36 (ZN). 88 Intermediate conn.-A27 + Intermediate conn.-B-5 Etc. 37 12% 'H NMR (400 MHz, DMSO-Db, t=100°C): δ 7.41 (d, 1 = 9.88 Hz, 1H), 7.28 (d, 1 = 3.28 Hz, W) , 7.14 (d, 1 = 10 Hz, 1H), 6.96 (br, 1H), 6.07 (s, W), 3.49-3.46 (m, W), 2.45 ( s, ZN), 1.75 (br, ZN), 1.36(br, ZN), 1.10-1.00 (m, 4H).

Examples in table. 5 were synthesized by analogy with example 1.

Table 5

Etc. No. Intermediates Catalyst Solvent Exit (%) LC-MS (M+N) ⁺ Ίΐ NMR 200 Intermediate conn.-B-1 + Intermediate conn.-A-ZO Bis(tri-tert-butylphosphine) palladium(O) THF 58% I NMR (DMSO-db) δ: 7.94 (d, 1H), 7.65 (d, 1H), 7.48 (t, 1H), 7.38 (d, 1H), 7.20 (d , 1H), 6.82 (d, 1H), 6.71 (d, 1H), 3.86 (yert, 1H), 2.51 (d, 3H), 1.57 (s, 3H), 1 .52 (s, 3N), 1.24 (t, 6H) 201 Intermediate conn.-B-1 + Intermediate conn.-A-31 Bis(tri-tert-butylphosphine) palladium(O) THF 44% H NMR (DMSO-db) δ: 7.96 (d, 1H), 7.68 (d, 1H), 7.48 (t, 1H), 7.38 (d, 1H), 7.22 - 7 .18 (m, 1H), 6.85 - 6.80 (m, 1H), 6.70 (d, 1H), 4.16 - 4.07 (m, 1H), 2.51 (d, ZN ), 1.94 (dt, 2H), 1.84 (dc, 2H), 1.71 - 1.61 (m, 2H), 1.57 (d, 5H), 1.52 (s, 3H) 207 Intermediate conn.-B-1 + Bis(tri-tert-butylphosphine) 81% 'H NMR (DMSO-db) δ: 7.84 (s, 1H), 7.67 (t, 1H), 7.36 (s, 1H), 7.19 (s, 1H), 6.86 - 6.80

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4(tetramethyl1,3,2dioxaborole an-2-yl)-6(trifluoromethyl)-1Nindole palladium(O) THF (m, 1H), 6.44 (s, 1H), 2.51 (d, ZN), 1.59 (s, ZN), 1.51 (s, ZN) 208 Intermediate conn.-B-1 + Intermediate conn.-A-l Bis(tri-tert-butylphosphine) palladium(O) THF 48% 'H NMR (DMSO-d ₆ ) δ: 11.31 (s, 1H), 7.40 (t, 1H), 7.28 (dd, 1H), 7.17 (d, 1H), 6.98 (dd, W), 6.86 - 6.71 (m, 1H), 6.28 (s, 1H), 2.51 (d, W), 1.57 (s, W), 1.51 ( s, zn) 212 Intermediate conn.-B-l + Intermediate conn.-A-32 Bis(tri-tert-butylphosphine) palladium(O) THF 48% Ή NMR (DMSO-d ₆ ) δ: 7.44 (d, 1H), 7.30 (d, 1H), 7.21 (dd, 1H), 7.12 (d, 1H), 7.08 ( d, 1H), 6.81 (dd, 1H), 6.30 - 6.25 (m, 1H), 5.19 (s, 2H), 3.14 (s, ZN), 2.88 (s , ZN), 2.51 2.49 (m, ZN), 1.59 (s, ZN), 1.50 (s, ZN) 213 Intermediate conn.-B-1 + Intermediate conn.-A-ZZ Bis(tri-tert-butylphosphine) palladium(O) THF 38% Ή NMR (DMSO-%) δ: 8.44 (d, 1H), 7.84 (d, 1H), 7.47 (t, 1H), 7.35 (s, 1H), 7.19 (d , 1H), 6.82 (dd, 1H), 6.65 (d, 1H), 4.79 (s, 2H), 3.45 (s, 3H), 2.53 - 2.48 (m, ZN), 1.59 (s, ZN), 1.51 (s, ZN) 214 Intermediate compound-B-1 + pinacol ester of 5fluoro-1Nindole-4boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 64% 'H NMR (DMSO-d ₆ ) δ: 11.45 - 11.25 (m, 1H), 7.51 (ddd, 1H), 7.47 (t, 1H), 7.23 - 7.18 ( m, 1H), 7.08 (dd, 1H), 6.82 (dd, 1H), 6.29 (p, 1H), 2.49 (d, 3H), 1.58 (s, 3H), 1.51 (s, ZN) 219 Intermediate conn.-B-1 + Intermediate conn.-A-49 Bis(tri-tert-butylphosphine) palladium(O) THF 44% Ή NMR (DMSO-%) δ: 7.58 (d, 1H), 7.40 (d, 1H), 7.25 (dd, 1H), 7.14 - 7.07 (m, 2H), 6 .80 (dd, 1H), 6.30 - 6.25 (m, 1H), 4.48 (t, 2H), 3.60 (s, 3H), 2.90 (t, 2H), 2, 49 (d, WN), 1.58 (s, WN), 1.51 (d, WN) 221 Intermediate comp.-B-1 + 1 -methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa borolan-2- sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 62% 'H NMR (DMSO-d ₆ ) δ: 7.96 (s, 1H), 7.72 (d, 1H), 7.51 (dd, 1H), 7.23 (d, 1H), 7.21 (l, w), 6.86 - 6.80 (m, 1H), 4.10 (s, ZN), 2.51 (k, ZN), 1.55 (s, 6H) 222 Intermediate compound-B-1 + 2-methyl-4 (4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-2Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 52% 'H NMR (DMSO-%) δ: 8.28 (s, 1H), 7.67 (d, 1H), 7.35 (dd, 1H), 7.19 (d, 1H), 7.12 ( d, 1H), 6.82 (dd, 1H), 4.16 (s, ZN), 2.53 - 2.51 (m, ZN), 1.55 (s, 6H) 225 Intermediate conn.-B-1 + 4- Bis(tri-tertbutylphosphine) palladium(O) 76% 'H NMR (DMSO-d ₆ ) δ: 7.58 (d, 1H), 7.41 (t, 1H), 7.22 (d, 1H), 7.16 (d, 1H), 6.89 (s, 1H), 6.81 (d, 1H), 2.49 (s, 3H), 1.57 (s, 3H), 1.53

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(tetramethyl1,3,2dioxaborol an-2-yl)-2(trifluoromethyl)-1Nindole THF (s, zn) 228 Intermediate conn.-B-1 + Intermediate conn.-A-34 Bis(tri-tert-butylphosphine) palladium(O) THF 72% Ή NMR (DMSO-d ₆ ) δ: 7.54 (d, 1H), 7.37 (d, 1H), 7.24 (t, 1H), 6.98 (t, 1H), 6.79 ( dd, 1H), 6.27 (t, 1H), 4.26 (t, 2H), 2.49 (d, 3N), 1.58 (s, 3N), 1.49 (s, 3N), 1.36 (s, 9H), 1.13 (s, 2H) 232 Intermediate compound-B-1 + 4-(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 31% 'H NMR (DMSO-d ₆ ) δ: 7.98 (s, 1H), 7.62 (d, 1H), 7.46 (dd, 1H), 7.20 (dd, 2H), 6.86 6.79 (m, 1H), 2.53 (d, 3N), 1.55 (s, 6H) 233 Intermediate conn.-B-1 + Intermediate conn.-A-3b Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 80% Ή NMR (DMSO-d ₆ ) δ: 7.98 (d, 1H), 7.78-7.73 (m, 1H), 7.49 (dd, 1H), 7.24-7.19 (m, 2H), 6.83 (dd, 1H), 4.61 (t, 2H), 3.80 (t, 2H), 3.23 (s, 3H), 2.53 (s, 3H), 1, 55 (s, 6H) 234 Intermediate conn.-B-1 + Intermediate conn.-A-35 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 29% Ή NMR (DMSO-d ₆ ) δ: 8.57 (d, 1H), 8.10 8.04 (m, 1H), 7.76 (dd, 1H), 7.60-7.50 (m, 1H), 7.30 (t, 1H), 6.85 (dd, 1H), 3.17 (tt, 1H), 2.54 (d, 3H), 1.56 (s, 6H), 1, 36 - 1.24 (m, 2H), 1.22-1.11 (m, 2H) 235 Intermediate conn.-B-1 + Intermediate conn.-A-37 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 57% Ή NMR (DMSO-d ₆ ) δ: 7.97 (s, W), 7.79 (dd, 1H), 7.49 (dd, 1H), 7.24-7.19 (m, 2H), 6.83 (dd, 1H), 4.35 (d, 2H), 2.52 (d, ZN), 1.55 (s, 6H), 1.38 - 1.27 (m, 1H), 0 .56 - 0.48 (m, 2H), 0.49-0.41 (m, 2H) 236 Intermediate conn.-B-1 + Intermediate conn.-A-38 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 72% 'H NMR (DMSO-%) δ: 7.97 (s, 1H), 7.76 (d, 1H), 7.50 (dd, 1H), 7.22 (d, 2H), 6.86 - 6.80 (m, 1H), 4.49 (c, 2H), 2.53 (s, 3H), 1.55 (s, 6H), 1.44 (t, 3H) 237 Intermediate conn.-B-1 + Intermediate conn.-A-39 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 99% Ή NMR (DMSO-d ₆ ) δ: 8.33 (s, 1H), 7.68 (d, 1H), 7.35 (dd, 1H), 7.18 (d, 1H), 7.12 ( d, 1H), 6.82 (dd, 1H), 4.45 (c, 2H), 2.53 (s, 3H), 1.55 (s, 6H), 1.51 (t, 3H) 238 Intermediate compound-B-1 + tert-butyl4-(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole-1carboxylate Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 41% 'H NMR (DMSO-%) δ: 8.38 (s, 1H), 8.18 (d, 1H), 7.73 (dd, 1H), 7.48 (d, 1H), 7.29 ( s, 1H), 6.85 (d, 1H), 2.53 (d, 3H), 1.68 (s, 9H), 1.56 (s, 6H) 239 Intermediate conn.-B-1 + Intermediate Tetrakis(triphenylphosphine)-palladium (0) 66% 'H NMR (DMSO-d ₆ ) δ: 8.57 (s, br), 8.08 (dd, 1H), 7.75 (dd, 1H), 7.52 (d, 1H), 7.30 (d, 1H), 6.85 (dd, 1H), 3.66 (d, 2H), 2.54 (d,

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conn.-A-40 Toluene/Ethanol 3H), 1.56 (s, 6H), 0.81 (tg, 1H), 0.31 - 0.25 (m, 2H), -0.02 (d, 2H) 240 Intermediate comp.-B-b +1methyl-4(4,4,5,5tetramethyl[1,3,2]dioxa borolan-2- sil)-1Nindazole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 64% 'H NMR (DMSO-d ₆ ) δ: 7.74 (s, 1H), 7.70 (d, 1H), 7.51 (ddd, 1H), 7.13 (d, 1H), 6.82 (d, 1H), 6.77 (s, 1H), 4.10 (s, 3H), 2.79 (s, 2H), 1.99 (s, 3H), 1.49 (s, 6H) , 1.26 (t, ZN) 241 Intermediate conn.-V-b + Intermediate, conn.-A-22 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 60% 'H NMR (DMSO-d ₆ ) δ: 8.35 (s, 1H), 8.05 (dt, 1H), 7.75 (dd, 1H), 7.45 (d, 1H), 6.85 (d, 2H), 3.55 (s, 3H), 2.81 (s, 2H), 2.02 (s, 3H), 1.50 (s, 6H), 1.28 (t, 3H) 242 Intermediate conn.-V-b + Intermediate conn.-A-41 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 18% Ή NMR (DMSO-d ₆ ) δ: 7.76 (d, 1H), 7.71 (s, 1H), 7.53 (dd, 1H), 7.15 (d, 1H), 6.81 ( d, 1H), 6.77 (s, 1H), 3.84 - 3.77 (m, 1H), 2.79 (s, 2H), 1.99 (s, 3H), 1.52 (s , 6H), 1.26 (t, 3H), 1.18-1.14 (m, 4H) 243 Intermediate, conn.-B-1 + Interm. conn.-A-41 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 34% Ή NMR (DMSO-d ₆ ) δ: 7.93 (s, 1H), 7.78 (d, 1H), 7.55-7.51 (m, 1H), 7.24 (d, 1H), 7.22 (d, 1H), 6.82 (dd, 1H), 3.79 (tg, 1H), 2.53 2.49 (m, 3H), 1.54 (s, 6H), 1, 20 - 1.12 (m, 4H) 244 Intermediate comp.-V-b + pinacol ether 5fluoro-1Nindole-4boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 55% 'H NMR (DMSO-d ₆ ) δ: 11.32 (s, 1H), 7.49 7.44 (m, 2H), 7.06 (dd, 1H), 6.80 (d, 1H), 6.77 (s, 1H), 6.08 (s, 1H), 2.77 (s, 2H), 2.00 (s, 3H), 1.64-1.36 (m, 6H), 1 .24 (t, ZN) 247 Intermediate conn.-V-b + Intermediate, conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 47% Ή NMR (DMSO-d ₆ ) δ: 7.92 (d, 1H), 7.63 (d, 1H), 7.49 (t, 1H), 7.30 (d, 1H), 6.82 ( d, 1H), 6.77 (s, 1H), 6.45 (s, 1H), 3.52 (s, 3H), 2.79 (s, 2H), 1.98 (s, 3H), 1.71 - 1.34 (m, 6N), 1.26 (t, ZN) 248 Intermediate conn.-B-25 + Intermediate, conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 90% Ή NMR (DMSO-d ₆ ) δ: 7.91 (d, 1H), 7.61 (d, 1H), 7.48 (dd, 1H), 7.35 (d, 1H), 6.96 ( s, 1H), 6.74 (d, 1H), 6.59 (d, 1H), 3.52 (s, 3N), 3.20 (s, 3N), 1.59 (s, 3N), 1.46 (s, ZN), 1.29 (D, ZN) 249 Intermediate conn.-B-25 + Intermediate, conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 92% Ή NMR (DMSO-d ₆ ) δ: 10.67 - 10.59 (m, 1H), 7.29 (dd, 1H), 7.15 (d, 1H), 6.97 - 6.91 (m , 2H), 6.72 (d, 1H), 3.22 (s, ZN), 2.52 2.50 (m, ZN), 2.28 - 2.25 (m, ZN), 1.57 (s, ZN), 1.49 (s, ZN) 250 Intermediate conn.-B-25 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 64% Ή NMR (DMSO-d ₆ ) δ: 7.69 (dd, 1H), 7.63 (d, 1H), 7.29 (dd, 1H), 7.03 (s, 1H), 6.74 ( d, 1H), 6.61 - 6.57 (m, 1H), 3.59 - 3.56 (m, ZN), 3.24 (s, ZN), 2.50 (d, ZN), 1 .59 (s, ZN), 1.46 (s, ZN) 251 Intermediate conn.-B-24 + Intermediate Tetrakis(triphenylphosphine)-palladium (0) 73% 'H NMR (DMSO-d ₆ ) δ: 10.54 (d, 1H), 7.24 (dd, 1H), 7.15-7.11 (m, 1H), 6.88 (dd, 1H) , 6.61 (s, 1H), 3.70 (s, 3N), 2.47 (d, 3N), 2.27

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conn.-A-15 Toluene/Ethanol - 2.23 (m, ZN), 1.55 (s, ZN), 1.53 (s, ZN) 252 Intermediate compound-B-27 + 4(tetramethyl1,3,2dioxaborol an-2-yl)-2(trifluoromethyl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 86% 'H NMR (DMSO-d ₆ ) δ: 12.39 (d, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 7.27-6.94 (m, 3H) , 6.85 (s, 1H), 6.82 (s, 1H), 2.47 (d, 3N), 1.57 (s, 3N), 1.53 (s, 3N) 253 Intermediate conn.-B-1 + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 53% H NMR (DMSO-d ₆ ) δ: 7.66 (d, 1H), 7.44 (d, 1H), 7.29 (t, 1H), 7.18-7.10 (m, 2H), 6.82 (d, 1H), 6.53 - 6.30 (m, 2H), 4.75 (td, 2H), 2.52 (d, WN), 1.60 (s, WN), 1 .55 - 1.47 (m, ZN) 254 Intermediate compound-B-26 + 4(tetramethyl1,3,2dioxaborol an-2-yl)-2(trifluoromethyl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 41% 'H NMR (DMSO-d ₆ ) δ: 12.45 - 12.42 (m, 1H), 7.60 - 7.54 (m, 1H), 7.42 (dd, 1H), 7.17 ( dd, 1H), 7.10 (d, 1H), 7.06 (d, 1H), 6.86 6.82 (m, 1H), 2.46 (d, 3H), 1.57 (s, ZN), 1.53 (s, ZN) 255 Intermediate conn.-B-24 + Intermediate conn.-A-2 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 72% 1H NMR (DMSO-db) δ: 7.65 (ddd, 1H), 7.60 (d, 1H), 7.22 (dd, 1H), 6.99 (d, 1H), 6.63 (d , 1H), 6.59 (dd, 1H), 3.72 (s, 3N), 3.56 (s, 3N), 2.47 (d, 3N), 1.56 (s, 3N), 1 .50 (s, ZN) 256 Intermediate compound-B-24 + indole-4boronic acid Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 47% 1H NMR (DMSO-db) δ: 11.10 (s, 1H), 7.40 (dt, 1H), 7.32 (t, 1H), 7.13 (dd, 1H), 6.96 (dd , 1H), 6.82 (d, 1H), 6.61 (d, 1H), 6.15 (dt, 1H), 3.68 (s, 3N), 2.45 (d, 3N), 1 .56 (s, ZN), 1.48 (s, ZN) 257 Intermediate compound-B-24 + 4(tetramethyl1,3,2dioxaborol an-2-yl)-2(trifluoromethyl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 63% 'H NMR (DMSO-d ₆ ) δ: 12.30 (d, 1H), 7.50 (dt, 1H), 7.36 (dd, 1H), 7.12 (dd, 1H), 6.88 (d, 1H), 6.74 - 6.70 (m, 1H), 6.62 (d, 1H), 3.69 (s, ZN), 2.45 (d, ZN), 1.55 ( s, ZN), 1.51 (s, ZN) 260 Intermediate compound-B-25 + 1,1dimethylethyl 4-(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole-1carboxylate Bis(tri-tert-butylphosphine) palladium(O) THF 51% 'H NMR (DMSO-c> _b ) δ: 8.13 (d, 1H), 7.70 (d, 1H), 7.43 (dd, 1H), 7.29 (dt, 1H), 6, 94 (s, 1H), 6.73 (d, 1H), 6.46 (dt, 1H), 3.16 (s, 3H), 2.50 (s, 3H), 1.66 (s, 9H ), 1.57 (s, ZN), 1.47 (s, ZN)

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263 Intermediate conn.-B-24 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF thirty% Ή NMR (DMSO-d ₆ ) δ: 7.89-7.84 (m, 1H), 7.58 (d, 1H), 7.44 (t, 1H), 7.29 (d, 1H), 6.92 (d, 1H), 6.63 (s, 1H), 6.56 (d, 1H), 3.70 (s, 3H), 3.49 (s, 3H), 2.46 (d , ZN), 1.56 (s, ZN), 1.50 (s, ZN) 264 Intermediate compound-B-25 + 1 -methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa boron-2- sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 66% 'H NMR (DMSO-d ₆ ) δ: 7.86-7.82 (m, 1H), 7.69-7.66 (m, 1H), 7.50 (s, 1H), 7.19 ( d, 1H), 6.96 (s, 1H), 6.74 (d, 1H), 4.09 (s, 3N), 3.16 (s, 3N), 2.52 (s, 3N), 1.52 (d, 6H) 266 Intermediate compound-B-24 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 70% 'H NMR (DMSO-d ₆ ) δ: 10.39 (d, 1H), 7.48 (d, 1H), 7.06-7.02 (m, 2H), 7.01 (dd, 1H) , 6.87 - 6.79 (m, 1H), 6.60 (s, 1H), 3.67 (s, ZN), 2.46 (d, ZN), 2.29 (s, ZN), 1.56 (s, ZN), 1.52 (s, ZN) 267 Intermediate conn.-B-27 + Intermediate conn.-A-15 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 32% Ή NMR (DMSO-d ₆ ) δ: 10.69 (d, 1H), 7.31 (dd, 1H), 7.22-7.07 (m, 3H), 6.98-6.92 (m , 1H), 6.81 (s, 1H), 2.51 - 2.46 (m, ZN), 2.35 2.17 (m, ZN), 1.57 (s, ZN), 1.54 (s, zn) 268 Intermediate conn.-B-27 + Intermediate conn.-A-2 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 34% Ή NMR (DMSO-d ₆ ) δ: 7.73-7.68 (m, 1H), 7.64 (d, 1H), 7.30-7.23 (m, 2H), 7.09 (d , 1H), 6.83 (s, 1H), 6.67 (d, 1H), 3.57 (s, 3N), 2.49 (d, 3N), 1.58 (s, 3N), 1 .51 (s, ZN) 269 Intermediate compound-B-24 + 1-methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa borolan-2- sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 77% 'H NMR (DMSO-d ₆ ) δ: 7.81 (s, 1H), 7.63 (d, 1H), 7.45 (dd, 1H), 7.13 (d, 1H), 6.93 (d, 1H), 6.65 - 6.61 (m, 1H), 4.07 (s, ZN), 3.70 (s, ZN), 2.47 (d, ZN), 1.57 ( s, ZN), 1.50 (s, ZN) 270 Intermediate compound-B-25 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 56% 'H NMR (DMSO-d ₆ ) δ: 10.50 (d, 1H), 7.55-7.50 (m, 1H), 7.11-7.03 (m, 3H), 6.86 (s , 1H), 6.71 (d, 1H), 3.18 (s, 3N), 2.50 (s, 3N), 2.30 (d, 3N), 1.57 (s, 3N), 1 .49 (s, ZN) 272 Intermediate compound-B-26 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol Bis(tri-tert-butylphosphine) palladium(O) THF 31% 'H NMR (DMSO-d ₆ ) δ: 10.60 (d, 1H), 7.58 7.53 (m, 1H), 7.12-7.08 (m, 2H), 7.08-7 .03 (m, ZN), 2.46 (d, ZN), 2.30 (d, ZN), 1.58 (s, ZN), 1.54 (s, ZN)

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an-2-yl)-1Nindol 273 Intermediate compound-B-27 + 1-methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa boron-2- sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 41% 'H NMR (DMSO-%) δ: 7.91 (d, 1H), 7.69 (dd, 1H), 7.50 (dd, 1H), 7.27 - 7.00 (m, 3H), 6.83 (s, 1H), 4.09 (s, 3N), 2.49 (d, 3N), 1.59 (s, 3N), 1.51 (s, 3N) 275 Intermediate conn.-B-27 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 58% Ή NMR (DMSO-d ₆ ) δ: 7.93-7.89 (m, 1H), 7.62 (d, 1H), 7.48 (dd, 1H), 7.32 (dd, 1H), 7.19 (s, 1H), 7.12 (t, 1H), 6.83 (s, 1H), 6.66 (d, 1H), 3.51 (s, 3H), 2.48 (d , ZN), 1.58 (s, ZN), 1.51 (s, ZN) 276 Intermediate conn.-B-1 + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF thirty% Ή NMR (DMSO-%) δ: 8.59 (s, 1H), 7.78 (DDD, 1H), 7.52 (dd, 1H), 7.37 (d, 1H), 6.86 (dd , 1H), 3.59 (s, 3H), 2.55 (d, 3H), 1.56 (s, 6H) 277 Intermediate conn.-B-26 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 29% Ή NMR (DMSO-%) δ: 7.73 (ddd, 1H), 7.65 (d, 1H), 7.31 (dd, 1H), 7.20 (d, 1H), 7.07 (d , 1H), 6.66 (dd, 1H), 3.60 (s, 3N), 2.48 (d, 3N), 1.58 (s, 3N), 1.52 (s, 3N) 278 Intermediate conn.-V-Z + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 57% Ή NMR (DMSO-d ₆ ) δ: 7.54 (dd, 1H), 7.38 (d, 1H), 7.23 (dd, 1H), 6.99 (d, 1H), 6.79 ( d, 1H), 6.70 (s, 1H), 6.09 (d, 1H), 4.43 - 4.32 (m, 2H), 3.71 (t, 2H), 3.26 (s , ZN), 2.44 (s, ZN), 1.98 (s, ZN), 1.54 (s, ZN), 1.44 (s, ZN) 279 Intermediate conn.-V-Z + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF 71% Ή NMR (DMSO-d ₆ ) δ: 8.39 (s, 1H), 7.75 (dd, 1H), 7.49 (dd, 1H), 6.93 (s, 1H), 6.85 ( d, 1H), 3.58 (s, 3N), 2.49 (s, 3N), 2.06 (s, 3N), 1.51 (s, 3N), 1.49 (s, 3N) 280 Intermediate conn.-B-26 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 58% Ή NMR (DMSO-d ₆ ) δ: 7.57 (dt, 1H), 7.38 (d, 1H), 7.24 (dd, 1H), 7.07 (s, 1H), 7.06 ( d, 1H), 7.03 (dd, 1H), 6.22 - 6.18 (m, 1H), 4.38 (tt, 2H), 3.71 (t, 2H), 3.26 (s , ZN), 2.45 (d, ZN), 1.58 (s, ZN), 1.50 (s, ZN) 281 Intermediate conn.-B-25 + Promezh. conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 31% 'H NMR (DMSO-d ₆ ) δ: 7.54 (dd, 1H), 7.36 (d, 1H), 7.22 (dd, 1H), 7.05 (d, 1H), 6.86 (s, 1H), 6.71 (d, 1H), 6.18 (d, 1H), 4.42-4.31 (m, 2H), 3.71 (t, 2H), 3.26 ( e, ZN), 3.17 (s, ZN), 2.49 (s, ZN), 1.57 (s, ZN), 1.47 (s, ZN) 282 Intermediate compound-B-27 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 71% 'H NMR (DMSO-%) δ: 10.56 (d, 1H), 7.54 (dd, 1H), 7.18-6.93 (m, 5H), 6.81 (s, 1H), 2.47 (d, ZN), 2.29 (d, ZN), 1.58 (s, ZN), 1.53 (s, ZN) 283 Intermediate conn.-B-26 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 19% Ή NMR (DMSO-d ₆ ) δ: 10.81 (d, 1H), 7.29 (dd, 1H), 7.22 (dd, 1H), 7.12-7.05 (m, 2H), 7.01 (dd, 1H), 6.88 (d, 1H), 2.57 (d, WN), 2.26 (d, WN), 1.52 (s, 6H)

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(dechlorination) 284 Intermediate conn.-B-26 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 48% % NMR (DMSO-d ₆ ) δ: 7.94 (d, 1H), 7.63 (d, 1H), 7.50 (dd, 1H), 7.34 (d, 1H), 7.15 ( d, 1H), 7.07 (d, 1H), 6.64 (d, 1H), 3.53 (s, 3N), 2.46 (d, 3N), 1.58 (s, 3N), 1.51 (s, ZN) 285 Intermediate compound-B-26 + 1-methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa borolan-2- sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 62% 'H NMR (DMSO-<) ₆ ) δ: 7.90 (s, 1H), 7.72 (d, 1H), 7.52 (dd, 1H), 7.20-7.13 (m, 2H ), 7.07 (d, 1H), 4.09 (s, 3N), 2.46 (d, 3N), 1.59 (s, 3N), 1.51 (s, 3N) 286 Intermediate compound-B-25 + 1H-indol-4ylboronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 18% Ή NMR (DMSO-d ₆ ) δ: 11.16 (s, 1H), 7.45 (dd, 1H), 7.34 (t, 1H), 7.18 (dd, 1H), 7.02 ( d, 1H), 6.84 (s, 1H), 6.70 (d, 1H), 6.18 (td, 1H), 3.15 (s, 3H), 2.49 (s, 3H), 1.56 (s, ZN), 1.47 (s, ZN) 287 Intermediate conn.-B-27 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 43% Ή NMR (DMSO-d ₆ ) δ: 7.54 (dd, 1H), 7.37 (d, 1H), 7.22 (dd, 1H), 7.12-7.10 (m, 1H), 7.08 (t, 1H), 7.03 (dd, 1H), 6.81 (s, 1H), 6.22 (d, 1H), 4.37 (td, 2H), 3.71 (t , 2H), 3.25 (s, 3N), 2.46 (d, 3N), 1.58 (s, 3N), 1.49 (s, 3N) 288 Intermediate conn.-B-24 + Intermediate conn.-A-43 Bis(tri-tert-butyl phosphine) palladium(O) THF 69% Ή NMR (DMSO) δ: 7.48 (dd, 1H), 7.32 (d, 1H), 7.18 (dd, 1H), 6.99 (dd, 1H), 6.83 (d, 1H ), 6.61 (d, 1H), 6.14 (t, 1H), 4.35 (t, 2H), 3.70 (t, 2H), 3.67 (s, 3H), 3.26 (s, ZN), 2.44 (d, ZN), 1.56 (s, ZN), 1.48 (s, ZN) 290 Intermediate conn.-B-26 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 9% Ή NMR (DMSO-d ₆ ) δ: 10.73 (d, 1H), 7.33 (dd, 1H), 7.18 (dd, 1H), 7.12 (d, 1H), 7.06 ( d, 1H), 6.95 (dd, 1H), 2.47 (d, WN), 2.26 (d, WN), 1.58 (s, WN), 1.54 (s, WN) 292 Intermediate conn.-B-28 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 45% % NMR (DMSO-A) δ: 7.55 (d, 1H), 7.35 (d, 1H), 7.21 (dd, 1H), 7.13 (s, 1H), 7.06 - 7 .01 (m, 2H), 6.87 (t, 1H), 6.08 (s, 1H), 4.43 4.31 (m, 2H), 3.71 (t, 2H), 3.26 (s, ZN), 2.47 (s, ZN), 1.85-1.12 (m, 6N) 293 Intermediate compound-B-26 + 1H-indol-4ylboronic acid Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 91% 'H NMR (DMSO-d ₆ ) δ: 11.22 (s, 1H), 7.48 (dt, 1H), 7.36 (t, 1H), 7.19 (dd, 1H), 7.05 (d, 2H), 7.00 (dd, 1H), 6.20 (td, 1H), 2.45 (d, WN), 1.58 (s, WN), 1.49 (d, WN) 294 Intermediate compound-B-28 + 1-methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa boron lan-2 - sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 46% 'H NMR (DMSO-d ₆ ) δ: 7.74 (s, 1H), 7.69 (dt, 1H), 7.47 (dd, 1H), 7.21 (s, 1H), 7.17 7.12 (m, 1H), 7.06 (d, 1H), 6.94 (d, 1H), 4.09 (s, WN), 2.48 (s, WN), 1.89 - 1 .19 (m, 6H) 295 Intermediate conn.-B-29 + Bis(tri-tert-butylphosphine) 39% 'H NMR (DMSO-d ₆ ) δ: 7.62 (dt, 1H), 7.41 (d, 1H), 7.26 (dd, 1H), 7.23 (s, 1H), 7.15 (d,

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Intermediate conn.-A-43 palladium(O) THF 1H), 7.01 (d, 1H), 6.46 (t, 1H), 6.21 (d, 1H), 4.39 (q, 2H), 3.72 (t, 2H), 3, 27 (s, ZN), 2.47 (d, ZN), 1.60 (s, ZN), 1.50 (s, ZN) 296 Intermediate conn.-B-29 + Intermediate conn.-A-15 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 39% Ή NMR (DMSO-d ₆ ) δ: 10.75 (d, 1H), 7.36 (dd, 1H), 7.26-7.17 (m, 3H), 6.92 (dd, 1H), 6.58 (t, 1H), 2.47 (s, ZN), 2.27 (d, ZN), 1.60 (s, ZN), 1.53 (s, ZN) 297 Intermediate compound-B-27 + 1H-indol-4ylboronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 12% Ή NMR (DMSO-d ₆ ) δ: 11.19 (s, 1H), 7.46 (dt, 1H), 7.36 (t, 1H), 7.17 (dd, 1H), 7.11 7 .09 (m, 1H), 7.08 - 6.94 (m, 2H), 6.81 (s, 1H), 6.22 (dt, 1H), 2.47 (d, 3H), 1, 58 (s, ZN), 1.50 (s, ZN) 298 Intermediate conn.-B-29 + Intermediate conn.-A-2 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol thirty% Ή NMR (DMSO-d ₆ ) δ: 7.78 - 7.72 (m, 1H), 7.65 (d, 1H), 7.36 - 7.14 (m, 3H), 6.82 - 6 .47 (m, 2H), 3.59 (d, ZN), 2.48 (d, ZN), 1.60 (s, ZN), 1.51 (s, ZN) 299 Intermediate conn.-V-b + Intermediate conn.-A-43 Bis(tri-tert-butyl phosphine) palladium(O) THF 50% Ή NMR (DMSO-d ₆ ) δ: 7.54 (dd, 1H), 7.39 (d, 1H), 7.23 (dd, 1H), 6.98 (d, 1H), 6.79 ( d, 1H), 6.68 (s, 1H), 6.07 (s, 1H), 4.43 - 4.32 (m, 2H), 3.71 (t, 2H), 3.26 (s , ZN), 2.78 (s, 2N), 1.98 (s, ZN), 1.65 - 1.31 (m, 6N), 1.25 (t, ZN) 302 Intermediate conn.-B-28 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 13% Ή NMR (DMSO-d ₆ ) δ: 10.61 (d, 1H), 7.29 (dd, 1H), 7.19 (s, 1H), 7.14 (dd, 1H), 7.067 .02 (m, 1H), 6.97 - 6.85 (m, 2H), 2.49 (s, ZN), 2.26 (d, ZN), 1.86 - 1.17 (m, 6N ) 306 Intermediate compound-B-29 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 63% 'H NMR (DMSO-d ₆ ) δ: 10.65 (d, 1H), 7.59 (d, 1H), 7.24 (s, 1H), 7.16-7.09 (m, 3H) , 7.02 (d, 1H), 6.48 (t, 1H), 2.48 (d, ZN), 2.30 (s, ZN), 1.61 (s, ZN), 1.53 ( s, zn) 309 Intermediate conn.-B-31 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 60% Ή NMR (DMSO-d ₆ ) δ: 7.88 (dt, 1H), 7.58 (d, 1H), 7.49 (dd, 1H), 7.20-7.15 (m, 1H), 6.84 (s, 1H), 6.38 (s, 1H), 6.34 (d, 1H), 3.51 (s, 3H), 2.39 (s, 3H), 1.89 (s , ZN), 1.86 (s, ZN), 1.50 (s, ZN), 1.44 (s, ZN) 310 Intermediate conn.-B-32 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF thirty% 'H NMR (DMSO-d ₆ ) δ: 7.89 - 7.84 (1H), 7.56 - 7.53 (1H), 7.44 - 7.39 (1H), 7.29 7.13 (2H), 7.01 - 6.98 (1H), 6.54 - 6.30 (1H), 3.64 - 3.60 (ZN), 3.53 - 3.48 (ZN), 2, 49 - 2.36 (ZN), 1.80 - 1.27 (6N) 313 Intermediate conn.-B-26 Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 65% Ή NMR (DMSO-d ₆ ) δ: 7.64 (d, 1H), 7.41 (d, 1H), 7.28 (dd, 1H), 7.09-7.07 (m, 2H), 7.06 (d, 1H), 6.42 (tt, 1H), 6.29 (d, 1H), 4.93 4.61 (m, 2H), 2.45 (d, 3H), 1, 58 (s, ZN), 1.50 (s, ZN) 314 Intermediate conn.-B-24 + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 47% Ή NMR (DMSO-d ₆ ) δ: 7.55 (d, 1H), 7.35 (d, 1H), 7.23 (dd, 1H), 7.04 (dd, 1H), 6.85 ( d, 1H), 6.61 (d, 1H), 6.40 (tt, 1H), 6.24 (d, 1H), 4.71 (td, 2H), 3.68 (s, 3H), 2.44 (d, ZN), 1.57 (s, ZN), 1.49 (s, ZN) 315 Intermediate Bis(three-tert- 69% Ή NMR (DMSO-d ₆ ) δ: 7.91 (dt, 1H), 7.59

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conn.-B-28 + Intermediate conn.-A-12 butylphosphine) palladium(O) THF (d, 1H), 7.45 (dd, 1H), 7.38 -7.28 (m, 1H), 7.22 (s, 1H), 7.06 (d, 1H), 6.92 ( d, 1H), 6.48 (s, 1H), 3.51 (s, 3N), 2.47 (s, 3N), 1.90 - 1.17 (m, 6H) 317 Intermediate conn.-V-3Z + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 62% 4 NMR (DMSO-d ₆ ) δ: 7.90 (dd, 1H), 7.61 (d, 1H), 7.50 (dd, 1H), 7.28-7.22 (m, 1H), 7.08 (s, 1H), 6.76 (s, 1H), 6.43 (d, 1H), 3.53 (s, 3H), 2.41 (s, 3H), 1.91 (s , ZN), 1.53 (s, ZN), 1.46 (s, ZN) 318 Intermediate conn.-B-35 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 85% 'H NMR (DMSO-d ₆ ) δ: 7.89 (dt, 1H), 7.61 (d, 1H), 7.48 (dd, 1H), 7.26-7.22 (m, 1H) , 7.12 - 6.78 (m, ZN), 6.45 (d, 1H), 3.51 (s, ZN), 2.43 (s, ZN), 1.92 (s, ZN), 1.53 (s, ZN), 1.45 (s, ZN) 319 Intermediate compound-B-28 + 1H-indol-4ylboronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 39% Ή NMR (DMSO-d ₆ ) δ: 11.18 (s, 1H), 7.45 (d, 1H), 7.33 (t, 1H), 7.16 (t, 1H), 7.11 ( s, 1H), 7.04 (d, 1H), 7.00 (d, 1H), 6.86 (t, 1H), 6.08 (s, 1H), 2.47 (s, 3H), 1.85 - 1.10 (m, 6H) 320 Intermediate compound-B-28 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 12% 'H NMR (DMSO-d ₆ ) δ: 10.56-10.40 (m, 1H), 7.62-7.43 (m, 1H), 7.13 (s, 1H), 7.086 .99 (m, 4H), 6.87 (t, 1H), 2.49 (s, ZN), 2.30 (d, ZN), 1.88 - 1.04 (m, 6H) 321 Intermediate conn.-B-34 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine) palladium(O) THF 22% Ή NMR (DMSO-d ₆ ) δ: 7.91 (dt, 1H), 7.60 (d, 1H), 7.49 (dd, 1H), 7.28 (dd, 1H), 6.82 ( s, 1H), 6.80 (d, 1H), 6.53 (d, 1H), 3.52 (s, 3N), 2.44 (d, 3N), 2.02 (s, 3N), 1.56 (s, ZN), 1.49 (s, ZN) 324 Intermediate conn.-B-31 + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 13% Ή NMR (DMSO-%) δ: 7.56 (d, 1H), 7.36 (d, 1H), 7.27 (dd, 1H), 6.92 (dd, 1H), 6.82 (s , 1H), 6.52 - 6.32 (m, 1H), 6.31 (s, 1H), 6.04 (d, 1H), 4.72 (td, 2H), 2.38 (s, ZN), 1.89 (s, ZN), 1.86 (s, ZN), 1.52 - 1.47 (m, ZN), 1.43 (s, ZN) 325 Intermediate compound-B-29 + 1-methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxa borolan-2- sil)-1Nindazole Bis(tri-tert-butylphosphine) palladium(O) THF 64% 'H NMR (DMSO-d ₆ ) δ: 7.92 (d, 1H), 7.75 (dt, 1H), 7.52 (dd, 1H), 7.26-7.20 (m, 2H) , 7.12 (d, 1H), 6.57 (t, 1H), 4.10 (s, 3N), 2.48 (d, 3N), 1.61 (s, 3N), 1.50 ( s, zn) 327 Intermediate conn.-V-3Z + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol thirty% Ή NMR (DMSO-%) δ: 7.59 (d, 1H), 7.38 (d, 1H), 7.28 (dd, 1H), 7.06 (s, 1H), 6.97 (d , 1H), 6.69 (s, 1H), 6.42 (tt, 1H), 6.12 (d, 1H), 4.72 (td, 2H), 2.40 (s, 3H), 1 .90 (s, ZN), 1.53 (s, ZN), 1.44 (s, ZN) 328 Intermediate conn.-B-31 + Intermediate Bis(tri-tertbutylphosphine) palladium(O) 80% 'H NMR (DMSO-d ₆ ) δ: 7.68-7.63 (m, 1H), 7.60 (d, 1H), 7.14 (dd, 1H), 6.84 (s, 1H) , 6.43 (s, 1H), 6.32 (d, 1H), 3.56 (s, 3H), 2.40

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conn.-A-2 THF (s, ZN), 1.91 (s, ZN), 1.88 (s, ZN), 1.49 (s, ZN), 1.45 (s, ZN) 329 Intermediate conn.-B-32 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 55% Ή NMR (DMSO-d ₆ ) δ: 7.69 - 7.63 (1H), 7.60 - 7.53 (1H), 7.29 - 7.05 (2H), 7.046.96 ( 1H), 6.56 - 6.29 (1H), 3.68 - 3.62 (ZN), 3.61 - 3.54 (ZN), 2.48 - 2.35 (ZN), 1.78 - 1.28 (6H) 330 Intermediate conn.-V-Z + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 54% ³ H NMR (DMSO-d ₆ ) δ: 7.61 (d, 1H), 7.41 (d, 1H), 7.28 (dd, 1H), 7.04 (d, 1H), 6.79 (d, 1H), 6.71 (s, 1H), 6.41 (tt, 1H), 6.18 (d, 1H), 4.73 (tdd, 2H), 2.44 (s, 3H) , 1.98 (s, ZN), 1.53 (s, ZN), 1.44 (s, ZN) 331 Intermediate conn.-V-Z 1 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 47% 1H NMR (DMSO-db) δ: 7.49 (dt, 1H), 7.34 (d, 1H), 7.23 (dd, 1H), 6.87 (dd, 1H), 6.82 (s , 1H), 6.29 (s, 1H), 5.97 (d, 1H), 4.36 (t, 2H), 3.73 (t, 2H), 3.26 (s, 3H), 2 .38 (s, ZN), 1.90 (s, ZN), 1.86 (s, ZN), 1.50 (s, ZN), 1.43 (s, ZN) 332 Intermediate conn.-B-34 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 89% 'H NMR (DMSO-d ₆ ) δ: 7.69 (ddd, 1H), 7.62 (d, 1H), 7.25 (dd, 1H), 6.85 (d, 1H), 6.82 (s, 1H), 6.55 (d, 1H), 3.59 (s, 3N), 2.46 (d, 3N), 2.05 (s, 3N), 1.56 (s, 3N) , 1.49 (s, ZN) 333 Intermediate conn.-B-3Z + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 72% Ή NMR (DMSO-d ₆ ) δ: 7.69 (ddd, 1H), 7.63 (d, 1H), 7.22 (dd, 1H), 7.08 (s, 1H), 6.81 ( s, 1H), 6.43 (d, 1H), 3.59 (s, 3N), 2.43 (s, 3N), 1.95 (s, 3N), 1.52 (s, 3N), 1.47 (s, ZN) 334 Intermediate conn.-B-32 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 15% 'H NMR (DMSO-d ₆ ) δ: 7.55 - 7.45 (1H), 7.32 - 7.24 (1H), 7.18 - 7.11 (1H), 7.10 7.01 (1H), 6.98 - 6.85 (2H), 6.09 - 5.93 (1H), 4.38 - 4.31 (2H), 3.74 - 3.69 (2H), 3, 62 - 3.57 (ZN), 3.27 - 3.22 (ZN), 2.48 2.34 (ZN), 1.79 - 1.27 (6N) 335 Intermediate conn.-B-35 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 72% Ή NMR (DMSO-s) ₆ ) δ: 7.67 (ddd, 1H), 7.62 (d, 1H), 7.20 (dd, 1H), 7.01 (t, 1H), 6.85 (d, 2H), 6.44 (d, 1H), 3.57 (s, 3N), 2.44 (s, 3N), 1.95 (s, 3N), 1.52 (s, 3N) , 1.46 (s, ZN) 336 Intermediate conn.-B-35 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 65% Ή NMR (DMSO-db) δ: 7.51 (dt, 1H), 7.36 (d, 1H), 7.22 (dd, 1H), 7.06-6.77 (m, 3H), 6 .72 (s, 1H), 6.05 (d, 1H), 4.40 - 4.33 (m, 2H), 3.72 (t, 2H), 3.26 (s, 3H), 2, 41 (s, ZN), 1.91 (s, ZN), 1.54 (s, ZN), 1.43 (s, ZN) 337 Intermediate conn.-B-34 + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 58% Ή NMR (DMSO-db) δ: 7.53 (dd, 1H), 7.35 (d, 1H), 7.22 (dd, 1H), 6.96 (dd, 1H), 6.80 (s , 1H), 6.71 (d, 1H), 6.16 - 6.04 (m, 1H), 4.37 (q, 2H), 3.71 (t, 2H), 3.26 (d, ZN), 2.43 (d, ZN), 2.01 (s, ZN), 1.55 (s, ZN), 1.48 (s, ZN) 338 Intermediate conn.-B-3Z + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 40% 'H NMR (DMSO-db) δ: 7.53 (dt, 1H), 7.36 (d, 1H), 7.24 (dd, 1H), 7.05 (s, 1H), 6.93 ( dd, 1H), 6.68 (s, 1H), 6.03 (d, 1H), 4.37 (td, 2H), 3.72 (t, 2H), 3.26 (s, 3H), 2.40 (s, ZN), 1.91 (s, ZN), 1.54 (s, ZN), 1.44 (s, ZN) 339 Intermediate conn.-B-25 + Promezh. conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF thirty% Ή NMR (DMSO-db) δ: 8.45 (s, 1H), 7.76 7.72 (m, 1H), 7.46 (dd, 1H), 7.14 (s, 1H), 6, 78 (d, 1H), 3.59 (d, WN), 3.25 (d, WN), 2.55 (d, WN), 1.62 (s, WN), 1.45 (s, WN ) 341 Intermediate Bis(three-tert- 42% 'H NMR (DMSO-db) δ: 10.46 - 10.42 (m,

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conn.-B-31 + Intermediate conn.-A-15 butylphosphine) palladium(O) THF 1H), 7.23 (dd, 1H), 7.10 (dd, 1H), 6.84 (s, 1H), 6.76 (dd, 1H), 6.36 (s, 1H), 2, 42 (s, ZN), 2.26 (d, ZN), 1.91 (s, ZN), 1.86 (s, ZN), 1.54 (d, 6H), 1.42 (s, ZN ) 342 Intermediate conn.-B-25 + Promezh. conn.-A-22 Bis(tri-tert-butylphosphine) palladium(O) THF 67% Ή NMR (DMSO-d ₆ ) δ: 8.43 (d, 1H), 8.03 (dd, 1H), 7.74 (dd, 1H), 7.49 (d, 1H), 7.07 ( s, 1H), 6.78 (d, 1H), 3.55 (s, 3N), 3.20 (s, 3N), 2.55 (d, 3N), 1.62 (s, 3N), 1.45 (s, ZN) 343 Intermediate compound-B-29 + 1H-indol-4ylboronic acid Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 73% 'H NMR (DMSO-d ₆ ) δ: 11.33 - 11.29 (m, 1H), 7.52 (dt, 1H), 7.39 (t, 1H), 7.25 - 7.19 ( m, 2H), 7.14 (d, 1H), 6.98 (d, 1H), 6.45 (t, 1H), 6.20 (tg, 1H), 2.47 (d, 3H), 1.59 (s, ZN), 1.51 (s, ZN) 344 Intermediate conn.-B-3b + Intermediate conn.-A-43 Bis(tri-tert-butylphosphine) palladium(O) THF 36% Ή NMR (DMSO-d ₆ ) δ: 7.45 (d, 1H), 7.31 (d, 1H), 7.18 (t, 1H), 6.88 (d, 1H), 6.65 ( s, 1H), 6.42 (s, 1H), 6.00 (d, 1H), 4.35 (dt, 2H), 3.71 (t, 2H), 3.59 (s, 3H), 3.26 (s, ZN), 2.39 (s, ZN), 1.86 (s, ZN), 1.52 (s, ZN), 1.43 (s, ZN) 345 Intermediate conn.-B-3b + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 33% 'H NMR (DMSO-d ₆ ) δ: 10.39 (s, 1H), 7.19 (dd, 1H), 7.08 (dd, 1H), 6.76 (dd, 1H), 6.66 (s, 1H), 6.48 (s, 1H), 3.61 (s, 3N), 2.44 (s, 3N), 2.25 (d, 3N), 1.87 (s, 3N) , 1.54 (s, ZN), 1.44 (s, ZN) 346 Intermediate conn.-B-28 + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF 24% Ή NMR (DMSO-d ₆ ) δ: 8.42 (s, 1H), 7.76 (dd, 1H), 7.45 (d, 1H), 7.35 (s, 1H), 7.21 7 .00 (m, 2N), 3.60 (d, ZN), 2.51 (d, ZN), 1.83 - 1.24 (m, 6N) 347 Intermediate conn.-B-3Z + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF 31% Ή NMR (DMSO-d ₆ ) δ: 8.34 (s, 1H), 7.75 (dd, 1H), 7.41 (dd, 1H), 7.10 (s, 1H), 6.89 ( s, 1H), 3.60 (s, 3N), 2.45 (s, 3N), 1.98 (s, 3N), 1.53 (s, 3N), 1.48 (s, 3N) 348 Intermediate conn.-V-b + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF 36% Ή NMR (DMSO-d ₆ ) δ: 8.36 (s, 1H), 7.79 7.73 (m, 1H), 7.49 (s, 1H), 6.91 (s, 1H), 6 .85 (d, 1H), 3.59 (s, 3H), 2.81 (s, 2H), 2.05 (s, 3H), 1.62 - 1.37 (m, 6H), 1, 28 (t, 3N) 351 Intermediate conn.-B-25 + Intermediate conn.-A-24 Bis(tri-tert-butylphosphine) palladium(O) THF 57% Ή NMR (DMSO-d ₆ ) δ: 7.43 (ddd, 1H), 7.36 (d, 1H), 6.97-6.89 (m, 2H), 6.71 (d, 1H), 6.18 (dt, 1H), 4.34 (c, 2H), 3.69 (t, 2H), 3.25 (d, 3H), 3.20 (d, 3H), 2.49 (d , ZN), 1.57 (s, ZN), 1.47 (s, ZN) 353 Intermediate conn.-B-24 + Intermediate conn.-A-24 Bis(tri-tert-butylphosphine) palladium(O) THF 59% 1H NMR (DMSO-db) δ: 7.37 (ddd, 1H), 7.33 (d, 1H), 6.90 - 6.88 (m, 1H), 6.87 (dd, 1H), 6 .61 (d, 1H), 6.16 (d, 1H), 4.32 (t, 2H), 3.69 (s, 3H), 3.68 (t, 2H), 3.25 (d, ZN), 2.45 (d, ZN), 1.56 (s, ZN), 1.48 (s, ZN) 354 Intermediate conn.-B-l + 3-Methyl-1Nindazole-7boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 20% 'H NMR (DMSO-d ₆ ) δ: 12.65 (s, 1H), 7.79 (dd, 1H), 7.37 (d, 1H), 7.24-7.15 (m, 2H) , 6.82 (dd, 1H), 2.53 (s, 3N), 1.56 (s, 6H) 356 Intermediate compound-B-31 + 3-methyl-7(4,4,5,5- Bis(tri-tert-butylphosphine) palladium(O) THF 42% 'H NMR (DMSO-d ₆ ) δ: 10.31 (s, 1H), 7.52 7.44 (m, 1H), 7.09 (dd, 1H), 7.02 (dd, 1H), 6.87 (dd, 1H), 6.83 (s, 1H), 6.31 (s, 1H), 2.42 (s, WN), 2.30 (d, WN), 1.89 (s , ZN), 1.84

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tetramethyl1,3,2dioxaborole an-2-yl)-1Nindole (s, ZN), 1.55 (s, ZN), 1.41 (s, ZN) 357 Intermediate compound-B-32 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 26% 'H NMR (DMSO-E ₆ ) δ: 10.41 - 10.27 (1H), 7.51 - 7.44 (1H), 7.09 - 7.03 (1H), 7.03 6.86 (4N), 3.63 - 3.50 (ZN), 2.44 - 2.42 (ZN), 2.36 - 2.23 (ZN), 1.81 - 1.31 (6N) 358 Intermediate compound-B-33 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 84% 'H NMR (DMSO-d ₆ ) δ: 10.47 (s, 1H), 7.51 (d, 1H), 7.15-7.03 (m, 3H), 6.92 (dd, 1H) , 6.74 - 6.65 (m, 1H), 2.43 (s, ZN), 2.30 (d, ZN), 1.88 (s, ZN), 1.57 (s, ZN), 1.44 (s, ZN) 359 Intermediate compound-B-34 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 22% 'H NMR (DMSO-d ₆ ) δ: 10.47 (d, 1H), 7.52 (dd, 1H), 7.17-7.01 (m, 2H), 6.99 (dd, 1H) , 6.81 (s, 1H), 6.71 (s, 1H), 2.45 (d, 3N), 2.30 (d, 3N), 2.00 (s, 3N), 1.57 ( s, ZN), 1.50 (s, ZN) 360 Intermediate compound-B-35 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 34% 'H NMR (DMSO-d ₆ ) δ: 10.42 (s, 1H), 7.50 (d, 1H), 7.10 - 7.04 (m, 2H), 6.94 (dd, 1H) , 6.90 (t, 1H), 6.85 (s, 1H), 6.72 (s, 1H), 2.45 (s, 3H), 2.30 (t, 3H), 1.88 ( s, ZN), 1.57 (s, ZN), 1.44 (s, ZN) 361 Intermediate, compound-B-3 + 3-Methyl-1Nindazole-7boronic acid Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 22% 'H NMR (DMSO-d ₆ ) δ: 12.57 (s, 1H), 7.79 7.72 (m, 1H), 7.25 (d, 1H), 7.21-7.16 (m , 1H), 6.81 (d, 1H), 6.76 (s, 1H), 2.53 (s, 3N), 2.49 (s, 3N), 1.96 (s, 3N), 1 .56 (s, ZN), 1.45 (s, ZN) 362 Intermediate conn.-B-25 + Intermediate conn.-A-8 Bis(tri-tert-butylphosphine) palladium(O) THF 53% 'H NMR (DMSO-d ₆ ) δ: 7.68 (ddd, 1H), 7.64 (d, 1H), 7.29 (dd, 1H), 7.03 (s, 1H), 6.75 (d, 1H), 6.62 - 6.57 (m, 1H), 3.73 (cd, 2H), 3.23 (s, ZN), 2.51 (s, ZN), 1.58 ( s, ZN), 1.47 (s, ZN), 1.12 (t, ZN). 363 Intermediate conn.-B-3Z + Intermediate, conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 92% 'H NMR (DMSO-d ₆ ) δ: 10.60 (d, 1H), 7.28 (dd, 1H), 7.14 (dd, 1H), 7.07 (s, 1H), 6.83 (dd, 1H), 6.73 (s, 1H), 2.44 (s, 3H), 2.26 (d, 3H), 1.91 (s, 3H), 1.50 (d, 6H)

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364 Intermediate conn.-B-34 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 78% 'H NMR (DMSO-d ₆ ) δ: 10.62-10.58 (m, 1H), 7.28 (dd, 1H), 7.14 (dd, 1H), 6.89 (dd, 1H) , 6.81 (s, 1H), 6.76 (d, 1H), 2.46 (d, 3H), 2.26 (d, 3H), 2.02 (s, 3H), 1.56 ( s, ZN), 1.51 (s, ZN) 365 Intermediate conn.-B-35 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 39% Ή NMR (DMSO-d ₆ ) δ: 10.54 (d, 1H), 7.26 (dd, 1H), 7.13 (dd, 1H), 6.93 (s, 1H), 6.84 ( d, 2H), 6.77 (s, 1H), 2.45 (s, 3N), 2.26 (d, 3N), 1.91 (s, 3N), 1.56 (s, 3N), 1.45 (s, ZN) 367 Intermediate compound-B-28 + 3-Methyl-1Nindazole-7boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 27% 'H NMR (DMSO-d ₆ ) δ: 12.51 (s, 1H), 7.74 (d, 1H), 7.31-7.24 (m, 1H), 7.18 (s, 1H) , 7.14 (dd, 1H), 7.07 - 6.84 (m, 2H), 2.52 (s, ZN), 2.50 (s, ZN), 1.91 - 1.15 (m , 6H) 368 Intermediate compound-B-33 + 3-Methyl-1Nindazole-7boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 28% 'H NMR (DMSO-d ₆ ) δ: 12.53 (s, 1H), 7.76 7.72 (m, 1H), 7.21-7.16 (m, 2H), 7.08 (s , 1H), 6.74 (s, 1H), 2.53 (s, 3N), 2.45 (s, 3N), 1.89 (s, 3N), 1.56 (s, 3N), 1 .45 (s, ZN) 369 Intermediate conn.-B-32 + Intermediate conn.-A-8 Bis(tri-tert-butylphosphine) palladium(O) THF 29% 'H NMR (DMSO-d ₆ ) δ: 7.68 - 7.62 (1H), 7.59 - 7.55 (1H), 7.31 - 7.08 (2H), 7.03 6.96 (1H), 6.58 - 6.30 (1H), 3.76 - 3.70 (2H), 3.66 - 3.63 (ZN), 2.47 - 2.36 (ZN), 1, 78 - 1.28 (6N), 1.12 - 1.03 (ZN) 370 Intermediate conn.-V-Z + Intermediate conn.-A-8 Bis(tri-tert-butylphosphine) palladium(O) THF 74% 'H NMR (DMSO-d ₆ ) δ: 7.71-7.61 (m, 2H), 7.34-7.22 (m, 1H), 6.88-6.78 (m, 2H), 6.49 (d, 1H), 3.73 (q, 2H), 2.45 (s, 3N), 2.01 (s, 3N), 1.50 (s, 3N), 1.47 (s , ZN), 1.12 (t, ZN) 371 Intermediate conn.-B-32 + Intermediate conn.-A-47 Bis(tri-tert-butylphosphine) palladium(O) THF 16% 'H NMR (DMSO-d ₆ ) δ: 7.91 - 7.78 (1H), 7.56 - 7.53 (1H), 7.43 - 7.38 (1H), 7.30 7.13 (2H), 7.01 - 6.98 (1H), 6.57 - 6.28 (1H), 3.70 - 3.63 (2H), 3.64 - 3.60 (3H), 2, 47 - 2.36 (ZN), 1.77 - 1.28 (6N), 1.10 1.00 (ZN) 372 Intermediate conn.-V-Z + Intermediate conn.-A-47 Bisari-tert-butylphosphine) palladium(O) THF 42% 'H NMR (DMSO-d ₆ ) δ: 7.91 (d, 1H), 7.64 (d, 1H), 7.49 (dd, 1H), 7.31 (d, 1H), 6.86 - 6.76 (m, 2H), 6.49 (d, 1H), 3.72 - 3.64 (m, 2H), 2.45 (s, ZN), 1.98 (s, ZN), 1.52 (s, ZN), 1.46 (s, ZN), 1.10 (t, ZN) 373 Intermediate conn.-V-Z 1 + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF 66% Ή NMR (DMSO-d ₆ ) δ: 8.24 (s, 1H), 7.74-7.69 (m, 1H), 7.34-7.28 (m, 1H), 6.86 (s, 1H), 6.50 (s, 1H), 3.59 (s, 3N), 2.43 (s, 3N), 1.93 (s, 3N), 1.91 (s, 3N), 1, 53 (s, ZN), 1.43 (s, ZN) 376 Intermediate conn.-B-32 + Intermediate conn.-A-23 Bis(tri-tert-butylphosphine) palladium(O) THF eleven% 'H NMR (DMSO-d ₆ ) δ: 8.52-8.22(1H), 7.77-7.70(1H), 7.47-7.26(2H), 7.07-7.00 (1N), 3.69 - 3.65 (ZN), 3.62 - 3.56 (ZN), 2.49 - 2.42 (ZN), 1.77 - 1.30 (6N) 377 Intermediate conn.-V-Z + Intermediate conn.-A-22 Bis(tri-tert-butylphosphine) palladium(O) THF 54% Ή NMR (DMSO-d ₆ ) δ: 8.39 (s, 1H), 8.04 (d, 1H), 7.75 (t, 1H), 7.46 (d, 1H), 6.92 - 6.78 (m, 2N), 3.60 - 3.50 (m, ZN), 2.48 (s, ZN), 2.02 (s, ZN), 1.53 (s, ZN), 1 .48 (s, ZN) 379 Intermediate conn.-B-24 + Bis(tri-tert-butylphosphine) 35% 'H NMR (DMSO-d ₆ ) δ: 7.36 (dd, 1H), 7.35 7.33 (m, 1H), 6.89 (d, 1H), 6.87 (dd, 1H),

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Intermediate conn.-A-20 palladium(O) THF 6.61 (s, 1H), 6.16 (d, 1H), 4.21 (t, 2H), 3.75 (c, 2H), 3.70 (s, 3H), 2.45 (d , ZN), 1.57 (s, ZN), 1.48 (s, ZN) 380 Intermediate conn.-B-25 + Promezh. conn.-A-20 Bis(tri-tert-butylphosphine) palladium(O) THF 62% Ή NMR (DMSO-d ₆ ) δ: 7.41 (dd, 1H), 7.37 (d, 1H), 6.96-6.91 (m, 2H), 6.71 (d, 1H), 6.18 (d, 1H), 4.98 - 4.92 (m, 1H), 4.22 (c, 2H), 3.76 (c, 2H), 3.21 (s, 3H), 2 .49 (s, ZN), 1.57 (s, ZN), 1.47 (s, ZN) 381 Intermediate compound-B-25 + 3-Methyl-1Nindazole-7boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 37% 'H NMR (DMSO-d ₆ ) δ: 12.53 (s, 1H), 7.75 (d, 1H), 7.30 (d, 1H), 7.17 (t, 1H), 6.93 (s, 1H), 6.73 (d, 1H), 3.19 (s, 3N), 2.53 (s, 3N), 2.51 (d, 3N), 1.57 (s, 3N) , 1.49 (s, ZN) 382 Intermediate conn.-B-28 + Intermediate conn.-A-22 Bis(tri-tert-butylphosphine) palladium(O) THF 27% Ή NMR (DMSO-d ₆ ) δ: 8.39 (s, 1H), 8.05 (d, 1H), 7.72 (dd, 1H), 7.48-7.42 (m, 1H), 7.30 (s, 1H), 7.15 - 6.91 (m, 2H), 3.55 (s, ZN), 2.50 (d, ZN), 1.81 - 1.21 (m, 6H) 383 Intermediate conn.-B-1 + Intermediate conn.-A-46 Bis(tri-tert-butylphosphine) palladium(O) THF 9% 'H NMR (DMSO-d ₆ ) δ: 7.70 - 7.54 (1H), 7.51 - 7.41 (1H), 7.31 - 7.20 (1H), 7.15 6.77 (3H), 6.36 - 6.23 (1H), 4.84 - 4.25 (2H), 3.77 - 3.16 (2H), 2.50 - 2.48 (3H), 2, 27 - 2.18 (6N), 1.63 - 1.55 (ZN), 1.53 1.47 (ZN) 384 Intermediate conn.-B-35 + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol eleven% % NMR (DMSO-d ₆ ) δ: 7.58 (d, 1H), 7.38 (d, 1H), 7.26 (dd, 1H), 7.07-6.71 (m, 4H), 6.42 (tt, 1H), 6.14 (d, 1H), 4.72 (td, 2H), 2.41 (s, 3H), 1.91 (s, 3H), 1.54 (s , ZN), 1.43 (s, ZN) 385 Intermediate conn.-B-29 + Intermediate conn.-A-20 Bis(tri-tert-butylphosphine) palladium(O) THF 22% Ή NMR (DMSO-d ₆ ) δ: 7.49 (dd, 1H), 7.41 (d, 1H), 7.21 (d, 2H), 6.92 (dd, 1H), 6.54 ( t, 1H), 6.20 (d, 1H), 4.94 (td, 1H), 4.23 (c, 2H), 3.76 (c, 2H), 2.47 (d, 3H), 1.59 (s, ZN), 1.50 (s, ZN) 386 Intermediate conn.-B-3Z + Intermediate conn.-A-22 Bis(tri-tert-butylphosphine) palladium(O) THF 50% Ή NMR (DMSO-d ₆ ) δ: 8.34 (s, 1H), 8.04 (d, 1H), 7.78-7.71 (m, 1H), 7.38 (d, 1H), 7.11 (s, 1H), 6.84 (s, 1H), 3.56 (s, 3H), 2.45 (s, 3H), 1.94 (s, 3H), 1.54 (s , ZN), 1.47 (s, ZN) 387 Intermediate conn.-B-32 + Intermediate conn.-A-22 Bis(tri-tert-butylphosphine) palladium(O) THF 21% 'H NMR (DMSO-d ₆ ) δ: 8.48 - 8.20 (1H), 8.05 - 7.98 (1H), 7.70 - 7.65 (1H), 7.45 7.20 (2H), 7.04 - 6.99 (1H), 3.67 - 3.63 (ZN), 3.57 - 3.53 (ZN), 2.48 - 2.41 (ZN), 1, 80 - 1.29 (6H) 388 Intermediate conn.-B-31 + Intermediate conn.-A-22 Bis(tri-tert-butylphosphine) palladium(O) THF 43% 'H NMR (DMSO-d ₆ ) δ: 8.23 (s, 1H), 8.05 7.91 (m, 1H), 7.74 (ddd, 1H), 7.33-7.28 (m , 1H), 6.86 (s, 1H), 6.46 (d, 1H), 3.55 (d, 3N), 2.42 (d, 3N), 1.90 (s, 3N), 1 .87 (s, ZN), 1.54 (s, ZN), 1.42 (s, ZN) 390 Intermediate conn.-B-28 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 33% Ή NMR (DMSO-d ₆ ) δ: 7.69 (dd, 1H), 7.62 (d, 1H), 7.60 (d, 1H), 7.27 (d, 1H), 7.18 ( d, 1H), 7.03 (t, 1H), 6.48 (s, 1H), 3.57 (s, ZN), 2.47 (s, ZN), 1.97 - 1.05 (m , 6H) 392 Intermediate conn.-B-34 + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 51% Ή NMR (DMSO-A) δ: 7.60 (d, 1H), 7.38 (d, 1H), 7.27 (ddd, 1H), 7.01 (dd, 1H), 6.80 (s , 1H), 6.72 (d, 1H), 6.41 (tt, 1H), 6.22 - 6.18 (m, 1H), 4.73 (tt, 2H), 2.43 (d, ZN), 2.01 (s, ZN), 1.55 (s, ZN), 1.48 (s, ZN)

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393 Intermediate conn.-B-27 + Intermediate conn.-A-42 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 55% Ή NMR (DMSO-d ₆ ) δ: 7.61 (d, 1H), 7.40 (d, 1H), 7.29-6.96 (m, 4H), 6.82 (s, 1H), 6.54 6.28 (m, 2N), 4.73 (tt, 2N), 2.47 (d, ZN), 1.58 (s, ZN), 1.50 (s, ZN) 394 Intermediate conn.-B-27 + Intermediate conn.-A-24 Bis(tri-tert-butylphosphine) palladium(O) THF 48% H NMR (DMSO-d ₆ ) δ: 7.48-7.42 (m, 1H), 7.38 (d, 1H), 7.26-6.99 (m, 2H), 6.94 (dd , 1H), 6.81 (s, 1H), 6.27 - 6.22 (m, 1H), 4.34 (td, 2H), 3.69 (t, 2H), 3.26 (d, ZN), 2.48 (d, ZN), 1.58 (s, ZN), 1.50 (s, ZN) 395 Intermediate conn.-B-27 + Intermediate conn.-A-20 Bis(tri-tert-butylphosphine) palladium(O) THF 37% 'H NMR (DMSO-d ₆ ) δ: 7.43 (dd, 1H), 7.39 (d, 1H), 7.25-6.99 (m, 2H), 6.93 (dd, 1H) , 6.81 (s, 1H), 6.24 (d, 1H), 4.92 (t, 1H), 4.22 (q, 2H), 3.75 (q, 2H), 2.47 ( d, ZN), 1.58 (s, ZN), 1.49 (s, ZN) 396 Intermediate conn.-B-29 + Intermediate conn.-A-24 Bis(tri-tert-butylphosphine) palladium(O) THF 28% Ή NMR (DMSO-d ₆ ) δ: 7.51 (dd, 1H), 7.40 (d, 1H), 7.22 (s, 1H), 7.19 (d, 1H), 6.93 ( dd, 1H), 6.55 (t, 1H), 6.21 (d, 1H), 4.36 (c, 2H), 3.70 (t, 2H), 3.27 (s, 3H), 2.47 (d, ZN), 1.59 (s, ZN), 1.50 (s, ZN) 397 Intermediate conn.-B-25 + Promezh. conn.-A-42 Bis(tri-tert-butylphosphine) palladium(O) THF 28% Ή NMR (DMSO-A) δ: 7.61 (d, 1H), 7.39 (d, 1H), 7.27 (dd, 1H), 7.10 (d, 1H), 6.87 (s , 1H), 6.71 (d, 1H), 6.42 (tt, 1H), 6.27 (d, 1H), 4.73 (tdd, 2H), 3.16 (s, 3H), 2 .49 (s, ZN), 1.57 (s, ZN), 1.47 (s, ZN) 398 Intermediate conn.-B-28 + Intermediate conn.-A-42 Bis(tri-tert-butylphosphine) palladium(O) THF 55% Ή NMR (DMSO-d ₆ ) δ: 7.61 (d, 1H), 7.37 (d, 1H), 7.25 (dd, 1H), 7.14 (s, 1H), 7.06 ( dd, 2H), 6.89 (t, 1H), 6.42 (tt, 1H), 6.16 (s, 1H), 4.72 (tdd, 2H), 2.47 (s, 3H), 1.83 - 1.14 (m, 6H) 399 Intermediate compound-B-3 + 1H-indol-4ylboronic acid Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 34% Ή NMR (DMSO-d ₆ ) δ: 11.21 (s, 1H), 7.45 (d, 1H), 7.37 (t, 1H), 7.19 (t, 1H), 6.96 ( d, 1H), 6.78 (d, 1H), 6.69 (s, 1H), 6.09 (t, 1H), 2.44 (s, 3H), 1.98 (s, 3H), 1.54 (s, ZN), 1.44 (s, ZN) 400 Intermediate conn.-B-28 + Intermediate conn.-A-ZO Bis(tri-tert-butylphosphine) palladium(O) THF 42% Ή NMR (DMSO-d ₆ ) δ: 7.91 (d, 1H), 7.58 (dd, 1H), 7.47-7.41 (m, 1H), 7.31 (d, 1H), 7.21 (s, 1H), 7.10 - 6.84 (m, 2H), 6.48 (s, 1H), 3.85 (pd, 1H), 2.47 (s, 3H), 1 .94 - 1.24 (m, 6H), 1.20 (dt, 6H) 401 Intermediate conn.-B-28 + Intermediate conn.-A-48 Bis(tri-tert-butylphosphine) palladium(O) THF 40% Ή NMR (DMSO-d ₆ ) δ: 7.95 (d, 1H), 7.60 (dd, 1H), 7.47-7.41 (m, 1H), 7.31 (d, 1H), 7.22 (s, 1H), 7.11 - 6.83 (m, 2H), 6.47 (s, 1H), 3.17 (ddd, 1H), 2.48 (s, 3H), 1 .90 - 1.33 (m, 6H), 1.29 (tt, 2H), 1.17 - 1.07 (m, 2H) 402 Intermediate conn.-B-28 + Intermediate conn.-A-24 Bis(tri-tert-butylphosphine) palladium(O) THF 23% Ή NMR (DMSO-d ₆ ) δ: 7.44 (dd, 1H), 7.35 (d, 1H), 7.18 (s, 1H), 7.04 (d, 1H), 6.986 .85 (m, 2H), 6.08 (s, 1H), 4.43 - 4.22 (m, 2H), 3.70 (t, 2H), 3.26 (s, 3H), 2, 47 (s, 3N), 1.88-1.14 (m, 6N) 403 Intermediate conn.-B-37 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine) palladium(O) THF 40% Ή NMR (DMSO-d ₆ ) δ: 7.70 (dd, 1H), 7.64 (d, 1H), 7.21 (d, 1H), 7.02 (s, 1H), 6.95 ( s, 1H), 6.46 (d, 1H), 3.58 (d, 3N), 2.45 (d, 3N), 1.97 (d, 3N), 1.54 (s, 3N), 1.46 (s, ZN) 404 Intermediate conn.-B-26 + Intermediate Bis(tri-tertbutylphosphine) palladium(O) 13% H NMR (DMSO-d ₆ ) δ: 7.50-7.44 (m, 1H), 7.38 (d, 1H), 7.12 (d, 1H), 7.05 (s, 1H), 6.95 (dd, 1H), 6.22 (d, 1H), 4.35 (t, 2H), 3.70 (t,

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conn.-A-24 THF 2H), 3.26 (d, 3N), 2.46 (d, 3N), 1.58 (s, 3N), 1.50 (s, 3N) 405 Intermediate compound-B-37 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole Bis(tri-tert-butylphosphine) palladium(O) THF 31% 'H NMR (DMSO-d ₆ ) δ: 10.48 (d, 1H), 7.52 (d, 1H), 7.12-7.04 (m, 2H), 7.01 (d, 1H) , 6.92 (d, 1H), 6.81 (s, 1H), 2.47 (s, 3N), 2.30 (d, 3N), 1.89 (s, 3N), 1.59 ( s, ZN), 1.42 (s, ZN) 406 Intermediate conn.-B-37 + Intermediate conn.-A-15 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 59% Ή NMR (DMSO-d ₆ ) δ: 10.60 (d, 1H), 7.29 (dd, 1H), 7.17-7.13 (m, 1H), 7.01 (d, 1H), 6.87 (s, 1H), 6.82 (dd, 1H), 2.48 (s, 3N), 2.26 (s, 3N), 1.92 (s, 3N), 1.58 (s , ZN), 1.43 (s, ZN) 407 Intermediate conn.-B-32 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 19% 'H NMR (DMSO-d ₆ ) δ: 10.54 - 10.43 (1H), 7.26 - 7.20 (1H), 7.16 - 7.06 (2H), 7.02 6.95 (1H), 6.92 - 6.72 (1H), 3.66 - 3.59 (ZN), 2.45 - 2.41 (ZN), 2.30 - 2.21 (ZN), 1, 78 - 1.29 (6H) 445 Intermediate compound-B-1 + indole-4boronic acid Bis(tri-tert-butylphosphine) palladium(O) THF 50% 'H NMR (DMSO-d ₆ ) δ: 11.23 (s, 1H), 7.48 (d, 1H), 7.39 (t, 1H), 7.19 (t, 1H), 7.10 (d, 1H), 7.06 (d, 1H), 6.80 (dd, 1H), 6.27 (s, 1H), 2.50 (d, 3N), 1.58 (s, 3N) , 1.49 (d, 3N) 458 Intermediate conn.-B-37 + Intermediate conn.-A-15 Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 19% 1H NMR (DMSO-d ₆ ) δ: 10.60 (s, 1H), 7.31 7.26 (m, 1H), 7.17-7.13 (m, 1H), 7.01 (d, 1H), 6.87 (s, 1H), 6.84 - 6.79 (m, 1H), 2.48 (s, 3N), 2.26 (s, 3N), 1.92 (s, 3N ), 1.58 (s, ZN), 1.43 (s, ZN). 459 Intermediate conn.-B-32 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine) palladium(O) THF 19% Ή NMR (DMSO-d ₆ ) δ: 10.55 - 10.41 (1H), 7.26 - 7.20 (1H), 7.15 - 7.06 (2H), 7.00 6.95 ( 1H), 6.92 - 6.71 (1H), 3.65 - 3.58 (ZN), 2.46 - 2.33 (ZN), 2.28 - 2.22 (ZN), 1.79 - 1.29 (6H) 460 Intermediate conn.-B-37 + Intermediate conn.-A-43 Bis(tri-tertbutylphosphine)palladium(0) THF 42% 'H NMR (DMSO-d ₆ ) δ: 7.54 (d, 1H), 7.38 (d, 1H), 7.27-7.20 (m, 1H), 7.00 (d, 1H) , 6.93 (d, 1H), 6.82 (s, 1H), 6.05 (d, 1H), 4.37 (t, 2H), 3.73 (t, 2H), 3.25 ( s, ZN), 2.43 (s, ZN), 1.93 (s, ZN), 1.56 (s, ZN), 1.43 (s, ZN) 461 Intermediate conn.-B-28 + Intermediate conn.-A-47 Bis(tri-tertbutylphosphine)palladium(0) THF 77% H NMR (DMSO-d ₆ ) δ: 7.91 (d, 1H), 7.59 (d, 1H), 7.45 (t, 1H), 7.32 (d, 1H), 7.22 ( s, 1H), 7.11-6.81 (m, 2H), 6.48 (s, 1H), 3.67 (c, 2H), 2.47 (s, 3H), 1.90 - 1 .17 (m, 6N), 1.07 (t, ZN) 462 Intermediate conn.-B-44 + Intermediate conn.-A-12 Bis(tri-tertbutylphosphine)palladium(0) THF 39% 'H NMR (DMSO-d ₆ ) δ: 7.93-7.87 (1H), 7.67-7.56 (1H), 7.52-7.24 (2H), 6.86 6.79 (2H), 6.68 - 6.40 (1H), 3.53 - 3.48 (3H), 2.61 - 2.54 (3H), 1.81 - 1.09 (6H), 0, 71--0.42 (5H) 463 Intermediate compound-B-44 + 3-methyl-7(4,4,5,5tetramethyl- Bis(tri-tertbutylphosphine)palladium(0) THF 54% 'H NMR (DMSO-d ₆ ) δ: 10.66-10.37 (1H), 7.53-7.48 (1H), 7.17-6.96 (3H), 6.85 6.75 (1H), 6.74 - 6.71 (1H), 2.64 - 2.53 (ZN), 2.33 - 2.27 (ZN), 1.76 - 1.16 (6H), 0, 62 - -0.24 (5H)

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1,3,2dioxaborol an-2-yl)-1Nindole 464 Intermediate conn.-B-4 + Intermediate conn.-A-1 Bis(tri-tert-butylphosphine)palladium(O) THF 77% Ή NMR (DMSO-d ₆ ) δ: 11.32-11.23 (1H), 7.46-7.38 (1H), 7.39-7.32 (1H), 7.32-7.11 ( 2H), 7.06 - 6.85 (1H), 6.24 - 6.03 (1H), 2.50 - 2.40 (3H), 1.86 - 1.24 (6H) 465 Intermediate conn.-B-37 + Intermediate conn.-A-12 Tetra acid (triphenylphosphine)-palladium (0) Toluene/Ethanol 18% % NMR (DMSO-%) δ: 7.92 (d, 1H), 7.62 (d, 1H), 7.49 (t, 1H), 7.24 (d, 1H), 7.02 (s , 1H), 6.90 (s, 1H), 6.46 (d, 1H), 3.53 (d, 3N), 2.45 (s, 3N), 1.94 (s, 3N), 1 .56 (s, ZN), 1.44 (s, ZN) 466 Intermediate conn.-B-28 + Intermediate conn.-A-1 Bis(tri-tert-butylphosphine)palladium(O) THF 41% Ή NMR (DMSO-d ₆ ) δ: 11.24 (s, 1H), 7.33 (m, 1H), 7.24 (d, 1H), 7.18-7.13 (m, 1H), 7.08 - 6.82 (m, ZN), 6.08 (s, 1N), 2.47 (s, ZN), 1.90 - 1.27 (m, 6N) 467 Intermediate compound-B-4 + indole-4boronic acid Bis(tri-tert-butylphosphine)palladium(O) THF 54% 'H NMR (DMSO-%) δ: 11.29-11.13(1H), 7.51-7.44(1H), 7.39-7.32(2H), 7.21-7.10( 2H), 7.08 - 6.94 (1H), 6.18 - 6.06 (1H), 2.49 - 2.39 (3H), 1.80 - 1.29 (6H) 468 Intermediate conn.-B-25 + Intermediate conn.-A-1 Bis(tri-tert-butylphosphine)palladium(O) THF 86% Ή NMR (DMSO-%) δ: 11.23 (s, 1H), 7.35 (t, 1H), 7.24 (dd, 1H), 7.01-6.86 (m, 2H), 6 .71 (d, 1H), 6.19 (t, 1H), 3.19 (s, 3H), 2.50 (s, 3H), 1.56 (s, 3H), 1.48 (s, ZN) 469 Intermediate conn.-B-37 + Intermediate conn.-A-56 Bis(tri-tert-butylphosphine)palladium(O) THF 36% Ή NMR (DMSO-d ₆ ) δ: 7.90 (s, 1H), 7.72 (d, 1H), 7.16-7.05 (m, 1H), 7.03 (s, 1H), 6.96 (d, 1H), 6.67 - 6.32 (m, 1H), 4.96 (tt, 2H), 2.47 (d, ZN), 1.98 (d, ZN), 1 .55 (s, ZN), 1.46 (s, ZN). 470 Intermediate compound-B-3 + 4(tetramethyl1,3,2dioxaborol an-2-yl)-6(trifluoromethyl yl)-1Nindole Bis(tri-tert-butylphosphine)palladium(O) THF 77% 'H NMR (DMSO-%) δ: 11.64 (s, 1H), 7.78 (d, 1H), 7.64 (t, 1H), 7.36 (d, 1H), 7.28 ( d, 1H), 6.67 (d, 1H), 6.47 (t, 1H), 3.15 (s, 3H), 2.57 (s, 3H), 1.57 (s, 6H) 471 Intermediate conn.-B-37 + Intermediate conn.-A-20 Bis(tri-tert-butylphosphine)palladium(O) THF 33% Ή NMR (DMSO-d ₆ ) δ: 7.42 (dd, 1H), 7.39 (d, 1H), 7.00 (s, 1H), 6.87 (s, 1H), 6.83 ( dd, 1H), 6.05 (d, 1H), 4.92 (t, 1H), 4.23 (td, 2H), 3.77 (c, 2H), 2.43 (s, 3H), 1.96 (s, ZN), 1.55 (s, ZN), 1.44 (s, ZN) 472 Intermediate conn.-B-28 + Intermediate conn.-A-56 Bis(tri-tert-butylphosphine)palladium(O) THF 46% Ή NMR (DMSO-d ₆ ) δ: 7.91 (s, 1H), 7.80 7.62 (m, 1H), 7.28 (s, 1H), 7.20-6.96 (m, ZN), 6.48 (tt, 1N), 5.09 - 4.73 (m, 2N), 2.49 (s, ZN), 1.95-1.19 (m, 6N) 473 Intermediate compound-B-4 + 4(tetramethyl1,3,2dioxaborol Bis(tri-tert-butylphosphine)palladium(O) THF 66% 'H NMR (DMSO-%) δ: 7.87 - 7.81 (1H), 7.65 - 7.59 (1H), 7.48 - 7.25 (2H), 7.21 7.12 ( 1H), 6.39 - 6.19 (1H), 2.50 - 2.41 (3H), 1.78-1.31 (6H)

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an-2-yl)-6(trifluoromethyl yl)-1Nindole 474 Intermediate compound-B-25 + 4(tetramethyl1,3,2dioxaborol an-2-yl)-6(trifluoromethyl)-1Nindole Bis(tri-tert-butylphosphine)palladium(O) THF 82% 'H NMR (DMSO-d ₆ ) δ: 11.63 (s, 1H), 7.80 (s, 1H), 7.62 (t, 1H), 7.31 (d, 1H), 6.94 (s, 1H), 6.73 (d, 1H), 6.33 (t, 1H), 3.19 (s, 3N), 2.50 (s, 3N), 1.58 (s, 3N) , 1.47 (s, ZN) 475 Intermediate comp.-B-33 + 4(tetramethyl1,3,2dioxaborol an-2-yl)-6(trifluoromethyl yl)-1Nindole Bis(tri-tert-butylphosphine)palladium(O) THF 2% 'H NMR (DMSO-d ₆ ) δ: 7.82-7.78 (m, 1H), 7.62 (t, 1H), 7.21 (d, 1H), 7.08 (s, 1H) , 6.74 (s, 1H), 6.20 - 6.16 (m, 1H), 2.42 (s, 3N), 1.92 (s, 3N), 1.54 (s, 3N), 1.46 (s, ZN) 476 Intermediate conn.-B-4 + Intermediate conn.-A-54 Bis(tri-tert-butylphosphine)palladium(O) THF 58% 'H NMR (DMSO-d ₆ ) δ: 7.78 - 7.74 (1H), 7.53 - 7.50 (1H), 7.47 - 7.41 (1H), 7.24 7.13 (2H), 6.61 - 6.41 (1H), 3.53 - 3.49 (3H), 2.53 - 2.42 (6H), 1.79 - 1.30 (6H) 477 Intermediate conn.-B-25 + Promezh. conn.-A-54 Bis(tri-tert-butylphosphine)palladium(O) THF 55% H NMR (DMSO-d ₆ ) δ: 7.72 (t, 1H), 7.51 (d, 1H), 7.18 (d, 1H), 6.94 (s, 1H), 6.72 ( d, 1H), 6.52 (dd, 1H), 3.49 (s, 3N), 3.21 (s, 3N), 2.52 (s, 3N), 2.50 (s, 3N), 1.59 (s, ZN), 1.46 (s, ZN) 478 Intermediate conn.-B-28 + Intermediate conn.-A-54 Bis(tri-tert-butylphosphine)palladium(O) THF 34% 'H NMR (DMSO-d ₆ ) δ: 7.72 (dd, 1H), 7.49 (d, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 7.07 6.82 (m, 2H), 6.41 (s, 1H), 3.49 (s, ZN), 2.51 (s, ZN), 2.47 (s, ZN), 2.05 - 1 .10 (m, 6H) 479 Intermediate conn.-B-4 + Intermediate conn.-A-62 Bis(tri-tert-butylphosphine)palladium(O) THF 44% 'H NMR (DMSO-A) δ: 8.02 - 7.97 (1H), 7.69 - 7.65 (1H), 7.51 - 7.34 (2H), 7.20 7.13 (1H), 6.39 - 6.24 (1H), 2.51 - 2.41 (3H), 1.79-1.31 (6H) 480 Intermediate conn.-B-37 + Intermediate conn.-A-58 Bis(tri-tert-butylphosphine)palladium(O) THF 72% 'H NMR (DMSO-d ₆ ) δ: 7.80 (s, 1H), 7.66 7.61 (m, 1H), 7.05-6.99 (m, 2H), 6.95 (s , 1H), 4.62 - 4.53 (m, 2H), 3.85 - 3.75 (m, 2H), 3.22 (s, 3H), 2.47 (s, 3H), 1, 99 (s, 3N), 1.55 (s, 3N), 1.46 (s, 3N). 481 Intermediate conn.-B-28 + Intermediate conn.-A-59 Bis(tri-tert-butylphosphine)palladium(O)THF) 24% H NMR (DMSO-d ₆ ) δ: 7.49 (d, 1H), 7.32 (d, 1H), 7.23 (dd, 1H), 7.12 (s, 1H), 7.04 ( d, 2H), 6.86 (t, 1H), 6.06 (s, 1H), 3.83 (s, 3H), 2.46 (s, 3H), 1.91-1.14 (m , 6H) 482 Intermediate conn.-B-32 + Intermediate conn.-A-16 Bis(tri-tert-butylphosphine)palladium(O) THF thirty% 'H NMR (DMSO-d ₆ ) δ: 10.56 - 10.45 (1H), 7.36 - 7.30 (1H), 7.15 - 7.10 (1H), 7.02 6.95 (2H), 6.92 - 6.73 (1H), 3.65 - 3.59 (3H), 2.47 - 2.40 (3H), 1.96 - 1.87 (1H), 1, 81 - 1.30 (6H), 0.96 - 0.55 (4H) 483 Intermediate Bis(three-tert- 31% 'H NMR (DMSO-d ₆ ) δ: 10.64 (d, 1H), 7.38

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conn.-B-25 + Promezh. conn.-A-16 butylphosphine)pal ladium(O) THF (dd, 1H), 7.06 (dd, 1H), 6.95 (dd, 1H), 6.92 (s, 1H), 6.71 (d, 1H), 3.22 (s, 3H) , 2.50 (s, ZN), 1.97 - 1.88 (m, 1H), 1.57 (s, ZN), 1.48 (s, ZN), 0.86 (dd, 2H), 0.67 - 0.57 (m, 2H) 484 Intermediate conn.-B-4 + Intermediate conn.-A-BO Bis(tri-tert-butylphosphine)palladium(O) THF 53% Ή NMR (DMSO-d ₆ ) δ: 7.71 - 7.66 (1H), 7.51 - 7.45 (1H), 7.43 - 7.28 (2H), 7.19 7.14 ( 1H), 6.67 - 6.45 (1H), 3.76 - 3.72 (ZN), 2.49 - 2.39 (ZN), 1.80 - 1.29 (6N) 485 Intermediate conn.-V-3Z + Intermediate conn.-A-16 Bis(tri-tert-butylphosphine)palladium(O) THF 31% Ή NMR (DMSO-d ₆ ) δ: 10.62 (d, 1H), 7.37 (dd, 1H), 7.09-7.03 (m, 2H), 6.84 (dd, 1H), 6.73 (s, 1H), 2.44 (s, 3N), 1.97 - 1.89 (m, 1H), 1.90 (s, 3N), 1.56 (s, 3N), 1 .52 - 1.40 (m, ZN), 0.91 - 0.82 (m, 2N), 0.63 (td, 2N) 486 Intermediate conn.-V-Z + Intermediate conn.-A-59 Bis(tri-tert-butylphosphine)palladium(O) THF 27% Ή NMR (DMSO-d ₆ ) δ: 7.49 (dd, 1H), 7.35 (d, 1H), 7.26 (dd, 1H), 7.00 (d, 1H), 6.78 ( d, 1H), 6.70 (s, 1H), 6.09 (d, 1H), 3.84 (s, 3N), 2.43 (s, 3N), 1.97 (s, 3N), 1.53 (s, ZN), 1.44 (s, ZN) 487 Intermediate conn.-B-25 + Promezh. conn.-A-59 Bis(tri-tert-butylphosphine)palladium(O) THF 23% 'H NMR (DMSO-d ₆ ) δ: 7.48 (dt, 1H), 7.33 (d, 1H), 7.25 (dd, 1H), 7.06 (d, 1H), 6.85 (s, 1H), 6.70 (d, 1H), 6.17 (d, 1H), 3.83 (s, 3N), 3.14 (s, 3N), 2.49 (s, 3N) , 1.56 (s, ZN), 1.47 (s, ZN) 488 Intermediate conn.-B-3Z + Intermediate conn.-A-59 Bis(tri-tert-butylphosphine)palladium(O) THF 52% 'H NMR (DMSO-d ₆ ) δ: 7.47 (d, 1H), 7.32 (d, 1H), 7.26 (dd, 1H), 7.06 (s, 1H), 6.94 (dd, 1H), 6.68 (s, 1H), 6.02 (d, 1H), 3.84 (s, 3N), 2.39 (s, 3N), 1.90 (s, 3N) , 1.53 (s, ZN), 1.45 (s, ZN) 489 Intermediate conn.-B-1 + Intermediate conn.-A-56 Bis(tri-tert-butylphosphine)palladium(O) THF 51% Ή NMR (DMSO-d ₆ ) δ: 8.12 (s, 1H), 7.84 7.66 (m, 1H), 7.30 (d, 1H), 7.23 (dd, 1H), 6 .84 (dd, 1H), 6.47 (tt, 1H), 4.96 (td, 2H), 2.53 (d, 3H), 1.55 (s, 6H) 490 Intermediate compound-B-25 + 4-(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole Bis(tri-tert-butylphosphine)palladium(O) THF 19% 'H NMR (DMSO-d ₆ ) δ: 13.14 (s, 1H), 7.86 (d, 1H), 7.59 (dt, 1H), 7.45 (dd, 1H), 7.16 (d, 1H), 6.95 (s, 1H), 6.74 (d, 1H), 3.17 (s, 3N), 2.53 (s, 3N), 1.59 (s, 3N) , 1.46 (s, ZN) 491 Intermediate conn.-V-3Z + Intermediate conn.-A-54 Bis(tri-tert-butylphosphine)palladium(O) THF 39% 'H NMR (DMSO-d ₆ ) δ: 7.71 (d, 1H), 7.51 (d, 1H), 7.08 (s, 1H), 7.07 (s, 1H), 6.74 (s, 1H), 6.36 (d, 1H), 3.50 (s, 3N), 2.52 (s, 3N), 2.41 (s, 3N), 1.92 (s, 3N) , 1.52 (s, ZN), 1.46 (s, ZN) 492 Intermediate conn.-B-1 + Intermediate conn.-A-54 Bis(tri-tert-butylphosphine)palladium(O) THF 50% Ή NMR (DMSO-d ₆ ) δ: 7.75 (d, 1H), 7.55 (d, 1H), 7.22 (s, 1H), 7.19 (d, 1H), 6.81 ( dd, 1H), 6.63 (d, 1H), 3.49 (s, ZN), 2.51 - 2.48 (m, 6H), 1.58 (s, ZN), 1.50 (s , ZN) 493 Intermediate conn.-V-Z + Intermediate conn.-A-54 Bis(tri-tert-butylphosphine)palladium(O) THF 42% Ή NMR (DMSO-d ₆ ) δ: 7.72 (d, 1H), 7.53 (d, 1H), 7.15 (s, 1H), 6.80 (d, 1H), 6.77 ( s, 1H), 6.43 (d, 1H), 3.49 (s, 3N), 2.52 (s, 3N), 2.45 (s, 3N), 1.99 (s, 3N), 1.52 (s, ZN), 1.45 (s, ZN) 494 Intermediate conn.-V-Z + Bis(tri-tertbutylphosphine)pal 14% 'H NMR (DMSO-d ₆ ) δ: 7.96 (t, 1H), 7.69 (t, 1H), 7.38 (d, 1H), 6.81 (d, 1H), 6.78 (s, 1H),

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Intermediate conn.-A-62 ladium(0) THF 6.25 (t, 1N), 2.46 (s, ZN), 1.99 (s, ZN), 1.55 - 1.45 (m, 6N) 495 Intermediate conn.-V-Z + Intermediate conn.-A-bZ Bis(tri-tertbutylphosphine)palladium(0) THF 59% Ή NMR (DMSO-d ₆ ) δ: 7.91 (d, 1H), 7.60 (d, 1H), 7.47 (dd, 1H), 7.29 (d, 1H), 6.81 ( d, 1H), 6.79 (s, 1H), 6.50 (d, 1H), 3.61 (d, 2H), 2.45 (s, 3H), 1.98 (s, 3H), 1.52 (s, ZN), 1.46 (s, ZN), 0.89 - 0.78 (m, 1H), 0.39 - 0.27 (m, 2H), -0.04-- 0.13 (m, 2H) 496 Intermediate compound-B-28 + 7-fluoro-4(4,4,5,5tetramethyl[1,3,2]dioxa boron-2- silt)-1Nindol Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 61% 'H NMR (DMSO-d ₆ ) δ: 11.69 (t, 1H), 7.39 (t, 1H), 7.13 (s, 1H), 7.04 (d, 1H), 7.02 6.78 (m, 3H), 6.15 (s, 1H), 2.46 (s, 3H), 1.57 (s, 6H) 497 Intermediate comp.-B-l + 7-fluoro-4(4,4,5,5tetramethyl[1,3,2]dioxa boron-2yl)-1Nindole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 38% 'H NMR (DMSO-d ₆ ) δ: 11.76 (s, 1H), 7.46 (t, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 7.03 (s, 1H), 6.79 (dd, 1H), 6.36 (s, 1H), 2.49 (s, 3N), 1.58 (s, 3N), 1.50 (s, 3N) 498 Intermediate conn.-B-48 + Intermediate conn.-A-12 Bis(tri-tertbutylphosphine)palladium(0) THF 80% 'H NMR (DMSO-d ₆ ) δ: 7.95-7.88 (1H), 7.63-7.57 (1H), 7.48-7.16 (5H), 6.63 6.45 (1H), 3.57 - 3.47 (ZN), 2.50 - 2.46 (ZN), 1.84 - 1.23 (6N) 499 Intermediate conn.-B-48 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine)palladium(O) THF 89% 'H NMR (DMSO-d ₆ ) δ: 7.74-7.68 (1H), 7.65-7.58 (1H), 7.40-7.16 (4H), 6.63 6.45 (1H), 3.60 - 3.55 (ZN), 2.53 - 2.46 (ZN), 1.78 - 1.27 (6N) 500 Intermediate conn.-B-32 + Intermediate conn.-A-42 Bis(tri-tertbutylphosphine)palladium(0) THF eleven% 'H NMR (DMSO-d ₆ ) δ: 7.57 - 7.52 (1H), 7.33 - 7.28 (1H), 7.23 - 7.18 (1H), 7.11 7.05 (1H), 7.03 - 6.90 (2H), 6.55 - 6.29 (1H), 6.19 - 6.01 (1H), 4.75 - 4.65 (2H), 3, 63 - 3.58 (ZN), 2.46 - 2.35 (ZN), 1.77 1.28 (6N) 501 Intermediate compound-B-1 + 7-fluoro-4(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole Bis(tri-tertbutylphosphine)palladium(0) THF 12% 'H NMR (DMSO-d ₆ ) δ: 8.12 - 8.07 (m, 1H), 7.32 (dd, 1H), 7.20 (d, 1H), 7.19 - 7.12 ( m, 1H), 6.85 - 6.79 (m, 1H), 2.52 (d, ZN), 1.55 (s, 6H) 502 Intermediate conn.-B-28 + Intermediate conn.-A-bZ Bis(tri-tertbutylphosphine)palladium(0) THF 74% 'H NMR (DMSO-%) δ: 7.90 (d, 1H), 7.55 (d, 1H), 7.43 (dd, 1H), 7.30 (d, 1H), 7.21 ( s, 1H), 7.09 - 6.87 (m, 2H), 6.48 (s, 1H), 3.59 (d, 2H), 2.48 (s, 3H), 2.07 (s , ZN), 1.94 1.20 (m, 6H), 0.91 - 0.71 (m, 1H), 0.41 - 0.15 (m, ZN), -0.14 (d, 2H ) 503 Intermediate Bis(three-tert- 65% 'H NMR (DMSO-d ₆ ) δ: 10.47 - 10.43 (1H),

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compound-B-48 + 3-methyl-7(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindole butylphosphine)palladium(0) THF 7.54 - 7.48 (1H), 7.32 - 7.16 (2H), 7.11 7.08 (1H), 7.08 - 6.95 (ZN), 2.51 - 2.47 (ZN), 2.31 - 2.27 (ZN), 1.80 - 1.26 (6N) 504 Intermediate, compound-B-3 + 7-fluoro-4(4,4,5,5tetramethyl[1,3,2]dioxa boron-2yl)-1Nindole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 17% 'H NMR (DMSO-d ₆ ) δ: 11.73 (t, 1H), 7.44 (t, 1H), 7.02 (dd, 1H), 6.94 (dd, 1H), 6.78 (d, 1H), 6.71 (s, 1H), 6.17 (c, 1H), 2.44 (s, 3N), 1.98 (s, 3N), 1.53 (s, 3N) , 1.44 (s, ZN) 505 Intermediate, compound-B-4 + 7-fluoro-4(4,4,5,5tetramethyl[1,3,2]dioxa boron-2yl)-1Nindole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 15% 'H NMR (DMSO-E ₆ ) δ: 11.76-11.70 (1H), 7.44-7.35 (2H), 7.18-7.11 (1H), 7.07 6.91 (2H), 6.30 - 6.13 (1H), 2.49 - 2.39 (3H), 1.78-1.31 (6H) 506 Intermediate compound-B-33 + 7-fluoro-4(4,4,5,5tetramethyl[1,3,2]dioxa boron-2yl)-1Nindole Tetrakis(triphenylphosphine)-palladium (0) Toluene/Ethanol 36% 'H NMR (DMSO-d ₆ ) δ: 11.71 (t, 1H), 7.41 (t, 1H), 7.06 (s, 1H), 7.02 (dd, 1H), 6.87 (dd, 1H), 6.69 (s, 1H), 6.11 (c, 1H), 2.40 (s, 3N), 1.91 (s, 3N), 1.53 (s, 3N) , 1.45 (s, ZN) 507 Intermediate conn.-B-48 + Intermediate conn.-A-15 Bis(tri-tertbutylphosphine)palladium(0) THF 62% 'H NMR (DMSO-d ₆ ) δ: 10.62 - 10.55 (1H), 7.33 - 7.21 (3H), 7.17 - 7.12 (2H), 7.01 6.81 (1H), 2.51 - 2.48 (ZN), 2.30 - 2.23 (ZN), 1.79 - 1.27 (6N) 508 Intermediate, conn.-B-26 + Intermediate conn.-A-56 Bis(tri-tertbutylphosphine)palladium(0) THF 10% Ή NMR (DMSO-d ₆ ) δ: 8.08 (s, 1H), 7.75 (dt, 1H), 7.23 (d, 1H), 7.19 (dd, 1H), 7.08 ( d, 1H), 6.48 (tg, 1H), 4.96 (td, 2H), 2.49 (d, 3N), 1.60 (s, 3N), 1.51 (s, 3N) 509 Intermediate conn.-B-32 + Intermediate conn.-A-59 Bis(tri-tertbutylphosphine)palladium(0) THF 64% 'H NMR (DMSO-d ₆ ) δ: 7.58 - 7.39 (1H), 7.35 - 7.23 (1H), 7.21 - 7.13 (1H), 7.10 7.03 (1H), 7.00 - 6.72 (2H), 6.08 - 5.92 (1H), 3.84 - 3.80 (ZN), 3.62 - 3.55 (ZN), 2, 45 - 2.34 (ZN), 1.76 - 1.28 (6N) 510 Intermediate, compound-B-3 + 4-(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole Bis(tri-tertbutylphosphine)palladium(0) THF 14% 'H NMR (DMSO-d ₆ ) δ: 13.20 (s, 1H), 7.80 (s, 1H), 7.60 (d, 1H), 7.46 (dd, 1H), 7.11 (d, 1H), 6.81 (d, 1H), 6.78 (s, 1H), 2.47 (s, 3N), 2.00 (s, 3N), 1.53 (s, 3N) , 1.46 (s, ZN)

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511 Intermediate conn.-B-1 + Intermediate conn.-A-69 Bis(tri-tert-butylphosphine)palladium(O) THF 53% 'H NMR (DMSO-d ₆ ) δ: 11.38 (t, 1H), 7.54 (dd, 1H), 7.44 (t, 1H), 7.27-7.16 (m, 1H) , 7.10 (d, 1H), 6.81 (dd, 1H), 6.32 - 6.28 (m, 1H), 2.49 (s, 3H), 1.57 (s, 3H), 1.50 (s, ZN) 512 Intermediate conn.-B-28 + Intermediate conn.-A-72 Bis(tri-tert-butylphosphine)palladium(O) THF 20% 'H NMR (DMSO-d ₆ ) δ: 7.72-7.51 (m, 1H), 7.24 (d, 1H), 7.19 (s, 1H), 7.04 (d, 1H) , 6.94 (t, 1H), 6.38 (s, 1H), 3.63 (s, 3N), 2.81 (s, 3N), 2.46 (s, 3N), 1.89 - 1.12 (m, 6H) 513 Intermediate conn.-V-Z + Intermediate conn.-A-69 Bis(tri-tert-butylphosphine)palladium(O) THF 89% 'H NMR (DMSO-d ₆ ) δ: 11.35 (s, 1H), 7.50 (dd, 1H), 7.42 (t, 1H), 7.02 (d, 1H), 6.79 (d, 1H), 6.75 (s, 1H), 6.12 (t, 1H), 2.44 (s, 3N), 1.99 (s, 3N), 1.52 (s, 3N) , 1.45 (s, ZN) 514 Intermediate conn.-B-28 + Intermediate conn.-A-44 Bis(tri-tert-butylphosphine)palladium(O) THF 41% ³ H NMR (DMSO-d ₆ ) δ: 7.62 (d, 1H), 7.31 (d, 1H), 7.25 (dd, 1H), 7.13 (s, 1H), 7.05 (dd, 2H), 6.87 (t, 1H), 6.04 (s, 1H), 3.48 (tt, 1H), 2.46 (s, 3H), 1.83 - 1.15 ( m, 6H), 1.12 - 1.06 (m, 2H), 1.04-0.95 (m, 2H) 515 Intermediate conn.-B-28 + Intermediate conn.-A-71 Bis(tri-tert-butylphosphine)palladium(O) THF 5% 416.1 516 Intermediate conn.-B-4 + Intermediate conn.-A-71 Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, tert-amyl alcohol 3% 434.2 517 Intermediate conn.-B-32 + Intermediate conn.-A-73 Bis(tri-tert-butylphosphine)palladium(O) THF 37% Ή NMR (DMSO-d ₆ ) δ: 7.33 - 7.29 (1H), 7.27 - 7.23 (1H), 7.15 - 7.07 (1H), 6.99 6.96 ( 1H), 6.93 - 6.72 (1H), 6.11 - 5.91 (1H), 3.80 - 3.77 (ZN), 3.62 - 3.58 (ZN), 2.45 - 2.35 (ZN), 1.77 - 1.29 (6N) 518 Intermediate conn.-V-Z + Intermediate conn.-A-73 Bis(tri-tert-butylphosphine)palladium(O) THF 17% 'H NMR (DMSO-d ₆ ) δ: 7.40-7.36 (m, 1H), 7.35 (d, 1H), 6.92 (dd, 1H), 6.79 (d, 1H) , 6.75 (s, 1H), 6.08 (d, 1H), 3.80 (s, 3N), 2.44 (s, 3N), 1.99 (s, 3N), 1.52 ( s, ZN), 1.45 (s, ZN) 519 Intermediate conn.-B-3Z + Intermediate conn.-A-73 Bis(tri-tert-butylphosphine)palladium(O) THF 7% 'H NMR (DMSO-d ₆ ) δ: 7.38-7.34 (m, 1H), 7.33 (d, 1H), 7.05 (s, 1H), 6.85 (dd, 1H) , 6.73 (s, 1H), 6.02 (d, 1H), 3.80 (s, 3N), 2.40 (s, 3N), 1.93 (s, 3N), 1.52 ( s, ZN), 1.46 (s, ZN) 520 Intermediate conn.-B-34 + Intermediate conn.-A-73 Bis(tri-tert-butylphosphine)palladium(O) THF 19% Ή NMR (DMSO-d ₆ ) δ: 7.36 (ddd, 1H), 7.33 (d, 1H), 6.89 (dd, 1H), 6.80 (s, 1H), 6.76 ( d, 1H), 6.10 (d, 1H), 3.80 (s, 3N), 2.43 (d, 3N), 2.02 (s, 3N), 1.54 (s, 3N), 1.48 (s, ZN) 521 Intermediate conn.-B-28 + Intermediate conn.-A-73 Bis(tri-tert-butylphosphine)palladium(O) THF 36% Ή NMR (DMSO-d ₆ ) δ: 7.38 (dd, 1H), 7.31 (d, 1H), 7.18 (s, 1H), 7.08-6.82 (m, 3H), 6.07 (s, 1H), 3.80 (s, ZN), 2.46 (s, ZN), 1.88 -1.17 (m, 6H) 522 Intermediate conn.-B-48 + Intermediate conn.-A-73 Bis(tri-tert-butylphosphine)palladium(O) THF thirty% 430.2 523 Intermediate conn.-B-32 + Intermediate conn.-A-44 Bis(tri-tert-butylphosphine)palladium(O) THF 21% 'H NMR (DMSO-d ₆ ) δ: 7.59 - 7.53 (1H), 7.26 - 7.23 (1H), 7.22 - 7.17 (1H), 7.10 7.03 (1H), 7.02 - 6.88 (2H), 6.05 - 5.90 (1H), 3.60 - 3.57 (ZN), 3.48 - 3.44 (1H),

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2.46 - 2.32 (ZN), 1.80 - 1.26 (6N), 1.13 0.95 (4N) 524 Intermediate compound-B-3 + 7-fluoro-4(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole Bis(tri-tert-butylphosphine)palladium(O) THF 15% 'H NMR (DMSO-d ₆ ) δ: 7.91 (d, 1H), 7.29 (dd, 1H), 7.08 (dd, 1H), 6.81 (d, 1H), 6.79 (s, 1H), 2.46 (s, 3N), 2.00 (s, 3N), 1.52 (s, 3N), 1.46 (s, 3N) 525 Intermediate conn.-V-Z + Intermediate conn.-A-76 Bis(tri-tert-butylphosphine)palladium(O) THF 16% Ή NMR (DMSO-d ₆ ) δ: 7.75 (d, 1H), 7.54 (d, 1H), 7.32 (d, 1H), 6.84-6.77 (m, 2H), 6.46 (d, 1H), 3.89 (s, 3N), 2.44 (s, 3N), 1.97 (s, 3N), 1.51 (s, 3N), 1.46 (s , ZN) 526 Intermediate conn.-B-52 + Intermediate conn.-A-2 Bis(tri-tert-butylphosphine)palladium(O) THF 72% Ή NMR (DMSO-d ₆ ) δ: 7.66 (dd, 1H), 7.59 (d, 1H), 7.27-7.17 (m, 3H), 7.06 (t, 1H), 7.00 (s, 1H), 6.47 (s, 1H), 3.55 (s, 3H), 2.51 (s, 3H), 1.49 (s, 6H) 527 Intermediate conn.-B-52 + Intermediate conn.-A-15 Bis(tri-tert-butylphosphine)palladium(O) THF 67% Ή NMR (DMSO-d ₆ ) δ: 10.46 (d, 1H), 7.24 (dd, 1H), 7.22-7.15 (m, 2H), 7.13-7.09 (m , 1H), 7.06 - 6.82 (m, ZN), 2.52 (s, ZN), 2.25 (s, ZN), 1.92-1.13 (m, 6H) 528 Intermediate conn.-B-52 + Intermediate conn.-A-12 Bis(tri-tert-butylphosphine)palladium(O) THF 53% 'H NMR (DMSOO δ: 7.88 (d, 1H), 7.58 (d, 1H), 7.43 (t, 1H), 7.30 (s, 1H), 7.22 (d, 1H ), 7.17 (d, 1H), 6.99 (t, 1H), 6.94 (s, 1H), 6.48 (s, 1H), 3.49 (s, 3H), 2.50 (s, ZN), 1.78 1.20 (m, 6H) 529 Intermediate conn.-B-1 + Intermediate conn.-A-74 Bis(tri-tert-butylphosphine)palladium(O) THF 46% Ή NMR (DMSO-d ₆ ) δ: 11.65-11.60 (m, 1H), 7.47 (t, 1H), 7.28 (d, 1H), 7.15 (d, 1H), 7.08 (d, 1H), 6.81 (dd, 1H), 6.41 - 6.36 (m, 1H), 2.49 (s, WN), 1.57 (s, WN), 1 .50 (s, ZN) 530 Intermediate conn.-B-4 + Intermediate conn.-A-74 Bis(tri-tert-butylphosphine)palladium(O) THF 27% Ή NMR (DMSO-d ₆ ) δ: 11.63 - 11.58 (1H), 7.45 - 7.38 (2H), 7.28 - 7.25 (1H), 7.17 7.13 ( 1H), 7.11 - 6.97 (1H), 6.32 - 6.16 (1H), 2.48 - 2.40 (3H), 1.79 - 1.29 (6H) 531 Intermediate conn.-B-4 + Intermediate conn.-A-75 Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, tert-amyl alcohol 44% 'H NMR (DMSO-d ₆ ) δ: 12.20 - 12.11 (1H), 7.72 - 7.67 (1H), 7.55 - 7.51 (1H), 7.50 7.46 (1H), 7.30 - 7.15 (2H), 6.44 - 6.27 (1H), 2.49 - 2.41 (3H), 1.78 - 1.24 (6H) 532 Intermediate conn.-B-4 + Intermediate conn.-A-73 Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, tert-amyl alcohol 29% 'H NMR (DMSO-d ₆ ) δ: 7.45-7.38 (2H), 7.35-7.31 (1H), 7.20-7.11 (1H), 7.086.89 (1H) , 6.21 - 6.05 (1H), 3.84 - 3.78 (ZN), 2.50 - 2.40 (ZN), 1.79 - 1.29 (6N) 533 Intermediate conn.-B-3Z + Intermediate conn.-A-44 Bis(tri-tert-butylphosphine)palladium(O) THF 17% Ή NMR (DMSO-d ₆ ) δ: 7.61 (dt, 1H), 7.33 (d, 1H), 7.28 (dd, 1H), 7.05 (s, 1H), 6.96 ( dd, 1H), 6.68 (s, 1H), 6.00 (d, 1H), 3.49 (dc, 1H), 2.39 (s, 3N), 1.90 (s, 3N), 1.53 (s, ZN), 1.44 (s, ZN), 1.14 - 1.06 (m, 2H), 1.03 - 0.98 (m, 2H) 534 Intermediate conn.-V-Z + Intermediate conn.-A-75 Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, tert-amyl alcohol 91% Ή NMR (DMSO-d ₆ ) δ: 12.17 - 12.12 (m, 1H), 7.70 (d, 1H), 7.54 (t, 1H), 7.17 (d, 1H), 6.81 (t, 2H), 6.30 (t, 1H), 2.44 (s, 3H), 1.98 (s, 3H), 1.53 (s, 3H), 1.45 (s , ZN) 535 Intermediate conn.-B-4 + Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, 25% 'H NMR (DMSO-d ₆ ) δ: 8.09 - 7.90 (1H), 7.49 - 7.44 (1H), 7.32 - 7.27 (1H), 7.21 -

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7-fluoro-4(4,4,5,5tetramethyl1,3,2dioxaborol an-2-yl)-1Nindazole tert-amyl alcohol 7.06 (ZN), 2.49 - 2.43 (ZN), 1.78 - 1.31 (6N) 536 Intermediate conn.-B-4 + Intermediate conn.-A-77 Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, tert-amyl alcohol 24% 'H NMR (DMSO-d ₆ ) δ: 7.49 - 7.43 (3H), 7.18 - 7.13 (1H), 7.10 - 6.93 (1H), 6.57 6.37 (1Н), 3.90 - 3.84 (ЗН), 2.48 - 2.40 (ЗН), 1.81-1.28 (6Н) MeO is hidden by the water peak 537 Intermediate conn.-V-Z + Intermediate conn.-A-77 Xphos/ Pd ₂ dba ₃ , 1,4-dioxane, tert-amyl alcohol 54% 'H NMR (DMSO-d ₆ ) δ: 7.47 (d, 1H), 7.44 7.39 (m, 1H), 6.95 (d, 1H), 6.83-6.77 (m , 2H), 6.39 (d, 1H), 3.88 (s, 3N), 3.49 (s, 3N), 2.45 (s, 3N), 2.00 (s, 3N), 1 .51 (s, ZN), 1.43 (D, ZN)

Examples in table. 6 were synthesized by standard chemical reactions that are known to the person skilled in the art.

Table 6

Etc. No. Intermediates Synthesis is similar Exit (%) Ίΐ NMR 202 Etc. 445 + chloromethylcyclopropan Example 35 38% Ή NMR (DMSOO δ: 7.60 (d, 1H), 7.49 (d, 1H), 7.24 (t, 1H), 7.12 (d, 1H), 7.08 (d, 1H) , 6.80 (dd, 1H), 6.31 - 6.25 (m, 1H), 4.09 (d, 2H), 2.51 (c, ZN), 1.59 (s, ZN), 1.50 (s, 3N), 1.29 (dtd, 1N), 0.58 - 0.49 (m, 2N), 0.47 - 0.38 (m, 2N) 203 Etc. 445 + tetrahydropyran-4sulfonyl chloride 29% Ή NMR (DMSO-d ₆ ) δ: 7.96 (d, 1H), 7.65 (d, 1H), 7.49 (t, 1H), 7.39 (d, 1H), 7.21 ( d, 1H), 6.82 (dd, 1H), 6.71 (d, 1H), 4.05 (tg, 1H), 3.92 - 3.86 (m, 2H), 3.30 (d , 2H), 2.54 - 2.48 (m, ZN), 1.70 (ddt, 4H), 1.57 (s, ZN), 1.52 (s, ZN) 204 Etc. 445 + 1-chloro-2 methoxyethane Example 35 36% Ή NMR (DMSO-d ₆ ) δ: 7.57 (dd, 1H), 7.40 (q, 1H), 7.27-7.21 (m, 1H), 7.12 (s, 1H), 7.11 - 7.06 (m, 1H), 6.81 (dd, 1H), 6.27 (s, 1H), 4.38 (q, 2H), 3.70 (q, 2H), 3 .28 - 3.23 (m, ZN), 2.49 (d, ZN), 1.58 (s, ZN), 1.50 (s, ZN) 205 Etc. 445 + cyclopropane lfonyl chloride 20% Ή NMR (DMSO-d ₆ ) δ: 7.98 (dd, 1H), 7.66 (d, 1H), 7.49 (dd, 1H), 7.38 (d, 1H), 7.21 ( d, 1H), 6.83 (dd, 1H), 6.69 (d, 1H), 3.15 (tg, 1H), 2.51 (d, 3H), 1.58 (s, 3H), 1.51 (s, 3N), 1.32 - 1.27 (m, 2N), 1.12 (dt, 2N) 210 Etc. 445 + cyclopropylmethanesulfonyl chloride 28% Ή NMR (DMSO-d ₆ ) δ: 7.94 (d, 1H), 7.62 (d, 1H), 7.47 (t, 1H), 7.37 (d, 1H), 7.20 ( d, 1H), 6.83 (dd, 1H), 6.70 (d, 1H), 3.61 (d, 2H), 2.52 - 2.48 (m, 3H), 1.58 (s , ZN), 1.52 (s, ZN), 0.82 (tg, 1H), 0.41 - 0.34 (m, 2H), -0.01 (td, 2H) 223 Etc. 445 + 2(dimethylamino)acetyl chloride (HC1-salt) Example 4 19% Ή NMR (DMSO-d ₆ ) δ: 8.43 (d, 1H), 7.98 (d, 1H), 7.45 (t, 1H), 7.34 (d, 1H), 7.19 ( d, 1H), 6.82 (dd, 1H), 6.63 - 6.58 (m, 1H), 3.81 (s, 2H), 2.51 (d, 3H), 2.36 (s , 6H), 1.59 (s, ZN), 1.50 (s, ZN) 224 Etc. 214 + Methanesulfonylchloride 25% Ή NMR (DMSO-d ₆ ) δ: 7.97 (dd, 1H), 7.73 (d, 1H), 7.41 (t, 1H), 7.31 (d, 1H), 6.85 ( dd, 1H), 6.74 (d, 1H), 3.55 (s, ZN), 2.52 - 2.50 (m, ZN), 1.58 (s,

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ZN), 1.52 (s, ZN) 229 Etc. 230 + 2,2 difluoropropanoic acid (TFR combination) 49% Ή NMR (DMSO-d ₆ ) δ: 8.83 (t, 1H), 7.62-7.54 (m, 1H), 7.36 (d, 1H), 7.26 (dd, 1H), 7.15 - 7.06 (m, 2H), 6.79 (dd, 1H), 6.29 (dd, 1H), 4.36 (t, 2H), 3.60-3.51 (m, 2H), 2.49 (d, ZN), 1.60 (t, ZN), 1.58 (s, ZN), 1.50 (s, ZN) 230 Removal of Vos from Ave. 228 36% % NMR (DMSO-d ₆ ) δ: 7.59 (d, 1H), 7.43 (dd, 1H), 7.28-7.21 (m, 1H), 7.14-7.06 (m , 2H), 6.80 (dd, 1H), 6.27 (d, 1H), 4.21 (td, 2H), 2.97 (s, 2H), 2.49 (d, 3H), 1 .58 (s, ZN), 1.50 (s, ZN) 258 Demethylation Ex. 233 (DL-methionine) 9% 'H NMR (DMSO-d ₆ ) δ: 7.97 (s, 1H), 7.74 (d, 1H), 7.48 (dd, 1H), 7.20 (d, 2H), 6.83 (dd, 1H), 4.91 (t, 1H), 4.49 (t, 2H), 3.85 (c, 2H), 2.53 (s, 3H), 1.55 (s, 6H) 259 Etc. 252 + 1-chloro-2 methoxyethane Example 35 42% 'H NMR (DMSO-d ₆ ) δ: 7.82-7.63 (m, 1H), 7.46 (dd, 1H), 7.22-7.18 (m, 1H), 7.16 ( d, 1H), 7.12 (t, 1H), 6.94 (s, 1H), 6.82 (s, 1H), 4.63-4.28 (m, 2H), 3.71 (h , 2H), 3.24 (s, 3N), 2.47 (d, 3N), 1.58 (s, 3N), 1.52 (s, 3N) 271 Etc. 225 + methanesulfonyl chloride 32% % NMR (DMSO-d ₆ ) δ: 8.13 (d, 1H), 7.71 (dd, 1H), 7.53 (d, 2H), 7.25 (d, 1H), 6.83 ( dd, 1H), 3.58 (s, ZN), 2.50 (s, ZN), 1.59 (s, ZN), 1.52 (s, ZN) 289 Etc. 225 + 1-chloro-2 methoxyethane Example 35 15% % NMR (DMSO-d ₆ ) δ: 7.59 (d, 1H), 7.43 (dd, 1H), 7.24 (d, 1H), 6.99 (dd, 1H), 6.89 ( s, 1H), 3.64 (t, 2H), 3.51 (t, 2H), 3.26 (s, 3H), 2.49 (d, 3H), 1.61 (s, 3H), 1.58 (s, ZN) 312 Etc. 225 + cyclopropylboronic acid Example 2 49% 'H NMR (DMSO-d ₆ ) δ: 7.83-7.78 (m, 1H), 7.49 (dd, 1H), 7.27 (d, 1H), 7.18 (d, 1H) , 6.97 (s, 1H), 6.81 (dd, 1H), 3.46 (tt, 1H), 2.48 (d, 3H), 1.57 (s, 3H), 1.52 ( s, ZN), 1.28 - 1.23 (m, 2H), 1.19 - 1.13 (m, 2H)

Table 7

Etc. No. Intermediates Synthesis is similar Yield (% mol) 'H-NMR 447 Intermediate conn.-A-20 + Intermediate conn.-B-4 Etc. 446 24% 'H NMR (400 MHz, DMSO-db): δ 7.34-7.40 (m, 2H), 7.14 (d, 2H), 6.91 (br, 1H), 6.10 (s, 1H), 4.62 (s, 1H), 4.22 (d, 2H), 3.81 (c, 2H), 2.45 (s, 3H), 1.75 (br, 3H), 1, 37 (br, ZN). 448 Intermediate conn.-A-50 + Intermediate conn.-B-4 Etc. 446 13% 'H NMR (400 MHz, DMSO-d ₆ ): δ 8.38 (s, 1H), 7.81 (d, 1H), 7.44 (s, 1H), 7.33 (s, 1H), 7.20 (d, 1H), 3.75 (c, 2H), 1.78 (br, 3N), 1.35 (br, 3N), 1.15 (t, 3N); (CL ₃ - DMSO is missing). 449 Intermediate conn.-A-21 + Intermediate conn.-B-4 Etc. 446 32% Ή NMR (400 MHz, DMSO-d ₆ ): δ 7.77 (br, 1H), 7.56 (d, 1H), 7.24 (s, 1H), 7.17 (d, 1H), 7 .07 (br, 1H), 4.58 (s, 1H), 4.45 (d, 2H), 3.88 (c, 2H), 2.49 (s, 3H), 1.77 (br, ZN), 1.37 (br, ZN). 451 Intermediate conn.-A-20 + Intermediate conn.-B-40 Etc. 450 61% 1H NMR (400 MHz, DMSO-db): δ 7.39-7.35 (m, 2H), 7.14 (d1H), 6.95 (d, J=8 Hz, 1H), 6.88- 6.85 (m, 1H), 6.49 (s, 1H), 6.14 (s, 1H), 4.90 (t, 1H), 4.22 (t, 2H), 3.75-3 .71 (m, 2H), 2.06 (s, 3H), 1.46 (s, 6H); (CH ₃ - missing DMSO). 452 Intermediate conn.-A-15 + Intermediate Etc. 450 59% 1H NMR (400 MHz, DMSO-db): δ 10.55 (s, 1H), 7.25-7.22 (m, 1H), 7.14-7.12 (m, 2H), 6.97 -6.95 (m, W), 6.84-6.81 (m, 1H), 6.50 (s, 1H), 2.52 (s, W), 2.25 (s, W), 1.99 (s, 3N), 1.47 (br, 6H).

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conn.-B-40 453 Intermediate conn.-A-2 + Intermediate compound-B-40 Etc. 450 42% 1H NMR (400 MHz, DMSO-db): δ 7.68-7.62 (m, 2H), 7.24-7.22 (m, 1H), 7.15-7.13 (m, W) , 6.98-6.96 (m, 1H), 6.58-6.52 (m, 2H), 3.55 (s, ZN), 2.06 (s, ZN), 1.46 (br , 6H); (SN _G omitted by DMSO). 454 Intermediate conn.-A-23 + Intermediate conn.-B-4 Etc. 446 15% SH NMR (400 MHz, DMSO-d ₆ ): δ 8.38 (s, br), 7.80 (d, 1H), 7.45 (br, 1H), 7.34 (s, 1H), 7 .20 (d, 1H), 3.55 (s, 3N), 2.49 (s, 3N), 1.78 (br, 3N), 1.37 (br, 3N). 455 Intermediate conn.-A-47 + Intermediate conn.-B-4 Etc. 446 16% ^! H NMR (400 MHz, DMSO-db): δ 7.96 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.46 (t, W), 7.33 ( br, W), 7.16 (d, 2H), 6.54 (br, W), 3.61 (c, 2H), 2.45 (s, 3N), 1.78 (br, 3N), 1.37 (br, ZN), 1.12 (t, ZN). 456 Intermediate connection-A-51 + Intermediate compound-B-4 Etc. 446 20% Ή NMR (400 MHz, DMSO-d ₆ ; t=100°C): δ 8.34 (br, 1H), 8.09 (d, br), 7.73 (t, 1H), 7.45 ( br, 1H), 7.27 (s, W), 7.19 (d, W), 3.50 (s, W), 2.49 (s, W), 1.78 (br, W), 1.48 (br, ZN). 457 Intermediate conn.-A-22 + Intermediate conn.-B-40 Etc. 450 53% W NMR (400 MHz, DMSO-db): δ 8.38 (s, 1H), 8.00 (d, 1H), 7.73 (t, 1H), 7.43-7.41 (m, 1H ), 7.19 (d, 1H), 7.01 (d, 1H), 6.61 (s, 1H), 3.52 (s, 3H), 2.52 (s, 3H), 2.07 (s, 3H), 1.47 (s, 6H).

Molecular structures and chemical names of the examples presented in Table. 4, 5, 6 and 7 are given in table. 8 below.

Table 8

Etc. No. Structure Name 45 X No. 2-[4-(9-Ethyl-7-fluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-6-fluoro-1Nindazol-1-yl]-ethanol 46 F /X # Mil ° vvUm y mm ^x 9-Ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a ]quinoxaline 47 χχχ ^xz - \ / 9-Ethyl-7-fluoro-8-(5-fluoro-3-methyl-1 H-indol-7-yl)-1,4,4trimethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 50 XXXL JII hmm H 9-Ethyl-7-fluoro-1,4,4-trimethyl8-(1-methylsulfonyl-1Nindol-4-yl)-5H- [1,2,4]triazolo[4,3a]quinoxaline 51 htX X Χΐ CCk A / : J %° -X 1mm / n τ H 9-Ethyl-7-fluoro-1,4,4-trimethyl- 8-(1-methylsulfonyl- 1Nindazol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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52 χχΧ- % _N XX _F ~ ^p ' n 9-Ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indazol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3a] quinoxaline 67 4АХР n 1-Benzyl-7,9-difluoro-8-(5-fluoro- 3-methyl-1 H-indol-7-yl)-4,4dimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 68 Ϊ Г11 ⁿ v ⁿ %A^A ΧΧΧΤΓ / NF H H 1-Benzyl-7,9-difluoro-4,4dimethyl-8-(3-methyl-1H-indol7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 71 ^P^x >h /Xv-z ZI ^Xn 7,9-Difluoro-8-(5-fluoro-3-methyl1 H-indol-7-yl)-4,4-dimethyl-1 (pyridin-4-yl-methyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 72 rX X7 / II v-~ ²¹ xxm 7,9-Difluoro-4,4-dimethyl-8-(3methyl-1 H-indol-7-yl)-1(pyridin-4-yl-methyl)-5H[1,2,4]triazolo[4 ,3 a]quinoxaline 73 Ha ιζ II GL 7,9-Difluoro-8-(5-fluoro-3-methyl- 1 H-indol-7-yl)-4,4-dimethyl-1 (pyridin-3 -yl-methyl)-5H- [1,2,4]triazolo[4,3- a] quinoxaline

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74 o _F 1lX AND Η 7,9-Difluoro-8-(5-fluoro-3-methyl- 1 H-indol-7-yl)-4,4-dimethyl-1 (pyridin-2-yl-methyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 75 Vzi Hi 7,9-Difluoro-4,4-dimethyl-8-(3methyl-1 H-indol-7-yl)-1(pyridin-2-yl-methyl)-5H[1,2,4]triazolo[4 ,3 a]quinoxaline 80 Η 1 -(Cyclopropyl-methyl)-7,9difluoro-8-(1H-indol-7-yl)-4,4dimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 81 / \__~ZT Z I 1-Cyclopropyl-7,9-difluoro-8(1 H-indol-7-yl)-4,4-d-imethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 82 i O F^F 8-(3-Cyclopropyl-1H-indol-7yl)-1,4,4,9-tetramethyl-7(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 83 F °4 8-(6-Fluoro-1-methylsulfonyl1H-IID0L-4-IL)-1,4,4,9tetramethyl-7-(trifluoromethyl)5H-[1,2,4]triazolo[4,3a]quinoxaline

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84 cCvQxM / L ^{-F n} L 1,4,4,9-Tetramethyl-8-(1 methylsulfonyl-1 H-indol-4yl)-7-(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 85 XvVQla -ΧΧΧν- ^Ώ Η 9-Chloro-8-(3-cyclopropyl-1Nindol-7-yl)-7-fluoro-1,4,4trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 86 F Λ=6+ ^F IITu H 7-Fluoro-8-(1H-indol-7-yl)1,4,4-trimethyl-9- (trifluoromethyl)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 88 H 8-(1-Cyclopropyl-6-fluoro-1Nindol-4-yl)-7-fluoro-1,4,4trimethyl-9-(trifluoromethyl)5Н-[1,2,4]triazolo[4,3a]quinoxaline 200 cXuQ v XXX A r H 7,9-Difluoro-8-[1- (isopropylsulfonyl)-1Nindol-4-yl]-1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 201 &Y H 8-[ 1 -(Cyclopentylsulfonyl)- 1 H-indol-4-yl]-7,9-difluoro- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline

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202 K / K g 8-[ 1 -(Cyclopropyl-methyl)- 1Ηindol-4-yl]-7,9-difluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 203 .Uy. cm l° θα 7,9-Difluoro-1,4,4-trimethyl-8[ 1 -(tetrahydro-pyran-4ylsulfonyl)-1H-indol-4-yl]5H-[1,2,4]triazolo[4,3a]quinoxaline 204 Lr I YU W XX '= ^{/ GH} ' ^L / ^X NF H 7,9-Difluoro-8-[1 -(2-methoxyethyl)-1 H-indol-4-yl] -1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 205 κχ L’ Gr V 8-[ 1 -(Cyclopropylsulfonyl)- 1 H-indol-4-yl]-7,9-difluoro- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 207 F /-K Ϊ GU XT Ύ d' ^Hun Η 7,9-Difluoro-1,4,4-trimethyl-8[6-(trifluoromethyl)-1 H-indol-4yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 208 F /L 1 Gg Μ Λ JL Κ/ ^ΝΗ Η 7,9-Difluoro-8-(6-fluoro-1Nindol-4-yl)-1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline

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210 .zh to Χ-Χί 8-[1-(Cyclopropylmethylsulfonyl)-1H-indol-4yl]-7,9-difluoro-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 212 a ^W -L/ Ύχ/ 2-(4-(7,9-Difluoro-1,4,4- trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)- 1H-indol- 1 -yl]X,Xdimethyl-acetamide 213 / \ Ρ Η 1 - (4- (7,9-Difluoro-1,4,4- trimethyl-5H- [ 1,2,4]triazolo[4,3 - a]quinoxalin-8-yl)-1H-indol1-yl]-2-methoxy-ethanone 214 τ ^h\ 7,9-Difluoro-8-(5-fluoro-1Nindol-4-yl)-1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 219 ί Κι / XX ζ X Τ Η 3 -[4-(7,9-Difluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 - a]quinoxalin-8-yl)-1H-indol1-yl]-propionic acid methyl ester 221 „X already γΟ ² -Ж \ 7,9-Difluoro-1,4,4-trimethyl-8- (1-methyl-1 H-indazol-4-yl)-5H[1,2,4]triazolo[4,3 a]quinoxaline 222 .__// Κ \Γ zhL ΚΫ 7,9-Difluoro-1,4,4-trimethyl-8(2-methyl-2H-indazol-4-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline

I

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223 H 1-[4-(7,9-Difluoro-1,4,4- trimethyl-5H- [ 1,2,4]triazolo[4,3 - a]quinoxalin-8-yl)-1H-indol1-yl]-2-dimethylamino-ethanone 224 COOQ v H 7,9-Difluoro-8-(5-fluoro-1methylsulfonyl-1H-indol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 225 AND . 1ζΡ “Π 7,9-Difluoro-1,4,4-trimethyl-8[2-(trifluoromethyl)-1 H-indol-4yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 228 c<Λ ΠX, \Ζ \^--χ Η ΑΤ'' ADL V H 0 K-[2-[4-(7,9-Difluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-1H-indol1-yl]-ethyl]-carbamic acid tert-butyl ester 229 ! [GU khUU- _y , Η 0 K-[2-[4-(7,9-Difluoro-1,4,4trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-1H-indol1-yl] - ethyl]-2,2-d iffluoropropionamide

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230 /XIX VvXX X 1 T χχ\--ΝΗ ₂ H 2-[4-(7,9-Difluoro-1,4,4- trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-1H-indol1-yl]-ethyl amine 232 | ^Ν ·ν ^Ν ^^ΧχΛ T ΎΎ Xr LX^^X ^N H 7,9-Difluoro-8-(1H-indazol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 233 /ΛίΛ H 7,9-Difluoro-8-[ 1 -(2-methoxyethyl)-1H-indazol-4-yl]-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 234 >D X ^m Chl [1)=/ l° co 8-[ 1 -(Cyclopropylsulfonyl)- 1 H-ind azol-4-yl]-7,9-difluoro- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 235 Hi P. f% H 8-[ 1 -(Cyclopropyl-methyl)- 1Nindazol-4-yl]-7,9-difluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 236 ^χΌχ yXiy H 8-(1-Ethyl-1H-indazol-4-yl)7,9-difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 237 rX HH Xx 8-(2-Ethyl-2H-indazol-4-yl)7,9-difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3а]quinoxaline

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238 γγ-% 'Η 4-(7,9-Difluoro-1,4,4-trimethyl5Н-[1,2,4]triazolo[4,3- a]quinoxalin-8-yl)-1Nindazole-1-carboxylic acid tert-butyl ester 239 AchHOL. J 8-[ 1 -(Cyclopropylmethylsulfonyl)- 1H-indazol4-yl]-7,9-difluoro-1,4,4- trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 240 ^Ν χ Χγχχ —Ν Ν F Η 1-Ethyl-7-fluoro-4,4,9-trimethyl8-(1-methyl-1H-indazol-4-yl)5H-[1,2,4]triazolo[4,3a]quinoxaline 241 Ν— / ' X v ΪΎΤΑ N F Η 1-Ethyl-7-fluoro-4,4,9-trimethyl- 8-(1-methylsulfonyl-1Nindazol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 242 Λ γγ Ηί 8-(1-Cyclopropyl-1 H-indazol4-yl)-1-ethyl-7-fluoro-4,4,9trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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243 K1D d 11 U / - \ / - ^Ν Η 8-(1-Cyclopropyl-1 H-indazol4-yl)-7,9-d iftoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 244 1 -Ethyl-7-fluoro-8- (5 -fluoro-1Nindol-4-yl) -4,4,9-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 247 V ζ /=<J UCH \_--z ζ t XX—(X ^ζ 1 1-Ethyl-7-fluoro-4,4,9-trimethyl8-(1-methylsulfonyl-1Nindol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 248 U UCH °\ XLx^ H 7-Fluoro-9-methoxy-1,4,4- trimethyl-8-(1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 249 , __/ \___Z t νχ . V/4 Chi- 7-Fluoro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-9-methoxy-1,4,4trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 250 F v/ C 111 o, Wi* ⁷ Η 7-Fluoro-8-(6-fluoro-1 - methylsulfonyl-1 H-indol-4yl)-9-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3a]quinoxaline

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251 .Yak χχ “Π 9-Fluoro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-7-methoxy-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 252 Ha. 4.xXrP: um X ΤΊ 7-(Difluoro-methoxy)-9-fluoro1,4,4-trimethyl-8-[2- (trifluoromethyl)-1H-indol-4yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 253 u_ rp GT, ΪΓ 8-[1-(2,2-Difluoro-ethyl)- 1Nindol-4-yl]-7,9-difluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 254 X ί [Xi PT IP U/ ^{NH H} Xr ^F FF 7-Chloro-9-fluoro-1,4,4-trimethyl8-[2-(trifluoromethyl)-1H-indol4-yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 255 G <X l XI °\/° XXjCw% ^H 1 9-Fluoro-8-(6-fluoro-1- methylsulfonyl-1 H-indol-4yl)-7-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3а]quinoxaline 256 Ha RL cP I 9-Fluoro-8-(1H-indol-4-yl)-7methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline

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257 '4 SU - Gr /| X 9-Fluoro-7-methoxy-1,4,4- trimethyl-8-[2-(trifluoromethyl)1H-indol-4-yl]-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 258 4 g XI X χΧ'Γ ^/Ν '^- ^όη ' Η 2-[4-(7,9-Difluoro-1,4,4trimethyl-5H[1,2,4]triazolo[4,3a]quinoxalin-8-yl)-1Nindazol-1-yl]-ethanol 259 RRi 4 7-(Difluoro-methoxy)-9-fluoro-8[ 1 -(2-methoxy-ethyl)-2(trifluoromethyl)-1 H-indol-4yl]-1,4,4-trimethyl-5H[ 1 ,2,4]triazolo[4,3a]quinoxaline 260 H 4-(7-Fluoro-9-methoxy-1,4,4trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)- 1H-indol- 1-carboxylic acid tert-butyl ester 263 %/ 0^ O_/W W' 9-Fluoro-7-methoxy-1,4,4- trimethyl-8-(1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 264 Chd t z ^z ^\ /=\1 XX 'Ul rw g 7-Fluoro-9-methoxy-1,4,4trimethyl-8-(1-methyl-1Nindazol-4-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline

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266 ^H1 9-Fluoro-7-methoxy-1,4,4trimethyl-8-(3-methyl-1H-indol7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 267 Pl zz z-A O\ rA T) 7-(Difluoro-methoxy)-9-fluoro-8(5-fluoro-3-methyl-1 H-indol-7yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3a]quinoxaline 268 F »cClZk w Л ΪΎ X/Λ ^|\T ^H 1 7-(Difluoro-methoxy)-9-fluoro-8(6-fluoro-1-methylsulfonyl-1Nindol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3a]quinoxaline 269 ^/N ^ Ϊ 41 χόδ> ^H 1 9-Fluoro-7-methoxy-1,4,4trimethyl-8-(1-methyl-1Nindazol-4-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline 270 Χχ /L / ΙχΛ 7-Fluoro-9-methoxy-1,4,4trimethyl-8-(3-methyl-1H-indol7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 271 Lml< n /V ^F FF 7,9-Difluoro-1,4,4-trimethyl-8[1-methylsulfonyl-2(trifluoromethyl)-1H-indol-4yl]-5H-[1,2,4]triazolo[4,3а]quinoxaline

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272 /y ⁷ ϊ YY X d Y X/ Λΐ\Γ Η 7-Chloro-9-fluoro-1,4,4-trimethyl8-(3-methyl-ΙΗ-indol-7-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline 273 \ /L /K J Λα M / g 7-(Difluoro-methoxy)-9-fluoro- 1,4,4-trimethyl-8-(1-methyl-1Nindazol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 275 D1D v HGd ^{x n} L 7-(Difluoro-methoxy)-9-fluoro- 1,4,4-trimethyl-8-(1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 276 F Lchgl Λ\ _Ν Λ\^Λ _Ρ — ^Ν Η 7,9-Difluoro-8-(6-fluoro-1- methyl sulfonyl-1 H-indazol-4yl)-1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 277 DH AL ' TO J=o and 7-Chloro-9-fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a ]quinoxaline 278 L I Λ τχΓ- Η 7-Fluoro-8-[1-(2-methoxy-ethyl)1H-indol-4-yl]-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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279 F W d -a G Ύ χ X/ ^N ^ ^x Η 7-Fluoro-8-(6-fluoro-1 - methyl sulfonyl-1 H-indazol-4yl)-1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 - a] quinoxaline 280 Χχχχ /ХМ' Η 7-Chloro-9-fluoro-8-[ 1 -(2-methoxyethyl)-1 H-indol-4-yl] -1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 281 _o / /=0 χχ /°Х ZX XX 7-Fluoro-9-methoxy-8-[1-(2methoxy-ethyl)-1H-indol-4-yl]1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3a]quinoxaline 282 / HN XXX χχχχ λ F F 7-(Difluoro-methoxy)-9-fluoro- 1,4,4-trimethyl-8-(3-methyl-1Nindol-7-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 283 F X lii VvVvLΧΧΧΎΧ N H 'H 9-Fluoro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3а]quinoxaline 284 / ^N X Ϊ xx ⁱⁿ XX V ⁰ XIXX ^x X/XSi ' H 7-Chloro-9-fluoro-1,4,4-trimethyl8-(1-methylsulfonyl-1Nindol-4-yl)-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline

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285 Cl 'H 7-Chloro-9-fluoro-1,4,4-trimethyl8-(1-methyl-1H-indazol-4-yl)5H-[1,2,4]triazolo[4,3a]quinoxaline 286 /=( L' Hi ZZ H 7-Fluoro-8-(1 H-indol-4-yl)-9methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 287 i I Z Z--'\ 0Z 0=/ o / 7-(Difluoro-methoxy)-9-fluoro-8[ 1 -(2-methoxy-ethyl)-1 H-indol4-yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo [4,3 a]quinoxaline 288 No. 0z^ "°zi 0=/ o Z 9-Fluoro-7-methoxy-8- [ 1 -(2methoxy-ethyl)-1H-indol-4-yl]- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 289 z-um '0 Oh / 7,9-Difluoro-8-[ 1 -(2-methoxyethyl)-2-(trifluoromethyl)-1Nindol-4-yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo[4 ,3 a]quinoxaline 290 FZZ- 'H 7-Chloro-9-fluoro-8-(5-fluoro-3 methyl-1 H-indol-7-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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292 .TA 04 O Z 9-(Difluoro-methyl)-7-fluoro-8-[ 1 (2-methoxy-ethyl)-1 H-indol-4yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo [4,3 a]quinoxaline 293 /Ύ ί if% Хх5Х=/ ⁿ ' n 7-Chloro-9-fluoro-8-( 1 H-indol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 294 ,>A YY th / 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(1-methyl-1Nindazol-4-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline 295 ⁿ /f 7-(Difluoro-methyl)-9-fluoro-8-[ 1 (2-methoxy-ethyl)-1 H-indol-4yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo [4,3 a]quinoxaline 296 / HN YZm ^f n 1 F 7-(Difluoro-methyl)-9-fluoro-8-(5fluoro-3-methyl-1 H-indol-7-yl)1,4,4-trimethyl-5H[ 1,2,4]triazolo[4 ,3 a]quinoxaline 297 »COjOl -ΧΧχΎΥ ν ρ ^Η λ FF 7-(Difluoro-methoxy)-9-fluoro-8(1 H-indol-4-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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298 Well UZH / A / O 7-(Difluoro-methyl)-9-fluoro-8-(6fluoro-1-methylsulfonyl-1Nindol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3a]quinoxaline 299 1 MJ ΣΕ Z Ζ--A (GJ 1 -Ethyl-7-fluoro-8- [ 1 - (2-methoxyethyl) -1 H-indol-4-yl] -4,4,9trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 302 / fA HN JL / ^ν Ά ι Υη Х'А' H 9-(Difluoro-methyl)-7-fluoro-8-(5fluoro-3-methyl-1 H-indol-7-yl) 1,4,4-trimethyl-5H[ 1,2,4]triazolo[4, 3a]quinoxaline 306 / H. N. J. y® η 1 F 7-(Difluoro-methyl)-9-fluoro-1,4,4trimethyl-8-(3-methyl-1H-indol7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 309 d _r Ae A \ H 1,4,4,7,9-Pentamethyl-8-( 1 methylsulfonyl-1 H-indol-4yl)-5H-[ 1,2,4]triazolo[4,3 a]quinoxaline 310 7-Methoxy-1,4,4-trimethyl-8-(1 methylsulfonyl-1H-indol-4yl)-9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3a]quinoxaline

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312 XU n / X ^F FF 8-[1-Cyclopropyl-2(trifluoromethyl)-! N-indol-4yl]-7,9-difluoro-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 313 W H 7-Chloro-8-[1-(2,2-difluoro-ethyl)1H-indol-4-yl]-9-fluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 314 8-[ 1 - (2,2-Difluoro-ethyl) - 1H- indol-4-yl]-9-fluoro-7-methoxy- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 315 H 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 317 X. yy ^Ω Jy already K° Λ 7-Chloro-1,4,4,9-tetramethyl-8-(1 methylsulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 318 uh - XX K uh F y° 7-(Difluoro-methoxy)-1,4,4,9- tetramethyl-8-(1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline

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319 Η 9-(Difluoro-methyl)-7-fluoro-8(1 H-indol-4-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 320 Χα ΟΧ ⁷ ΥJ Χ/\ 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(3-methyl-1H-indol7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 321 XX X Ζ Ζ--Η. (γ χΧ χΜ Χ° A 9-Fluoro-1,4,4,7-tetramethyl-8-(1methylsulfonyl-1H-indol-4yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 324 ~0χΧ DHdL^A Η 8-[1-(2,2-Difluoro-ethyl)- 1Nindol-4-yl]-1,4,4,7,9pentamethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 325 ί ίΓΑ χόΧ FT U-F η 1 F 7-(Difluoro-methyl)-9-fluoro-1,4,4trimethyl-8-(1-methyl-1Nindazol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 327 Η 7-Chloro-8-[1-(2,2-difluoro-ethyl)1H-indol-4-yl]-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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328 УУ J x ζ ζ—Ч UD 0=^ \ /° Y) 8-(6-Fluoro-1-methylsulfonyl1H-indol-4-yl)-1,4,4,7,9pentamethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 329 y/ \ /=O λ--/ o— huuu Chguu 8-(6-Fluoro-1-methylsulfonyl1H-indol-4-yl)-7-methoxy1,4,4-trimethyl-9- (trifluoromethyl)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 330 ssihu xxx and N F H 8-[1-(2,2-Difluoro-ethyl)- 1Nindol-4-yl]-7-fluoro-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 331 1 r^J x ζ ζ—X YX 0= ⁷ ; 8-[ 1 -(2-Methoxy-ethyl)- 1Nindol-4-yl]-1,4,4,7,9pentamethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 332 F XdX 9-Fluoro-8-(6-fluoro-1- methylsulfonyl-1 H-indol-4yl)-1,4,4,7-tetramethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 333 χχχ V0 ^Ω Jv Г)=/ X° L 7-Chloro-8-(6-fluoro-1- methylsulfonyl-1 H-indol-4yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline

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334 // ''ή ΣΕ Ζ Ζ-^\ 0= ⁷ > ο / 7-Methoxy-8-[1-(2-methoxyethyl)-1H-indol-4-yl]-1,4,4trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4, 3a]quinoxaline 335 - wow 4~° Uo V η 7-(Difluoro-methoxy)-8-(6-fluoro- 1-methylsulfonyl-1 H-indol-4yl)-1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 336 ^Η 1 F^T 7-(Difluoro-methoxy)-8-[ 1 -(2methoxy-ethyl)-1H-indol-4-yl]1,4,4,9-tetramethyl-5H[ 1,2,4]triazolo[4,3 a] quinoxaline 337 /ίX ΧΧχΧΧ-Α Η 9-Fluoro-8-[1-(2-methoxy-ethyl)- 1 H-indol-4-yl]-1,4,4,7 tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 338 XX- 'Η 7-Chloro-8-[1-(2-methoxy-ethyl)- 1 H-indol-4-yl]-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 339 F / Ί ό XpXuX° “ΓΑ Η 7-Fluoro-8-(6-fluoro-1 - methylsulfonyl-1 H-indazol-4yl)-9-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3a]quinoxaline

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341 ζχ 8-(5-Fluoro-3-methyl-1H-indol-7yl)-1,4,4,7,9-pentamethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 342 zz ZzZ _F H 7-Fluoro-9-methoxy-1,4,4- trimethyl-8-(1- methyl sulfonyl-1 H-indazol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 343 z^ Ϊ УУ χπχ H 1 F 7-(Difluoro-methyl)-9-fluoro-8(1 H-indol-4-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 344 zz 1 7-Methoxy-8-[1-(2-methoxyethyl)-1 H-indol-4-yl]-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 345 z00 0 00-- 8-(5-Fluoro-3-methyl-1 H-indol-7 yl)-7-methoxy-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 346 %IXK V Y YYXX -7\ -N / No. F H 9-(Difluoro-methyl)-7-fluoro-8-(6fluoro-1-methylsulfonyl-1Nindazol-4-yl)-1,4,4-trimethyl5H-[1.2.4]triazolo[4.3а ]quinoxaline

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347 V oY /=< J XT _o UCH Ύ 7-Chloro-8-(6-fluoro-1 - methyl sulfonyl-1 H-indazol-4yl)-1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 - a] quinoxaline 348 1 r^l X Z Str Zy=/ l 1 -Ethyl-7-fluoro-8-(6-fluoro-1 methylsulfonyl-1 H-indazol-4yl) -4,4,9-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 351 F XCO n 7-Fluoro-8-[6-fluoro-1 -(2-methoxyethyl)-1 H-indol-4-yl] -9methoxy-1,4,4-trimethyl-5H[ 1,2,4]triazolo[ 4,3 a]quinoxaline 353 _Ι γχ <χχ υυ g ¹ o 9-Fluoro-8-[6-fluoro-1 -(2-methoxyethyl)-1 H-indol-4-yl] -7 methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo [4,3 a]quinoxaline 354 Ν—-/ p L?1 ^/ \ III / F H H 7,9-Difluoro-1,4,4-trimethyl-8(3-methyl-1H-indazol-7-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline 356 Υ ι P X χχΥΥ / tg n n 1,4,4,7,9-Pentamethyl-8-(3methyl-1 H-indol-7-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline

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357 F / F ₄ 1 L / X / L । Lx ^N vXX\XXX\ -XXX lt / N O H ^H 1 7-Methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3a]quinoxaline 358 K1A ί XXix / A Cl H H 7-Chloro-1,4,4,9-tetramethyl-8-(3- methyl-1 H-indol-7-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 359 _N /=f ί jQ XxLi H 9-Fluoro-1,4,4,7-tetramethyl-8-(3- methyl-1 H-indol-7-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 360 cOjCi 4 XX u / N O H ^H 1 F^^ 7-(Difluoro-methoxy)-1,4,4,9tetramethyl-8-(3-methyl-1Nindol-7-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 361 +X 1 O XX 'H 7-Fluoro-1,4,4,9-tetramethyl-8-(3 methyl-1 H-indazol-7-yl)-5H[1,2,4]triazolo[4,3а]quinoxaline 362 F ΑχΛν /For A > H 8-[1-(Ethylsulfonyl)-b-fluoro1H-indol-4-yl]-7-fluoro-9methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline

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363 F OSdlZl and / N - Cl Η 'Η 7-Chloro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 364 ΛΛνΛ· 9-Fluoro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-1,4,4,7-tetramethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 365 Ε ΛύΧλΧ / Ν 0 Η ^Η 1 F^^F 7-(Difluoro-methoxy)-8-(5-fluoro- 3 -methyl-1 H-indol-7-yl)- 1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 367 ~<Y +11 ΛΛ / Ν F Η Η 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(3-methyl-1Nindazol-7-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 368 dx st ° ml 7lm 7-Chloro-1,4,4,9-tetramethyl-8-(3methyl-1 H-indazol-7-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline 369 LAa / th | 8-[1-(Ethylsulfonyl)-b-fluoro1H-indol-4-yl]-7-methoxy- 1,4,4-trimethyl-9(trifluoromethyl)-5Н[1,2,4]triazolo[4,3a]quinoxaline

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370 F XXX Η 8-[1-(Ethylsulfonyl)-b-fluoro1H-indol-4-yl]-7-fluoro-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 371 vX-G ν MM) ⁿ 1 8-[1-(Ethylsulfonyl)-1Nindol-4-yl]-7-methoxy-1,4,4trimethyl-9-(trifluoromethyl)5Н-[1,2,4]triazolo[4,3a]quinoxaline 372 MjM 'Η 8-[1-(Ethylsulfonyl)-1Nindol-4-yl]-7-fluoro-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 373 Έ ^ν ννχ£χ γ° ' Η 8-(6-Fluoro-1-methylsulfonyl1 H-indazol-4-yl)-1,4,4,7,9pentamethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 376 I z z-^z. umg -Ο X—y /χ [1 \=/ η 8-(6-Fluoro-1-methylsulfonyl1H-indazol-4-yl)-7-methoxy1,4,4-trimethyl-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3 a]quinoxaline 377 ΧχΠ m mmm MM Ai Η 7-Fluoro-1,4,4,9-tetramethyl-8-(1methylsulfonyl-1H-indazol-4yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline

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379 F Η a Ια TYYua n 1 2-[6-Fluoro-4-(9-fluoro-7-methoxy1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)- 1H-indol- 1-yl]-ethanol 380 τ about ? /=<Jf v/Ch ιΡ\ 2-[6-Fluoro-4-(7-fluoro-9-methoxy1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)- 1H-indol- 1-yl]-ethanol 381 lu ⁷ 4 PP ϊνν / Τ Η Η 7-Fluoro-9-methoxy-1,4,4trimethyl-8-(3-methyl-1Nindazol-7-yl)-5H[1,2,4]triazolo[4,3a]quinoxaline 382 44 ΑΛΑ Η 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(1- methylsulfonyl-1 H-indazol-4yl)-5H-[ 1,2,4]triazolo[4,3 - a] quinoxaline 383 4 ί Π ls4< Η [2-[4-(7,9-Difluoro-1,4,4- trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-1H-indol1-yl]-ethyl]-dimethylamine 384 4^ Η “L / 4 8-[1-(2,2-Difluoro-ethyl)-1Nindol-4-yl]-7-(difluoromethoxy)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3а ]quinoxaline

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385 /Y ⁷ j A y y T XK^u H / > 2-[4-[7-(Difluoro-methyl)-9-fluoro1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxalin-8-yl]-6-fluoro-1Nindol-1-yl]-ethanol 386 sssh v YyCX ^x 7-Chloro-1,4,4,9-tetramethyl-8-(1methylsulfonyl-1H-indazol-4yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 387 Y ξ/\/Χχ ^{N n} 1 7-Methoxy-1,4,4-trimethyl-8-(1 methylsulfonyl-1 H-indazol-4yl)-9-(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 388 at / N n 1,4,4,7,9-Pentamethyl-8-(1methylsulfonyl-1H-indazol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 390 YX n 9-(Difluoro-methyl)-7-fluoro-8-(6fluoro-1-methylsulfonyl-1Nindol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3a]quinoxaline 392 /A | ίΧ XXJJ /Ν\Ζ\F Η 8-[1-(2,2-Difluoro-ethyl)- 1Nindol-4-yl]-9-fluoro-1,4,4,7tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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393 Λ ί (Π Xft 8-[1-(2,2-Difluoro-ethyl)- 1Nindol-4-yl]-7-(difluoromethoxy)-9-fluoro-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 394 / Y 0 η Ι F I 7-(Difluoro-methoxy)-9-fluoro-8[6-fluoro-1 -(2-methoxy-ethyl)-1Nindol-4-yl]-1,4,4-trimethyl-5Н[ 1,2,4 ]triazolo[4,3a]quinoxaline 395 X Ml \__Z Z X 2-[4-[7-(Difluoro-methoxy)-9fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 - a]quinoxalin-8-yl]-6-fluoro-1Nindol-1-yl]-ethanol 396 F diA n 1 F 7-(Difluoro-methyl)-9-fluoro-8-[6fluoro-1 -(2-methoxy-ethyl)-1Nindol-4-yl]-1,4,4-trimethyl-5H[ 1,2,4] triazolo[4,3a]quinoxaline 397 F already GJ ^z ^z -p 8-[ 1 - (2,2-Difluoro-ethyl) - W- indol-4-yl]-7-fluoro-9-methoxy- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 398 us uiL [G0 8-[1-(2,2-Difluoro-ethyl)-1Nindol-4-yl]-9-(difluoro-methyl)7-fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo [4,3 a]quinoxaline

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399 ClAAA t Ια Α/ ^η η 7-Fluoro-8-( 1 H-indol-4-yl)- 1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 400 AM g 9-(Difluoro-methyl)-7-fluoro-8-[ 1 (isopropylsulfonyl)-1Nindol-4-yl]-1,4,4-trimethyl-5H[1.2.4]triazolo[4.3а] quinoxaline 401 α^ιΜ^αα 'Ya H 8-[1-(Cyclopropylsulfonyl)1H-indol-4-yl]-9-(difluoromethyl)-7-fluoro-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 402 / A / F Λ N—/ Y A Zh1 ItA- H 9-(Difluoro-methyl)-7-fluoro-8-[6fluoro-1 -(2-methoxy-ethyl)-1Nindol-4-yl]-1,4,4-trimethyl-5Н[ 1,2,4] triazolo[4,3a]quinoxaline 403 A* H γί | t F 8-(6-Fluoro-1-methylsulfonyl1H-indol-4-yl)-1,4,4,9tetramethyl-7- (trifluoromethyloxy)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 404 F Ya Λ Ityxa_^ YM ^x 7-Chloro-9-fluoro-8-[6-fluoro-1 -(2methoxy-ethyl)-1H-indol-4-yl]1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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405 XX IZ O ^- : % fX A ¥0/ 1,4,4,9-Tetramethyl-8-(3-methyl- 1 H-indol-7-yl)-7(trifluoromethyloxy)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 406 / ^HN \ sssh XXX ' h F 8-(5-Fluoro-3-methyl-1H-indol-7yl)-1,4,4,9-tetramethyl-7(trifluoromethyloxy)-5H[1,2,4]triazolo[4,3a] quinoxaline 407 lXX Λ 8-(5-Fluoro-3-methyl-1H-indol-7yl)-7-methoxy-1,4,4-trimethyl9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3 a ]quinoxaline 445 /X 1 X ν ^Ν ΖΜχ\ 4ΪΙ W ^H ' Η 7,9-Difluoro-8-(1H-indol-4-yl)1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 447 Η 2-[6-Fluoro-4-[7-fluoro-1,4,4trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3- a]quinoxalin-8-yl]-1H-indol1-yl]-ethanol 448 0Xr Η 8-[1-(Ethylsulfonyl)-6-fluoro1H-indazol-4-yl]-7-fluoro-1,4,4trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3a] quinoxaline

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449 Η 2-[6-Φτορ-4-[7-φτορ-1,4,4trimethyl-9-(trifluoromethyl)5Н-[1,2,4]triazolo[4,3a]quinoxalin-8-yl]-1Ηindazol-1 -yl]-ethanol 451 ΑΧ- Η 2-[6-Fgor-4-(1,4,4,9- tetramethyl-5H[1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-1H-indol1-yl]-ethanol 452 F /Ο ιΡ ^m pA\A\X%X\ X ΎΎ X/ Η 8-(5-Fluoro-3-methyl-1 H-indol-7 yl)-1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 453 1 Ar 1 |Τ1 ⁰ Ο /X AL γ° ςσΓ 1 I 8-(6-Fluoro-1-methylsulfonyl1 H-indol-4-yl)-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 454 1 1 /XX 0 ^ν Χ ^ν Ο^ΧΧ χ° X ΎΎ X/ ⁴ χχ^ 7-Fluoro-8-(6-fluoro-1 - methyl sulfonyl-1 H-indazol-4yl)-1,4,4-trimethyl-9- (trifluoromethyl)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 455 8-[1-(Ethylsulfonyl)-1Nindol-4-yl]-7-fluoro-1,4,4trimethyl-9-(trifluoromethyl)5Н-[1,2,4]triazolo[4,3a]quinoxaline

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456 X id xX 2-[4-[7-Fluoro-1,4,4-trimethyl-9- (trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 - a]quinoxalin-8-yl]-1H-indol1-yl]-ethanol 457 Md G\=/ A L 1,4,4,9-Tetramethyl-8-( 1 - methylsulfonyl-1 H-indazol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 458 e ιζ ζ^Λ. With γ* L/=0 τι 8-(5-Fluoro-3-methyl-1H-indol-7yl)-1,4,4,9-tetramethyl-7(trifluoromethyloxy)-5H[1,2,4]triazolo[4,3 a ]quinoxaline 459 F l G Λ D XX D Ν O/ \ _{0 Η} ^Η 1 8-(5-Fluoro-3-methyl-1 H-indol-7 yl)-7-methoxy-1,4,4-trimethyl9-(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 460 Λ I Λ Λ/c ALD 1shD ΊΨ XT ^F Η GC F 8-[ 1 - (2-Methoxy-ethyl) - 1H- indol-4-yl]-1,4,4,9-tetramethyl- 7-(trifluoromethyloxy)-5Н- [1,2,4]triazolo[4,3- a] quinoxaline 461 AXAja n 9-(Difluoro-methyl)-8-[ 1 - (ethylsulfonyl)- 1H-indol-4yl]-7-fluoro-1,4,4-trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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462 yX Η 9-Cyclopropyl-7-fluoro-1,4,4trimethyl-8-(1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 463 / X^-z X xX . x~O Xu 9-Cyclopropyl-7-fluoro-1,4,4trimethyl-8-(3-methyl-1H-indol7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 464 F /U T ιΓί Xu H 7-Fluoro-8-(6-fluoro-1H-indol-4yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 465 ft (χ X /% 1,4,4,9-Tetramethyl-8-( 1 methylsulfonyl-1 H-indol-4yl)-7-(trifluoromethyloxy)-5H[1,2,4]triazolo[4,3 a]quinoxaline 466 ΗΎ Λ ^Νχ ν^\ΧΑΑ JU and ⁿ H 9-(Difluoro-methyl)-7-fluoro-8-(6fluoro-1 H-indol-4-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 467 F /X X Χί uu H 7-Fluoro-8-(1H-indol-4-yl)1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

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468 Η 7-Fluoro-8-(6-fluoro-1H-indol-4yl)-9-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 469 -υΥλΔ αΧΧΥΥ'' η Υ ^{f F} F ^F 8-[1-(2,2-Difluoro-ethyl)-6-fluoroIII-indazol-4-yl]-1,4,4,9tetramethyl-7- (trifluoromethyloxy)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 470 F /γ/ ι fiX ΎΎ Υ Υ 4 JO γ/ ^ΝΗ H 7-Fluoro-1,4,4,9-tetramethyl-8-[6(trifluoromethyl)-1 H-indol-4yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 471 I Y A Λ ^ΪΤό^ ' γ- ^ Υχ .F H [\ F 2-[6-Fgor-4-[1,4,4,9- tetramethyl-7- (trifluoromethyloxy)-5H- [ 1,2,4]triazolo[4,3 - a]quinoxalin-8-yl]-1H-indol- 1 -yl]-ethanol 472 F aYY Λ Y^K/wY H 8-[1-(2,2-Difluoro-ethyl)-6-fluoro1 H-indazol-4-yl]-9-(difluoromethyl)-7-fluoro-1,4,4-trimethyl5H-[1,2, 4]triazolo[4,3a]quinoxaline 473 F Y ^F Y ιΓί ^ν αΖ\Υ\ΧΎΥ Ο ΪΎ O ^NH Z ^FF ^F H 7-Fluoro-1,4,4-trimethyl-9(trifluoromethyl)-8-[6(trifluoromethyl)-1 H-indol-4yl]-5H-[1,2,4]triazolo[4,3a] quinoxaline

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474 Αχ nAh ^z t 7-Fluoro-9-methoxy-1,4,4- trimethyl-8-[6-(trifluoromethyl)- 1H-indol-4-yl]-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 475 F 1 Γί 0 TXw ^H H 7-Chloro-1,4,4,9-tetramethyl-8-[6(trifluoromethyl)-1H-indol-4yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 476 SA H 7-Fluoro-1,4,4-trimethyl-8-(6methyl-1-methylsulfonyl-1Nindol-4-yl)-9-(trifluoromethyl)5Н-[1,2,4]triazolo[4,3a]quinoxaline 477 Αζώ YHdA^ / V F H 7-Fluoro-9-methoxy-1,4,4trimethyl-8-(6-methyl-1methylsulfonyl-1H-indol-4yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 478 yaU / ^χ ν Α/ \ _F H 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(6-methyl-1- methyl sulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 479 _F l( X ^F X 0 'Ά\Α AA X XX Xz H 4-[7-Fluoro-1,4,4-trimethyl-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3 - a]quinoxalin-8-yl]- 1H-indole6-carbonitrile

- 161 043276

480 No. ' ^Z ^2L J 8-[6-Fluoro-1-(2-methoxy-ethyl)1H-indazol-4-yl]-1,4,4,9tetramethyl-7(trifluoromethyloxy)-5H[1,2,4]triazolo[4, 3a]quinoxaline 481 LL, X 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl-8-(1-methyl-1 H-indol4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 482 ^N L L LL \ /d XXI / N O Η n I 8-(3-Cyclopropyl-5-fluoro-1Nindol-7-yl)-7-methoxy-1,4,4trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3a]quinoxaline 483 ld” Lud Chl 8-(3-Cyclopropyl-5-fluoro-1H- indol-7-yl)-7-fluoro-9-methoxy- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 484 F / K ,F .F Hol H 7-Fluoro-8-(7-fluoro-1- methylsulfonyl-1 H-indol-4yl)-1,4,4-trimethyl-9- (trifluoromethyl)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 485 w /4 ^Ω lX_. xz-\ / 7-Chloro-8-(3-cyclopropyl-5fluoro-1H-indol-7-yl)-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

- 162 043276

486 uch uch hu 7-Fluoro-1,4,4,9-tetramethyl-8-( 1 methyl-1 H-indol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 487 JOSU XXX n 7-Fluoro-9-methoxy-1,4,4trimethyl-8-(1-methyl-1H-indol4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 488 । A Ah, ^ooo n 7-Chloro-1,4,4,9-tetramethyl-8-(1- methyl-1 H-indol-4-yl)-5H[1,2,4]triazolo[4,3 a]quinoxaline 489 XXu guA X -η 8-[1-(2,2-Difluoro-ethyl)-6-fluoro- 1 H-ind azol-4-yl]-7,9-difluoro- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline 490 yuuh PM 1 X a /\X\ -~ ^N n 7-Fluoro-8-(1H-indazol-4-yl)-9methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 491 / y ⁷ | Y o XXXSU n 7-Chloro-1,4,4,9-tetramethyl-8-(6methyl-1-methylsulfonyl-1Nindol-4-yl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

- 163 043276

492 ί g X μ χ 1 A. A ν MCA Η 7,9-Difluoro-1,4,4-trimethyl-8(6-methyl-1-methylsulfonyl1H-indol-4-yl)-5H[1,2,4]triazolo[4,3 a]quinoxaline 493 χΧχΟ\ μ AZ ^{w 4} Η 7-Fluoro-1,4,4,9-tetramethyl-8-(6- methyl-1 -methylsulfonyl-1Nindol-4-yl) -5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 494 Η 4-(7-Fluoro-1,4,4,9-tetramethyl- 5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl)- 1H-indole6-carbonitrile 495 X D Χλ Α ΧΖΧ ι 8-[ 1 - (Cyclopropyl- methylsulfonyl)-1H-indol-4yl]-7-fluoro-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 496 Ο\ ΞΕ 9-(Difluoro-methyl)-7-fluoro-8-(7fluoro-1 H-indol-4-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

- 164 043276

497 No. (O ^m St OCH I 7,9-Difluoro-8-(7-fluoro-1 Hindol-4-yl)- 1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 498 VXjQ a Google H 1,4,4-Trimethyl-8-( 1 - methyl sulfonyl-1 H-indol-4yl)-9-(trifluoromethyl)-5H[1.2.4]triazolo[4.3- a] quinoxaline 499 FFI /F ₄ I /FA^ r/ T ill ° 44^4444 40 uklRU ⁴ H 8-(6-Fluoro-1-methylsulfonyl- 1 H-indol-4-yl)-1,4,4-trimethyl9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3 a]quinoxaline 500 4 La'cP TI 8-[1-(2,2-Difluoro-ethyl)-1Nindol-4-yl]-7-methoxy-1,4,4trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[4, 3a]quinoxaline 501 X/V Hj v/v chl 7,9-Difluoro-8-(7-fluoro-1Nindazol-4-yl)-1,4,4-trimethyl5Н-[1,2,4]triazolo[4,3а]quinoxaline 502 №№ > i№ 2 8-[ 1 - (Cyclopropylmethylsulfonyl) - 1H-indol-4yl] -9- (d iftor-methyl) -7-fluoro- 1,4,4-trimethyl-5Н- [ 1,2,4]triazolo[4,3 a]quinoxaline

- 165 043276

503 νγχχχχ ACOiX Η Η 1,4,4-Τ rimethyl-8-(3-methyl-1Nindol-7-yl)-9-(trifluoromethyl)5H-[1,2,4]triazolo[4,3a]quinoxaline 504 A ι AT χΧ Η 7-Fluoro-8-(7-fluoro-1H-indol-4yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3а]quinoxaline 505 χχχχχ Η 7-Fluoro-8-(7-fluoro-1H-indol-4yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3a]quinoxaline 506 A ι ΓΛ X XX Χχ η 7-Chloro-8-(7-fluoro-1 H-indol-4yl)-1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 507 αΑΛ X XX XX η 8-(5-Fluoro-3-methyl-1 H-indol-7 yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 508 F /X ί A Τ Τι Hsu ΖΧ-'Χ - Ν / ClF Η 7-Chloro-8-[1-(2,2-difluoro-ethyl)6-fluoro-1 H-indazol-4-yl] -9fluoro-1,4,4-trimethyl-5H[ 1,2,4 ]triazolo[4,3a]quinoxaline

- 166 043276

509 l l l yes ⁿ 1 7-Methoxy-1,4,4-trimethyl-8-(1 methyl-1 H-indol-4-yl)-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3 a]quinoxaline 510 X 1 l ^m f ^s \ Azh \ A \ 1 Ud LJ \ -N N 7-Fluoro-8-( 1 H-indazol-4-yl)- 1,4,4,9-tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 511 CI AlLH hahh? n 8-(6-Chloro-1H-indol-4-yl)-7,9difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 512 .zh i) Ji—O AND 9-(Difluoro-methyl)-7-fluoro-1,4,4trimethyl- 8 -(7-methyl-1 methylsulfonyl-1 H-indol-4yl)-5H-[1,2,4]triazolo[4 ,3 a]quinoxaline 513 CI LH n 8-(6-Chloro-1 H-indol-4-yl)-7 fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 514 /K A LJ / , LJ 'n 8-(1-Cyclopropyl-1 H-indol-4yl)-9-(difluoro-methyl)-7-fluoro- 1,4,4-trimethyl-5Н- [1,2,4]triazolo[4,3a]quinoxaline

- 167 043276

515 Ηγ Λ γχχ γ Η 9-(Difluoro-methyl)-7-fluoro-8-(5φτορ-1 H-indol-7-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 516 Η 7-Fluoro-8-(5-fluoro-1H-indol-7yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 517 Μ ° )—< γυ ΐ 8-(6-Fluoro-1-methyl-1H-indol-4yl)-7-methoxy-1,4,4-trimethyl9-(trifluoromethyl)-5Н[1,2,4]triazolo[4,3 a ]quinoxaline 518 1 UCH m 7-Fluoro-8-(6-fluoro-1-methyl-1Nindol-4-yl)-1,4,4,9-tetramethyl5Н-[1,2,4]triazolo[4,3 a]quinoxaline 519 F Y ΐ (Γί and UxUCH ¹ Η 7-Chloro-8-(6-fluoro-1-methyl-1Nindol-4-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3 a]quinoxaline 520 F γγ ΧΧΧΜ ¹ Η 9-Fluoro-8-(6-fluoro-1-methyl-1Nindol-4-yl)-1,4,4,7-tetramethyl5H-[1,2,4]triazolo[4,3a]quinoxaline

- 168 043276

521 F γγ A VvmyA Xux ¹ Η 9-(Difluoro-methyl)-7-fluoro-8-(6φτορ-1-methyl-1 H-indol-4-yl)1,4,4-trimethyl-5H[ 1,2,4]triazolo[4 ,3 a]quinoxaline 522 Mother 1 8-(6-Fluoro-1-methyl-1H-indol-4yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3a]quinoxaline 523 >γ ..............γ _ο ^ζ \--zh Λ 8-(1-Cyclopropyl-1 H-indol-4yl)-7-methoxy-1,4,4-trimethyl9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3a]quinoxaline 524 /A ι ΜΥ αΓ ΪΎ Xr AM ΜΑΜΑ -ν Η 7-Fluoro-8-(7-fluoro-1H-indazol4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3a]quinoxaline 525 / ΥΙ /μο ΜΥΜ muam^y Η 8-(7-Chloro-1-methylsulfonyl- 1 H-indol-4-yl)-7-fluoro-1,4,4,9tetramethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 526 κχΛ * Υ Xju^° Η 9-(Difluoro-methyl)-8-(6-fluoro-1methylsulfonyl-1 H-indol-4yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3a] quinoxaline

- 169 043276

527 Z αχά _Η Η 9-(Difluoro-methyl)-8-(5-fluoro-3methyl-1 H-indol-7-yl)-1,4,4trimethyl-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 528 A / \ D X Ζ \ζΜ Oud 9-(Difluoromethyl)-1,4,4trimethyl-8-(1- methylsulfonyl-1H-indol-4yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 529 _ X ο ζ ν/κ Μ 8-(7-Chloro-1H-indol-4-yl)-7,9difluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 a]quinoxaline 530 γγ dss xxdo Ν F Η 8-(7-Chloro-1 H-indol-4-yl)-7 fluoro-1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline 531 /f D φ ΑΖ Ζ&χ Η 4-[7-Fluoro-1,4,4-trimethyl-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3 - a]quinoxalin-8-yl]- 1H-indole7-carbonitrile 532 / ^N F MMU^ Η 7-Fluoro-8-(6-fluoro-1-methyl-1Nindol-4-yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H- [ 1,2,4]triazolo[4,3 a]quinoxaline

- 170 043276

533 T 1 Υ χγ ' Η 7-Chloro-8-(1-cyclopropyl-1Ηindol-4-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3a]quinoxaline 534 X XX Xr Η 4-(7-Fluoro-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3- a]quinoxalin-8-yl)- 1H-indole7-carbonitrile 535 Ύ Υυ ίι \=/ X 7-Fluoro-8-(7-fluoro-1H-indazol4-yl)-1,4,4-trimethyl-9- (trifluoromethyl)-5Н[ 1,2,4]triazolo[4,3 a]quinoxaline 536 ΥΥ Η 7-Fluoro-8-(6-methoxy-1 methylsulfonyl-1 H-indol-4yl)-1,4,4-trimethyl-9(trifluoromethyl)-5H[1,2,4]triazolo[4,3 a] quinoxaline 537 \ Ο ι A h ΥΎ Υ ⁴ ? Η 7-Fluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3a]quinoxaline

Biological research

Agonistic mode of action on the glucocorticoid receptor.

The CHO-Gal4/GR reporter cell line consisted of a Chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing the firefly luciferase gene under the control of a ligand-binding domain of GR fused to GAL4 DNA binding domain (DBD) (GAL4 DBD-GR) stably integrated into CHO cells. This cell line was generated by stable transfection of CHO cells with the GAL4-UAS-luciferase reporter construct. In the next step, the GR ligand-binding domain cloned into pIRES2-EGFP-GAL4 containing the GAL4 DNA-binding domain from pFAAT2 was transfected. This hybrid construct activated firefly luciferase expression under the control of a multimerized upstream GAL4 activating sequence (UAS). The emitted luminescence signal was recorded using FLIPR ^tetra . This made it possible to specifically detect ligand-induced GR activation and thus identify compounds with agonistic properties. The GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which served as an internal positive control for transfection efficiency.

The complete culture medium for analysis was as follows:

Mix DMEM F-12 (1:1) (LONZA, cat. no.: BE04-687F/U1) 500 ml;

ml 100 mM sodium pyruvate (LONZA, cat no.: BE12-115E);

ml 7.5% sodium bicarbonate (LONZA, cat no.: BE17-613E);

6.5 ml 1 M Hepes (LONZA, cat no.: BE17-737E);

ml 100X penicillin/streptomycin (LONZA, cat no.: DE17-602E);

ml fetal bovine serum (Euroclone, cat. no.: ECS 0180L);

0.25 ml 10 mg/ml puromycin (InvivoGen, cat: ant-pr-1);

0.5 ml 100 mg/ml zeocin (InvivoGen, cat: ant-zn-1).

Cryopreserved CHO-Gal4/GR cells were suspended in complete medium, 5000 cells/25 μl/well were plated in wells of 384-well polystyrene assay plates (Thermo Scientific, Cat # 4332) and cultured at 37°C, 5% CO ₂ and humidity 95%. After 24 hours, growth medium

- 171 043276 but removed and replaced with 30 µl Opti-MEM (GIBCO, Cat # 31985062) as assay buffer. For compound testing, an 8-point semi-log dilution curve of the compound in 100% DMSO was prepared, starting with a 2 mM stock solution, and then the compounds were diluted in OptiMEM at a ratio of 1:50. 10 μl of compounds were then added to wells containing 30 μl of Opti-MEM resulting in a final assay concentration range of 10 μM to 0.003 μM in 0.5% DMSO. Compounds were tested at 8 concentrations in four replicated data points. Cells were incubated for 6 hours with the compounds and beclomethasone (Sigma, cat # Y0000351) as control compound at 37° C., 5% CO ₂ and 95% humidity in a total volume of 40 μl. Finally, the cells were lysed with 20 µl of the triton/luciferin solution and the emitted luminescence signal was recorded with FLIPR ^tetra for 2 min.

Compound relative potency (% effect) was calculated based on the total effect of the beclomethasone agonist:

% effect = ((compound - min)/(max - min)) x 100

[min=Opti-MEM only, max=beclomethasone]

To calculate the EC ₅₀ , maximum, minimum and slope for each compound, the concentration response curve was fitted by plotting the % effect versus compound concentration using a 4-parameter logistic equation:

y = A + (B-A)/(l+((10C)/x)D)

[A=min y, B=max y, C=logECso, O=slope]

Antagonistic mode of action on the glucocorticoid receptor.

The CHO-Gal4/GR reporter cell line consisted of a Chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ - German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing the firefly luciferase gene under the control of a ligand-binding domain of GR fused to GAL4 DNA binding domain (DBD) (GAL4 DBD-GR) stably integrated into CHO cells. This cell line was generated by stable transfection of CHO cells with the GAL4-UAS-luciferase reporter construct. In the next step, the GR ligand-binding domain cloned into pIRES2-EGFP-GAL4 containing the GAL4 DNA-binding domain from pFAAT2 was transfected. This hybrid construct activated firefly luciferase expression under the control of a multimerized upstream GAL4 activating sequence (UAS). The emitted luminescence signal was recorded using FLIPR ^tetra . This made it possible to specifically detect the antagonistic properties of the compounds by measuring the ligand-induced inhibition of beclomethasone-activated GH. The GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which served as an internal positive control for transfection efficiency. The complete culture medium for analysis was as follows:

Mix DMEM F-12 (1:1) (LONZA, cat. no.: BE04-687F/U1) 500 ml;

ml 100 mM sodium pyruvate (LONZA, cat no.: BE12-115E);

ml 7.5% sodium bicarbonate (LONZA, cat no.: BE17-613E);

6.5 ml 1 M Hepes (LONZA, cat no.: BE17-737E);

ml 100X penicillin/streptomycin (LONZA, cat no.: DE17-602E);

ml fetal bovine serum (Euroclone, cat. no.: ECS 0180L);

0.25 ml 10 mg/ml puromycin (InvivoGen, cat: ant-pr-1);

0.5 ml 100 mg/ml zeocin (InvivoGen, cat: ant-zn-1).

Cryopreserved CHO-Gal4/GR cells were suspended in complete medium, 5000 cells/25 µl/well were plated in wells of 384-well polystyrene assay plates (Thermo Scientific, Cat # 4332) and cultured at 37°C, 5% CO2 and humidity 95%. After 24 hours, the growth medium was carefully removed and replaced with 20 µl Opti-MEM (GIBCO, Cat # 31985062) as assay buffer. For compound testing, an 8-point semi-log dilution curve of the compound in 100% DMSO was prepared, starting with a 2 mM stock solution, and then the compounds were diluted in OptiMEM at a ratio of 1:50. To test compounds in antagonistic mode, 10 µl of compounds were then added to wells containing 20 µl of Opti-MEM and incubated for 10 min. After this pre-incubation, 10 µl of the reference agonist beclomethasone (Sigma, Cat # Y0000351) was added at an EC ₅₀ of 2.5 nM resulting in a final assay concentration range of 10 µM to 0.003 µM in 0.5% DMSO in a total volume of 40 µl. Compounds were tested at 8 concentrations in four replicated data points. Cells were incubated for 6 h with compounds and mifepristone as a control compound (Sigma, Cat # M8046) at 37° C., 5% CO ₂ and 95% humidity. Finally, the cells were lysed with 20 µl of Triton/luciferin solution and the emitted luminescence signal was recorded by FLIPR for 2 min.

Compound relative potency (% effect) was calculated based on the total effect of the mifepristone antagonist:

- 172 043276 % effect = ((connection - min) / (max - min)) x -100

[min=Opti-MEM only, max=mifepristone]

To calculate the IC50, maximum, minimum, and slope for each compound, the concentration response curve was fitted by plotting the % effect versus compound concentration using a 4-parameter logistic equation:

y \u003d A + (B-A) / (l + ((10C) / x) D)

[A=min y, B=max y, C=logICso, O=slope]

In table. 9 below summarizes the IC50 or EC50 ranges in the examples that were observed in the agonist assay or antagonist assay described above.

Table 9 (A < 100 nM; B = 100 nM-1 μM; C = 1 μM-15 μM; ND = not determined)

Etc. No. IC50 or EC50 Etc. No. IC50 or EC50 Etc. No. IC50 or EC50 1 A 253 IN 390 A 2 A 254 IN 392 WITH 3 A 255 With 393 WITH 4 A 256 With 394 WITH 5 IN 257 V 395 n.a. 6 WITH 258 n.a. 396 WITH 9 IN 259 WITH 397 V 10 V 260 V 398 V eleven V 263 With 399 A 12 With 264 V 400 WITH 13 V 266 V 401 V 14 n.a. 267 V 402 V 15 WITH 268 With 403 A 16 V 269 n.a. 404 IN 17 V 270 IN 405 V 18 V 271 With 406 V 19 V 272 V 407 A 20 V 273 With 445 A 21 V 275 With 446 IN 22 V 276 V 447 IN 23 A 277 n.a. 448 V 24 A 278 n.a. 449 A 25 IN 279 A 450 IN 26 n.a. 280 WITH 451 V 27 A 281 IN 452 A 28 A 282 IN 453 A 29 A 283 n.a. 454 IN thirty A 284 IN 455 A 31 A 285 With 456 IN 32 n.a. 286 V 457 IN 33 A 287 n.a. 458 IN 34 n.a. 288 WITH 459 A 35 IN 289 With 460 IN

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36 IN 290 IN 461 A 37 A 292 IN 462 A 39 IN 293 n.a. 463 A 40 A 294 A 464 n.a. 41 A 295 WITH 465 A 42 A 296 IN 466 A 43 A 297 WITH 467 A 44 IN 298 With 468 A 45 IN 299 With 469 IN 46 A 302 A 470 IN 47 A 306 IN 471 IN 50 n.a. 309 A 472 A 51 IN 310 IN 473 IN 52 A 312 IN 474 V 67 WITH 313 n.a. 475 V 68 IN 314 WITH 476 V 69 A 315 IN 477 V 70 A 317 With 478 V 71 n.a. 318 V 479 V 72 N.d. 319 n.a. 480 V 73 IN 320 n.a. 481 V 74 A 321 WITH 482 A 75 A 324 V 483 A 76 A 325 n.a. 484 IN 77 IN 327 IN 485 A 78 WITH 328 V 486 A 79 WITH 329 V 487 IN 80 n.a. 330 A 488 IN 81 n.a. 331 WITH 489 A 82 n.a. 332 With 490 IN 83 WITH 333 A 491 A 84 N.d. 334 WITH 492 A 85 IN 335 V 493 A 86 IN 336 With 494 IN 87 IN 337 With 495 n.a. 88 A 338 V 496 A 89 IN 339 V 497 IN 200 WITH 341 V 498 IN 201 WITH 342 With 499 IN 202 A 343 With 500 V 203 n.a. 344 With 501 V 204 IN 345 V 502 V 205 IN 346 V 503 V 207 IN 347 V 504 V

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208 A 348 WITH 505 IN 210 A 351 A 506 IN 212 WITH 353 WITH 507 A 213 A 354 IN 508 IN 214 A 356 A 509 IN 219 WITH 357 A 510 V 221 IN 358 A 511 A 222 WITH 359 IN 512 WITH 223 A 360 IN 513 V 224 IN 361 WITH 514 V 225 A 362 A 515 V 228 WITH 363 A 516 V 229 WITH 364 IN 517 V 230 n.a. 365 WITH 518 A 232 IN 367 V 519 A 233 IN 368 V 520 IN 234 With 369 V 521 A 235 A 370 n.a. 522 IN 236 IN 371 IN 523 IN 237 With 372 A 524 V 238 V 373 IN 525 V 239 V 376 WITH 526 V 240 With 377 V 527 A 241 n.a. 379 n.a. 528 IN 242 WITH 380 WITH 529 V 243 V 381 With 530 V 244 With 382 With 531 V 247 With 383 With 532 A 248 V 384 With 533 A 249 A 385 With 534 IN 250 A 386 With 535 n.a. 251 IN 387 n.a. 536 IN 252 V 388 n.a. 537 IN

CLAIM

Claims (12)

[1,2,4]triazolo[4,3-a]quinoxaline, in the form of a free compound or a physiologically acceptable salt thereof. [1,2,4]triazolo[4,3-a]quinoxaline; 533) 7-chloro-8-(1-cyclopropyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 534) 4-(7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indole-7-carbonitrile ; 535) 7-fluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1.2.4]triazolo[4.3a ]quinoxaline; 536) 7-fluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 537) 7-fluoro-8-(6-methoxy-1-methylsulfonyl-1 H-indol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 526) 9-(difluoro-methyl)-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3-a]quinoxaline; 527) 9-(difluoro-methyl)-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 528) 9-(difluoro-methyl)-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 529) 8-(7-chloro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 530) 8-(7-chloro-1H-indol-4-yl)-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3а ]quinoxaline; 531) 4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-1H-indole -7-carbonitrile; 532) 7-fluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 524) 7-fluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 525) 8-(7-chloro-1-methylsulfonyl-1 H-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H- - 185 043276 [1,2,4]triazolo[4,3-a]quinoxaline; 522) 8-(6-fluoro-1-methyl-1 H-indol-4-yl)- 1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4, 3- a] quinoxaline; 523) 8-(1-cyclopropyl-1H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 518) 7-fluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 519) 7-chloro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 520) 9-fluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4,7-tetramethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 521) 9-(difluoro-methyl)-7-fluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 515) 9-(difluoro-methyl)-7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 516) 7-fluoro-8-(5-fluoro-1 H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4, 3- a] quinoxaline; 517) 8-(6-fluoro-1-methyl-1H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 513) 8-(6-chloro-III-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 514) 8-(1-cyclopropyl-1 H-indol-4-yl)-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 510) 7-fluoro-8-(1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 511) 8-(6-chloro-1H-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 512) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(7-methyl-1-methylsulfonyl-1 H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 509) 7-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 501) 7,9-difluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 502) 8-[1 -(cyclopropyl-methylsulfonyl)-1 H-indol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl5H-[1,2,4] triazolo[4,3-a]quinoxaline; 503) 1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 504) 7-fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 505) 7-fluoro-8-(7-fluoro-III-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 506) 7-chloro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 507) 8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3a ]quinoxaline; 508) 7-chloro-8-[1-(2,2-difluoro-ethyl)-6-fluoro-III-indazol-4-yl]-9-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 500) 8-[1-(2,2-difluoro-ethyl)-III-indol-4-yl]-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 499) 8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 496) 9-(difluoro-methyl)-7-fluoro-8-(7-fluoro-N-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 497) 7,9-difluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 498) 1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 494) 4-(7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-III-indole-6-carbonitrile ; 495) 8-[1-(cyclopropylmethylsulfonyl)-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; - 184 043276 490) 7-fluoro-8-(III-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 491) 7-chloro-1,4,4,9-tetramethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3- a] quinoxaline; 492) 7,9-difluoro-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-III-indol-4-yl)-5H[1,2,4]triazolo[4,3- a] quinoxaline; 493) 7-fluoro-1,4,4,9-tetramethyl-8-(6-methyl-1-methylsulfonyl-III-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 485) 7-chloro-8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 486) 7-fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 487) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 488) 7-chloro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 489) 8-[1-(2,2-difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 483) 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-7-fluoro-9-methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4, 3-a]quinoxaline; 484) 7-fluoro-8-(7-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 481) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 482) 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 479) 4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]-1H-indole -6-carbonitrile; 480) 8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indazol-4-yl]-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 477) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4, 3-a]quinoxaline; 478) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 474) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3а ]quinoxaline; 475) 7-chloro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 476) 7-fluoro-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 466) 9-(difluoro-methyl)-7-fluoro-8-(6-fluoro-N-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 467) 7-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 468) 7-fluoro-8-(6-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 469) 8-[1-(2,2-difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H[1, 2,4]triazolo[4,3-a]quinoxaline; 470) 7-fluoro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 471) 2-[6-fluoro-4-[1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8yl]- 1 H-indol-1-yl]-ethanol; 472) 8-[1-(2,2-difluoro-ethyl)-6-fluoro-1H-indazol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl- 5H[1,2,4]triazolo[4,3-a]quinoxaline; 473) 7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 463) 9-cyclopropyl-7-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 464) 7-fluoro-8-(6-fluoro-III-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 465) 1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-7-(trifluoromethyloxy)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 462) 9-cyclopropyl-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 456) 2-[4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl]- 1Nindol-1-yl]-ethanol; 457) 1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; - 183 043276 458) 8-(5-fluoro-3-methyl-N-indol-7-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H[1,2,4]triazolo[4, 3-a]quinoxaline; 459) 8-(5-fluoro-3-methyl-1H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 460) 8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 461) 9-(difluoro-methyl)-8-[1 -(ethylsulfonyl)-1 H-indol-4-yl] -7-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 447) 2-[6-fluoro-4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8yl ]-1 H-indol-1-yl]-ethanol; 448) 8-[1-(ethylsulfonyl)-6-fluoro-1H-indazol-4-yl]-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4] triazolo[4,3-a]quinoxaline; 449) 2-[6-fluoro-4-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8yl ]-1 H-indazol-1 -yl]-ethanol; 450) 1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 451) 2-[6-fluoro-4-(1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 1-yl]-ethanol; 452) 8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 453) 8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline; 454) 7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 455) 8-[1-(ethylsulfonyl)-1H-indol-4-yl]-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 445) 7,9-difluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 446) 7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 407) 8-(5-fluoro-3-methyl-1H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 405) 1,4,4,9-tetramethyl-8-(3-methyl-1H-indol-7-yl)-7-(trifluoromethyloxy)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 406) 8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 404) 7-chloro-9-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 402) 9-(difluoro-methyl)-7-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo[4,3-a]quinoxaline; 403) 8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyloxy)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 399) 7-fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 400) 9-(difluoro-methyl)-7-fluoro-8-[1-(isopropylsulfonyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 401) 8-[1 -(cyclopropylsulfonyl)-1 H-indol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 398) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 394) 7-(difluoro-methoxy)-9-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo[4,3-a]quinoxaline; 395) 2-[4-[7-(difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl ]-6fluoro-1 H-indol-1 -yl]-ethanol; 396) 7-(difluoro-methyl)-9-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-III-indol-4-yl]-1,4,4-trimethyl-5H[ 1,2,4]triazolo[4,3-a]quinoxaline; 397) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-7-fluoro-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 385) 2-[4-[7-(difluoro-methyl)-9-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl ]-6fluoro-1 H-indol-1 -yl]-ethanol; - 182 043276 386) 7-chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline; 387) 7-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-III-indazol-4-yl)-9-(trifluoromethyl)-5H[1,2,4]triazolo[4,3- a] quinoxaline; 388) 1,4,4,7,9-pentamethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline; 390) 9-(difluoro-methyl)-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4] triazolo[4,3-a]quinoxaline; 392) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-9-fluoro-1,4,4,7-tetramethyl-5H-[1,2,4]triazolo [4,3- a] quinoxaline; 393) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-7-(difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 383) [2-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indole -1-yl]-ethyl]-dimethylamine; 384) 8-[1 -(2,2-difluoro-ethyl)-1 H-indol-4-yl]-7-(difluoro-methoxy)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 372) 8-[1-(ethylsulfonyl)-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 373) 8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,7,9-pentamethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 376) 8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo[ 4,3-a]quinoxaline; 377) 7-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline; 379) 2-[6-fluoro-4-(9-fluoro-7-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl )-1H-indol-1-yl]-ethanol; 380) 2-[6-fluoro-4-(7-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl )-1Nindol-1-yl]-ethanol; 381) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 382) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indazol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 371) 8-[1-(ethylsulfonyl)-III-indol-4-yl]-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 367) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 368) 7-chloro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 369) 8-[1-(ethylsulfonyl)-6-fluoro-1H-indol-4-yl]-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4] triazolo[4,3-a]quinoxaline; 370) 8-[1-(ethylsulfonyl)-6-fluoro-N-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 363) 7-chloro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; [1,2,4]triazolo[4,3-a]quinoxaline; 358) 7-chloro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 359) 9-fluoro-1,4,4,7-tetramethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 360) 7-(difluoro-methoxy)-1,4,4,9-tetramethyl-8-(3-methyl-N-indol-7-yl)-5H-[1.2.4]triazolo[4.3 - a] quinoxaline; 361) 7-fluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 362) 8-[1-(ethylsulfonyl)-6-fluoro-III-indol-4-yl]-7-fluoro-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 354) 7,9-difluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 356) 1,4,4,7,9-pentamethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 357) 7-methoxy-1,4,4-trimethyl-8-(3-methyl-III-indol-7-yl)-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 341) 8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,7,9-pentamethyl-5H-[1,2,4]triazolo[4,3-a ]quinoxaline; 342) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a] quinoxaline; 343) 7-(difluoro-methyl)-9-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline ; - 181 043276 344) 7-methoxy-8-[1-(2-methoxy-ethyl)-III-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 345) 8-(5-fluoro-3-methyl-N-indol-7-yl)-7-methoxy-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a ]quinoxaline; 346) 9-(difluoro-methyl)-7-fluoro-8-(6-fluoro-1-methylsulfonyl-III-indazol-4-yl)-1,4,4-trimethyl-5H[1,2,4] triazolo[4,3-a]quinoxaline; 347) 7-chloro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3- a] quinoxaline; 348) 1-ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-III-indazol-4-yl)-4,4,9-trimethyl-5H[1,2,4]triazolo[4, 3-a]quinoxaline; 351) 7-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4-yl]-9-methoxy-1,4,4-trimethyl-5H[1,2, 4]triazolo[4,3-a]quinoxaline; 353) 9-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-III-indol-4-yl]-7-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 337) 9-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,7-tetramethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 338) 7-chloro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 339) 7-fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 336) 7-(difluoro-methoxy)-8-[ 1 -(2-methoxy-ethyl)-1 H-indol-4-yl] -1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 319) 9-(difluoro-methyl)-7-fluoro-8-(1 H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 320) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(3-methyl-N-indol-7-yl)-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 321) 9-fluoro-1,4,4,7-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 324) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-1,4,4,7,9-pentamethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 325) 7-(difluoro-methyl)-9-fluoro-1,4,4-trimethyl-8-(1-methyl-III-indazol-4-yl)-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 327) 7-chloro-8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo [4,3- a] quinoxaline; 328) 8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,7,9-pentamethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 329) 8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 330) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo [4,3- a] quinoxaline; 331) 8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,7,9-pentamethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 332) 9-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,7-tetramethyl-5H[1,2,4]triazolo[4,3- a] quinoxaline; 333) 7-chloro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3- a] quinoxaline; 334) 7-methoxy-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4] triazolo[4,3-a]quinoxaline; 335) 7-(difluoro-methoxy)-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 317) 7-chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 318) 7-(difluoro-methoxy)-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 315) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 313) 7-chloro-8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-9-fluoro-1,4,4-trimethyl-5H-[1,2,4 ]triazolo[4,3a]quinoxaline; 314) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-9-fluoro-7-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 312) 8-[1 -cyclopropyl-2-(trifluoromethyl)-1 H-indol-4-yl] -7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 299) 1-ethyl-7-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-4,4,9-trimethyl-5H-[1,2,4]triazolo [4,3- - 180 043276 a] quinoxaline; 302) 9-(difluoro-methyl)-7-fluoro-8-(5-fluoro-3-methyl-N-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4] triazolo[4,3-a]quinoxaline; 306) 7-(difluoro-methyl)-9-fluoro-1,4,4-trimethyl-8-(3-methyl-N-indol-7-yl)-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 309) 1,4,4,7,9-pentamethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 310) 7-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 297) 7-(difluoro-methoxy)-9-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 298) 7-(difluoro-methyl)-9-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 296) 7-(difluoro-methyl)-9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 293) 7-chloro-9-fluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 294) 9-(difluoro-methyl)-7-fluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 295) 7-(difluoro-methyl)-9-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 290) 7-chloro-9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 292) 9-(difluoro-methyl)-7-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 289) 7,9-difluoro-8-[1-(2-methoxy-ethyl)-2-(trifluoromethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 288) 9-fluoro-7-methoxy-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 282) 7-(difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 283) 9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 284) 7-chloro-9-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 285) 7-chloro-9-fluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 286) 7-fluoro-8-(1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 287) 7-(difluoro-methoxy)-9-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 280) 7-chloro-9-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H-[1,2,4]triazolo [4,3- a] quinoxaline; 281) 7-fluoro-9-methoxy-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 278) 7-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 279) 7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 277) 7-chloro-9-fluoro-8- (6-fluoro-1-methylsulfonyl-1H-indol-4-yl) -1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 276) 7,9-difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 275) 7-(difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 272) 7-chloro-9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3-a ]quinoxaline; 273) 7-(difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-(1-methyl-1 H-indazol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; - 179 043276 264) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 266) 9-fluoro-7-methoxy-1,4,4-trimethyl-8-(3-methyl-III-indol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 267) 7-(difluoro-methoxy)-9-fluoro-8-(5-fluoro-3-methyl-1 H-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4 ]triazolo[4,3-a]quinoxaline; 268) 7-(difluoro-methoxy)-9-fluoro-8-(6-fluoro-1-methylsulfonyl-N-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4] triazolo[4,3-a]quinoxaline; 269) 9-fluoro-7-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 270) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 271) 7,9-difluoro-1,4,4-trimethyl-8-[1-methylsulfonyl-2-(trifluoromethyl)-1 H-indol-4-yl] -5H- [1,2,4]triazolo[4,3-a]quinoxaline; 256) 9-fluoro-8-(1H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 257) 9-fluoro-7-methoxy-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3a ]quinoxaline; 258) 2-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indazol- 1-yl]ethanol; 259) 7-(difluoro-methoxy)-9-fluoro-8-[1-(2-methoxy-ethyl)-2-(trifluoromethyl)-1H-indol-4-yl]-1,4,4trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 260) 4-(7-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indole-1carboxylic acid tert-butyl ester; 263) 9-fluoro-7-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl) -5H- [1,2,4]triazolo[4,3-a]quinoxaline; 253) 8-[1-(2,2-difluoro-ethyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo [4,3- a] quinoxaline; 254) 7-chloro-9-fluoro-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 255) 9-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-7-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 251) 9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-7-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 252) 7-(difluoro-methoxy)-9-fluoro-1,4,4-trimethyl-8-[2-(trifluoromethyl)-1H-indol-4-yl]-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 249) 7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 250) 7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 240) 1-ethyl-7-fluoro-4,4,9-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 241) 1-ethyl-7-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 242) 8-(1-cyclopropyl-1H-indazol-4-yl)-1-ethyl-7-fluoro-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 243) 8-(1-cyclopropyl-1H-indazol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5Н-[1,2,4]triazolo[4,3- a] quinoxaline; 244) 1-ethyl-7-fluoro-8-(5-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3-a ]quinoxaline; 247) 1-ethyl-7-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 248) 7-fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl) -5H- [1,2,4]triazolo[4,3-a]quinoxaline; 236) 8-(1-ethyl-1H-indazol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 237) 8-(2-ethyl-2H-indazol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 238) 4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1 H-indazol-1 - carboxylic acid tert-butyl ester; 239) 8-[1 -(cyclopropyl-methylsulfonyl)-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 235) 8-[1-(cyclopropyl-methyl)-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 212) 2-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triαzolo[4,3-α]quinoxalin-8-yl)-1H-indol- 1-yl]- K,K-dimethylacetamide; 213) 1-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 1-yl]-2methoxyethanone; 214) 7,9-difluoro-8-(5-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 219) 3-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 1-yl]-propionic acid methyl ester; 221) 7,9-difluoro-1,4,4-trimethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 222) 7,9-difluoro-1,4,4-trimethyl-8-(2-methyl-2H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 223) 1-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triαzolo[4,3-α]quinoksalin-8-yl)-1H-indol- 1-yl]-2- - 178 043276 diethylamino-ethanone; 224) 7,9-difluoro-8-(5-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3- a] quinoxaline; 225) 7,9-difluoro-1,4,4-trimethyl-8-[2-(trifluoromethyl)-III-indol-4-yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 228) K-[2-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H -indol-1-yl]-ethyl]-carbamic acid tert-butyl ester; 229) K-[2-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H -indol-1-yl]-ethyl]-2,2-difluoropropionamide; 230) 2-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 1-yl]-ethylamine; 232) 7,9-difluoro-8-(1H-indazol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 233) 7,9-difluoro-8-[ 1 -(2-methoxy-ethyl)-1 H-indazol-4-yl] -1,4,4-trimethyl-5H-[ 1,2,4]triazolo[ 4.3- a] quinoxaline; 234) 8-[1-(cyclopropylsulfonyl)-1H-indazol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 207) 7,9-difluoro-1,4,4-trimethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 208) 7,9-difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 210) 8-[1 - (cyclopropyl-methylsulfonyl) -1 H-indol-4-yl] -7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 202) 8-[1 -(cyclopropyl-methyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a ]quinoxaline; 203) 7,9-difluoro-1,4,4-trimethyl-8-[1-(tetrahydro-pyran-4-ylsulfonyl)-1H-indol-4-yl]-5H[1,2,4]triazolo[ 4,3-a]quinoxaline; 204) 7,9-difluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 205) 8-[1-(cyclopropylsulfonyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 89) 7-[7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triαzolo[4,3-α]quinoksalin-8-yl]-1H-indole -3 - carbonitrile; 200) 7,9-difluoro-8-[1 -(isopropylsulfonyl)-1 H-indol-4-yl] -1,4,4-trimethyl-5H-[1.2.4]triazolo[4.3a] quinoxaline; 201) 8-[1-(cyclopentylsulfonyl)-1H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 88) 8-(1-cyclopropyl-6-fluoro-1H-indol-4-yl)-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 85) 9-chloro-8-(3-cyclopropyl-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 86) 7-fluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 87) 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 84) 1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-7-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 80) 1-(cyclopropyl-methyl)-7,9-difluoro-8-(III-indol-7-yl)-4,4-dimethyl-5H-[1.2.4]triazolo[4.3- a] quinoxaline; 81) 1-cyclopropyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 82) 8-(3-cyclopropyl-1 H-indol-7-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyl)-5H-[1.2.4]triazolo[4.3а] quinoxaline; 83) 8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-7-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; [1,2,4]triazolo[4,3-a]quinoxaline; 73) 7,9-difluoro-8-(5-fluoro-3-methyl-N-indol-7-yl)-4,4-dimethyl-1-(pyridin-3-yl-methyl)-5H[1, 2,4]triazolo[4,3-a]quinoxaline; 74) 7,9-difluoro-8-(5-fluoro-3-methyl-N-indol-7-yl)-4,4-dimethyl-1-(pyridin-2-yl-methyl)-5H[1, 2,4]triazolo[4,3-a]quinoxaline; 75) 7,9-difluoro-4,4-dimethyl-8- (3 -methyl-1 H-indol-7-yl) -1 - (pyridin-2-yl-methyl) -5H- [1,2,4]triazolo[4,3-a]quinoxaline; 72) 7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-1-(pyridin-4-yl-methyl)-5H- - 177 043276 [1,2,4]triazolo[4,3-a]quinoxaline; 70) 1-but-2-ynyl-7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 71) 7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-1-(pyridin-4-yl-methyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 67) 1-benzyl-7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 68) 1-benzyl-7,9-difluoro-4,4-dimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 69) 1-but-2-ynyl-7,9-difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4-dimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 47) 9-ethyl-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 50) 9-ethyl-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1 H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 51) 9-ethyl-7-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline ; 52) 9-ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 39) 4-[7-(7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 3-yl]-2-methyl-but-3-yn-2-ol; 40) [3-[7-(7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H- indol-3-yl]-1,1dimethyl-prop-2-ynyl]-amine; 41) 9-chloro-8-(3-cyclobutyl-1H-indol-7-yl)-7-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 42) 7-fluoro-1,4,4,9-tetramethyl-8-(3-tetrahydro-furan-3-yl-1 H-indol-7-yl)-5H-[1,2,4]triazolo[ 4,3a]quinoxaline; 43) 8-(3-ethyl-5-fluoro-1H-indol-7-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 44) 2-[4-(9-ethyl-7-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6- fluoro-1H-indol-1-yl]-ethanol; 45) 2-[4-(9-ethyl-7-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6- fluoro-1H-indazol-1-yl]-ethanol; 46) 9-ethyl-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 37) 7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 36) 1-ethyl-7-fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4-yl]-4,4,9-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 22) 7,9-difluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triαzolo[4,3- - 176 043276 a] quinoxaline; 23) 7-fluoro-8-[5-fluoro-3-(2,2,2-trifluoro-ethyl)-1H-indol-7-yl]-1,4,4,9-tetramethyl-5H[1, 2,4]triazolo[4,3-a]quinoxaline; 24) 7-fluoro-1,4,4,9-tetramethyl-8-[3-(2,2,2-trifluoro-ethyl)-III-indol-7-yl]-5H-[1,2,4 ]triazolo[4,3a]quinoxaline; 25) 7-fluoro-8-(1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 26) 7-fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 27) 8-(1-cyclopropyl-1 H-indol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 28) 7-fluoro-1,4,4,9-tetramethyl-8-(3-prop-1-ynyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 29) 7-fluoro-1,4,4-trimethyl-8-(3-methyl-III-indol-7-yl)-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 30) 9-chloro-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3- a] quinoxaline; 31) 7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 32) 7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 33) 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a ]quinoxaline; 34) 1-ethyl-7-fluoro-8-(6-fluoro-1H-indol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3-a ]quinoxaline; 35) 8-[1 - (cyclopropyl-methyl) -6-fluoro-1 H-indol-4-yl] -1 -ethyl-7-fluoro-4,4,9-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline; 20) 1-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 1-yl]- ethanone; 21) 7,9-difluoro-8-[6-fluoro-1-(2,2,2-trifluoro-ethyl)-1H-indol-4-yl]-1,4,4-trimethyl-5H- 1) 7,9-difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline ; 1. Compound corresponding to the general formula (II) or (III) where R ¹ represents C _1-10 alkyl; C _3-10 cycloalkyl; phenyl or pyridyl; where C _3-10 cycloalkyl, phenyl and pyridyl may optionally be connected via a C _1-6 alkylene bridge; R ² is F; Cl; Br; I; C _1-10 alkyl; C _3-10 cycloalkyl or O-C _1-10 alkyl; R ³ is H; F; Cl; Br; I; C _1-1 oalkyl or O-C _1-10 alkyl; R ⁵ and R ⁶ are unsubstituted C _1-4 alkyl; X is N or NR ⁷ ; Z is N, NR ⁷ or CR ⁹ ; provided that where X is NR ⁷ , Z is N or CR ⁹ ; when X is N, Z is NR ⁷ ; R ⁷ is H or LR ⁸ ; Where L is a bond; S(O); S(O) ₂ ; C _1-6 alkylene; C(O); C _1-6 alkylene-C(O); C(O)-O; C _1-6 alkyleneC(O)-O or C _1-6 alkylene-N(H)-C(O)-O; R ⁸ is C _1-10 alkyl; C _3-10 cycloalkyl or 3-7 membered heterocycloalkyl; where C _3-10 cycloalkyl and 3-7-membered heterocycloalkyl may optionally be connected via a C _1-6 alkylene bridge; R ⁹ and R ¹⁰ are independently H; F; Cl; Br; I; CN; C _1-10 alkyl; C _3-1 ocycloalkyl or 3-7 membered heterocycloalkyl; - 175 043276 R ¹¹ is F; Cl; Br; I; CN; C _1-10 alkyl or O-Ci-ualkyl; n is 0, 1 or 2; where C _1-10 alkyl, C _1-4 alkyl and C ₁ . _{the 6} alkylenes are in each case independently of one another linear or branched, saturated or unsaturated; where 3-7-membered heterocycloalkyl means heterocycloaliphatic saturated residues having from 3 to 7 ring members, in each case at least one carbon atom is replaced by O; where C _1-10 αkyl and C _1-4 alkyl, in each case independently of each other are unsubstituted, mono - or polysubstituted with one or more substituents selected from F; Cl; Br; I; _CF3 ; _CF2H ; CFH2; HE; O-C ₁ . ₆ alkyl; NH2; N(H)(C _{1 .6} alkyl) and N(C _{1 .6} alkyl) ₂ ; where phenyl and pyridyl in each case are unsubstituted; in the form of the free compound or its physiologically acceptable salt. 2) 8-(1-cyclopropyl-6-fluoro-N-indol-4-yl)-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 2. A compound according to claim 1 wherein R ⁵ and R ⁶ are both CH3. 3 64) 9-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,7-tetramethyl-5H-[1,2,4]triazolo[4, 3a]quinoxaline; 365) 7-(difluoro-methoxy)-8-(5-fluoro-3-methyl-III-indol-7-yl)-1,4,4,9-tetramethyl-5H- 3) 7,9-difluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4, 3a]quinoxaline; 3. A compound according to claim 1 or 2, wherein X is NR ⁷ and Z is N or CR ⁹ . 4) 1-[4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro- 1H-indol-1yl]-ethanone; 4. A compound according to any one of the preceding claims, wherein R ⁷ is H. 5) 7,9-difluoro-8-(6-fluoro-2-methyl-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline; 5. Connection according to any one of paragraphs.1-4, where R ⁷ represents LR ⁸ ; Where L is a bond; S(O); S(O) ₂ ; _C1 . ₄ alkylene; C(O); _C1 . ₄ alkylene-C(O); C(O)-O; C ₁ _ ₄ alkyleneC(O)-O or C ₁ _ ₄ alkylene-N(H)-C(O)-O; R ⁸ is C ₁ . ₆ alkyl; _C3 . ₆ cycloalkyl or 3-6 membered heterocycloalkyl; where C ₃ . ₆ cycloalkyl and 3-6 membered heterocycloalkyl may optionally be connected via C ₁ . ₄ alkylene bridge. 6) 4-(7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1H-indole -2- carbonitrile; 6. Connection according to any of the previous paragraphs, where R ⁹ represents H; F; CN; methyl; ethyl; n-propyl; 2-propyl; _CF3 ; CH2CF3; CHF2; CH2CHF2; CH2F or CH2CH2F. 7 6) 7-fluoro-8-(5-fluoro-3-prop-1-inyl-1 H-indol-7-yl)-1 -(methoxymethyl)-4,4,9-trimethyl-5H[1, 2,4]triazolo[4,3-a]quinoxaline; 77) [7-fluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[ 4.3- a]quinoxalin-1-yl]-meOH; 78) 1-[7-fluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-[1,2,4] triazolo[4,3- a]quinoxalin-1-yl]-ethanol; 79) 7-fluoro-8-(5-fluoro-3-prop-1-inyl-1 H-indol-7-yl)- 1 -(2-methoxy-ethyl)-4,4,9-trimethyl-5H - 7. Connection according to any of the previous paragraphs, where R ¹⁰ represents H; F; Cl; Br; CN; _C1 . ₆ alkyl; _C3 . ₆ cycloalkyl; and 3-6 membered heterocycloalkyl. 8. Connection according to any of the previous paragraphs, where R ¹¹ represents F; Cl; Br; I; CN; _C1 . ₆ alkyl or OC ₁ _ ₆ alkyl. 9) 7,9-difluoro-8-(1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 9. A compound according to any of the preceding paragraphs, selected from the group consisting of: 10. Dosage form containing a compound according to any one of claims 1-9. 10) 7,9-difluoro-1,4,4-trimethyl-8-[3-(trifluoromethyl)-1H-indol-7-yl]-5H-[1,2,4]triazolo[4,3- a] quinoxaline; 11. The use of a compound according to any one of claims 1 to 9 for the treatment and/or prevention of pain and/or inflammation. 11) 1-ethyl-7,9-difluoro-8-(1H-indol-7-yl)-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline; 12) 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1 H-indol- 3 - carbonitrile; 13) 1-ethyl-7,9-difluoro-4,4-dimethyl-8-(3-prop-1-ynyl-1 H-indol-7-yl)-5H-[1,2,4]triazolo[ 4.3- a] quinoxaline; 14) 1-ethyl-7,9-difluoro-8-(5-fluoro-1H-indol-7-yl)-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a ]quinoxaline; 15) 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-5H-[1.2.4]triazolo[4,3-a]quinoxalin-8-yl)-5-fluoro-1H -indole3-carbonitrile; 16) 1-ethyl-7,9-difluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-4,4-dimethyl-5H-[1,2,4 ]triazolo[4,3a]quinoxaline; 17) 7-(1-ethyl-7,9-difluoro-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-5-methyl-1Nindole -3 - carbonitrile; 18) 8-[1 -(ethylsulfonyl)-6-fluoro-N-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3a]quinoxaline; 19) 8-[1 -(cyclopropylsulfonyl)-6-fluoro-1 H-indol-4-yl]-7,9-difluoro-1,4,4-trimethyl-5H- 12. Use according to claim 11 for the treatment and/or prevention of inflammatory pain.