EA045285B1 - ADDITIONALLY SUBSTITUTED TRIAZOLO-QUINOXALINE DERIVATIVES - Google Patents

Description

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

which act as glucocorticoid receptor modulators and can be used for the treatment and/or prevention of 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 such conditions. However, the chronic treatment of inflammatory diseases with GCs is hampered by the side effects associated with GCs. Such undesirable side effects include insulin resistance, diabetes, hypertension, glaucoma, depression, osteoporosis, adrenal suppression, and muscle wasting, with osteoporosis and diabetes being the most severe from a medical perspective (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 GCs cause adrenal suppression, prednisolone withdrawal syndrome can be severe if the drug is abruptly stopped when all signs of the disease have disappeared. Therefore, gradually reducing the dose of GC to physiological levels is often part of treatment protocols in order 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 the development of GC-related side effects. It has been demonstrated that most of these effects are mediated by various GR-dependent genomic mechanisms called transactivation and transrepression. The anti-inflammatory effects of GCs are mainly due to the transrepression of inflammatory genes, while certain side effects are predominantly mediated by the transactivation of several genes. According to the nature of the ligand, GR can be selectively modulated into a specific conformation that favors transrepression over transactivation, resulting in 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 have yet been approved for clinical use.

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

It is an object of the present invention to provide new compounds which are glucocorticoid receptor modulators and which preferably have advantages over prior art compounds. The new compounds should in particular 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 object has been achieved in accordance with the subject of the claims.

Surprisingly, it has been found that the compounds of the present invention are highly effective glucocorticoid receptor modulators.

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

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(II) (HI) where

R ¹ represents C _1-10 alkyl or C _3-10 cycloalkyl;

R ² represents CN; C _1-10 alkyl; C _3-10 cycloalkyl; O-C _1-10 alkyl; N(H)(C _1-10 alkyl) or N(C _1-10 alkyl) ₂ ;

R ³ represents H; F; Cl; Br or I; R ⁴ represents F or Cl;

R ⁵ and R ⁶ represent, independently of each other, unsubstituted C _1-4 alkyl;

X represents N or NR ⁷ ;

Z is N, NR ⁷ or CR ⁹ ;

with the proviso that where X is NR ⁷ , Z is N or CR ⁹ ;

when X is N, Z is NR ⁷ ;

R ⁷ represents H or LR ⁸ ; where L represents a bond; S(O) or S(O)2; R ⁸ is C1-10 alkyl or C _3-10 cycloalkyl;

wherein the C _3-10 cycloalkyl may optionally be connected via a C _1-6 α alkylene bridge;

R ⁹ and R ¹⁰ are independently of each other H; C _1-10 alkyl or C _3-10 cycloalkyl;

R ¹¹ represents F; Cl; Br; I; CN; C _1-10 alkyl or O-C _1-10 alkyl; n is 0, 1 or 2;

where C _1-10 alkyl, C _1-4 alkyl and C _1-6 alkylene are in each case independently of each other linear or branched, and saturated;

wherein C _1-10 alkyl, C _1-4 alkyl or C _3-10 cycloalkyl are each independently unsubstituted, mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CF ₃ ; _CF2H ; CFH ₂ ; HE; =O; OC _1-6 αlkyl; _NH2 ; N(H)(C _1-6 αlkyl) or N(C _1-6 alkyl) ₂ ;

in the form of the free compound or a physiologically acceptable salt thereof.

In a preferred embodiment, the compound of the present invention is present in the form of a free compound. The term 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 or salt form are known to one 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. It is also possible to use a 1H NMR spectrum recorded in solution to account for the presence of protonation.

In another preferred embodiment, the compound of the present invention is present in the form of a physiologically acceptable salt. The term physiologically acceptable salt preferably refers to a salt prepared from a compound of the present invention and a physiologically acceptable acid or base.

The compound of the present invention may be present in any possible form, including solvates, cocrystals and polymorphs. 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) individual molecular equivalents of one or more solvents.

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

A compound of the present invention may be present in the form of isotopic isomers, 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 the compound of the invention can generally be prepared by conventional procedures known to one skilled in the art.

In accordance with the present invention, the terms C _1-10 alkyl, C _1-8 alkyl, C _1-6 αlkyl and C _1-4 alkyl preferably mean acyclic saturated or unsaturated aliphatic (i.e. non-aromatic) hydrocarbon radicals, 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 from 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 from 1 to 4 (i.e. 1, 2, 3 or 4) carbon atoms, respectively. In a preferred embodiment, C _1-10 alkyl, C _1-8 alkyl, C _1-6 alkyl and

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Smalkil are saturated. In another preferred embodiment, C1-1oalkyl, _C1 . ₈ alkyl, C _1-6 alkyl and C _1-4 alkyl are unsaturated. According to the present embodiment, C _1-10 alkyl, C ₁ . ₈ alkyl, C ₁ . ₆ alkyl and C _1-4 alkyl contain at least one C-C double bond (C=C bond) or at least one C-C triple bond (C^C bond). In yet another preferred embodiment _{, C 1_10 alkyl} , C ₁ . ₈ alkyl, C ₁ . ₆ alkyl and C ₁ _ ₄ alkyl are (i) saturated or (ii) unsaturated, with C ₁ _ ₁₀ alkyl, C ₁ . ₈ αlkyl, C ₁ . ₆ alkyl and C ₁ _ ₄ alkyl contain at least one, preferably one, C-C triple bond (C^C bond). Preferred _C1-10 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 ₃ , -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, 3methylbut-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, 3methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably from methyl, ethyl, npropyl, 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, tert-butyl, npentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 2-pentenyl, 1 -pentynyl, 2-pentynyl, 2-methylbutyl, 3methylbutyl, 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 C ₁ . ₈ alkyl groups selected 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, 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, 2-dimethylpropyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methylpentyl, 4-methylpentyl, 4-methylpent-2-yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3-dimethylbutyl 2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3methylpent-3-yl; more preferably from methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2propynyl, 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, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 1-pentenyl, 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 C ₁ . ₆ alkyl groups selected from methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, nbutyl, isobutyl, sec-butyl, tert-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-methylpent-2- yl, 2-methylpent-2-yl, 3,3-dimethylbutyl, 3,3dimethylbut-2-yl, 3-methylpentyl, 3-methylpent-2-yl and 3-methylpent-3-yl; more preferably from 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, 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 C _1-6 alkyl groups are selected from C 1 ₄ alkyl groups. Preferred C _1-4 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 ₃ , -C(=CH ₂ )CH ₃ ), n-butyl, 1-butynyl, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl, tert-butyl and 3-methylbut-1-ynyl .

Moreover, in accordance with the present invention, the terms C ₁ . ₆ alkylene; C _1-4 alkylene and C ₁ . ₂ alkylene refers to linear or branched, preferably linear, and preferably saturated aliphatic radicals, 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, C ₁ . _{The 6} alkylene is selected from C _1-4 alkylene, more preferably from C ₁ . ₂ alkylene.

Moreover, in accordance with the present invention, the terms C ₃ . ₁₀ cycloalkyl and C ₃ . ₆ cycloalkyl preferably means cyclic aliphatic hydrocarbons containing 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms and 3, 4, 5 or 6 carbon atoms, respectively, the hydrocarbons in each case being saturated or unsaturated ( but not aromatic), unsubstituted or mono- or polysubstituted. Preferably _C3 . ₁₀ cycloalkyl and C ₃ . ₆ cycloalkyl are saturated. C ₃ . ₁₀ cycloalkyl and C ₃ . ₆ cycloalkyl may be linked to a suitable overall higher order structure via any desired and possible ring member of a cycloalkyl group. C ₃ . ₁₀ cycloalkyl and C _3-6 cycloalkyl groups can also be fused with additional saturated, (partially) unsaturated, (hetero)cyclic, aromatic or heteroaromatic ring systems, i.e. with cycloalkyl, heterocyclyl, aryl

- 3 045285 or heteroaryl radicals, which in each case may in turn be unsubstituted or mono- or polysubstituted. In addition, C ₃ . ₁₀ cycloalkyl and C ₃ . ₆ cycloalkyl may contain one or more bridges, 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 contain bridged bonds. More preferably, C ₃ . ₁ ocycloalkyl and C _{3_6} cycloalkyl are neither fused with additional ring systems nor _containing bridged bonds, and are saturated. Preferred C ₃ . ₁ ocycloal groups are selected from a group consisting of cyclopropil, cyclobulal, cyclopentil, cyclogli, cyclopentenil, cycloggeplane, cycloopriel, cyclonely, cyclodecil, adamantil, cyclopentenil, cyclogeptenil, cyclooocotenil, bicyro [2.2.1] heipdles and bucilia and bucilia and bitsi Claus [2.2 .2]octyl. Particularly preferred C _3-10 cycloalkyl groups are selected from C ₃ . ₆ alkyl groups. Preferred C _3-6 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.

The compounds of the present invention are defined by substituents, for example R ¹ , R ² and R ³ (1st generation substituents), which themselves can be replaced 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 = C1.10 alkyl (1st generation substituent), then C1.10 alkyl can in turn be substituted, for example, with N(H)(C1-6 alkyl) (2nd generation substituent). This allows us to obtain the functional group R ¹ = (C1. ₁₀ alkyl-NH-C _{1. 6} alkyl). NH-C ₁ . _{The 6} alkyl in turn can then be substituted, for example, with Cl ( ^3rd generation substituent). In general, this allows us to obtain the functional group R ¹ = Cl.l ₀ alkyl-NH-C1.6alkyl, where C ₁ . ₆ alkyl from NH-C ₁ . ₆ alkyl substituted with Cl. However, in the preferred embodiment, the 3rd generation substituents will not be substituted, i.e. 4th generation deputies will be absent. More preferably, the 2nd generation substituents will not be replaced, i.e. 3rd generation deputies will be absent.

If a residue occurs multiple times in a molecule, then that residue may accordingly have different meanings for different substituents: if, for example,

R ² and R ³ represent C ₁ . ₆ alkyl, then C ₁ . ₆ alkyl may, for example, be ethyl for R and may be methyl for R ³ .

In connection with the terms C ₁ . ₁₀ alkyl, C ₁ . ₆ alkyl, C^alkyl, C ₃ . ₁₀ cycloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₆ alkylene, Smalkylene and C ₁ . ₂ alkylene is the term substituted in the sense of the present invention and, in relation to the corresponding radicals or groups, refers to single substitution (mono-substitution) or multiple substitution (poly-substitution), for example, disubstitution or tri-substitution; more preferably to mono-substitution or dis-substitution; one or more hydrogen atoms independently of each other by at least one substituent. In 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 the same atoms, for example, trisubstituted on the same carbon atom, as in the case of CF ₃ , CH2CF3, or disubstituted, as in the case of 1,1- difluorocyclohexyl, or in different places, as in the case of CH(OH)-CH=CH-CHCl ₂ or 1-chloro-3-fluorocyclohexyl. Multiple substitution can be carried out using one or different substituents.

In accordance with the present invention, C ₁ is preferred. ₁₀ alkyl, C ₁ . ₆ alkyl, C ₁ .4 alkyl, C ₃ . ₁₀ cycloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₆ alkylene, C ₁ .4 alkylene and C ₁ . ₂ alkylene are in each case independently of each other unsubstituted, mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; =O; OC ₁ . ₆ alkyl; NH2; N(H)(C ₁ . ₆ alkyl); N(C ₁ . ₆ alkyl) ₂ .

Preferred substituents for C ₁ . ₁₀ alkyl, C ₁ . ₆ alkyl, C ₁ .4 alkyl, C _3-10 cycloalkyl, C ₃ . ₆ cycloalkyl, C ₁ . ₆ alkylene and C ₁ .4 alkylene are selected from the group consisting of F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; OC ₁ . ₆ alkyl; NH2; N(H)(C ₁ . ₆ alkyl); N(C ₁ . ₆ alkyl) ₂ ; and preferably specifically F, CF ₃ ; CF2H; CFH2; OH, NH2, OCH ₃ , N(CH ₃ ) ₂ . According to this embodiment, C ₁ . ₁₀ alkyl, C ₁ . ₆ alkyl, C ₁ .4 alkyl, C ₃ . ₁₀ cycloalkyl, C ₃ . ₆ cycloalkyl, preferably each independently unsubstituted, mono-, di- or tri-substituted, more preferably unsubstituted or mono-substituted, or disubstituted with a substituent selected from the group consisting of F; Cl; Br; I; CF ₃ ; _CF2H ; CFH ₂ ; HE; OC ₁ . ₆ alkyl; NH2; N(H)(C ₁ . ₆ alkyl); N(C ₁ . ₆ alkyl) ₂ . Preferably _C1 . ₆ alkylene groups and ^^alkylene groups are unsubstituted.

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

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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 a preferred embodiment, R ¹ represents C _1-6 alkyl or _C3-6 cycloalkyl. According to this embodiment, it is preferred that C _1-6 alkyl and C _{3 -6} cycloalkyl are each independently unsubstituted or mono-, di- or tri-substituted with one or more substituents selected from F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; OC _1-6 alkyl; NH2; N(H)(C _1-6 alkyl); N(C _1-6 alkyl) ₂ ; and particularly preferably F, CF ₃ ; CF2H; CFH2; OH, NH2, OCH ₃ , N(CH ₃ )2.

In another preferred embodiment, R ¹ represents C _1-4 alkyl or C _3-6 cycloalkyl; wherein preferably C _1-4 alkyl and C _3-6 cycloalkyl are each independently unsubstituted, mono-, di- or tri-substituted with one or more substituents selected from the group consisting of F, CF ₃ ; _CF2H ; CFH ₂ ; OH, NH ₂ , OCH ₃ , N(CH ₃ ) ₂ .

In another preferred embodiment, R ¹ represents CH ₃ , CF ₃ , CF ₂ H; CFH2; 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, 2-butynyl, 1-butenyl, 2-butenyl, isobutyl, sec-butyl; tert-butyl; (CH2)1-2OCН3; (CH2)i-2OH; (CH2)o-2C(H)(OH)-(CH2)o-2CH3; (СН^ЖСНзь

Preferably R ² represents CN; C _1-6 alkyl; C _3-6 cycloalkyl; O-C _1-6 alkyl; N(H)(C _1-6 alkyl), N(C _1-6 alkyl) ₂ .

In a preferred embodiment, R ² represents CN; C _1-6 alkyl; C _3-6 cycloalkyl; O-C _1-6 alkyl; where preferably C _1-6 alkyl and C _3-6 cycloalkyl are each independently unsubstituted, mono-, di- or tri-substituted with one or more substituents selected from the group consisting of F, CF ₃ ; CF2H; CFH2; OH, NH2, OCH ₃ , N(CH ₃ ) ₂ .

In a particular preferred embodiment, R ² represents CN; methyl; ethyl; ethenyl (vinyl); n-propyl; 2-cut; 1-propynyl; 2-propynyl; propenyl (-CH ₂ CH=CH ₂ ; -CH=CH-CH ₃ ; -C(=CH2)-CH3); n-butyl; isobutyl; sec-butyl; tert-butyl; CF3; CH2CF3; CHF2; CH2CHF2; CH2F; CH2CH2F; OCH ₃ ; OCH ₂ CH ₃ ; OC(H)(CH ₃ ) ₂ ; OCH ₂ CH ₂ CH ₃ ; OC(CH ₃ ) ₃ ; OCF ₃ ; OCH2CF3; OCHF2; OCH2CHF2; OCH2F; OCH2CH2F; CH2OH; CH2CH2OH; CH2C(H)(OH)CH3; CH2CH2CH2OH; CH2CH2CH2CH2OH; C(CH ₃ ) ₂ CH ₂ OH; cyclopropyl; cyclobutyl; cyclopentyl; cyclohexyl.

Preferably R ³ represents H; F; Cl; Br.

In a preferred embodiment

R ² represents CN; C _1-6 alkyl; C _3-6 cycloalkyl; O-C _1-6 alkyl; and/or

R ³ represents H; F; Cl; Br.

In accordance with the present invention, R ⁴ represents F or Cl.

In accordance with the present invention, R ⁵ and R ⁶ are, independently of each other, unsubstituted C1-4 alkyl. Preferably, R ⁵ and R ⁶ are, independently of each other, CH3, CH ₂ CH ₃ ; CH ₂ CH ₂ CH ₃ , CH (CH ₃ ) ₂ or CH ₂ CH ₂ CH ₂ CH ₃ , more preferably H, CH ₃ , CH ₂ CH ₃ or CH ₂ CH ₂ CH ₃ ; even more preferably CH ₃ or CH ₂ CH ₃ ; most preferably CH ₃ . In a particular preferred embodiment, R ⁵ and R ⁶ are both CH ₃ .

In a particular preferred embodiment, the compound of the present invention has the general formula (II) or (III), where X is NR ⁷ and Z is N or CR ⁹ , more preferably CR ⁹ , and where R ⁵ and R ⁶ are both _CH3 .

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

X represents NR ⁷ and Z represents 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 represents 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 represents

- 5 045285 is NH and Z is CR ⁹ .

Still according to this embodiment, the compound of the present invention preferably has the general formula (II) or (III), where X represents NH and Z represents 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 .

In a preferred embodiment, L represents a bond; S(O); S(O)2.

More preferably, L represents a bond; S(O); S(O)2; communication most preferred; S(O) ₂ .

In a preferred embodiment, R ⁸ represents C1_balkyl or C _{3_bCycloalkyl} ; where C3_bCycloalkyl may optionally be connected through a Smalkylene bridge; and preferably wherein C1_balkyl and C3_bCycloalkyl are in each case independently unsubstituted or mono or polysubstituted with one or more substituents selected from the group consisting of F; Cl; Br; I; CF ₃ ; _CF2H ; CFH ₂ ; HE; O-C1_ ₆ alkyl; _NH2 ; X(H)(C1_ ₆ alkyl); X(C1_ ₆ alkyl) ₂ .

More preferably, R ⁸ is C1_balkyl selected from the group consisting of methyl, ethyl, ethenyl (vinyl), n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, t-butyl, npentyl, 2-pentyl , 3-pentyl, 2-methylbutyl, 3-methylbutyl, 3-methylbut-2-yl, 2-methylbut-2-yl, 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 3methylpent-3 -ila; 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; Cs_bCycloalkyl, which is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl and cyclohexenyl; preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl;

where C3_bCycloalkyl may optionally be connected through a C^alkylene bridge; and wherein C1_balkyl and C3_bCycloalkyl are each independently unsubstituted or mono or polysubstituted with one or more substituents selected from the group consisting of F, CF ₃ ; _CF2H ; CFH ₂ ; OH, NH ₂ , OCH3, N(CH ₃ ) ₂ .

More preferably, R ⁸ is 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, CHFCH ₃ , CHFCH ₂ F, CHFCHF ₂ , CHFCF ₃ , CF ₂ CH ₃ , cf ₂ ch ₂ f, cf ₂ chf ₂ , cf ₂ cf ₃ , ch ₂ ch ₂ cf ₃ , ch ₂ ch ₂ chf ₂ , ch ₂ ch ₂ ch ₂ f, ch ₂ chfch ₃ , CH2CHFCH2F, CH2CHFCHF2, ch ₂ chfcf ₃ , ch ₂ cf ₂ ch ₃ , CH2CF2CH2F, CH2CF2CHF2, CH ₂ CF ₂ CF ₃ , CH ₂ OH, CH2CH2OH, C(H)(OH)CH ₃ , CH2CH2CH2OH, C(CH ₃ ) ₂ OH, C(H)(OH)CH ₂ CH ₃ , C(H)(CH ₃ )-CH ₂ OH, CH ₂ C (H)(OH)-CH ₃ , CH2CH2CH2CH2OH, CH ₂ CH ₂ C(H)(OH)CH ₃ , CH ₂ C(H)(OH)CH ₂ CH ₃ , C(H)(OH)CH ₂ CH ₂ CH ₃ , CH ₂ -C(CH ₃ ) ₂ -OH, C(CH ₃ ) ₂ CH ₂ OH, C(H)(OH)CH ₂ CF ₃ , C(H)(OH)CH ₂ CHF ₂ , C(H)(OH)CH ₂ CH ₂ F, CH ₂ C(H)(OH)-CF ₃ , CH ₂ C(H)(OH)-CHF ₂ , CH ₂ C(H)(OH)-CH ₂ F, CH ₂ OCH ₃ , CH ₂ CH ₂ OCH ₃ , C(H)(CH ₃ )-OCH ₃ , CH ₂ CH ₂ CH ₂ OCH ₃ , C(CH ₃ ) ₂ OCH ₃ , C(H)( OCH ₃ )CH ₂ CH ₃ , C(H)(CH ₃ )CH ₂ OCH ₃ , CH ₂ C(H)(OCH ₃ )-CH ₃ , Cl l ₂ CI l ₂ CI l ₂ CI FOCI l ₃ , CH ₂ CH ₂ C(H)(OCH ₃ )CH ₃ , CH ₂ C(H)(OCH ₃ )CH ₂ CH ₃ , C(H)(OCH ₃ )CH ₂ CH ₂ CH ₃ , CH ₂ -C(CH ₃ ) ₂ -OCH ₃ , C(CH ₃ ) ₂ CH ₂ OCH ₃ , CH2NH2, CH ₂ CH ₂ NH ₂ , CH2CH2CH2NH2, C(CH ₃ ) ₂ NH ₂ , C(H)(NH ₂ )CH ₂ CH ₃ , C(H)(CH ₃ )-CH ₂ NH ₂ , CH ₂ C(H)(NH ₂ )-CH ₃ , CH2CH2CH2CH2NH2,

CH ₂ CH ₂ C(H)(NH ₂ )CH ₃ , CH ₂ C(H)(NH ₂ )CH ₂ CH ₃ , C(H)(NH ₂ )CH ₂ CH ₂ CH ₃ , CH ₂ -C( CH ₃ ) ₂ -NH ₂ , C(CH ₃ ) ₂ CH ₂ NH ₂ , CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ N(CH ₃ ) ₂ , CH ₂ CH ₂ CH2N(CH ₃ )2, C(CH ₃ ) ₂ N(CH ₃ ) ₂ , C(H)(N(CH ₃ ) ₂ )CH ₂ CH ₃ , C(H)(CH ₃ )-CH ₂ N(CH ₃ ) ₂ , CH ₂ C(H)(N(CH ₃ ) ₂ )-CH ₃ , CH ₂ CH2CH ₂ CH2N(CH ₃ )2,

CH ₂ CH ₂ C(H)(N(CH ₃ ) ₂ )CH ₃ , CH ₂ C(H)(N(CH ₃ ) ₂ )CH ₂ CH ₃ , C(H)(N(CH ₃ ) ₂ ) CH ₂ CH ₂ CH ₃ , CH ₂ -C(CH ₃ ) ₂ -N(CH ₃ ) ₂ , C(CH ₃ ) ₂ CH ₂ N(CH ₃ ) ₂ .

Preferred embodiments include those wherein L and R ⁸ have the meanings set forth in the table below:________________________________________________________________

L R ⁸ E1 connection (CH ₂ )o-b-C1-1o-alkyl E2 connection (CH ₂ )o-b-C ₃ .1o-cycloalkyl E4 S(O) (CH ₂ )o-b-C1-1o-alkyl E5 S(O) (CH ₂ )o-b-C ₃ .1o-cycloalkyl E7 S(O) ₂ ( _CH2 ) _o.b -C1.1o-alkyl E8 S(O) ₂ (CH ₂ )o-b-C ₃ .1o-cycloalkyl

Preferably

L represents bond; S(O); S(O) ₂ ; And

R ⁸ represents Sbalkyl or C ₃ -Cycloalkyl; where C _{3_bCycloalkyl} may optionally be connected through a Smalkylene bridge.

More preferable

L represents bond; S(O); S(O) ₂ ; communication most preferred; S(O) ₂ ; And

R ⁸ represents C1_balkyl or _{C3_bCycloalkyl} ; where C ₃ _bCycloalkyl may optionally be

-6045285 is connected via a ^^alkylene bridge; and preferably where Ci-balkyl and C ₃ . _b cycloalkyl is in each case independently unsubstituted or mono or polysubstituted with one or more substituents selected from the group consisting of F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; OC _1-6 αlkyl; NH2; N(H)(C _1-6 alkyl); N(C _1-6 alkyl) ₂ .

Preferably R ⁹ is H; C ₁ . _b alkyl or C ₃ . _b cycloalkyl, preferably where C ₁ . _b alkyl and C ₃ . _b cycloalkyl is unsubstituted in each case.

More preferably, R ⁹ is H; methyl, ethyl, n-propyl, 2-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CF ₃ , CHF2, CH2F, CH ₂ CF ₃ , CH2CHF2, CH2CH2F, cyclopropyl, cyclobutyl.

In a particular preferred embodiment, R ⁹ represents H; methyl; ethyl; npropyl; 2-cut; CF3; CH2CF3; CHF2; CH2CHF2; CH2F; CH2CH2F.

Preferably R ¹⁰ represents H; C^alkyl; C ₃ . _b cycloalkyl; and preferably where C ₁ . _b alkyl and C ₃ . _b cycloalkyl is in each case independently unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; OC ₁ . _b alkyl; NH2; N(H)(C1- _b -alkyl); N(C ₁ . _b alkyl) ₂ .

In another preferred embodiment, R ¹⁰ represents H; C _1-6 alkyl; C ₃ .bcycloalkyl; where preferably C ₁ . _b alkyl and C3. _b cycloalkyl is in each case independently unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; O-C _1.4alkyl ; NH2; N(H)(C ₁ .4alkyl); N(C ₁ .4 alkyl) ₂ ; more preferably F, Cl, Br, CF ₃ , OCH ₃ , OH and NH ₂ .

More preferably, R is H; methyl, ethyl, n-propyl, 2-propyl, 1-propynyl, 2propynyl, 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, 3-methyl-1-butynyl, n-butyl, isobutyl, sec-butyl, tert-butyl, CF ₃ , CHF2, CH2F, CH2CF3, CH2CHF2, CH2CH2F , 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, CΞC-C(H)(OH)CH3, C(H)(OH)-CΞC-CH3, CΞC-C(CH3)(OH)CH3, C(CH3) (OH)-СΞС-CHз, 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)(OCH ₃ )CH ₂ CH ₂ CH ₃ , CH ₂ -C(CH ₃ ) ₂ -OCH ₃ , C(CH ₃ ) ₂ CH ₂ OCH ₃ , 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, C C-C(H)(NH2)CH3, C(H)(NH2)-C C-CH3, C C-C(CH3)(NH2)CH3, C(CH3)(NH2)-C CCH3, 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.

In a preferred embodiment, at least one of ^R9 and ^R10 is H.

According to the present invention, n is 0, 1 or 2. 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.

Preferably R ¹¹ represents F; Cl; Br; I; CN; C ₁ . _b alkyl; OC ₁ . _b alkyl; preferably where C ₁ . _b alkyl is unsubstituted or mono- or polysubstituted with one or more substituents selected from the group consisting of F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; OC ₁ .4alkyl; NH2; N(H)(C ₁ .4alkyl); N(C ₁ .4 alkyl) ₂ ; more preferably F, Cl, Br, CF ₃ , OCH ₃ , OH and NH2.

In a particular preferred embodiment, R ¹¹ represents F; Cl; Br; I; CN; C ₁ . _b alkyl or OC ₁ . _b alkyl; preferably where C ₁ . _b alkyl is in each case 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 O-CH ₂ CH ₃ .

In a particular preferred embodiment, R ¹¹ represents F; Cl; Br; I; CN; C ₁ . _b alkyl or OC ₁ . _b alkyl; and/or n is 0, 1 or 2.

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

- 7 045285

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

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

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

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

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

2-[6-Fluoro-4-(6-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl)- 1H- indol-1-yl]-EUN

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

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

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

1 -Cyclopropyl-6-fluoro-8-(6-fluoro-1-methyl sulfonyl-1H-indol-4-yl)-9- 8 045285 methoxy-4,4-dimethyl-5H-[1,2,4] triazolo[4,3-a]quinoxaline

1-Cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-8-(1-methylsulfonyl-1Nindol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline

2-[4-(1-Cyclopropyl-6-fluoro-9-methoxy-4,4-d imethyl-5H-[1,2,4]triazolo[4,3 a]quinoxalin-8-yl)-6- fluoro-1H-indol-1-yl]-EUN

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

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

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

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

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

300 6-Fluoro-8-[1 -(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

301 2-[4-(6-Fluoro-1,4,4,9-tetramethyl-5E1-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-

N-ind ol-1 -yl]-EUN

304 6-Fluoro-1,4,4,9-tetramethyl-8-(1 -methyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

305 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

308 1 -Ethyl-6-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-

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

316 1-Ethyl-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4,9-trimethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline

322 1 -Ethyl-6-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-4,4,9-trimethyl-5H[1,2,4]triazolo[ 4,3-a]quinoxaline

- 9 045285

323 1-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-4,4,9-trimethyl5H-[1,2,4]triazolo[4,3- a]quinoxaline

326 8-[1-(2,2-Difluoroethyl)-1H-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4 ,3-a]quinoxaline

340 6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3-a] quinoxaline

349 6-Fluoro-8-[1 -(fluoromethylsulfonyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 -а ]quinoxaline

350 8-[1-(Ethylsulfonyl)-1H-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H-

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

352 6-Fluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol-7-yl)-5H-

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

355 1-Ethyl-6-fluoro-4,4,9-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-

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

366 6-Fluoro-8-[1 -(isopropylsulfonyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

374 1-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-4,4,9trimethyl-5H-[1,2,4]triazolo[4,3- a]quinoxaline

375 [2-[4-(6-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)1H-indol-1 -yl]-ethyl]-dimethyl-amine

378 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

389 1-Ethyl-6-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

391 8-[1-(Cyclopropylsulfonyl)-1H-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

446 8-[1-(Ethylsulfonyl)-6-fluoro-1H-indol-4-yl]-6,7-difluoro-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4, 3-a]quinoxaline

447 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl- 10 045285

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

448 6,7-Difluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

449 2-[4-(6,7-Difluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8yl)-6-fluoro-1 N-indol-1-yl]-EtOH

450 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline-9-carbonitrile

451 6,7-Difluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

452 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3- a]quinoxaline

453 [6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a] quinoxalin-9-yl]-MeOH

454 6-Chloro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 -а ]quinoxaline

455 9-(Difluoromethyl)-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo [4,3-a]quinoxaline

456 6-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

457 6-Chloro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3 -a ]quinoxaline

458 6-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-

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

459 9-(Difluoromethyl)-6-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4yl)-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

460 9-(Difluoromethyl)-8-[1 -(ethylsulfonyl)-b-fluoro-1H-indol-4-yl]-6-fluoro-1,4,4trimethyl-5H-[1,2,4] triazolo[4,3-a]quinoxaline

461 9-(Difluoromethyl)-8-[1-(ethylsulfonyl)-1H-indol-4-yl]-6-fluoro-1,4,4trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

- 11 045285

462 9-(Difluoromethyl)-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

463 2-[4-(6-Chloro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6fluoro-1 H- ind ol-1 -yl]-EUN

464 2-[4-(9-Ethyl-6-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8yl)-6-fluoro-1 N-ind ol-1 -yl]-EtOH

465 6-Fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

466 9-(Difluoromethyl)-6-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H[1,2,4]triazolo[4,3 -a]quinoxaline

467 9-Cyclopropyl-6-fluoro-8-(6-fluoro-1 - methyl sulfonyl-1H-indazol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

468 6-Fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

469 6-Fluoro-8-(1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

470 6-Fluoro-8-(6-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

471 9-Cyclopropyl-6-fluoro-8-(6-fluoro-1 - methyl sulfonyl-1 H-indol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

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

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

474 9-Cyclopropyl-6-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl) 5H-[1,2,4]triazolo[4,3- a]quinoxaline

475 6-Fluoro-1,4,4,9-tetramethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a ]quinoxaline

476 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4- 12 045285 yl)-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline

477 4-(6-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nindol-6-carbonitrile

478 8-(3-Cyclopropyl-5-fluoro-1H-indol-7-yl)-6-fluoro-9-methoxy-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3- a]quinoxaline

479 [8-[1-(Ethylsulfonyl)-b-fluoro-1H-indol-4-yl]-6-fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3- a]quinoxalin-9-yl]-methyl-amine

480 2-[6-Fluoro-4-(6-fluoro-1,4,4-trimethyl-9-methylamino-5H-[1,2,4]triazolo[4,3a]quinoxalin-8-yl)- 1H -indol-1-yl]-EUN

481 [8-( 1 -Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline-9- yl]-methyl-amine

482 6-Chloro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

483 6-Chloro-8-(6-fluoro-1 - methyl sulfonyl-1H-indol-4-yl)-9-methoxy-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

484 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline

485 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline

486 [6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a] quinoxalin-9-yl]-methyl-amine

487 [6-Fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a] quinoxalin-9-yl]-methyl-amine

488 6-Chloro-8-(6-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-

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

489 6-Fluoro-8-(7-fluoro-1H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-

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

490 6-Fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

- 13 045285

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

492 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-[1-methylsulfonyl-b-(trifluoromethyl)1H-indol-4-yl]-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

493 6-Chloro-8-(6-fluoro-1 - methyl sulfonyl-1H-indazol-4-yl)-9-methoxy-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

494 6-Fluoro-8-(7-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-

[1,2,4]tri-azolo[4,3-a]quinoxaline

495 6-Fluoro-8-(6-fluoro-1H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-

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

496 6-Fluoro-8-(6-fluoro-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline

497 8-[1-(Cyclopropyl-methylsulfonyl)-b-fluoro-1H-indol-4-yl]-6-fluoro-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

498 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-9-methoxy-1,4,4trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

499 6,7-Difluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl) 5H-[1,2,4]triazolo[4,3- a]quinoxaline

500 6,7-Difluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-9(trifluoromethyl)-5H-[1,2,4]triazolo[4,3 -a]quinoxaline

501 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-9-methoxy-1,4,4trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

502 6-Chloro-7-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3 -a ]quinoxaline

503 6-Chloro-7-fluoro-8-(6-fluoro-1 - methyl sulfonyl-1H-indol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

504 6-Fluoro-8-(1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

505 8-[1 -(Cyclopropylsulfonyl)-1H-indol-4-yl]-6-fluoro-9-methoxy-1,4,4- 14 045285 trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

506 8-(6-Chloro-1H-indol-4-yl)-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

507 6-Fluoro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indazol-4-yl]-5H-

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

508 6-Chloro-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-

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

509 6-Chloro-7-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)5H-[1,2,4]triazolo[4,3-a ]quinoxaline

510 6-Chloro-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline

511 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-9-methoxy-1,4,4-trimethyl-5H-

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

512 6,7-Difluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

513 6,7-Difluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indol-7-yl)-5H-

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

514 6,7-Difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-

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

515 6-Fluoro-8-(5-fluoro-1H-indol-7-yl)-9-methoxy-1,4,4-trimethyl-5H-

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

516 6,7-Difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-

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

517 6-Fluoro-8-(7-fluoro-1 H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-

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

518 6,7-difluoro-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

519 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-9 (trifluoromethyl)-5H-[1,2,4] triazolo[4,3-a]quinoxaline

- 15 045285

520 4-(6,7-Difluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)1 H-indol-7 -carbonitrile

521 6,7-Difluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-

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

522 6,7-Difluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3- a]quinoxaline

523 6-Fluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3-a] quinoxaline

524 6-Fluoro-9-methoxy-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3- a]quinoxaline

525 7-Chloro-6-fluoro-8-(6-fluoro-1 - methyl sulfonyl-1H-indazol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline

526 7-Chloro-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-

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

527 7-Chloro-6-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)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 can be synthesized by standard reactions in the field of organic chemistry known to one skilled in the art, or by the method described herein (see Reaction Scheme 1 below), or the like. The reaction conditions of the synthetic routes described herein are known to one skilled in the art and, for some cases, are shown in the examples described herein.

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 (see Metal Catalyzed Cross-Coupling Reactions and More, 3 Volume Set Wiley, 2014; Angew. Chem. Int. Ed, 2012, 51, 5062 - 5085). Favorable C-C cross-coupling reactions are cross-coupling reactions catalyzed by palladium (cf. Angew. Chem., 2005, 117, 4516 - 4563). Triazole cyclization of compound (II) gives compounds of general formula (III). Triazole formation on quinoxalines is known in the art (see Heterocycles, 1992, 34, 771-780; Biological and Pharmaceutical Bulletin, 2005, 28, 1216-1220). Electrophilic aromatic bromination of compound (III) gives compound (IV). Bromination reactions of aromatic compounds are well known (see Science of Synthesis, Compounds with One Saturated Carbon-Heteroatom Bond, Volume 35, Houben-Weyl, 2007). If desired, a compound of formula (II)

- 16 045285 can be brominated into compound (V), which can undergo a metal-catalyzed cross-coupling reaction to give compound (VI). The formation of a triazole leads to an alternative route to 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, 25312537). The compounds of formula (I) are commercially available or can be prepared by methods known in the art.

The compounds of the present invention may be prepared by the method described herein or in a similar manner.

In a preferred embodiment, the compounds of the present invention are glucocorticoid receptor modulators. For purposes of the present invention, the term selective glucocorticoid receptor modulator preferably means that the corresponding compound in a cellular target binding assay for glucocorticoid receptor agonist or antagonist activity exhibits a glucocorticoid receptor EC50 or IC50 value of no more than 15 µM (10 x 10'6 mol/L ) or no more than 10 µM; more preferably no 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 no 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 (agonist or antagonist) of glucocorticoid receptor activity. Preferred target binding assays for testing compounds for their agonist or antagonist activity (EC50, IC50) at the glucocorticoid receptor are described below herein.

Cellular assays of the glucocorticoid receptor.

Potential selective glucocorticoid receptor modulators of the present invention can be tested for modulation of glucocorticoid receptor activity using cell-based assays. Such assays use a Chinese hamster ovary (CHO) cell line that contains glucocorticoid receptor fragments 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 receptor ligands. More specifically, the ligand binding domain of the glucocorticoid receptor is fused to the DNA binding domain (DBD) of the transcription factor GAL4 (GAL4 DBD-GR) and stably integrated into a CHO cell line containing a GAL4-UAS-luciferase reporter construct. To identify selective glucocorticoid receptor modulators, a 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 produced by luciferase upon addition of substrate is detected and EC50 or IC50 values can be calculated. Engagement of molecules that induce gene expression by glucocorticoid receptor binding to DNA results in luciferase gene expression under the control of the GAL4 DBD-GR fusion protein and hence a dose-dependent increase in the luminescence signal. The binding of molecules that suppress beclomethasone-induced luciferase gene expression under the control of the GAL4 DBD-GR fusion protein leads to a dose-dependent decrease in the luminescence signal.

In a preferred embodiment, a compound of the present invention exhibits a glucocorticoid receptor EC50 or IC50 value of no more than 1 μM (10 ^-6 mol/L) in a cellular target binding assay for glucocorticoid receptor agonist or antagonist activity; 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 no 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 cellular 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 from 1 nM to 800 nM; even more preferably from 1 nM to 500 nM; even more preferably from 1 nM to 300 nM; most preferably from 1 nM to 100 nM; and in particular from 1 nM to 80 nM.

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

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

Thus, the present invention also provides a compound of the present invention for use in modulating glucocorticoid receptor activity.

Thus, another aspect of the present invention relates to a compound of the present invention for use in the treatment and/or prevention of a disorder mediated by

- 17 045285 at least partially by the 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.

A further aspect of the invention relates to the use of a compound of the present invention as a medicament.

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

The dosage form in accordance with the present invention is preferably prepared 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 on the route of administration, indication and severity of the disease. Preferably 0.001 to 100 mg/kg, more preferably 0.05 to 75 mg/kg, most preferably 0.05 to 50 mg of the compound of the present invention is administered per kg of body weight of the patient.

It is believed that the glucocorticoid receptor can potentially 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 of 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 of treating 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(P); Ar = argon; BISPIN (or Bis-Pin) = bis(pinacolato)diborane; dba = dibenzylideneacetone; DAST = (diethylamino)sulfur trifluoride; DXM = DXM; DIPEA = N,Ndiisopropylethylamine; DIBAL-H = diisobutylaluminum hydride; DMA = dimethylacetamide; DMADMFA = N,N-dimethylformamide dimethyl acetal; DMAP = 4-(dimethylamino)-pyridine; DMF = N,Ndimethylformamide; DMSO = dimethyl sulfoxide; dppf = 1.1';bis(diphenylphosphanyl)ferrocene; EtOAc = EtOAc; EtOH = EtOH; h = hour; LAH = lithium aluminum hydride; LDA = lithium diisopropylamide; LiHMDS = lithium bis(trimethylsilyl)amide; m _c = centered multiplet; MeOH = MeOH; min = minute; MTBE = methyl tert-butyl ether; n-BuLi = n-butyllithium; room pace. = room temperature; Rt = retention time; tert = tertiary; TEA = triethylamine; THF = tetrahydrofuran; p-TSA = paratoluenesulfonic acid; TMSCl = trimethylsilyl chloride; X-Phos = 2-dicyclohexylphosphino-2',4',6'triisopropylbiphenyl; XANTphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.

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

- 18 045285

Br i) DMADMF/dioxane bp. reverse, cold, pyrrolidine

i) LsOH/powder Feboil. from the reverse, cold.

Vg

Stage-1

Step 1: N,N-dimethylformamide dimethyl acetal (13 .3 ml, 100 mmol, 5 equiv.), pyrrolidine (1.47 ml, 20 mmol, 1 equiv.). Then the reaction mixture was stirred for 18 hours at 100°C. The reaction mixture was concentrated to obtain 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 hour. The reaction mixture was then cooled to room temperature and then filtered through a layer of celite. The filtrate was neutralized with 50% sodium hydroxide solution and then extracted with ESO Ac (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, 30%) as a brown liquid.

Step 2: Stirred suspension of 4-bromo-6-fluoro-1H-indole (1.1 g, 5.1 mmol, 1 eq.), bis(pinacolato)diborane (2.6 g, 10.2 mmol, 2 eq. .) and potassium acetate (2.0 g, 20.4 mmol, 4 eq.) in 1,4dioxane (20 ml) deoxygenated Ag for 10 min Pd ₂ (dba) ₃ (0.07 g, 0.07 mmol , 0.015 eq.) and tricyclohexylphosphine (0.102 g, 0.36 mmol, 0.07 eq.) were then added to the reaction mixture and Ag was deoxygenated again 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 yield crude material, which was purified by column chromatography to yield 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2yl)-1H-indole (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).

tricyclohexyl phosphine dioxane 1 U ^with C

KOLs

Pdidbaj

In between! connection A-2

Stage 2

Step 1: To a stirred solution of 4-bromo-6-fluoro-1H-indole (0.18 g, 0.841 mmol, 1 eq.) in DMF (5 ml), sodium hydride (60%, 0.07 g, 1.0 eq.) was added in portions. 68 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 minutes at room. 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 then stirred for 2 hours at room. pace. The reaction mixture was diluted with EA Ac (50 ml). The combined organic layers were washed with water (5x0 ml), brine (10 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-6-fluoro-1-2(methylsulfonyl)-1H-indole (0.1 g, 41%) as a white metallic solid.

Step 2: Stirred suspension of 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indole (1.2 g, 3.53 mmol, 1 eq.), bis-pinacolate diborane (1.79 g, 7.06 mmol, 2 eq.) and potassium acetate (1.39 g, 10.62 mmol, 4 eq.) in 1,4-dioxane (20 ml) deoxygenated Ag for 10 min Pd ₂ (dba) ₃ (0.048 g, 0.052 mmol, 0.015 eq) and tricyclohexylphosphine (0.071 g, 0.25 mmol, 0.07 eq) were then added to the reaction mixture and Ag was deoxygenated again 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 the 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 1-(ethylsulfonyl)-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole

- 19045285 (intermediate connection A-8).

trshclohexylphosphate -A-4^. dioxane by ^: with ''

Stage-? Intermediate connection a 8

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), sodium hydride (60%, 0.224 g, 9. 34 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 minutes at room. pace. Ethanesulfonyl 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 hours at room. 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 metallic solid.

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

Step 1: Sodium hydride (60%) (0.122 g, 3.06 mmol, 1.2 eq.) at 0°C and continued stirring at room. pace. over 30 min Acetyl chloride (0.02 mL, 3.06 mmol, 1.2 eq.) was then added to the reaction mixture and stirred again for a further 2 h. 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-Shindol-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 1,4dioxane (20 ml) was deoxygenated with Ar for 10 min Pd2(dba)3 (0.106 g, 0.1155 mmol, 0.08 eq.), Cy3P (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 filtrate was concentrated under reduced pressure to give crude material, which was purified by column chromatography to give 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanoneα (0.600 g , 92%) in the form of 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).

- 20 045285

Intermediate A 11

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 container. 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 the crude product, which was purified by flash column chromatography to obtain a mixture, which was further purified by preparative HPLC to obtain 4-bromo-6-fluoro-1-(2,2,2-trifluoroethyl)-1H-indole (0.400 g, 14%) as a white metallic solid.

Step 2: Stir solution of 4-bromo-6-fluoro-1-(2,2,2-trifluoroethyl)-1H-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 filtrate was concentrated under reduced pressure to obtain crude material, which

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).

°< _S C _Λ / MeSO ₂ CI 'S~ _o Bis-Ριη .'MaH.'THF

Stage-1 KOAc/CyjP.’θ

I PtUfdbaty O' O

Dioxane HO'CJ

Stage-2' '

Intermediate connection Λ 12

Step 1: To a stirred solution of 4-bromo-1H-indole (1.0 g, 5.1 mmol, 1 eq.) in DMF (20 ml), sodium hydride (60%, 0.245 g, 10.2 mmol, 2 eq.) at 0°C. The reaction mixture was then stirred for 30 minutes at room. 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 hours at room. 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 metallic solid.

Step 2: Stirred suspension of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole (0.36 g, 1.31 mmol, 1 eq.), bis(pinacolato)diborane (0.66 g, 2.62 mmol, 2 eq.) and potassium acetate (0.57 g, 5.25 mmol, 4 eq.) in 1,4-dioxane (10 l) deoxygenated Ar for 10 min Pd ₂ (dba) ₃ (0.018 g, 0.019 mmol, 0.015 eq.) and tricyclohexylphosphine (0.027 g, 0.094 mmol, 0.072 eq.) were then added to the reaction mixture and deoxygenated Ar again for 10 min The reaction mixture was then stirred for 14 hours 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 yield crude material, which was purified by column chromatography to yield 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III- indole (0.31 g, 73%) as a white solid with a metallic tint.

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

- 21 045285

Intermediate connection A-15

Step 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 eq.) at -60°C under nitrogen. The reaction mixture was then stirred at the same temperature for 4 hours. The reaction mixture was quenched with a saturated ammonium chloride solution at -60°C. The resulting mixture was then extracted with EtOAc (2x100 ml), washed with brine and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography to give 7-bromo-5-fluoro-3-methyl-1H-indole (0.3 g, 58%) in the form of a thick yellow liquid.

Step 2: KOAC (1, 43 g, 14.67 mmol, 4 eq.) and bispinacolatodiborane (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 refluxed for 16 hours. After completion of the reaction (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-1,3,2dioxaborolan-2-yl)-1H-indole (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).

Step 1: Powdered potassium hydroxide (4.56 g, 81.77 mmol, 2 .5 eq.). The reaction mixture was then stirred for 30 minutes at room. temp. 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 saline (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 brown solid matter.

Step 2: LiHMDS (1 M) was added dropwise 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). (91.15 ml, 91.15 mmol, 5 eq.) 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 heated to room temperature. pace. and then stirred for 16 hours. The reaction mixture was quenched by adding saturated ammonium chloride solution (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 an off-white solid.

Step 3. A stirred suspension of 7-bromo-5-fluoro-3-iodo-1-(methoxymethyl)-III-indole (2.7 g, 7.03 mmol, 1 eq.), cyclopropylboronic acid (1.84 g, 2.03 mmol, 3 eq.), K3PO4 (4.5 g, 21.05 mmol, 3 eq.) in 1,4-dioxane (45 ml) 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

- 22 045285 deoxygenated for 10 minutes. Finally, 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 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: Into a stirred solution of 7-bromo-3-cyclopropyl-5-fluoro-1-(methoxymethyl)-1H-indole (1.25 g, 4.19 mmol, 1 eq.) in a mixture of MeOH and 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 hours. The reaction mixture was cooled to room. pace. and concentrated under reduced pressure to obtain a residue. The residue was diluted with EtOAc (100 ml) and washed with water (2x40 ml) and saline (40 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-3-cyclopropyl-5-fluoro1H-indole (0.57 g, 54%) as a colorless liquid .

Step 5: Stirred suspension of 7-bromo-3-cyclopropyl-5-fluoro-1H-indole (0.57 g, 2.24 mmol, 1 eq.), bis-pinacolate diborane (1.7 g, 6.73 mmol, 3 eq.) and potassium acetate (0.66 g, 6.73 mmol, 3 eq.) in 1,4-dioxane (20 ml) were deoxygenated with Ar for 10 min Pd ₂ (dba) ₃ (0.031 g, 0.033 mmol , 0.015 eq.) and tricyclohesylphosphine (0.047 g, 0.168 mmol, 0.075 eq.) were then added to the reaction mixture and deoxygenated again 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. pace. and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to yield crude material, which was purified by column chromatography to yield 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 2-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethan-1-ol (intermediate connection A-20).

S71Ш4Я-1 St*yay-2

Joksdv 9O-S

SpaiZ

Intermediate connection A-20

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 eq.) at 0°C. The solution was stirred at room. pace. for 30 min followed by the addition of (2-bromoethoxy)(tert-butyl)dimethylsilane (1.17 g, 4.67 mmol, 2.0 eq.) and the reaction mixture was stirred at room temperature. pace. for 2 hours. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (20 ml) and the organic layer was washed with cold water (5x10 ml), saline (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-fluoro1H-indole (0.85 g, 98%) as a brown liquid containing (2- bromoethoxy)(tert-butyl)dimethylsilane as an impurity.

Step 2: Into a stirred solution of 4-bromo-1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-fluoroSH-indole (1.3 g, 3.49 mmol, 1 eq.) in THF (15 ml) TBAF (3.49 ml) (1 M) was added at rt. pace. and the mixture was stirred for 16 hours. After completion of the reaction (monitored 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), 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 2-(4-bromo-6-fluoro-1H-indol-1-yl)ethan-1-ol (0.55 g, 61%) as a brown liquid.

Step 3: Stir solution of 2-(4-bromo-6-fluoro-1H-indol-1-yl)ethan-1-ol (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 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through layer of celite. The filtrate was concentrated under reduced pressure to obtain crude 2-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl) ethan-1-ol, 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)ethan-1ol (intermediate A-21).

- 23 045285

Intermediate A-21

Step 1: K ₂ CO ₃ (0.38 g, 2 .79 mmol, 3.0 eq.) at room. pace. and the mixture was stirred for 20 min. Then bromoethane-1-ol (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 (monitored by TLC), the reaction mixture was quenched with ice water and extracted with EtOAc (3x20 ml), washed with H ₂ O (3x20 ml), brine (25 ml), dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography to give 2-(4-bromo-6-fluoro-1H-indazol-1yl)ethan-1-ol (0.12 g, 50%) as a white solid.

Step 2. Into a solution of 2-(4-bromo-6-fluoro-1H-indazol-1-yl)ethan-1-ol (0.9 g, 3.473 mmol, 1 eq.) in 1,4dioxane (60.0 ml) KOAc (1.02 g, 10.419 mmol, 3 eq.) and bispinacolatodiborane (1.76 g, 6.947 mmol, 2.0 eq.) were added. 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 refluxed for 16 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give 2-(6-fluoro-4-(4,4 ,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indazol-1-yl)ethan-1-ol (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).

Intermediate connection A-22

Step 1: To a stirred solution of 4-bromo-1H-indazole (1.0 g, 5.07 mmol, 1 eq.) in DMF (25 ml) add sodium hydride (60%, 0.406 g, 10.152 mmol, 2 eq.) in portions .) at 0°C. The reaction mixture was stirred for 30 minutes at room. 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 hours at room. 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 230400 mesh 10% EtOAc/hexane; R _g value -0.5) to give 4-bromo-1-(methylsulfonyl)-1H-indazole (0.95 g, 69%) as light -yellow solid.

Step 2: Stirred suspension of 4-bromo-1-(methylsulfonyl)-1H-indazole (0.95, 3.45 mmol, 1 eq.), bis(pinacolato)diborane (1.75 g, 6.91 mmol, 2 eq.) and potassium acetate (1.01 g, 10.36 mmol, 3 eq.) in 1,4-dioxane (35 ml) were 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 deoxygenated again with Ar for 10 minutes. The reaction mixture was stirred for 14 hours at 110°C. The reaction mixture was cooled to room. pace. and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to yield a crude material, which was purified by column chromatography (silica gel 230-400 mesh, 10% EtOAc/hexane; R _f -value -0.45) to yield 1-(methylsulfonyl)-4-(4.4 ,5,5-tetramethyl-1,3,2dioxaborolan-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).

- 24 045285

Step 1: To a stirred solution of 4-bromo-6-fluoro-1H-indazole (1.2 g, 5.58 mmol, 1 eq.) in DMF (30 ml), sodium hydride (60%, 0.446 g, 11 .16 mmol, 2 equiv.) at 0°C. The reaction mixture was then stirred for 30 minutes at room. 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 hours at room. 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: Into a stirring 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 equiv.), potassium acetate (1.3 g, 13.3 mmol, 3 equiv.) in 1,4-dioxane (45 ml) was deoxygenated with Ar for 10 min with Pd(ipp1)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 minutes. The reaction mixture was stirred for 14 hours 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 the crude material, which was purified by column chromatography (silica gel 230-400 mesh, 10% EtOAc/hexane; _Rί- value -0.45) to give 6-fluoro-1-(methylsulfonyl)-4- (4,4,5,5tetramethyl-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 eq.) at 0°C. The reaction mixture was then stirred for 30 minutes at room. 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 hours at room. 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 (230-400 mesh silica gel 20% EtOAc/hexane; R _g value -0.6) to give 4-bromo-6-fluoro-1-(2-methoxyethyl)-1Hindole (0.63 g, 99%) in the form of a brown resin.

Step 2: Into a stirring suspension of 4-bromo-6-fluoro-1-(2-methoxyethyl)-1H-indole (0.8 g, 2.94 mmol, 1 eq.), bis-pinacolate diboron (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 added

PyCl2(ipp1)-DCM (0.239 g, 0.29 mmol, 0.01 eq.) and the reaction mixture was stirred for 14 hours 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 the crude product, which was purified by column chromatography (silica gel 230-400 mesh 5% EtOAc/hexane; _Rί- 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 a light brown resinous 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 ).

- 25 045285

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, 2,2difluoroethyl 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 obtain the crude product, which was purified by column chromatography (silica gel 100-200 mesh; TLC system: EtOAc/ hexane (3:7); Rg-O.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) deoxygenated with Ar for 10 min Palladium(II) 1,1'-bis(diphenylphosphino)ferrocene complex dichloride and DCM (0.03 g, 0.0361 mmol, 0.05 eq.) were then added to the reaction mixture, and the reaction mixture was heated at 100°C for 16 h (LC-MS). The reaction mixture was then cooled to room. temp., filtered through a pad of celite, 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 1-cyclopropyl-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-III-indole (intermediate A-27).

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 hours at 65°C. The solvent was removed under reduced pressure and azeotroped twice with MeOH. The residue was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane; R _r value -0.6) to give 4-bromo-1-cyclopropyl-6-fluoro-1H-indole (0.85 g, 13% ) as a brown liquid.

Step 2: Stirred suspension of 4-bromo-1-cyclopropyl-6-fluoro-1H-indole (0.85 g, 3.35 mmol, 1 eq.), bis(pinacolato)diborane (1.7 g, 6.7 mmol, 2 eq.) and potassium acetate (1.31 g, 13.38 mmol, 4 eq.) in 1,4dioxane (20 ml) were deoxygenated with Ar for 10 min Pd ₂ (dba) ₃ (0.046 g, 0. 05 mmol, 0.015 eq) and ohmtricyclohexylphosphine (0.067 g, 0.24 mmol, 0.072 eq) were then added to the reaction mixture and deoxygenated again with Ar for 10 min. The reaction mixture was stirred for 14 h at 110°C. The reaction mixture was cooled to room. pace. and then filtered through a layer of celite. The filtrate was concentrated under reduced pressure to obtain a crude material, which was purified by column chromatography (silica gel 230-400 mesh, 20% EtOAc/hexane; R _g 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.

Ή NMR (400 MHz; DMSO-D 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)-III-indole (intermediate A-71).

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Intermediate A 71

Mixture of 7-bromo-5-fluoro-1H-indole (1 g, 4.7 mmol, 1 eq.), bis(pinacolato)diborane (2.02 g, 7.9 mmol, 1.7 eq.), acetate potassium (917 mg, 9.4 mmol, 2 eq.), 1,1'-bis(diphenylphosphino)ferrocenepalladium(P) dichloride complex and dichloromethane (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 (monitored by LC-MS), saturated 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-fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (940 mg, 77%).

Intermediates in table. 1 was synthesized in a similar manner to Intermediate A1 - Intermediate A-27._________________________________________________

Intermediate connection Synthesized similarly Structure Int. connection-A-ZO Int. connection-A-2 O(L * Int. connection-A-42 Int. connection-A-11 /V^p Ο-σί GM Int. connection-A-43 Int. connection-A-11 O^tn O

- 27 045285

Int. connection-A-44 Int. connection-A-27 Ο-αί Int. connection-A-45 Int. connection-A-2 O-CD -n^\\ O ABOUT Int. connection-A-46 Int. connection-A-P O-sp ^ζ Int. connection-A-47 Int. connection-A-2 Ο-αί \ ω- _η w ° О Int. connection-A-48 Int. connection-A-2 Ο-αί ^O Int. connection-A-54 Int. connection-A-22 ^>f^o O-SP Gu=/ 'O Int. connection-A-bZ Int. connection-A-22 Ο-αί ^,о l \ ° Int. connection-A-59 Int. connection-A-21 \Ζ co-O Int. conn.-A-bb Int. connection-A-22 O Ζ co-O

- 28 045285

Int. connection-A-68 Int. connection-A-22 F \jQ. Int. connection-A-72 Int. connection-A-22 Oh-so Int. connection-A-73 Int. connection-A-21 F Int. connection-A-75 Int. connection-A-71 Ο-πί rw Z Int. connection-A-76 Int. connection-A-22 o Z t-O Int. connection-A-77 Int. connection-A-22 Ch/ Z /=K J /°LO tn-O _ο γ<

Intermediates in table. 2 are commercially available.

Name Structure 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)6-(trifluoromethyl)-1H-indole Ο^αί 0=/ \ z X 5-fluoro-1H-indole-4-boronic acid pinacol ester

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2-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2H-indole U O V ^N \ 1-methyl-4-(4,4,5,5-tetramethyl- [1,3,2]dioxaborolan-2-yl)-1H-indazole X N^· 4-(tetramethyl-1,3,2-dioxaborolan-2-yl)2-(trifluoromethyl)-1H-indole y? Ek \-F F F 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-ind azole ex Y^NH tert-butyl-4-(4,4,5,5-tetramethyl-1,3,2d ioxaborolan-2-yl)-1 H-ind azol-1 carboxylate J o XoX =N ^X But. ^b'oh indole-4-boronic acid n-A n J 1,1-dimethylethyl-4-(4,4,5,5-tetramethyl1,3,2-dioxaborolan-2-yl)-1 H-ind ol-1 carboxylate z 3-methyl-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indol y? Qi (7-chloro-1 H-ind azol-4-yl)boronic acid BUT, D but 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2d ioxaborolan-2-yl) 1 H-ind azole A° F LX NH 7-methoxy-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-ind azole A°t X 1 IX 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-7-(trifluoromethyl)1H-indazole O--C0 ^^ ^CF 3 X Ύγιη

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(6-(trifluoromethyl)-1H-indazol-4yl)boronic acid CF ₃ no. "LL\ in y NH NO (6-fluoro-1H-indazol-4-yl)boronic acid F NO.LLD in y NH NO M 7-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indazole F Md ^NH Vo L 7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-indole cm Z -T1 I 7-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-indole O-so Um I 6-methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1 H-indole oV )=\ / SM ° ^z I (1H-indol-7-yl)boronic acid But. L L B γΜ BUT HN-/ 3-Methyl-1 H-indazole-7-boronic acid in\M BUT HN-n 4-(4,4,5,5-Tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-ind ol-6carbonitrile t Z /=< J “Ό 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-ind azole co-O 7-fluoro-4-(tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indole Ο-αί Ohm Ζ -p I

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6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-ind azole F ' ΝΗ A° 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indol CI _ΝΗ x° 7-chloro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indol Ooo UA GM 1 2 7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indol Ο-αί See -π I 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl) 1H-indazole τ / ^z 'z CQ-O 6-chloro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1 H-indol Cl M -V V NH x° 4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-6-(trifluoromethyl)1H-indazole fM Λ°'Λη V.O.

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

Intermediate B-7

Step 1: To a stirred solution of 5-fluoro-2-methyl-phenylamine (100 g, 0.8 mol) in DCM (1500 ml) was added pyridine (129 ml, 1.6 mol) followed by DMAP (1 g, 0.008 mol) at room pace. Pivalolyl chloride (109 mL, 0.88 mol) was added dropwise to this reaction mixture at 0°C. The resulting reaction mixture was stirred at 0°C for 2 hours. After consumption of the starting material, the reaction mixture was poured into ice-cold 1(N) HCl (1500 ml) and stirred for 30 minutes. The two layers were separated and the organic layer was washed with 1(N) solution. .) HCl (1000 ml) followed by washing with saturated NaHCO ₃ solution (1000 ml), brine (1000 ml), and then dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain

- 32 045285 crude product. The crude product was triturated using hexane to give N(5-fluoro-2-methyl-phenyl)-2,2-dimethylpropionamide (158 g, 95%) as a white solid.

Step 2: To a stirred solution of N-(5-fluoro-2-methyl-phenyl)-2,2-dimethylpropionamide (90 g, 0.43 mol) in toluene (2000 ml) was added p-toluenesulfonic acid monohydrate (82 .0 g, 0.43 mol), Pd(OAC) ₂ (9.66 g, 0.043 mol) followed by the addition of N-bromosuccinimide (84.5 g, 0.473 mol) at room. pace. The resulting reaction mixture was stirred at room. pace. for 48 hours. The reaction, monitored by TLC in 20% EA-Hex, showed the formation of the desired product (Rf0.4) along with ~60% of the starting material unreacted (Rf0.5). The reaction mixture was then concentrated and the resulting residue was diluted with EtOAc and washed with water (twice). The entire organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated to obtain the crude product. Two combined batches of crude product (prepared from 90 g and 100 g of N-(5-fluoro-2-methyl-phenyl)-2,2-dimethylpropionamide reaction mixture) were purified by flash chromatography to give N-(2-bromo- 3-fluoro-6-methyl-phenyl)-2,2-dimethyl-propionamide (60 g, 23%) as a white solid and N-(5-fluoro-2-methyl-phenyl)-2,2- dimethylpropionamide, which did not react (125 g).

Step 3. N-( ₂ - _bromo -3-fluoro-6-methyl-phenyl)-2,2-dimethylpropionamide (60 g, 0.208 mol) at 0°C. The resulting reaction mixture was stirred at room. pace. for 10 min and then heated to 100°C for 2 h. After consumption of the starting material (monitored by TLC in 10% EA-Hex, R _f 0.8), the reaction mixture was cooled to 0°C and the pH was adjusted to ~10 using 10% NaOH solution. The resulting bulk aqueous portion was extracted with EtOAc (3x500 ml). All organic layers were washed with water followed by brine, dried over anhydrous Na2SO4 and concentrated to give the crude product. The crude product was purified by column chromatography to give 2-bromo-3-fluoro-6-methyl-phenylamine (36 g, 85%) as a pale yellow liquid.

Step 4: To a stirred suspension of 2-bromo-3-fluoro-6-methyl-phenylamine (36 g, 0.1764 mol) in dry DMSO (540 ml) was added 2-amino-2-methyl-propionic acid (16.9 g, 0.164 mol) followed by the addition of K3PO4 (75 g, 0.353 mol) at room. pace. The resulting reaction mixture was degassed with nitrogen for 30 minutes, then CuCl (1.75 g, 0.0176 mol) was added and the reaction mixture was heated at 140°C for 5 hours. After consumption of the starting material (monitored by TLC, 20% EA- hexane, R _f 0.4) 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 (2500 ml). The resulting aqueous layer was extracted with EtOAc (2x750 ml). The entire organic portion was washed with water (2x750 ml) followed by brine (500 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain the crude product. The resulting crude product was triturated with hexane, filtered and dried to give 5fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (19 g, 52%) as a brown solid.

Step 5: To a solution of 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (19 g, 91.2 mmol) in toluene (380 ml) was added Lawesson's reagent (55 .5 g, 137 mmol) at room. pace. and the reaction mixture was refluxed at 120°C for 1 hour. After consumption of the starting material (monitored by TLC in 20% EA-hexane, R _f 0.7), the reaction mass was cooled to room. pace. and extinguished the saturation. NaHCO ₃ solution (250 ml), and the resulting aqueous layer was extracted with EtOAc (3x250 ml). The combined organic layers were washed with water (250 ml), then with brine (250 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to obtain the crude product. The resulting crude product was purified by column chromatography to give 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2-thione (19 g, 93%) as a yellow solid.

Step 6: To a stirred solution of 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2-thione (20.5 g, 91.5 mmol) in THF (512 ml) was added drops hydrazine hydrate (13.5 ml, 274.5 mmol) at 0°C. The reaction mixture was stirred at room. pace. over 16 hours. TEA (64 ml, 457.5 mmol), then acetyl chloride (21.5 ml, 274.5 mmol) was added dropwise to the reaction mixture at 0°C and stirred for 2 hours at room temperature. pace. After consumption of the starting material (the progress of the reaction was monitored using LC-MS), the reaction mixture was diluted with water (500 ml), extracted with 10% MeOH-DCM (5x500 ml). The entire organic portion was washed with brine (250 ml), dried over Na2SO4 and concentrated under reduced pressure to give (5-fluoro-3,3,8-trimethyl-3,4-dihydro-1Hquinoxalin-2-ylidene)-acetic acid hydrazide (21 g, 87%, crude) as a pale yellow solid.

Step 7: (5-Fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-ylidene)-acetic acid hydrazide (10.5 g, 0.04 mol) was placed in a round bottom flask ( 100 ml) and then cooled to -10°C. Phosphorus oxalyl chloride (18.5 ml, 0.2 mol) was then added dropwise, followed by dropwise addition

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TEA (5.6 ml, 0.04 mol). After this, the reaction mixture was stirred at -10°C for 10 minutes and then 10 minutes at room. pace. and finally refluxed for 1 hour. After consumption of the starting material (monitored by LC-MS), the reaction was cooled to 0°C and quenched with crushed ice water (100 ml). The aqueous portion was then made alkaline using cold aqueous ammonia (100 ml) dropwise. The resulting bulk aqueous portion was then extracted with EtOAc (3x150 ml). The entire organic portion was washed with brine (150 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude compound. The crude product was co-distilled with MTBE twice, then triturated with hexane and dried to give 6-fluoro-1,4,4,9-tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a] quinoxaline (6 g, 61%) as a pale yellow solid.

Step 8. Into a solution of 6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (12 g, 0.048 mol) in DMF ( 360 ml) NBS (9.39 g, 0.0528 mol) was added in portions at -10°C. The resulting reaction mixture was stirred at room. pace. for 4 hours. After consumption of the starting material (monitored by LC-MS), the reaction mixture was diluted with water (500 ml) and extracted with EtOAc (2x500 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 compound. The resulting crude product was purified by column chromatography followed by trituration with MTBE to give 8bromo-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3 -a]quinoxaline (9.1 g, 57%) as an off-white solid.

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

Become! ^SPI “ ²

Steel 7 cctmtm B-9

Step 1. Stirred suspension of Pd(dppf)Cl ₂ DCM (1.03 g, 1.27 mmol, 0.1 eq.) and Cs ₂ CO ₃ (16.5 g, 50.63 mmol, 4 eq.) in DMF (78 ml) deoxygenated Ar for 5 min with 5-Fluoro-2-iodaniline (3.0 g, 12.65 mmol, 1 equiv.) and triethylborane (1 M) (16.45 ml, 16.45 mmol , 1.5 eq.) was added to the reaction mixture and re-deoxygenated with Ar for 10 min. As a result, the reaction mixture was stirred for 16 h at 70°C. The reaction mixture was cooled to room. pace. and then diluted with EtOAc (100 ml). The organic layer was washed with water (5x20 ml) and brine (20 ml), dried over Na ₂ SO ₄ , concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (230-400 mesh silica gel; 10% EtOAc/hexane; R _f -0.5) to give 2-ethyl-5-fluoroaniline (1.20 g, 68%) as crude -white solid.

Step 2: Into a stirred solution of 2-ethyl-5-fluoroaniline (2.0 g, 14.38 mmol 1 eq), pyridine (2.31 ml, 28.77 mmol, 2 eq) and DmAp (0.018 g, 0.144 mmol, 0.01 eq.) in DCM (50 ml) was added dropwise pivaloyl chloride (1.91 g, 15.82 mmol, 1.1 eq.) at 0°C. The reaction mixture was then stirred for another 1 hour at 0°C and then poured into ice-cold HCl (20 mL) (1 M). The organic layer was separated and the aqueous layer was extracted with Et ₂ O (2x20 ml). The combined organic layer was washed with water (2x20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude material. The crude product was purified by column chromatography (230-400 mesh, silica gel; 10% EtOAc/hexane; Rf value - 0.5) to give N-(2-ethyl-5-fluorophenyl) pivalamide (2.3 g, 72% ) as an off-white solid.

Step 3: Add p-TSA (19.3 g, 112 .1 mmol, 1 eq.), Pd(OAc) ₂ (2.52 g, 11.21 mmol, 0.1 eq.) and NBS (21.5 g, 123.3 mmol, 1.1 eq.) respectively at room pace. The reaction mixture was stirred for 48 hours at room. pace. under environmental conditions. The solvent was evaporated and the residue was dissolved in EtOAc (1000 ml) and washed with water (2x200 ml) then brine (200 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude material. The crude product was purified by column chromatography (230

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400 mesh, silica gel; 10%EtOAc/hexane; Rf value - 0.45) to give N(2-bromo-6-ethyl-3fluorophenyl)pivalamide (5.0 g, 15%) as an off-white solid.

Step 4: 70% H ₂ SO ₄ (70 ml) was added to N-(2-bromo-6-ethyl-3-fluorophenyl)pivalamide (9.2 g, 30.46 mmol, 1 eq.) in a round bottom flask at 0°C. The reaction mixture was stirred for 20 minutes at 0°C and for 2 hours at 110°C. The reaction mixture was then cooled to 0°C and made alkaline with a 20% NaOH solution to pH~14. The aqueous portion was extracted with EtOAc (3x150 ml).

The combined organic layers were washed with water (2x100 ml) and brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude material. The crude product was purified by column chromatography (230-400 mesh silica gel; 5% EtOAc/hexane; Rf value -0.5) to give 2-bromo-6-ethyl-3fluoroaniline (5.9 g, 89%) as brown liquid.

Step 5: Suspension of 2-bromo-6-ethyl-3-fluoroaniline (4.9 g, 22.47 mmol, 1 eq.), 2-amino-2methylpropanoic acid (4.63 g, 44.94 mmol, 2 eq. .), K ₃ PO ₄ (9.54 g, 44.94 mmol, 2 eq.) and copper chloride (0.22 g, 2.247 mmol, 0.1 eq.) in dry DMSO (75 ml) in a hermetically sealed The test tube was deoxygenated with Ar for 20 min. The reaction mixture was then stirred at 140°C for 2 h. After completion of the reaction, the reaction mixture was cooled to room. pace. and 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 Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh, silica gel; 20% EtOAc/hexane; Rf value -0.4) to give 8-ethyl-5-fluoro-3,3-dimethyl-3,4dihydroquinoxaline-2( 1H)-one (2.83 g, 57%) as a light brown solid.

Step 6. Into a solution of 8-ethyl-5-fluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (3.4 g, 15.3 mmol, 1 eq.) in toluene (110 ml) Lawesson's reagent (8.03 g, 19.89 mmol, 1.3 eq.) was added at room. pace. and the reaction mixture was refluxed at 120°C for 40 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ solution (80 ml) followed by extraction with EtOAc (2x70 ml). The combined organic layers were washed with water (80 ml), brine (80 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 20% EtOAc/ hexane; Rf value -0.6) to give 8-ethyl-5-fluoro-3,3dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (3.0 g, 82%) as a yellow solid.

Step 7: Into a stirred solution of 8-ethyl-5-fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (3.0 g, 12.58 mmol, 1 eq.) in THF ( 50 ml) hydrazine hydrate (3.03 ml, 62.93 mmol, 5 eq.) was added dropwise at 0°C. The reaction mixture was stirred for 16 hours at room. pace. TEA (8.56 mL, 62.93 mmol, 5 eq.) was added to the reaction mixture and stirred for another 10 min. Acetyl chloride (2.7 mL, 37.74 mmol, 3 eq.) was added very slowly to the reaction mixture at 0°C and then stirred for 2 hours at room. pace. The reaction mixture was quenched with water (100 ml) and extracted with DCM (3x100 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 the crude material, which was purified by washing with diethyl ether to give N'-(8-ethyl5-fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2 (1H)-ylidene)acetohydrazide (3.4 g, 97%) as an off-white solid.

Step 8. N'-(8-Ethyl-5-fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-ylidene)acetohydrazide (3.4 g, 12.23 mmol, 1 eq. ) was placed in a round bottom flask (100 ml) and cooled to -10°C. Phosphorus oxychloride (11.7 mL, 122.3 mmol, 10 eq.) was then added dropwise to the compound, followed by dropwise addition of TEA (1.66 mL, 12.23 mmol, 1 eq.). The reaction mixture was stirred at -10°C for 10 minutes and then for 10 minutes at room. pace. and as a result, heated to reflux for 2 hours. The reaction mixture was cooled to 0°C and then added dropwise to crushed ice with constant stirring. A cold ammonia solution was slowly added to the aqueous part until pH ~12. The aqueous portion was extracted with DCM (3x100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain crude material. The crude product was purified by column chromatography (230-400 mesh, silica gel; 5% MeOH/DCM; Rf value -0.4) to give 9-ethyl-6-fluoro-1,4,4-trimethyl-4,5- Dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.4 g, 44%) as a light yellow solid.

Step 9: Stirred solution of 9-ethyl-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (1.4 g, 5.38 mmol , 1 eq.) in DMF (30 ml) at -10°C were treated in portions for 10 min with solid N-bromosuccinimide (1.01 g, 5.65 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), 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 Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (230-400) (5% MeOH/DCM; _R value 0.4) to give 8-bromo-9-ethyl-6-fluoro1,4,4- trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.45 g, 80%) as an off-white solid.

^1H NMR(400 MHz; DMSO^, 20°C): δ 7.54-7.56 (1H), 6.69 (s, 1H), 2.82-2.85 (2H), 2.38 (s, 3H), 1.46 (br s, 3H), 0.94-0.97 (3H).

Synthesis of 8-bromo-6-fluoro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-10).

Step 1. Into an ice-cold solution of 3-bromo-4-fluorophenol (100 g, 523.56 mmol, 1 eq.) and ammonium nickel(II) sulfate hexahydrate (103.4 g, 261.77 mmol, 0.5 eq. .) fuming nitric acid was added dropwise to DCM (1000 ml) and the reaction mixture was stirred at the same temperature for 3 hours (TLC). The reaction mixture was poured into crushed ice and diluted with DCM. The extracted organic layer was washed with saline; the organic layer was dried over Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography (230-400 mesh, silica gel, TLC system: EtOAc/hexane (2:8); R _f = 0.2) to give 3-bromo-4-fluoro-2-nitrophenol (35 g , 28%).

Step 2: Potassium carbonate (61.48 g, 444.91 mmol, 3 eq.) and iodomethane (63.15 g, 444.91 mmol, 3 eq.) and the reaction mixture was heated at 80°C for 4 hours. Once complete (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water . The extracted organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh, silica gel, TLC system: EtOAc/hexane (2:8); R _f = 0.6) to give 2-bromo-1-fluoro4-methoxy-3-nitrobenzene ( 35 g, 94%).

Step 3. Iron powder (78, 17 g, 1400 mmol, 10 eq.) and ammonium chloride (74.886 g, 1400 mmol, 10 eq.). The reaction mixture was heated to reflux for 12 hours. Once complete (monitored by TLC), the reaction mixture was filtered through a pad of celite. The filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (230-400 mesh, silica gel, TLC system: EtOAc/hexane (2:8); R _f = 0.6) to give 2-bromo-3-fluoro-6methoxyaniline (30 g, 97 %).

Step 4. Suspension of 2-bromo-3-fluoro-6-methoxyaniline (30 g, 136.36 mmol, 1 eq.), 2-aminoisobutyric acid (44.65 g, 340.83 mmol, 2.5 eq.), DBU (49.70 g, 272.21 mmol, 2 eq.) and copper iodide (2.59 g, 13.59 mmol, 0.1 eq.) in dry DMA (300 ml) in a round bottom flask were deoxygenated with Ar for 20 min The reaction mixture was then stirred at 120°C for 16 hours. Once the reaction was complete (monitored by TLC), it was filtered through a pad of celite and washed with EtOAc (500 ml), washed with water (3x500 ml), brine (500 ml) , dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (230-400 mesh, silica gel; TLC system: EtOAc/hexane (2:8); R _f = 0.3 ) to give 5-fluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (14 g, 46%) as a brown solid.

Step 5: Into a solution of 5-fluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (14 g, 62.22 mmol, 1 eq.) in toluene (150 ml) add Lawesson's reagent (37.75 g, 93.33 mmol, 1.5 eq.) at room. pace. and the reaction mixture was refluxed at 120°C for 1 hour. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ solution (200 ml) followed by extraction with EtOAc (2x200 ml). The combined organic layers were washed with water (300 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 using 230-400 mesh silica gel and 10% EtOAc in hexane as elution solvent to give 5-fluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (10 g,

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67%) as a yellow solid. TLC system: EtOAc/hexane (2:8); Rf0.4).

Step 6: A solution of 5-fluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (10 g, 41.61 mmol, 1 eq.) in n-BuOH (100 ml) acetic acid hydrazide (10.80 g, 145.93 mmol, 3.5 eq.) was added followed by acetic acid (10 ml) and then the reaction mixture was stirred at 140°C for 16 hours. After completion of the reaction ( monitored by TLC) the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2x50 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 using 5% MeOH in DCM as elution solvent and silica gel 230-400 mesh to obtain 6-fluoro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3.5 g, 32%) as an off-white solid (TLC system, 5% MeOH in DCM, Rf-0.2).

Step 7: Stirred solution of 6-fluoro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (3.5 g, 13.34 mmol , 1 eq.) in DMF (30 ml) at 0°C were treated in portions for 10 min with solid N-bromosuccinamide (2.48 g, 13.93 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 30 minutes. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (50 ml) and the organic layers were washed with water (3x100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure . The crude product was purified by column chromatography using 1.5% MeOH in DCM as elution solvent and 230-400 mesh silica gel to give 8-bromo-6-fluoro-9-methoxy-1,4,4-trimethyl-4 ,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.9 g, 42%) as an off-white solid (TLC system, 5% MeOH in DCM, Rf-0.4) .

^1H NMR (400 MHz; DMSO- _D6 , 20°C): δ 7.58 (d, 1H), 6.73 (s, 1H), 3.56 (s, 3H), 2.44 (s , 3H), 1.49 (s, 3H), 1.46 (s, 3H).

Synthesis of 8-bromo-1-cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (intermediate B-11).

Stage I Intermediate B-11

Step 1: A solution of 5-fluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (10 g, 41.61 mmol, 1 eq.) in n-BuOH (100 ml) cyclopropanecarbonyl hydrazide (14.58 g, 145.62 mmol, 3.5 eq.) was added followed by acetic acid (10 ml) and then the reaction mixture was stirred at 140°C for 16 hours. After completion of the reaction (monitored by TLC) reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2x50 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 using 5% MeOH in DCM as elution solvent and silica gel 230-400 mesh to give 1-cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2.6 g , 32%) as an off-white solid.

Step 2: Stirred solution of 1-cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2.6 g, 9. 02 mmol, 1 eq.) in DMF (30 ml) at 0°C were treated in portions for 10 min with solid N-bromosuccinamide (1.68 g, 9.43 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 30 minutes. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (50 ml) and the organic layers were washed with water (3x100 ml), brine (100 ml), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography using 1.5% MeOH in DCM as elution solvent and 230-400 mesh silica gel to give 8-bromo-1-cyclopropyl-6-fluoro-9-methoxy4,4-dimethyl-4 ,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.8 g, 55%) as an off-white solid.

Synthesis of 8-bromo-1-cyclopropyl-6-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-12).

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Step 1: Into a stirred solution of 5-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (1.7 g, 7.58 mmol, 1 eq.) in THF (40 ml ) hydrazine hydrate (1.72 mL, 37.94 mmol, 5 eq.) was added dropwise at 0°C. The reaction mixture was stirred for 16 hours at room. pace. TEA (5.13 mL, 37.94 mmol, 5 eq.) was added to the reaction mixture and stirred for an additional 10 min. Cyclopropanecarbonyl chloride (2.39 g, 22.76 mmol, 3 eq.) was added very slowly to the reaction mixture at 0°C and then stirred for 2 hours at room. pace. The reaction mixture was diluted with water (100 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 the crude product, which was purified by washing with diethyl ether to give N'-(5-fluoro-3,3,8-Ίrimethyl-3,4-dihydroquinoxaline-2( 1H)-ylidene)cyclopropancarbonylhydrazide (2.1 g, 95%) as an off-white solid.

Step 2: N'-(5-Fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-ylidene)cyclopropanecarbonylhydrazide (1.44 g, 4.96 mmol, 1 eq.) was added into a round bottom flask (50 ml) and then cooled to -10°C. Phosphorus oxychloride (4.7 mL, 49.65 mmol, 10 eq.) was then added dropwise to the compound, followed by dropwise addition of TEA (10.67 mL, 4.96 mmol, 1 eq.). After this, the reaction mixture was stirred at 10°C for 10 minutes and then 10 minutes at room. pace. and finally refluxed for 2 hours. The reaction mixture was cooled to 0°C and then added dropwise into crushed ice with constant stirring. A cold ammonia solution was slowly added to the aqueous part until pH ~12. The aqueous portion was extracted with DCM (3x50 ml). The combined organic layer was washed with brine (50 ml). The organic layer was dried over anhydrous Na2SO4, concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM; Rf value -0.4) to give 1-cyclopropyl-6-fluoro-4,4,9-trimethyl-4,5- Dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.24 g, 18%) as a light yellow solid.

Step 3. Stirred solution of 1-cyclopropyl-6-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.55 g, 2. 02 mmol, 1 eq.) in DMF (15 ml) at -10°C were treated in portions for 10 min with solid N-bromosuccinimide (0.36 g, 2.02 mmol, 1 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (80 ml) and the organic layers were washed with water (5x20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and the solvent were evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (230-400) (5% MeOH/DCM; Rf value -0.4) to give 8-bromo-1-cyclopropyl6-fluoro-4,4,9-trimethyl-4, 5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.55 g, 78%) as an off-white solid.

^1H NMR (400 MHz; DMSO- _O6 , 20°C): δ 7.58 (d, 1H), 6.58 (s, 1H), 2.45 (s, 3H), 1.71-1 .77 (1H), 1.44 (bs, 6H), 1.02-1.27 (4H).

Synthesis of 8-bromo-1-ethyl-6-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-30).

connection B-30

Step 1: To a stirred solution of 5-fluoro-2-methyl-phenylamine (100 g, 0.8 mol, 1 eq.) in DCM (1.5 L) was added pyridine (129 ml, 1.6 mol, 2 eq. ) followed by the addition of DMAP (1 g, 0.008 mol, 0.01 eq.) at room temperature. To this reaction mixture was added dropwise pivalolyl chloride (109 ml, 0.88 mol, 1.1 eq.) at 0°C and the resulting reaction mixture was stirred at 0°C for 2 hours. After consumption of the starting material (monitored by TLC in 10% EtOAc-Hex, R _f 0.7), the reaction mixture was poured into an ice-cold 1 N solution. HCl (1.5 L) and stirred for 30 min

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The two layers were separated and the organic layer was washed with 1N solution. HCl (1 L), then saturated Nai K'(')3 solution (1 L) and brine (1 L), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. This crude residue was triturated using hexane to give N-(5-fluoro-2-methyl-phenyl)-2,2-dimethylpropionamide (158 g, 95%) as a white solid.

Step 2: To a stirred solution of N-(5-fluoro-2-methyl-phenyl)-2,2-dimethylpropionamide (90 g, 0.43 mol, 1 eq.) in toluene (2 L) was added para- toluenesulfonic acid (82.0 g, 0.43 mol, 1 eq.) and Pd(OAc)2 (9.66 g, 0.043 mol, 0.1 eq.) followed by the addition of N-bromosuccinimide (84.5 g, 0.473 mol, 1.1 eq.) at room temperature and the resulting reaction mixture was stirred at room temperature for 48 hours. The reaction, which was monitored by TLC (20% EtOAc in hexanes), showed the formation of the desired product (Rf 0.4) together with ~60% of the starting material unreacted (Rf 0.5). The second batch was then run starting with 100 g of N(5-fluoro-2-methyl-phenyl)-2,2-dimethylpropionamide, following the same procedure as described above. The combined reaction mixtures from the two batches (total 190 g of starting material) were then concentrated and the resulting residue was dissolved in Et(Ac) and washed with water (twice). The combined organic layers were then dried over anhydrous Na ₂ S( ₄ and concentrated under reduced pressure. Crude residue purified by column chromatography (100-200 mesh silica gel; 1-5% EtOAc/hexane eluent) to give N-(2-bromo-3-fluoro-6-methyl-phenyl)-2,2dimethylpropionamide ( 60 g, 22.9%) as a white solid along with isolated unreacted starting material (125 g).

Step 3: To a pre-cooled solution of 70% H ₂ SO ₄ in water (430 ml) was added N-(2-bromo3-fluoro-6-methyl-phenyl)-2,2-dimethylpropionamide (60 g, 0.208 mol, 1 equiv.) in portions at 0°C and the resulting reaction mixture was stirred at room temperature for 10 minutes and then heated at 100°C for 2 hours. After consumption of the starting material (monitored by TLC in 10% EtOAc-hexane, Rf 0 ,8) the reaction mixture was cooled to 0°C and the pH was adjusted to ~10 using a 10% NaOH solution. The resulting bulk aqueous fraction was extracted with EtOAc (3x500 ml), the combined organic layers were washed successively with water and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain a crude residue. It was purified by column chromatography (silica gel, 100-200 mesh; 1-3% EtOAc/hexane eluent) to give 2-bromo-3-fluoro-6-methyl-phenylamine (36 g, 85%) as a pale -yellow liquid.

Step 4: To a stirred suspension of 2-bromo-3-fluoro-6-methyl-phenylamine (36 g, 0.1764 mol, 1 eq.) in dry DMSO (540 ml) was added 2-amino-2-methyl-propionic acid (16.9 g, 0.1636 mol, 0.93 eq.) followed by the addition of K ₃ PO ₄ (75 g, 0.3528 mol, 2 eq.) at room temperature. The resulting reaction mixture was degassed with nitrogen for 30 minutes, then CuCl (1.75 g, 0.0176 mol, 0.1 eq.) was added and the reaction mixture was heated at 140°C for 5 hours. After consumption of the starting material (monitored by TLC, 20% EtOAc-hexane, Rf 0.4) the reaction mixture was cooled to room temperature and filtered through a pad of celite. After washing with EtOAc (500 ml), the resulting filtrate was poured into ice water (2.5 L) and the resulting aqueous fraction was extracted with EtOAc (2x750 ml). The combined organic layers were washed with water (2x750 ml) and brine (500 ml), dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtain a crude residue. It was triturated with hexane, filtered and dried to give 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (19 g, 52%) as a brown solid.

Step 5: To a solution of 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (19 g, 91.2 mmol, 1 eq.) in toluene (380 ml) Lawesson's reagent (55.5 g, 137 mmol, 1.5 eq.) at room. pace. and the reaction mixture was refluxed at 120°C for 1 hour. After consumption of the starting material (monitored by TLC in 20% EtOAc-hexane, Rf 0.7), the reaction mass was cooled to room temperature and quenched with sat. NaHCO ₃ solution (250 ml) and the resulting aqueous fraction was extracted with EtOAc (3x250 ml). The combined organic layers were washed with water (250 ml) and brine (250 ml), dried over anhydrous Na2SO4 and evaporated under reduced pressure. The resulting crude residue was purified by column chromatography (silica gel 100-200 mesh; 3-5% EtOAc/hexane) to give 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1Hquinoxaline-2-thione (19 g, 93%) as a yellow solid.

Step 6: Into a stirred solution of 5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2-thione (9 g, 0.0401 mol, 1 eq.) in tetrahydrofuran (225 ml) hydrazine hydrate (6.02 g, 0.1203 mol, 3 eq.) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 hours. Triethylamine (27.8 ml, 0.2006 mol, 5 eq. .) and propanyl chloride (10.5 ml, 0.1203 mol, 3 eq.) were added dropwise to the reaction mixture at 0°C and it was stirred for 2 hours at room temperature. After consumption of the starting material (monitored by LC-MS), the reaction mixture was diluted with water (250 ml) and extracted with 10% MeOH-DCM (5x250 ml). United

- 39 045285 the organic layers were washed with saline (250 ml), dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain (5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2 -ylidene)propionic acid hydrazide (12.5 g crude material) as an off-white solid.

Step 7: Crude (5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-ylidene)-propionic acid hydrazide (12.5 g, 0.0449 mol, 1 eq.) placed in a round bottom flask, then cooled to -10°C. Phosphorus oxalyl chloride (20.9 mL, 0.2243 mol, 5 eq.) was then added dropwise to the compound, followed by dropwise addition of triethylamine (6.25 mL, 0.0449 mol, 1 eq.). The reaction mixture was then stirred at -10°C for 10 minutes, followed by stirring at room temperature for 10 minutes and finally refluxed for 4 hours. After consumption of the starting material (monitored 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 adding cold ammonia solution (250 ml) dropwise. The resulting bulk aqueous fraction was extracted with EtOAc (3x500 ml) and the combined organic layers were washed with brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by trituration using MTBE to give 1-ethyl-6-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (6.5 g, 56%) as an off-white solid.

Step 8. Into a solution of 1-ethyl-6-fluoro-4,4,9-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (10 g, 0.0384 mol, 1 eq.) in DMF (250 ml), NBS (7.52 g, 0.0422 mol, 1.1 eq.) was added in portions at -10°C and the resulting reaction mixture was stirred at room temperature for 4 hours. After consumption of the starting material material (monitored by LC-MS), the reaction mixture was diluted with water (500 ml) and extracted with EtOAc (2x250 ml). The combined organic layers were washed with water (500 ml) and brine (400 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM eluent) to give 8-bromo-1-ethyl-6-fluoro-4,4,9-trimethyl-4,5 -dihydro[1,2,4]triazolo[4,3a]quinoxaline (7.5 g, 58%) as an off-white solid.

Synthesis of 8-bromo-6,7-difluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-38).

connection B-38

Step 1: To a suspension of 4,5-difluoro-2-methylaniline (0.5 g, 3.49 mmol, 1 eq.) in DCM (30 ml) was added Br ₂ (0.55 g, 0.17 ml, 3 .49 mmol, 1 eq.) in DCM (20 ml) at 0°C. The reaction mixture was then stirred at room. pace. for 2 hours. After the starting material was consumed, the reaction mass was quenched with a saturated solution of NaHCO ₃ (50 ml). The organic layer was separated and the aqueous layer was extracted with DCM (50 ml). The combined organic layers were washed with water (150 ml), then brine (150 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 10% EtOAc /hexane; R _r value 0.6) to give 2-bromo-3,4-difluoro-6-methylaniline (0.4 g, 52%).

Step 2. Suspension of 2-bromo-3,4-difluoro-6-methylaniline (0.25 g, 1.13 mmol, 1 eq.), 2-aminobutyric acid (0.23 g, 2.26 mmol, 2 eq.) in DMA (10 ml) in a hermetically sealed tube, Ar was deoxygenated for 20 min, DBU (0.35 ml, 2.26 mmol, 2 eq.) and CuI (0.02 g, 0.113 mmol, 0.1 eq.) were added and the reaction mixture was stirred at 140°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 (100 ml) and washed with water (3x150 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain the crude product, which was purified using column chromatography (100 -200 mesh, silica gel; 30% EtOAc/hexane; R _r value 0.4) to give 5,6-difluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)one (0.2 g, 75%).

Step 3. Into a solution of 5,6-difluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1P)-one (3.66 g, 17.6 mmol,

- 40045285 eq.) in toluene (75 ml) was added Lavesson's reagent (10.67 g, 26.2 mmol, 1.5 eq.) at room. pace. and the reaction mixture was heated at 120°C for 40 minutes. After completion of the reaction (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), 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 (230-400 mesh, silica gel; 20% EtOAc/ hexane; _Rf value -0.4) to give 5,6-difluoro-3,3,8-trimethyl-3,4dihydroquinoxaline-2(1H)-thione (2.8 g, 71%) as a yellow solid .

Step 4: Into a stirred solution of 5,6-difluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (5.50 g, 24.55 mmol, 1 eq.) in THF ( 30 ml) hydrazine hydrate (5.17 ml, 122.76 mmol, 5 eq.) was added dropwise at 0°C. The reaction mixture was then stirred for 16 hours at room. pace. TEA (16.7 ml, 122.76 mmol, 5 eq.) was added to the reaction mixture and stirred for another 10 min. Acetyl chloride (5.78 g, 73.65 mmol, 3 eq.) was added very slowly at 0°C and then the mixture was stirred for 2 hours at room. pace. The reaction mixture was diluted 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 the crude material, which was purified by washing with diethyl ether to give N'-(5,6-difluoro3,3,8-trimethyl-3,4-dihydroquinoxaline-2 (1H)-ylidene)acetohydrazide (5.5 g, 85%) as a white solid.

Step 5 N'-(5,6-Difluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-ylidene)acetohydrazide (5.5 g, 20.8 mmol, 1 eq.) was placed into a round bottom flask (50 ml) and 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 dropwise addition of TEA (2.9 mL, 20.8 mmol, 1 eq.). After this, the reaction mixture was stirred at -10°C for 10 minutes and then 10 minutes at room. pace. and finally refluxed for 4 hours. The reaction mixture was cooled to 0°C and then added dropwise into crushed ice with constant stirring. Cold ammonia solution (100 ml) was slowly added to the aqueous part. The aqueous portion was extracted with DCM (2x100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 5% MeOH/DCM; Rf value - 0.4) to give 6. 7difluoro-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 6: Stirred solution of 6,7-difluoro-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 were treated in portions for 10 min with solid N-bromosuccinimide (3.1 g, 17.1 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), 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 were evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel (230-400) (5% MeOH/DCM; R _f -0.3) to give 8-bromo-6, 7-difluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3.3 g, 63%) as an off-white solid substances.

Synthesis of 8-bromo-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-carbonitrile (intermediate B-39).

Intermediate connection B-39

Stirred solution of 6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9carbonitrile (for synthesis, see intermediate B-41) (2 .0 g, 7.78 mmol, 1 eq.) in DMF (20 ml) at 0°C were treated in portions for 10 min with solid N-bromosuccinimide (1.38 g, 7.78 mmol, 1 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (100 ml) and the organic layers were washed with water (5x100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent were evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography on silica gel (230-400) (5% MeOH/DCM; R _f -0.3) to give 8-bromo-6- fluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-carbonitrile (1.5 g, 58%) as an off-white solid.

- 41 045285

Synthesis of (8-bromo-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-yl)MeOH (intermediate B- 41).

Step 1. Solution of 6-fluoro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (for synthesis, see intermediate B- 10) (12 g, 45.80 mmol, 1 eq.) in aqueous HBr (350 ml) was heated to 80°C and then acetic acid (100 ml) was added and heating was continued at 120°C for 48 hours. completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice water (1000 ml) and made alkaline with sodium bicarbonate (pH>8). The reaction mixture 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, which was purified by column chromatography using 3% MeOH in DCM as elution solvent and silica gel 230-400 mesh to give 6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-ol (8 g, 70 %) as an off-white solid (TLC system, 5% MeOH in DCM, Rp0.2).

Step 2. In an ice-cold solution of 6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-9-ol (8 g, 32.25 mmol , 1 eq.) in DCM, TEA (4.89 g, 48.32 mmol, 1.5 eq.) and DMAP (5.91 g, 48.37 mmol, 1.5 eq.) were added and the mixture was stirred at at the same temperature for 10 minutes. Then trifluoromethanesulfonic anhydride (10.92 g, 38.70 mmol, 1.2 eq.) was added dropwise and the mixture was stirred for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with ice-cold water (1000 ml) and the reaction mixture was extracted with DCM (2x500 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, which was purified by column chromatography using 2% MeOH in DCM as elution solvent and silica gel 230-400 mesh to obtain 6-fluoro-1,4-dimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-yl-trifluoromethanesulfonate (4 g, 33%) in the form of a liquid. (TLC system, 5% MeOH in DCM, Rf-0.5).

Step 3. Into an argon-purged solution of 6-fluoro-1,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-9-yl-trifluoromethanesulfonate (4 g, 10.52 mmol , 1 eq.) in 1,4-dioxane were added N,N'dimethylethylenediamine (0.611 g, 37.67 mmol, 0.5 eq.) and zinc cyanide (0.962 g, 10.52 mmol, 1 eq.) and the mixture stirred for 10 min. Then Pd ₂ (dba) ₃ (1.089 g, 1.052 mmol, 0.1 eq.) and xantphos (0.611 g, 1.05 mmol, 0.1 eq.) were added and the reaction mixture was purged for another 5 min, and the reaction mixture was heated to 100°C for 12 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite. The filtrate was concentrated in vacuo to give the crude product, which was purified by column chromatography using 4% MeOH in DCM as elution solvent and 230-400 mesh silica gel to give 6-fluoro1,4,4-trimethyl-4,5-dihydro [1,2,4]triazolo[4,3-a]quinoxaline-9-carbonitrile (3 g, 37%) as liquid (TLC system, 5% MeOH in DCM, Rf-0.4).

Step 4. Into a solution of 6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9carbonitrile (0.1 g, 0.389 mmol, 1 eq.) in toluene (5 ml) was added DIBAL-H (0.2 ml, 0.389 mmol, 1 eq.) at 0°C. The reaction mixture was stirred at the same temperature for 3 hours. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with NH ₄ Cl and extracted with EA. 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 the crude product, which was purified by column chromatography to give 6-fluoro-1,4,4trimethyl-4,5-dihydro [1,2,4]triazolo[4,3-a]quinoxaline-9-carbaldehyde (0.04 g, 34%) as a brown solid.

Step 5. Into a solution of 6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9carbaldehyde (0.04 g, 0.15 mmol , 1 eq.) in THF (5 ml) was added LAH (0.005 g, 0.15 mmol, 1 eq.) at 0°C. The reaction mixture was stirred at the same temperature for 3 hours. After completion of the reaction

- 42 045285 reaction (monitored by TLC), the reaction mixture was quenched with saturated Na ₂ SO ₄ solution and extracted with EA. 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 the crude product, which was purified by column chromatography to give (6-fluoro-1,4,4-trimethyl4,5- Dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-yl)MeOH (0.01 g, 25%) as a brown gum.

Step 6: Stir solution of (6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-9-yl) MeOH (0.18 g, 0.692 mmol, 1 eq.) in DMF (15 ml) at 0°C were treated in portions for 10 min with solid N-bromosuccinimide (0.123 g, 0.692 mmol, 1 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (30 ml) and the organic layers were washed with water (5x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent were evaporated under reduced pressure to give the crude product, which was purified by column chromatography on silica gel (230-400) (5% MeOH/DCM; R _r value 0.3) to give (8-bromo-6- fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-yl)MeOH (0.12 g, 50%) as dirty white solid.

Synthesis of 8-bromo-6-chloro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-42).

Step 1: A stirred solution of 5-chloro-2-methylaniline (25.0 g, 176.55 mmol, 1 eq.) in DMF (530 ml) at -10°C was treated in portions for 10 min with solid N-bromosuccinimide (69 .13 g, 388.4 mmol, 2.2 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 hours. After completion of the reaction, the reaction mixture was diluted with EtOAc (3000 ml) and the organic layers were washed with water (5x500 ml), brine (500 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated at reduced pressure to give the crude product, which was purified by silica gel column chromatography (230-400) (10% EtOAc/hexane; Rp0.6) to give 2,4-dibromo-3-chloro-6-methylaniline (35 g , 66%) as a brown solid.

Step 2: Solution of 2,4-dibromo-3-chloro-6-methylaniline (7.5 g, 25.08 mmol, 1 eq.), 2-amino-2methylpropanoic acid (5.16 g, 50.16 mmol, 2 equiv.) and DBU (9.54 g, 44.94 mmol, 2 equiv.) in dry DMA (112 ml) in a sealed tube were deoxygenated with Ar for 10 min. Copper iodide (0.479 g, 2.5 mmol, 0 .1 eq.) was added to the reaction mixture and deoxygenated again with Ar for 10 min. The reaction mixture was then stirred at 140°C for 16 h. After completion of the reaction, the reaction mixture was cooled to room. pace. and diluted with EtOAc (1000 ml) and washed with water (4x150 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure to obtain the crude product, which was purified using column chromatography (230- 400 mesh, silica gel; 20% EtOAc/hexane; Rp value 0.4) to give 6-bromo-5-chloro-3,3,8trimethyl-3,4-dihydroquinoxalin-2(1H)-one (2.2 g, 29%) as a light brown solid.

Step 3: Into a stirred solution of 6-bromo-5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)one (3.9 g, 12.87 mmol, 1 eq.) in the mixture 1,4-dioxane and water (1:1) (100 ml) added ammonium chloride (10.32 g, 193.06 mmol, 15 eq.) and zinc dust (12.26 g, 193.06 mmol, 15 eq. .). The reaction mixture was stirred for 16 hours at reflux. The reaction mixture was cooled to room. pace. and then filtered through a Schott funnel. The filtrate was concentrated under reduced pressure to obtain a residue, which was dissolved in EtOAc (100 ml) and washed with water (2x30 ml), then brine (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give 5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-one (2.3 g, 80%) as off-white solid.

Step 4: Into a solution of 5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)-oneα (2.3 g, 10.23 mmol, 1 eq.) in toluene (75 ml) add Lawesson's reagent (5.37 g, 13.3 mmol, 1.3 eq.) at room. pace. and the reaction mixture was refluxed at 120°C for 40 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ solution (80 ml)

- 43 045285 followed by extraction with EtOAc (2x70 ml). The combined organic layers were washed with water (80 ml), brine (80 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 20% EtOAc/ hexane; Rf value -0.6) to give 5-chloro-3,3,8trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (2.0 g, 81%) as a yellow solid.

Step 5: Into a stirred solution of 5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-thione (2.0 g, 8.33 mmol, 1 eq.) in THF (50 ml ) hydrazine hydrate (2.08 mL, 41.64 mmol, 5 eq.) was added dropwise at 0°C. The reaction mixture was stirred for 16 hours at room. pace. TEA (5.8 mL, 41.65 mmol, 5 eq.) was added and the reaction mixture was stirred for another 10 min. Acetyl chloride (1.78 mL, 24.99 mmol, 3 eq.) was added very slowly to the reaction mixture at 0 °C and then stirred for 2 hours at room. pace. The reaction mixture was diluted with water (50 ml) and extracted with DCM (3x100 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 the crude product, which was purified by washing with diethyl ether to give N'-(5-chloro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2( 1H)-ylidene)acetohydrazide (2.2 g, 94%) as an off-white solid.

Step 6: N'-(5-Chloro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H)-ylidene)acetohydrazide (5.2 g, 18.57 mmol, 1 eq.) was placed in round bottom flask (100 ml) and then cooled to -10°C. Phosphorus oxychloride (17.8 mL, 185.7 mmol, 10 eq.) was then added dropwise to the compound, followed by dropwise addition of TEA (2.52 mL, 18.57 mmol, 1 eq.). After this, the reaction mixture was stirred at -10°C for 10 minutes and then 10 minutes at room. pace. and finally refluxed for 2 hours. The reaction mixture was cooled to 0°C and added dropwise to crushed ice with constant stirring. A cold ammonia solution was slowly added to the aqueous part until pH ~12. The aqueous portion was extracted with DCM (3x100 ml). The combined organic layer was washed with brine (100 ml). The organic layer was dried over anhydrous Na ₂ SO ₄ , concentrated under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 5% MeOH/DCM; Rf value - 0.4) to give 6chloro- 1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3.25 g, 67%) as a light yellow solid.

Step 7: Stirred solution of 6-chloro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (3.25 g, 12.4 mmol, 1 eq.) in DMF (60 ml) at -10°C were treated in portions for 10 min with solid N-bromosuccinimide (2.32 g, 13.02 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (500 ml) and the organic layers were washed with water (5x100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent were evaporated under reduced pressure to give the crude product, which was purified by silica gel column chromatography (230-400) (5% MeOH/DCM; Rf value - 0.4) to give 8-bromo-6-chloro -1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (3.0 g, 71%) as an off-white solid.

Synthesis of 8-bromo-9-(difluoromethyl)-6-fluoro-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B- 43).

smzvvevve V-43

Step 1: To a stirred solution of 4-fluoro-2-nitrobenzaldehyde (20 g, 118.27 mmol, 1 eq.) in DCM (600 mL) was added DAST (23.26 mL, 177.51 mmol, 1.5 eq. ) at 0°C. The reaction mixture was stirred at room. pace. for 4 hours. After consumption of the starting material, the reaction mixture was quenched with sat. NaHCO ₃ solution and extracted with DCM (2x500 ml). The combined organic layers were washed with water (500 ml), then brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography using 2-3% EtOAc/hexane to give 1-(difluoromethyl)-4-fluoro-2-nitrobenzene (22 g, 88%) as a yellow liquid.

- 44 045285

Step 2: SnCl ₂ 2H ₂ O (47 g, 209, 46 mmol, 4 eq.) followed by the addition of conc. HCl (35 ml) at 0°C. The reaction mixture was stirred at room. pace. for 2 hours. After consumption of the starting material, the reaction mixture was concentrated, the residue was basified with 5 N. NaOH solution and extracted with MTBE (2x500 ml). The combined organic layers were washed with water (500 ml), then brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated. The crude product was purified by column chromatography using 2-3% EtOAc/hexane to give 2-(difluoromethyl)-5-fluoroaniline (7.0 g, 83%) as a yellow gum.

Step 3: To a solution of 2-(difluoromethyl)-5-fluoroaniline (4 g, 24 mmol, 1.0 eq.) in DMF (40 ml) was added portionwise NBS (13 g, 74 mmol, 3.0 eq.) at -10°C. The resulting reaction mixture was stirred at 0°C for 1 hour. After consumption of the starting material (monitored by LCMS), the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2x100 ml). The combined organic layers were washed with water (2x100 ml) and brine, dried over anhydrous Na2SO4 and concentrated to give crude 2,4-dibromo-6-(difluoromethyl)-3fluoroaniline (7 g, 85%), which was used in the next step without further cleaning.

Step 4: To a suspension of crude 2,4-dibromo-6-(difluoromethyl)-3-fluoroaniline (8 g, 25.2 mmol, 1 eq.) in DMSO (80 ml) was added 2-aminobutyric acid (5.2 g , 50 mmol, 2 equiv.) at room. pace. The reaction mixture was then deoxygenated with Ar for 20 min. K3PO4 (10.6 g, 50 mmol, 2 eq.) and CuCl (0.024 g, 2.5 mmol, 0.1 eq.) were added and 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 washed with EtOAc (100 ml). The filtrate was diluted with EtOAc (100 ml) and washed with water (3x150 ml), brine (200 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain the crude product, which was purified using column chromatography (100 -200 mesh, silica gel; 30% EtOAc/hexane; Rf value -0.4) to give 6bromo-8-(difluoromethyl)-5-fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)- she (1.5 g, 20%).

Step 5: Into a stirred solution of 6-bromo-8-(difluoromethyl)-5-fluoro-3,3-dimethyl-3,4dihydroquinoxalin-2(1H)-one (3.0 g, 9.3 mmol, 1 eq. ) in a mixture of 1,4-dioxane and water (1:1) (100 ml) was added NH ₄ Cl (7.47 g, 139.0 mmol, 15 eq.) and zinc dust (9.08 g, 139.0 mmol, 15 eq.). The reaction mixture was stirred for 16 hours at reflux. The reaction mixture was cooled to room. pace. and then filtered through a Schott funnel. The filtrate was concentrated under reduced pressure to give the product, which was dissolved in EtOAc (100 ml) and washed with water (2x30 ml), then brine (30 ml). The organic layer was dried over Na ₂ SO ₄ , concentrated under reduced pressure to give 8-(difluoromethyl)-5-fluoro-3,3-dimethyl-3,4dihydroquinoxalin-2(1H)-one (2.0 g, 90%) as an off-white solid.

Step 6. Into a solution of 8-(difluoromethyl)-5-fluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (1 g, 4.09 mmol, 1 eq.) in toluene (10 ml) Lawesson's reagent (2.48 g, 6.14 mmol, 1.5 eq.) was added at room temperature. pace. and the reaction mixture was refluxed at 120°C for 40 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO3 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 (230-400 mesh, silica gel; 20% etOAc/ hexane; Rf value -0.4) to give 8-(difluoromethyl)-5fluoro-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (0.6 g, 65%) as a yellow solid substances.

Step 7: Into a stirred solution of 8-(difluoromethyl)-5-fluoro-3,3-dimethyl-3,4dihydroquinoxaline-2(1H)-thione (2.5 g, 9.6 mmol, 1 eq.) in THF ( 30 ml) hydrazine hydrate (2.4 ml, 48 mmol, 5 eq.) was added dropwise at 0°C. The reaction mixture was then stirred for 16 hours at room. pace. The reaction mixture was then concentrated under reduced pressure to obtain crude material. Triethyl orthoacetate (20 ml) was then added to the reaction mixture. The reaction mixture was stirred at 140°C for 16 hours. After completion of the reaction (monitored by TLC), 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 the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 5% MeOH/DCM; Rf value - 0.4) to give 9-( difluoromethyl)-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (2.0 g, 74%) as an off-white solid .

Step 8: Stirred solution of 9-(difluoromethyl)-6-fluoro-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2.0 g, 7. 08 mmol, 1 eq.) in DMF (30 ml) at -10°C were treated in portions for 10 min with solid N-bromosuccinimide (1.3 g, 7.79 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 hours. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (300 ml)

- 45 045285 and the organic layers were washed with water (5x50 ml), brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvents were evaporated under reduced pressure to obtain the crude product, which was purified using silica gel column chromatography (230-400 ) (5% MeOH/DCM; Rf value -0.3) to give 8-bromo-9-(difluoromethyl)-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4 ]triazolo[4,3-a]quinoxaline (1.5 g, 75%) as an off-white solid.

Synthesis of 8-bromo-9-cyclopropyl-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-45).

Sing 5

Prfmezhutocham so*dvv»zh · V-45

Step 1: 2-Bromo-5-fluorophenylamine (50 g, 0.262 mol, 1 eq.) was dissolved in acetic anhydride (25 ml) at 10°C and stirred at room temperature for 3 hours. After completion of the reaction ( monitored by TLC, 10% EtOAc/hexane) the thick reaction mass was diluted with ngexane and filtered. The solid was washed with n-hexane and dried under reduced pressure to give N-(2-bromo-5-fluorophenyl)-acetamide (55 g, 90%) as an off-white solid.

Step 2: Tricyclohexylphosphine (7, 26 g, 0.0259 mol, 0.1 eq.) followed by the addition of K ₃ PO ₄ (192 g, 0.906 mol, 3.5 eq.) at room temperature and the mixture was degassed with argon for 30 min. Cyclopropylboronic acid (28.98 g, 0.336 mol, 1.3 eq) and subsequently Pd(OAc) ₂ (2.9 g, 0.0129, 0.05 eq) were added and the reaction mixture was heated at 100°C in for 16 hours. After completion of the reaction (monitored by TLC, 20% EtOAc-hexane, R _f 0.4), the reaction mixture was cooled to room temperature, diluted with EtOAc (1 L), washed with water (2x500 ml) and saline ( 500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 15-20% EtOAc/hexane eluent) to give N-(2cyclopropyl-4-fluorophenyl)-acetamide (36 g, 86%) in as a brownish solid.

Step 3: A stirred suspension of N-(2-cyclopropyl-4-fluorophenyl)-acetamide (54 g, 0.279 mol, 1 eq.) in aqueous HCl (2.1 L, 2 M) was heated at 90°C in for 16 hours. After completion of the reaction (monitored by TLC, 20% EtOAc-hexane, R _f 0.6), the reaction mixture was cooled to room temperature and made alkaline to pH ~ 13-14 with NaOH solution (2 M). This mixture was extracted with EtOAc (1 L), 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-5-fluorophenylamine (48 g, crude substance) in the form of a dark brown liquid.

Step 4: To a stirred solution of 2-cyclopropyl-5-fluorophenylamine (27 g, 0.18 mol, 1 eq) in DMF (480 ml) was added NBS (79.5 g, 0.447 mol, 2.5 eq) in portions .) at -10°C and the resulting reaction mixture was stirred at 0°C for 1 hour. After completion of the reaction (monitored by TLC, 20% EtOAc/hexane), the reaction mixture was diluted with water (1 L) and extracted with MTBE (2x750 ml). The combined organic layers were washed with cold brine (3x500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 5-10% EtOAc/hexane eluent) to give 2,4-dibromo-6-cyclopropyl-3-fluorophenylamine (22 g, 45% from two stages) in the form of a brownish liquid.

Step 5: To a stirred suspension of 2,4-dibromo-6-cyclopropyl-3-fluorophenylamine (20 g, 0.065 mol, 1 eq.) in dry DMA (300 ml) was added 2-amino-2-methylpropionic acid (13.35 g, 0.129 mol, 2 eq.) followed by the addition of DBU (19.2 mL, 0.129 mol, 2 eq.) at room temperature. The resulting reaction mixture was degassed with argon for 30 minutes, CuI (1.2 g, 0.006 mol, 0.1 eq.) was added and the reaction mixture was heated at 140°C for 16 hours. After consumption of the starting material (monitored by TLC, 30 % EtOAc-hexane, R _f 0.4), the reaction mixture was cooled to room temperature and filtered through a pad of celite, then washed with EtOAc (500 ml). The organic fraction was washed with water (2x750 ml) and brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (15-16% EtOAc-hexane) to give

- 46 045285

6-bromo-8-cyclopropyl-5-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (13 g, 64%) as a brown solid.

Step 6: Into a suspension of 6-bromo-8-cyclopropyl-5-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2one (10 g, 0.031 mol, 1 eq.) in dioxane:water (2:1, 200 ml), powdered zinc (12.52 g, 0.191 mol, 6 eq.) was added followed by ammonium chloride (10.25 g, 0.191 mol, 6 eq.) at room temperature and the reaction mixture was stirred at 100°C for 16 hours. After completion of the reaction (monitored by TLC, 30% EtOAc-hexane, Rf 0.4), the reaction mixture was cooled to room temperature and filtered through a pad of celite, then washed with EtOAc (500 ml). The organic fraction was washed with water (2x750 ml) and brine (500 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography using 15-20% EtOAc-hexane to give 8-cyclopropyl-5-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (4.3 g, 59%) as a brown solid.

Step 7: Into a solution of 8-cyclopropyl-6-fluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (4.3 g, 18.376 mmol, 1 eq.) in toluene (86 ml ) Lawesson's reagent (11.16 g, 27.564 mmol, 1.5 eq.) was added at room temperature and the reaction mixture was refluxed at 120°C for 1 hour. Once the reaction was complete (monitored by TLC in 20% EtOAc- hexane, Rf 0.6) the reaction mixture was cooled to room temperature and quenched sat. NaHCO ₃ solution. The resulting aqueous fraction was extracted with EtOAc (3x200 ml) and the combined organic layers were washed with water (200 ml) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh, silica gel; 5-10% EtOAc/hexane) to give 8-cyclopropyl-5-fluoro3,3-dimethyl-3,4-dihydro-1H-quinoxaline-2- thione (4.2 g, 92%) as a yellow solid.

Step 8: To a stirred solution of 8-cyclopropyl-5-fluoro-3,3-dimethyl-3,4-dihydro-1Hquinoxaline-2-thione (4 g, 16 mmol, 1 eq.) in tetrahydrofuran (80 ml) was added hydrazine (2.35 ml, 48 mmol, 3 eq.) dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 hours. The solvent was then evaporated and the residue was taken up in triethyl orthoacetate and heated at 140°C for 48 hours. The reaction mixture was concentrated under reduced pressure and purified by column chromatography (100-200 mesh silica gel; 2% MeOH/DCM eluent) to give 9-cyclopropyl-6-fluoro-1,4,4-trimethyl-4. 5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (2.7 g, 59%) as a white solid.

Step 9: Into a stirred solution of 9-cyclopropyl-6-fluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2.27 g, 8.345 mmol, 1 eq.) in DMF (40 ml), NBS (1.33 g, 7.511 mmol, 0.9 eq.) was added portionwise at -10°C and the resulting reaction mixture was stirred at 0°C for 1 hour. After consumption of the starting material material (monitored by LC-MS), the reaction mixture was diluted with water (20 ml) and extracted with EtOAc (2x30 ml). The combined organic layers were washed with water (2x50 ml) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude residue was combined with another batch (starting with 800 mg of 9-cyclopropyl-6fluoro-4,4-dimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline and following the same procedure, as described above) and the entire amount of crude material was then purified by column chromatography (100-200 mesh, silica gel; 5% MeOH/DCM as eluent) to give 8-bromo-9cyclopropyl-6-fluoro-1,4,4- trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (2.2 g, 56%) as an off-white solid.

Synthesis of 8-bromo-6-fluoro-N,1,4,4-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-amine (intermediate B-46 ).

- 47 045285

Prvmszhutochvo* smdpgavg V-44

Step 1: Add sodium bicarbonate (82.41 g, 981.07 mmol, 1.3 eq) to a stirred solution of 1,4-difluoro-2-nitrobenzene (120 g, 754.7 mmol, 1.0 eq) in DMF .) and the mixture was stirred for 10 min. Then N-methylbenzylamine (109.58 g, 905.6 mmol, 1.2 eq.) was added and the mixture was stirred at room temperature. pace. for 16 hours. Once complete (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water. The extracted organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by column chromatography (230-400 mesh, silica gel, TLC system: EtOAc/hexane (2:8); Rf = 0.3) to give N-benzyl-4-fluoro-N-methyl-2-nitroaniline (110 g, 56%).

Step 2: To an ice-cold solution of N-benzyl-4-fluoro-N-methyl-2-nitroaniline (110 g, 423.07 mmol, 1.0 eq.) in EtOH (800 ml) was added tin(II) chloride (381 .8 g, 1692.3 mmol, 4.0 eq.). The reaction mixture was stirred for 10 minutes at room. temp. Concentrated HCl (250 ml) was added dropwise at 0°C. The reaction mixture was stirred at room. pace. for 2 hours. Once complete (monitored by TLC), the reaction mixture was concentrated in vacuo. The residue was dissolved in cold water and made alkaline with NaOH granules to (pH~12) and the aqueous portion was diluted with EtOAc. The extracted organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (230-400 mesh, silica gel), (TLC system: EtOAc/hexane (2:8 ); Rf = 0.4) to obtain N ¹ -benzyl-4-fluoro-N1-methylbenzene-1,2-diamine (100 g, 100%).

Step 3. A stirred solution of N ¹ -benzyl-4-fluoro-N1-methylbenzene-1,2-diamine (100 g, 434.7 mmol, 1 eq.) in DMF at -10°C was treated in portions for 10 min with solid N-bromosuccinimide (81.26 g, 456.51 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), 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 Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography (230-400) (TLC system: EtOAc/hexane (2:8); Rf = 0.3) to give N ¹ -benzyl-5-bromo-4-fluoro-N ¹ -methylbenzene-1,2diamine (60 g, 45%) as a colorless liquid.

Step 4: A stirred solution of N ¹ -benzyl-5-bromo-4-fluoro-N ¹ -methylbenzene-1,2-diamine (60 g, 194.17 mmol, 1 eq.) in DMF at -10°C was treated in portions for 10 min with solid Nbromosuccinimide (34.56 g, 194.17 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 hours. After completion of the reaction (monitored by LCMS), 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 to obtain the crude product, which was purified by column chromatography on silica gel (230-400) (TLC system: EtOAc/hexane (2:8); Rf = 0.3) to obtain N ¹ -benzyl -3,5-dibromo-4-fluoro-N ¹ -methylbenzene-1,2-diamine (30 g, 40%) as an off-white solid.

Step 5. Suspension of N ¹ -benzyl-3,5-dibromo-4-fluoro-N ¹ -methylbenzene-1,2-diamine (30 g, 77.31 mmol, 1 eq.), 2-aminoisobutyric acid (15, 94 g, 154.63 mmol, 2 eq.), DBU (29.42 g, 193.29 mmol, 2.5 eq.) and copper iodide (1.47 g, 7.73 mmol, 0.1 eq. ) in DMA (300 ml) in a round bottom flask was deoxygenated with Ar for 20 min. The reaction mixture was then stirred at 130°C for 16 h. Once complete (monitored by TLC), the reaction mixture was diluted with EtOAc (500 ml) and water (5x100 ml), brine (100 ml), dried over anhydrous Na2SO4 and the solvent was evaporated under reduced pressure to obtain a crude product, which was purified using colo.

- 48 045285 overnight chromatography (230-400 mesh, silica gel; (TLC system: EtOAc/hexane (2:8); Rf = 0.2) to obtain 8-(benzyl(methyl)amino)-6-bromo-5- fluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (8.0 g, 26%) as a brown solid.

Step 6. Into a solution of 8-(benzyl(methyl)amino)-6-bromo-5-fluoro-3,3-dimethyl-3,4-dihydroquinoxalin2(1H)-one (8 g, 20.40 mmol, 1 eq. .) 10% Pd/C (2 g) was added to EtOH. The reaction was carried out in a standard autoclave under hydrogen atmosphere (200 psi) for 8 hours. After completion of the reaction, the reaction mixture was filtered through a pad of celite and washed with EtOAc. The filtrate was evaporated under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; (TLC system: EtOAc/hexane (4:6); Rf = 0.3) to give 5-fluoro-3 ,3-dimethyl-8-(methylamino)-3,4-dihydroquinoxalin-2(1H)-one (2.0 g, 22%) as a white solid.

Step 7. Into a solution of 5-fluoro-3,3-dimethyl-8-(methylamino)-3,4-dihydroquinoxalin-2(1H)-one (2 g, 8.95 mmol, 1 eq.) in toluene (30 ml) Lawesson's reagent (5.43 g, 13.43 mmol, 1.5 eq.) was added at room. pace. and the reaction mixture was heated to 120°C for 40 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ solution (100 ml) followed by extraction with EtOAc (2x200 ml). The combined organic layers were washed with water (300 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 (230-400 mesh, silica gel; (TLC system: EtOAc/hexane (4:6); Rf = 0.3) to give 5-fluoro-3,3-dimethyl8-(methylamino)-3,4-dihydroquinoxaline-2(1H)-thione (1.85 g, 86 %) as a yellow solid.

Step 8: Into a stirred solution of 5-fluoro-3,3-dimethyl-8-(methylamino)-3,4-dihydroquinoxaline2(1H)-thione (1.85 g, 7.73 mmol, 1 eq.) and acetic hydrazide acid (2 g, 27.05 mmol, 1 eq.) in nbutanol (20 ml), a catalytic amount of acetic acid was added and the mixture was heated to reflux for 16 hours. After completion of the reaction, the solvent was evaporated under reduced pressure to obtain the crude product , which was purified by column chromatography (230-400 mesh, silica gel; (TLC system: MeOH/DCM (1:9); Rf = 0.2) to obtain 6-fluoro-N,1,4,4tetramethyl-4, 5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-amine (1.0 g, 50%) as liquid.

Step 9. Stirred solution of 6-fluoro-N,1,4,4-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-9-amine (1.0 g, 3. 82 mmol, 1 eq.) in DMF (20 ml) at -10°C was treated in portions for 10 min with solid N-bromosuccinimide (0.681 g, 3.82 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), 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 were evaporated under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; (TLC system: MeOH/DCM (1:9); Rf = 0.4) to give 8 -bromo-6-fluoro-N,1,4,4-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxalin-9-amine (1.0 g, 77%) in form of liquid.

Synthesis of 8-bromo-6-chloro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-47).

o n-BuOH'AcOHi HO'С

Intermediately with dvvevve B-47

Element 5

Step 1: To an ice-cold solution of 5-chloro-2-methoxyaniline (25 g, 158.62 mmol, 1.0 eq.) in DMF was added a solution of N-bromosuccinimide (56.47 g, 317.25 mmol, 1.0 eq. .) portions and the mixture was stirred at the same temperature for 1 hour. Once complete (monitored by TLC), the reaction mixture was diluted with EtOAc and washed with water. The extracted organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (230-400 mesh, silica gel, TLC system: EtOAc/hexane (1:9); Rf = 0 ,5) to obtain 2,4-dibromo-3chloro-6-methoxyaniline (30 g, 60%).

Step 2. Suspension of 2,4-dibromo-3-chloro-6-methoxyaniline (30 g, 95.12 mmol, 1 eq.), 2-aminoisobutyric acid (24.92 g, 190.24 mmol, 2 eq.), DBU (43.44 g, 285.36 mmol, 3 eq.) and CuI (1.81 g, 9.51 mmol, 0.1 eq.) in DMA (300 ml) in a round bottom flask were deoxygenated with Ar for 20 min.

- 49 045285 the reaction mixture was then stirred at 130°C for 16 hours. Once complete (monitored by TLC), the reaction mixture was diluted with EtOAc (500 ml) and water (5x100 ml), brine (400 ml), dried over anhydrous Na ₂ SO ₄ and the solvent were evaporated under reduced pressure to obtain the crude product, which was purified by column chromatography (230-400 mesh, silica gel; (TLC system: EtOAc/hexane (2:8); Rf = 0.2) to obtain 6-bromo-5-chloro8-methoxy-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (3.0 g, 10%) as a brown solid.

Step 3. Stirred solution of 6-bromo-5-chloro-8-methoxy-3,3-dimethyl-3,4dihydroquinoxalin-2(1H)-one (3 g, 9.38 mmol, 1 eq.) in a mixture of water and 1,4-dioxane (1:1), zinc (8.94 g, 140.78 mmol, 15 eq.) and ammonium chloride (7.53 g, 140.74 mmol, 15 eq.) were added and the mixture was heated to boiling reflux for 16 hours. Once complete (monitored by TLC), the reaction mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc (500 ml) and water (5x100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain the crude product, which was purified using column chromatography (230- 400 mesh, silica gel; (TLC system: EtOAc/hexane (2:8); Rf = 0.4) to give 5-chloro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H) -one (2 g, 88%) as a white solid.

Step 4: A solution of 5-chloro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (2.5 g, 10.38 mmol, 1 eq.) in toluene (30 ml) Lawesson's reagent (6.30 g, 15.58 mmol, 1.5 eq.) was added at room. pace. and the reaction mixture was heated to 120°C for 40 minutes. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO ₃ solution (100 ml) followed by extraction with EtOAc (2x200 ml). The combined organic layers were washed with water (300 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 (230-400 mesh, silica gel; (TLC system: EtOAc/hexane (3:7); Rf = 0.3) to give 5-chloro-8-methoxy3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (2.1 g, 79%) as a yellow solid.

Step 5: Stir solution of 5-chloro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)thione (2.1 g, 8.17 mmol, 1 eq.) and acetic acid hydrazide ( 2.13 g, 28.75 mmol, 3.5 eq.) were taken up in n-butanol (20 ml) and a catalytic amount of acetic acid was added and the mixture was heated to reflux for 16 hours. After completion of the reaction, the solvent was evaporated at under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; (TLC system: MeOH/DCM (1:9); Rf = 0.2) to give 6-chloro-9-methoxy- 1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (1.2 g, 53%) as liquid.

Step 6: Stirred solution of 6-chloro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (1.2 g, 4.30 mmol , 1 eq.) in DMF (20 ml) at -10°C were treated in portions for 10 min with solid N-bromosuccinimide (0.804 g, 4.52 mmol, 1.05 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 1.5 h. After completion of the reaction (monitored by LC-MS), 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 were evaporated under reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; (TLC system: MeOH/DCM (1:9); Rf = 0.4) to give 8 -bromo-6-chloro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.9 g, 59%) in as a white solid.

Synthesis of 8-bromo-6,7-difluoro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-49 ).

Experience 4

Intermediate* “mdvvevve VC9

Step 1: Potassium carbonate (47.2 g, 342.68 mmol, 3 equiv) was added to a stirred solution of 4,5-difluoro-2-nitrophenol (20 g, 114.226 mmol, 1 eq.) in DMF (100 mL). and iodomethane (21.34 ml, 342.68 mmol, 3 eq.) to the reaction mixture at room temperature. pace. within 4 hours. After completion (track

- 50 045285 by TLC) the reaction mixture was diluted with EtOAc and washed with water. The extracted organic layer was washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (230-400 mesh, silica gel, TLC system: EtOAc/hexane (2:8); Rf = 0.6) to give 1,2-difluoro-4-methoxy-5-nitrobenzene (20 g, 93%).

Step 2: Pd/C (10.0 g, 10% moisture) and the reaction mixture was stirred using a hydrogen cylinder for 2 hours at room temperature. pace. Once complete (monitored by TLC, TLC system 20% EtOAc in hexane, Rf-0.4), the reaction mixture was filtered through a pad of celite and washed 2-3 times with MeOH. The filtrate was concentrated to obtain the desired 4,5-difluoro-2methoxyaniline (16.0 g, 95%).

Step 3: To a stirred solution of 4,5-difluoro-2-methoxyaniline (8.0 g, 50.273 mmol, 1 eq.) in MeOH:DCM (50 ml:100 ml) was added benzyltrimethylammonium tribromide (8.82 g, 60.328 mmol , 1.2 eq.) in portions at room. pace. The resulting reaction mixture was stirred at room. pace. for 12 hours. After consumption of the starting material, the reaction mixture was concentrated to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 15% EtOAc/hexane; Rf value - 0.4) to give 2-bromo- 3,4-difluoro-6methoxyaniline (0.5 g, 4%) as a yellow solid.

Step 4: To a stirred solution of 2-bromo-3,4-difluoro-6-methoxyaniline (0.413 g, 1.735 mmol, 1 eq.) in dry DMSO (10 ml) was added 2-amino-2-methyl-propionic acid (0.536 g, 5.205 mmol, 3.0 eq.) followed by the addition of K ₃ PO ₄ (0.919 g, 4.337 mmol, 2.5 eq.) at rt. pace. The resulting reaction mixture was degassed with Ar for 10 min, then CuI (0.033 g, 0.1735 mmol, 0.1 eq.) was added and the reaction mixture was heated at 140°C for 12 h. After consumption of the starting material, 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 washed with water (2x50 ml), then with brine (50 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated under reduced pressure to obtain the crude product, which was purified using column chromatography (100-200 mesh, silica gel; 20 % EtOAc/hexane; Rf value - 0.2) to give 5,6-difluoro-8-methoxy-3,3dimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.3 g, 71%) in as a brown solid.

Step 5. Into a solution of 5,6-difluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (0.3 g, 1.238 mmol, 1 eq.) in toluene (50 ml) Lawesson's reagent (0.65 g, 1.61 mmol, 1.5 eq.) was added at room. pace. and the reaction mixture was heated to 120°C for 1 hour. After consumption of the starting material, the reaction mass was cooled to room. pace. and quenched with saturated NaHCO ₃ solution (50 ml). The organic layer was separated and the aqueous layer was extracted with EtOAc (50 ml). The combined organic layers were washed with water (50 ml), then brine (50 ml), dried over anhydrous Na2SO4 and the solvent was evaporated to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 20% EtOAc/hexanes; Rf value - 0.6) to give 5,6-difluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (0.3 g, 94%) as a yellow solid substances.

Step 6. Into a solution of 5,6-difluoro-8-methoxy-3,3-dimethyl-3,4-dihydroquinoxaline-2(1H)-thione (0.1 g, 0.3871 mmol, 1 eq.) in n -BuOH (10 ml) was added acetic acid hydrazide (0.094 g, 1.277 mmol, 3.3 eq.) followed by the addition of acetic acid (1 ml) and then the reaction mixture was stirred at 140°C for 12 hours. After completion of the reaction ( monitored by TLC) the reaction mixture was diluted with water (10 ml) and extracted with EtOAc (2x20 ml). The combined organic layer was washed with water (20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography using 5% MeOH in DCM as the elution solvent. and silica gel 230-400 mesh to obtain 6,7-difluoro-9-methoxy-1,4,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.05 g , 46%) as an off-white solid.

Step 7: Stirred solution of 6,7-difluoro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.8 g, 2.854 mmol, 1 eq.) in DMF (20 ml) at 0°C was treated in portions for 10 min with solid N-bromosuccinamide (0.6 g, 3.425 mmol, 1.2 eq.). The reaction mixture was heated to room temperature. pace. and stirred for 30 minutes. After completion of the reaction (monitored by LC-MS), the reaction mixture was diluted with EtOAc (50 ml) and the organic layers were washed with water (3x50 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and the solvents were evaporated under reduced pressure to give the crude product, which was purified by column chromatography using 1.5% MeOH in DCM as elution solvent and 230-400 mesh silica gel to give 8-bromo-6,7-difluoro-9-methoxy-1,4 ,4-trimethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.25 g, 42%) as an off-white solid.

Synthesis of 8-bromo-6,7-difluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (intermediate B-50 ).

- 51 045285

Step 1: A solution of 1-bromo-4,5-difluoro-2-nitrobenzene (1.0 g, 4.2 mmol, 1 eq.) in DMF (15 ml) was degassed with Ar for 20 min followed by the addition of CuBr (0.06 g, 0.42 mmol, 0.1 eq.) and methyl 2,2-difluoro-2-(fluorosulfonyl) acetate (0.88 ml, 6.93 mmol, 1.65 eq.). The reaction mixture was stirred at 80°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with diethyl ether and washed with ice water (2-3 times). The combined organic layer was evaporated to give the crude product, which was purified by column chromatography using 100-200 mesh silica gel and hexane as elution solvent to give 1,2-difluoro-4-nitro-5-(trifluoromethyl)benzene (0. 6 g, 45%) as a light yellow liquid.

Step 2: A solution of 1,2-difluoro-4-nitro-5-(trifluoromethyl)benzene (0.25 g, 1.1 mmol, 1 eq.) in EtOH (10 ml) was cooled to 0°C. SnCl ₂ -2H ₂ O was added in portions (0.994 g, 4.4 mmol, 4.0 eq.) followed by dropwise addition of conc. HCl (2.5 ml). The reaction mixture was stirred at room. pace. for 2 hours. After completion of the reaction (monitored by TLC), the reaction mixture was basified with 6 N. NaOH solution and diluted with DCM. The organic layer was washed with water (2-3 times). The combined organic layer was evaporated to obtain the desired 4,5-difluoro-2-(trifluoromethyl)aniline (0.21 g, 93%) as a light yellow liquid.

Step 3: A solution of 4,5-difluoro-2-(trifluoromethyl)aniline (0.20 g, 1.01 mmol, 1 eq.) in DMF (10 ml) was cooled to 0°C. NBS was added portionwise (0.217 g, 1.21 mmol, 1.2 eq). The reaction mixture was gradually heated to room temperature. pace. for 5 hours. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with diethyl ether. The organic layer was washed with ice water (2-3 times). The combined organic layer was evaporated to give the crude product, which was purified by column chromatography using 100200 mesh silica gel and hexane as elution solvent to give 2-bromo-3,4-difluoro-6(trifluoromethyl)aniline (0.19 g, 63%) as a light yellow liquid compound.

Step 4: Solution of 2-bromo-3,4-difluoro-6-(trifluoromethyl)aniline (5.0 g, 18.11 mmol, 1 eq.), 2-aminoisobutyric acid (3.76 g, 36.23 mmol, 2 eq.), K ₃ PO ₄ (9.6 g, 45.28 mmol, 2.5 eq.) in dry DMSO (86 ml), placed in a sealed tube, deoxygenated with Ar. CuI (0.34 g, 1.8 mmol, 0.1 eq.) was added and re-reduced over 5 min. The reaction mixture was then stirred at 120°C for 6 h. Once the reaction was complete (monitored by TLC, 20% EtOAc in hexane, Rf-0.2), the reaction mixture was filtered through a pad of celite and washed with EtOAc (100 ml), washed with water (3x100 ml), brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated at reduced pressure to give the crude product, which was purified by column chromatography (230-400 mesh, silica gel; 20% EtOAc/hexane; Rf value -0.2) to give 5,6-difluoro-3,3-dimethyl-8-( trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (0.7 g, 14%) as a brown solid.

Step 5: Into a solution of 5,6-difluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (0.7 g, 2.5 mmol, 1 eq.) in toluene (15 ml) was added Lawesson's reagent (1.5 g, 3.75 mmol, 1.5 eq.) at room. pace. and the reaction mixture was refluxed at 120°C for 1.5 hours. After completion of the reaction (monitored by TLC, 20% EtOAc in hexanes, Rf-0.5), 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 using 230-400 mesh silica gel and 10% EtOAc in hexane as elution solvent to give 5,6-difluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4dihydroquinoxaline-2(1H)-thione (0.7 g, 94%) as a yellow solid .

Step 6: Into a solution of 5,6-difluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxaline-2(1H)-thione (0.7 g, 2.36 mmol, 1 eq.) in THF (30 ml) was added hydrazine hydrate (0.59 g, 11.82 mmol, 5.0 eq.) at room. pace. and the reaction mixture was stirred at room. pace. for 1 hour. After completion of the reaction (monitored by TLC, 5% MeOH-DCM, Rf-0.5), the reaction mixture was concentrated. The reaction mixture was dissolved in THF and cooled to 0°C. TEA (1.6 ml, 11.82 mmol, 5.0 eq.) and acetyl

- 52 045285 chloride (0.5 ml, 7.09 mmol, 3.0 eq.) was added and stirred at room temperature. pace. for 1 hour. After completion of the reaction (monitored by TLC, 5% MeOH-DCM, R _f -0.5), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give crude N'-(5,6difluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxaline-2( 1H)-ylidene)acetohydrazide, which was carried to the next step without further purification.

Step 7. A solution of N'-(5,6-difluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)ylidene)acetohydrazide (2.36 mmol, 1 eq.) in POCl ₃ (15 ml) was cooled to 0°C. TEA (0.33 mL, 2.36 mmol, 1.0 eq.) was added and the mixture was stirred at the same temperature for 10 min and then at reflux for 6 h. Once the reaction was complete (monitored by TLC, 50% acetone-hexane, Rf-0.5), the reaction mixture was concentrated. The reaction mixture was cooled to 0°C and made basic with aqueous ammonia and diluted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography using 230-400 mesh silica gel and 50% acetone in hexane as elution solvent to give 6,7-difluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.5 g, 66%) as brown solid.

Step 8. Solution of 6,7-difluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (0.5 g, 1 .57 mmol, 1 eq.) in DMF (15 ml) was cooled to 0°C. NBS (0.559 g, 6.28 mmol, 2.0 eq.) was added and the mixture was stirred at room temperature. pace. for 10 minutes and then reflux for 2 hours. After completion of the reaction (monitored by TLC, 50% acetone-hexane, Rf-0.5), the reaction mixture was diluted with EtOAc. The combined organic layers were washed with ice cold water, brine, dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified by column chromatography using 230-400 mesh silica gel and 50% acetone in hexane as elution solvent to give 8-bromo-6,7-difluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.45 g , 72%) as a brown solid.

Synthesis of 8-bromo-6-chloro-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-51 ).

Step 1: To a stirred solution of NiCl ₂ -6H ₂ O (12.54 g, 0.0527 mol, 1 eq.) in MeOH (526 ml) was added NaBH ₄ (5.97 g, 0.158 mol, 3 eq.) in portions at 0°C and the resulting suspension was stirred at 0°C for 1 hour. Then 1-chloro-2-fluoro-4-methyl-5-nitrobenzene (20 g, 0.1055 mol, 2 eq.) was added with followed by additional addition of NaBH ₄ (13.95 g, 0.369 mol, 7 eq.) in portions and the reaction mixture was stirred at 0°C for 2 hours. After consumption of the starting material (monitored by TLC), the reaction mixture was concentrated and the resulting residue was diluted with 1 n. HCl (150 ml), then aqueous ammonia (150 ml) and EtOAc (200 ml). This mixture was stirred at room temperature for 15 minutes, filtered through a pad of celite and the resulting aqueous filtrate was extracted with EtOAc (2x250 ml). The combined organic fractions were washed with water (350 ml) and brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated to give 5-chloro-4-fluoro-2-methyl-phenylamine (14 g, 83%) as off-white solid.

Step 2: To a solution of 5-chloro-4-fluoro-2-methyl-phenylamine (14 g, 0.087 mol, 1 eq.) in DCM (280 ml), a solution of Br ₂ (4.97 ml, 0.098 mol, 1.1 eq.) in DCM (70 ml) at 0°C and the resulting reaction mixture was stirred at 0°C for 2 hours. After consumption of the starting material (monitored by TLC in 10% EtOAc-hexane), the reaction mixture was diluted with water ( 300 ml) and extracted with DCM (2x150 ml). The combined organic layers were washed with water (2x250 ml), saturated sodium thiosulfate solution (2x250 ml) and brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 5% EtOAc/hexane eluent) to give 2-bromo-3-chloro-4-fluoro-6-methyl-phenylamine (11.2 g, 53%)

- 53 045285 in the form of a brown solid.

Step 3: To a stirred suspension of 2-bromo-3-chloro-4-fluoro-6-methyl-phenylamine (18 g, 0.075 mol, 1 eq) in dry DMAc (270 ml) was added 2-amino-2-methyl- propionic acid (15.56 g, 0.15 mol, 2 eq.) then DBU (22.57 ml, 0.15 mol, 2 eq.) at room temperature and the resulting reaction mixture was degassed with nitrogen for 30 min. CuI (1.43 g, 0.0075 mol, 0.1 eq) was then added and the reaction mixture was heated at 140°C for 16 hours. After consumption of starting material (monitored by TLC, 20% EtOAc-hexane, Rf 0 ,4) the reaction mixture was cooled to room temperature and poured into ice water (1 L). The resulting aqueous mixture was extracted with EtOAc (2x400 ml) and the combined organic fractions were washed with water (2x500 ml) and brine (400 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The resulting crude residue was triturated with hexane to give 5-chloro-6-fluoro-3,3,8-trimethyl-3,4dihydro-1H-quinoxalin-2-one (8 g, 44%) as a brown liquid.

Step 4. Into a solution of 5-chloro-6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (12 g, 0.049 mol, 1 eq.) in toluene (150 ml ) Lawesson's reagent (29.97 g, 0.074 mol, 1.5 eq.) was added at room temperature and the reaction mixture was refluxed at 120°C for 2 hours. After consumption of starting material (monitored by TLC in 20% EtOAc -hexane, Rf 0.6) the reaction mixture was quenched with sat. NaHCO ₃ solution (200 ml) and the resulting aqueous mixture was extracted with EtOAc (2x350 ml). The combined organic layers were washed with water (200 ml) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 10% EtOAc/hexane eluent) to give 5-chloro-6-fluoro-3,3,8-trimethyl-3,4dihydro-1H-quinoxaline -2-thione (128 g, 93%) as a yellow solid.

Step 5: Into a stirred solution of 5-chloro-6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2thione (11 g, 0.042 mol, 1 eq.) in tetrahydrofuran (275 ml) Hydrazine hydrate (6.38 g, 0.127 mol, 3 eq.) was added dropwise at 0°C and the resulting reaction mixture was stirred at room temperature for 16 hours. After formation of the imine intermediate, the reaction mixture was concentrated and azeotroped twice toluene. The resulting residue was dissolved in triethylorthoacetate (120 ml) and heated to reflux for 24 hours. After consumption of the starting material (monitored by LC-MS), the reaction mixture was concentrated and the resulting crude residue was purified by column chromatography (230-400 mesh, silica gel; 5% MeOH/DCM as eluent) to give 6-chloro-7-fluoro-1,4,4,9tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (8.5 g, 71%) as an off-white solid.

Step 6. Into a solution of 6-chloro-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (8 g, 0.028 mol, 1 eq.) in DMF (160 ml), NBS (5.07 g, 0.028 mol, 1 eq.) was added portionwise at 0°C and the resulting reaction mixture was stirred at room temperature for 3 hours. After consumption of the starting material (monitored by LC -MS) reaction mixture was diluted with water (500 ml) and extracted with EtOAc (2x250 ml). The combined organic layers were washed with water (2x250 ml) and brine (250 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (230-400 mesh silica gel; 5% MeOH/DCM eluent) to give 8-bromo-6-chloro-7-fluoro-1,4,4,9-tetramethyl-4 ,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (6.2 g, 60%) as an off-white solid.

Synthesis of 8-bromo-7-chloro-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-53 ).

Step 1: Into a stirred solution of 1-chloro-2-fluoro-5-methyl-4-nitro-benzene (10.0 g, 52.91 mmol, 1 eq.) in EtOH-water (1:1, 120 ml ) added conc. aqueous HCl solution (6 ml) followed by the addition of iron powder (10.3 g, 185.18 mmol, 3.5 eq.) at room temperature and the reaction mixture was stirred for 16 h at 110°C. After completion of the reaction (monitored by TLC, 20% EtOAc/hexane, Rf 0.3), the reaction mixture was filtered through a pad of celite and washed with EtOAc (200 ml x 3 ). The combined organic fractions were concentrated at reduced

- 54 045285 pressure, diluted with EtOAc (500 ml), washed with water (100 mlx2) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 20% EtOAc/hexane eluent) to give 4-chloro-5-fluoro-2-methyl-phenylamine (7.5 g, 89%) in as a light brown solid.

Step 2: A solution of Br ₂ (1.79 mL, 34.81 mmol, 1 eq.) in DCM (60 ml) dropwise at 0°C and the resulting reaction mixture was stirred at 0°C for 2 hours. After consumption of the starting material (monitored by TLC in 20% EtOAc-hexane, Rf 0.6), the reaction mixture was quenched with saturated NaHCO ₃ solution (400 ml) and the organic layer was separated. The aqueous fraction was extracted and the combined organic layers were washed with water (2x300 ml) and brine (200 ml), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 10% EtOAc/hexane eluent) to give 2-bromo-4-chloro-3-fluoro-6-methylaniline (4.5 g, 54% ) as a brown solid.

Step 3: To a stirred solution of 2-bromo-4-chloro-3-fluoro-6-methylaniline (5 g, 21.008 mmol, 1 eq.) in dry DMAc (100 ml) was added 2-amino-2-methyl-propionic acid (4.4 g, 42.016 mmol, 2 eq.) and DBU (5.46 mL, 42.016 mmol, 2 eq.) at room temperature and the resulting reaction mixture was degassed with nitrogen for 30 min. CuI (400 mg, 2.1006 mmol, 0.1 eq.) was added to this reaction mixture, which was heated at 140°C for 16 hours. After consumption of the starting material (monitored by TLC, 20% EtOAc-hexane, Rf 0 3) The reaction mixture was cooled to room temperature and filtered through a pad of celite, then washed with EtOAc (2x300 ml). The resulting filtrate was poured into ice water (200 ml) and extracted with EtOAc (2x400 ml). The combined organic fractions were washed with cold water (3x100 ml) and brine (100 ml), dried over anhydrous Na ₂ SO ₄ and evaporated under reduced pressure. The crude residue was purified by chromatography (100-200 mesh silica gel; 20% EtOAc/hexane eluent) to give 6-chloro-5-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxaline-2(1H )-she (28 g, 69%) as an off-white solid.

Step 4: Into a stirred solution of 6-chloro-5-fluoro-3,3,8-trimethyl-3,4-dihydroquinoxalin-2(1H)one (12 g, 49.58 mmol, 1 eq.) in toluene (240 mL), Lawesson's reagent (30.08 g, 74.38 mmol, 1.5 eq.) was added at room temperature and the reaction mixture was refluxed at 120°C for 2 hours. After consumption of the starting material (monitored by TLC in 20% EtOAc-hexane, Rf 0.6), the reaction mixture was concentrated under reduced pressure. The resulting solid residue was quenched with sat. NaHCO ₃ solution (500 ml) and the resulting aqueous phase was extracted with EtOAc (3x300 ml), after which the combined organic layers were washed with water (400 ml) and brine (200 ml), dried over anhydrous Na ₂ SO ₄ and evaporated at reduced pressure. The resulting crude residue was purified by column chromatography (100-200 mesh silica gel; 10% EtOAc/hexane eluent) to give 6-chloro-5-fluoro-3,3,8-trimethyl-3,4dihydro-1H-quinoxaline -2-thione (11.5 g, 90%) as a yellow solid.

Step 5: Into a stirred solution of 6-chloro-5-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2thione (8 g, 31.007 mmol, 1 eq.) in tetrahydrofuran (200 ml) hydrazine hydrate (6.209 g, 124 mmol, 4 eq.) was added dropwise at 0°C and the reaction mixture was stirred at room temperature for 16 hours. After consumption of starting material (monitored by TLC in 5% MeOHDCM, Rf 0.4 ) the reaction mixture was concentrated to give crude 7-chloro-8-fluoro-3hydrazinylidene-2,2,5-trimethyl-1,2,3,4-tetrahydroquinoxaline (8 g), which was used in the next step without further purification.

Step 6: To crude 7-chloro-8-fluoro-3-hydrazinylidene-2,2,5-trimethyl-1,2,3,4-tetrahydroquinoxaline (8 g, 34.06 mmol, 1 eq.) was added triethylorthoacetate ( 240 ml) at room temperature, and the solution was stirred at 140°C for 48 hours. After consumption of the starting material (monitored by LC-MS), the reaction mixture was concentrated and purified using column chromatography (100-200 mesh, silica gel; 2% MeOH /DCM as eluent) to give 7-chloro-6-fluoro1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (6 g, 69 % from two stages) as a white solid.

Step 7: Into a stirred solution of 7-chloro-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (3 g, 10.686 mmol, 1 eq.) in DMF (90 ml), NBS (1.99 g, 11.22 mmol, 1.05 eq.) was added portionwise at 0°C and the resulting reaction mixture was stirred at 0°C for 1 hour. After consumption starting material (monitored by LC-MS), the reaction mixture was diluted with water (60 ml) and extracted with EtOAc (2x100 ml). The combined organic layers were washed with water (2x60 ml) and brine, dried over anhydrous Na ₂ SO ₄ and concentrated under reduced pressure. Three batches (3 x 3 g) were run in parallel and the combined crude material was purified by column chromatography (100-200 mesh silica gel; 5% MeOH/DCM eluent) with

- 55 045285 by obtaining 8-bromo-7-chloro-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (7, 6 g, 66%) as a yellow solid.

Any of Intermediate-A may be coupled to any of Intermediate-B in standard chemical reactions known to one of ordinary skill in the art, such as those described herein below.

Example 38 8-(3-cyclopropyl-5-fluoro-1H-indol-7-yl)-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo [4,3-a]quinoxaline.

A 10% solution of Na ₂ CO ₃ (1.0 ml) and 3 -cyclopropyl-5-fluoro-7-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole (intermediate A-16) (0.361 g, 1.2 mmol, 1.3 eq.) in a hermetically sealed tube. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.053 g, 0.0461 mmol, 0.05 eq.), the reaction mixture was refluxed at 110°C for 16 h. When the reaction was complete, 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 the solvents were evaporated to give the crude product, which was purified using silica gel column chromatography (230-400) (5% MeOH/DCM ; value Rp0.4) to obtain 8-(3-cyclopropyl-5-fluoro-III-indol-7-yl)-6-fluoro1,4,4,9-tetramethyl-4,5-dihydro[1,2, 4]triazolo[4,3-a]quinoxaline (0.140 g, 36%) as an off-white solid.

^1H NMR (400 MHz, DMSO- _d6 ): δ 10.64 (s, 1H), 7.36 (d, 1H), 7.17 (d, 1H), 7.08 (s, 1H), 6.9 (d, 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, 2H), 0.60 (d, 2H).

Example 49 9-ethyl-6-fluoro-1,4,4-trimethyl-8-(1-(methylsulfonyl)-1H-indol-4-yl)-4,5-dihydro[1,2,4]triazolo [4,3-a]quinoxaline.

To a solution of intermediate B-9 (0.25 g, 0.737 mmol, 1 eq.) in 1,4-dioxane and water (15 ml and 1.5 ml) was added CsF (0.336 g, 2.21 mmol, 3 eq. .) and intermediate A-2 (0.344 g, 1.1 mmol, 1.5 eq.) in a sealed tube. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.043 g, 0.0368 mmol, 0.05 eq.). The reaction mixture was stirred at 90°C for 16 hours. After completion of the reaction (monitored by LC-MS), the solvents were evaporated to dryness and the residue was diluted with EtOAc (50 ml). The organic layer was washed with water (2x20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified using silica gel column chromatography (230-400) (5% MeOH/DCM ; R _r value 0.4) to give 9-ethyl-6-fluoro-1,4,4-trimethyl-8-(1(methylsulfonyl)-1H-indol-4-yl)-4,5-dihydro[1 ,2,4]triazolo[4,3-a]quinoxaline (0.08 g, 24%) as an off-white solid.

Ή NMR (400 MHz, DMSO-d6, at 100°C): 7.92 (d, 1H), 7.62 (s, 1H), 7.48 (t, 1H), 7.34 (d, 1H ), 7.08 (d, 1H), 6.58 (s, 1H), 6.21 (s, 1H), 3.43 (s, 3H), 2.68-2.66 (m, 2H) , 2.53 (s, 3H), 1.57 (s, 6H), 0.51 (t).

Example 58 1,2,4]triazolo[4,3-a]quinoxaline.

In a solution of intermediate B-10 (0.1 g, 0.294 mmol, 1 eq.) and intermediate A-25 (0.115 g, 0.353 mmol, 1.2 eq.) in a mixture of tert-amyl alcohol (3 ml)/ dioxane (3 ml)/water (0.3 ml) added K2CO3 (0.122 g, 0.882 mmol, 3 eq.). The solution was then degassed (N2) for 10 min followed by the addition of Attaphos catalyst (0.011 g, 0.0147 mmol, 0.05 eq). The reaction mixture was then heated at 100°C for 16 hours. Once complete (LC-MS), 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 preparative HPLC to give 8-(1-(2,2-difluoroethyl)-6fluoro-1H-indol-4-yl)-6-fluoro-9-methoxy- 1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.071 g, 50%).

- 56 045285

1H NMR (400 MHz; DMSOC) δ 7.51 (dd, 1H), 7.41 (d, 1H), 7.25 (d, 1H), 7.05 (dd, 1H), 6.67 (s , 1H), 6.54-6.27 (m, 2H), 4.71 (td, 1H), 3.16 (s, 3H), 2.55 (d, 3H), 1.55 (s, 3H).

Example 446 ]triazolo[4,3-a]quinoxaline.

Into a solution of 8-bromo-6,7-difluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-38) (0.6 g, 1.75 mmol, 1.0 eq.) in a mixture of tert-amyl alcohol: 1,4 dioxane: H ₂ O (3: 2: 1) (100 ml) was added K ₂ CO ₃ (0.725 g , 5.25 mmol, 3 eq.) at room. pace. The solution was degassed with Ar for 20 min followed by the addition of 1-(ethylsulfonyl)-6-fluoro-4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-8) (0.930 g, 2.63 mmol, 1.2 eq.) and Attaphos (0.062 g, 0.0875 mmol, 0.05 eq.). The reaction mixture was then placed in a preheated oil bath at 90°C for 2 hours. After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was diluted with water (100 ml) and extracted with EtOAc (2x250 ml). The organic layer was washed with brine (75 ml), dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to give the crude product, which was first purified by column chromatography using MeOH-DCM as eluent. It was then re-purified again using Combiflash column chromatography using acetone-hexane as eluent. The product was then washed with ether to give pure 8-(1-(ethylsulfonyl)-6-fluoro-III-indol-4-yl)-6,7-difluoro-1,4,4,9-tetramethyl-4,5dihydro[1 ,2,4]triazolo[4,3-a]quinoxaline (0.32 g, 38%) as a white solid.

1H NMR (400 MHz, DMSO- _d6 ): δ 7.71 (d, 1H), 7.66 (d, 1H), 7.37 (d, 1H), 6.93 (s, 1H), 6 .59 (d, 1H), 3.75 (k, 2H), 2.45 (s, 3H), 1.97 (s, 3H), 1.57 (s, 3H), 1.51 (s, 3H), 1.11 (t, 3H).

Example 448 ,3-a]quinoxaline.

Into a solution of 8-bromo-6,7-difluoro-1,4,4,9-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-38) (0.05 g, 0.146 mmol, 1 eq.) in 1,4-dioxane (9 ml) was added CsF (0.067 g, 0.438 mmol, 3 eq.) and 1-(methylsulfonyl)-4-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1Nindole (intermediate A-12) (0.07 g, 0.219 mmol, 1.5 eq.) in a sealed tube. The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.013 g, 0.0073 mmol, 0.05 eq.). The reaction mixture was refluxed at 110°C for 16 hours. After completion of the reaction (monitored 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 (2x20 ml), brine (20 ml), dried over anhydrous Na ₂ SO ₄ and the solvent was evaporated to give the crude product, which was purified using preparative HPLC (5% MeOH/DCM; Rf value - 0.4 ) to give 6,7-difluoro-1,4,4,9-tetramethyl-8-(1-(methylsulfonyl)-1H-indol-4-yl)-4,5dihydro[1,2,4]triazolo[4 ,3-a]quinoxaline (0.04 g, 61%) as a white solid.

1H NMR (DMSO- _d6 ) δ= 7.94 (d, 1H), 7.65 (d, 1H), 7.51 (t, 1H), 7.35 (d, 1H), 6.88 ( s, 1H), 6.57 (d, 1H), 3.53 (s, 3H), 2.44 (s, 3H), 1.95 (s, 3H), 1.58 (s, 3H), 1.49 (s, 3H).

Example 450 8-(1-cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3- a]quinoxaline-9-carbonitrile.

Into a solution of 8-bromo-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9-carbonitrile (intermediate B-39) 1-cyclopropyl-4-(4 ,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)1H-indole (intermediate A-44) (0.219 g, 0.776 mmol, 2.00 eq.). The solution was degassed with Ar for 20 min followed by the addition of Pd(PPh ₃ ) ₄ (0.022 g, 0.019 mmol, 0.05 eq.). The reaction mixture was then heated to 90°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite layer was washed with

- 57 045285 with the power of EtOAc. The combined organic layers were evaporated under reduced pressure to give the crude compound, which was purified by preparative HPLC to give 8-(1cyclopropyl-III-indol-4-yl)-6-fluoro-1,4,4-trimethyl-4,5- dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9carbonitrile (0.045g, 28.3%) as a white solid.

1H NMR (DMSO-d ₆ ) δ=δ 7.71 (d, 1H), 7.52-7.50 (m, 1H), 7.47 (d, 1H), 7.34-7.30 ( m, 1H), 7.26-7.25 (m, 1H), 7.13 (s, 1H), 6.42-6.41 (m, 1H), 3.52-3.49 (m, 1H), 2.75 (s, 3H), 1.57 (s, 6H), 1.11-1.08 (m, 2H), 1.02-1.00 (m, 2H).

Example 455 2,4]triazolo[4,3-a]quinoxaline.

Into a solution of 8-bromo-9-(difluoromethyl)-6-fluoro-1,4,4-trimethyl-4,5-dihydro-[1,2,4]triazolo[4,3a]quinoxaline (intermediate B-43 ) (0.470 g, 1.388 mmol, 1.50 eq.) in a mixture of tert-amyl alcohol: dioxane: water (3:2:1, 30 ml) was added K ₂ CO ₃ (0.287 g, 2.082 mmol, 3.00 eq. .) at ambient temperature. The solution was degassed with Ar for 20 min followed by the addition of 6fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-2) (0.250 g, 0.694 mmol, 1.00 eq) and Attaphos (0.025 g, 0.035 mmol, 0.05 eq). The reaction mixture was then heated to 90°C for 2 hours. After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over Na ₂ SO ₄ and evaporated under reduced pressure to obtain the crude compound. This crude material was then purified by column chromatography using MeOH-DCM as eluent and re-purified by column chromatography using acetone-hexane as eluent. The resulting material was then washed with ether to give 9-(difluoromethyl)-6-fluoro-8-(6-fluoro-1(methylsulfonyl)-1H-indol-4-yl)-1,4,4-trimethyl-4,5 -dihydro[1,2,4]triazolo[4,3-a]quinoxalineα (0.150 g, 42%) as a white solid. ^1H NMR (DMSO-66) δ= 7.68-7.65 (m, 1H), 7.61 (d, 1H), 7.29-7.26 (m, 2H), 7.18-6 .92 (m, 2H), 6.56-6.55 (m, 1H), 3.56 (s, 3H), 1.54 (lat, 6H); (CH ₃ -hidden by DMSO peak).

Example 465 ]quinoxaline.

6-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole (Intermediate A-1) (144.5 mg, 0.554 mmol, 2.0 eq.), 8bromo-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-7 ) (90.0 mg, 0.277 mmol, 1.0 eq.) and bis(tri-tert-butylphosphine)palladium(0) (14.2 mg, 0.028 mmol, 0.1 eq.). A magnetic stirring element was added, the vessel was sealed, and the vessel was purged with nitrogen for 5 min while stirring. THF (1.8 ml) and 2 M Na ₂ CO ₃ solution (0.6 ml) were then added and the mixture was heated to 60°C for 16 hours. The mixture was then cooled back to ambient temperature followed by the addition of DCM and water. The mixture was filtered through a hydrophobic inlet filter and the organic layer was evaporated under reduced pressure. The remaining crude material was then purified using silica gel column chromatography to provide 84.0 mg (80%) of 6-fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl -4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (Example 465) as a white solid. ^1H NMR (DMSO- _b6 ) δ: 11.30 (s, 1H), 7.40 (t, 1H), 7.22 (dd, 1H), 7.18 (d, 1H), 6.91 (dd, 1H), 6.46 (d, 1H), 6.19 (t, 1H), 2.50 (s, 3H), 2.05 (s, 3H), 1.53 (s, 6H) .

Example 466 9-(difluoromethyl)-6-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-4,5-dihydro[1,2,4]triazolo [4,3-a]quinoxaline.

Step 1. Into a solution of 8-bromo-9-(difluoromethyl)-6-fluoro-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3a]quinoxaline (intermediate B -43) (0.05 g, 0.138 mmol, 1 eq.) in dioxane (10.0 ml) added KOAc (0.041 g, 0.414 mmol, 3 eq.) and bispinacolatodiborane (0.42 g, 0.166 mmol, 1.2 eq.) The solution was degassed with Ar for 20 min followed by the addition of PdCl ₂ (dppf)·DCM (0.011 g, 0.0138 mmol, 0.01 eq.). The reaction mixture was refluxed for 16 hours. After completion of the reaction (monitored by TLC), the solvent was evaporated under reduced pressure to give the crude product, which was purified by column chromatography to give 9-(difluoromethyl)-6-fluoro-1,4 ,4-trimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)4,5-dihydro[1,2,4]triazolo[4,3-a] quinoxaline (0.05 g, 89%) as a brown solid.

Step 2. In a solution of 7-bromo-3-methyl-1H-indazole (0.10 g, 0.473 mmol, 1.0 eq.) in a mixture of tert-amyl alcohol: dioxane: H ₂ O (3: 2: 1) (30 ml) was added K ₂ CO ₃ (0.196 g, 1.419 mmol, 3 eq.) at rt. pace. The solution was degassed with Ar for 20 min followed by the addition of 9-(difluoromethyl)-6-fluoro-1,4,4trimethyl-8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2 -yl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.231 g, 0.568 mmol, 1.2 eq.) and Attaphos (0.017 g, 0.023 mmol, 0.05 eq.). The reaction mixture was then placed in a preheated oil bath at 90°C for 2 hours. After completion of the reaction (monitored by TLC and LC-MS), the reaction mixture was diluted with water and extracted with EA. The organic layer was washed with brine, dried over Na ₂ SO ₄ , filtered and the solvent was evaporated under reduced pressure to give the crude product, which was first purified by column chromatography using MeOH-DCM as eluent. It was then re-purified again using Combiflash column chromatography using acetone-hexane as eluent. The product was then washed with ether to give pure 9-(difluoromethyl)-6fluoro-1,4,4-trimethyl-8-(3-methyl-N-indazol-7-yl)-4,5-dihydro[1,2, 4]triazolo[4,3-a]quinoxaline (0.08 g, 40%) as a white solid.

^1H NMR (400 MHz, DMSO- _d6 ): δ 12.55 (s, 1H), 7.72 (d, 1H), 7.26-7.22 (m, 2H), 7.14-7 .12 (m, 1H), 7.116.82 (m, 2H), 2.51 (s, 3H), 1.54-1.51 (m, 6H).

Example 481 ,3-a] quinoxaline-9-amine.

G

In a solution of 8-bromo-6-fluoro-N,1,4,4-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxalin-9-amine (intermediate B- 46) (0.15 g, 0.44 mmol, 1 eq.) in a mixture of tert-amyl alcohol:dioxane (2:1) (5.0-2.5 ml) was added a 2 M solution of K ₂ CO ₃ (1 .0 ml) and 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole (intermediate A-44) (0.15 g, 0 .53 mmol, 1.2 eq.). The solution was degassed with Ar for 20 min followed by the addition of Attaphos (0.016 g, 0.02 mmol, 0.05 eq). The reaction mixture was heated to 90°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The combined organic layer was evaporated to give the crude product, which was purified by preparative HPLC (Rf value -0.3: 5% MeOH/DCM) to give 8-(1cyclopropyl-1H-indol-4-yl)-6-fluoro-N ,1,4,4-tetramethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-9amine (0.09 g, 49%) as a white solid.

^1H NMR (400 MHz, DMSO-de): δ 7.63-7.61 (m, 1H), 7.40 (d, 1H), 7.31-7.27 (m, 1H), 7. 08 (d, 1H), 7.006.98 (m, 1H), 6.46 (s, 1H), 6.20 (d, 1H), 4.07-4.05 (m, 1H), 3.48 -3.47 (m, 1H), 2.53 (s, 3H), 2.16-2.14 (m, 3H), 1.58-1.49 (m, 6H), 1.10-1 .08 (m, 2H), 0.99-0.98 (m, 2H).

Example 483 ]triazolo[4,3-a]quinoxaline.

F

Into a solution of 8-bromo-6-chloro-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-47) (0.150 g, 0.42 mmol, 1 eq.) in a mixture of tert-amyl alcohol: dioxane: H ₂ O (3: 2: 1) (10 ml) was added K ₂ CO ₃ (0.174 g, 1.26 mmol, 3 equiv.) and 6-fluoro-1(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A-2) (0.171 g, 0.50 mmol, 1.2 eq.). The solution was degassed with Ar for 20 min followed by the addition of Attaphos (0.015 g, 0.021 mmol, 0.05 eq). The reaction mixture was heated to 90°C for 30 min. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and the celite layer was washed with EtOAc. The combined organic layer was evaporated to give the crude product, which was purified by preparative HPLC (Rf value -0.3: 50% acetone/hexane) to give 6-chloro-8-(6-fluoro-1-(methylsulfonyl)-1Nindol- 4-yl)-9-methoxy-1,4,4-trimethyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.05 g, 24%) as

- 59 045285 white solid. 1H NMR (400 MHz, DMSO- _d6 ): δ 7.68-7.65 (m, 1H), 7.64-7.63 (m, 1H), 7.40 (s, 1H), 7. 33-7.30 (m, 1H), 6.68-6.67 (m, 1H), 6.33 (s, 1H), 3.56 (s, 3H), 3.21 (s, 3H) , 2.55 (s, 3H), 1.57 (s, 6H).

Example 490 3a]quinoxaline.

7-Fluoro-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-1H-indole (128.5 mg, 0.492 mmol, 2.0 equiv) was weighed into a microwave vessel .), 8-bromo-6-fluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-7) (80.0 mg , 0.246 mmol, 1.0 eq.) and Pd(PPh ₃ ) ₄ . A magnetic stirring element was added, the vessel was sealed, and the vessel was purged with nitrogen for 5 min while stirring. Toluene (2.1 ml), EtOH (0.6 ml) and 2 M Na2CO3 solution (0.5 ml) were then added sequentially. The reaction mixture was then heated to 90°C for 16 hours. The mixture was cooled to ambient temperature, diluted with water and DCM, and filtered through a hydrophobic inlet filter. The organic layer was evaporated under reduced pressure to give crude material, which was then purified by silica gel column chromatography and HPLC to give 6-fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9 -tetramethyl-4,5dihydro[1,2,4]triazolo[4,3-a]quinoxaline (Example 490) in 71% yield (66.0 mg) as a white solid.

1H NMR (DMSO- _d6 ) δ: 11.76 (t, 1H), 7.47 (t, 1H), 7.13 (d, 1H), 7.01 (dd, 1H), 6.96 ( dd, 1H), 6.42 (d, 1H), 6.27 (m, 1H), 2.49 (s, 3H), 2.02 (s, 3H), 1.52 (s, 6H).

Example 500 6,7-difluoro-1,4,4-trimethyl-8-(1-(methylsulfonyl)-1H-indol-4-yl)-9-(trifluoromethyl)4,5-dihydro[1,2 4]triazolo[4,3-a]quinoxaline.

Into a solution of 8-bromo-6,7-difluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[4,3a]quinoxaline (intermediate B -50) (0.07 g, 0.17 mmol, 1 eq.) in a mixture of tert-amyl alcohol: dioxane: H ₂ O (3: 2: 1) (3.0 ml: 2.0 ml: 1 ml ) added K2CO3 (0.073 g, 0.53 mmol, 3 eq.) and 1(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H- indole (intermediate A-12) (0.085 g, 0.26 mmol, 1.5 eq.). The solution was degassed with Ar for 20 min followed by the addition of Attaphos (0.006 g, 0.008 mmol, 0.05 eq). The reaction mixture was heated to 90°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The combined organic layer was evaporated to give the crude product, which was purified by preparative HPLC (R _r value 0.3: 50% acetone/hexane) to give 6,7-difluoro-1,4,4-trimethyl-8-(1- (methylsulfonyl)-1H-indol-4-yl)9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline (0.037 g, 39%) as a white solid substances.

1H NMR (400 MHz, DMSO-a ₆ ): δ 8.00-7.98 (m, 1H), 7.61 (s, 1H), 7.51-7.47 (m, 1H), 7. 38 (s, 1H), 7.25 (s, 1H), 6.63 (s, 1H), 3.46 (s, 3H), 2.49 (s, 3H), 1.85 (s, 3H ), 1.40 (s, 3H).

Example 518 dihydro[1,2,4]triazolo[4,3-a]quinoxaline.

Into a solution of 8-bromo-6,7-difluoro-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro-[1,2,4]triazolo[4,3a]quinoxaline (intermediate B -50) (0.07 g, 0.17 mmol, 1 eq.) in a mixture of tert-amyl alcohol:dioxane (1:1) (2.5 ml-2.5 ml) added K2CO3 (0.073 g, 0. 53 mmol, 3 equiv.) and 6-fluoro-1(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A -2) (0.09 g, 0.26 mmol, 1.5 eq.). The solution was degassed with Ar for 20 min followed by the addition of X-phos (0.017 g, 0.035 mmol, 0.2 eq) and Pd ₂ (dba) = (0.016 g, 0.017 mmol, 0.1 eq). The reaction mixture was refluxed at 90°C for 16 hours. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a pad of celite and washed with EtOAc. The combined organic layer was evaporated to give the crude product, which was purified by preparative HPLC (Rp0.3: 50% acetone/hexane) to give 6,7-difluoro-8-(6fluoro-1-(methylsulfonyl)-1H-indole -4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-4,5-dihydro[1,2,4]triazolo[4,3

- 60 045285

a]quinoxaline (0.037 g, 37%) as a white solid.

1H NMR (400 MHz, DMSO- _d6 ): δ 7.77 (d, 1H), 7.63 (d, 1H), 7.28-7.34 (m, 2H), 6.64 (s, 1H), 3.51 (s, 3H), 2.47 (s, 3H), 1.77 (s, 3H), 1.38 (S, 3H).

Example 520 indole-7-carbonitrile.

G

8-Bromo-6,7-difluoro-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline (intermediate B-38) was weighed into a microwave vessel. (60.0 mg, 0.175 mmol, 1.0 eq.), 4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carbonitrile (intermediate compound A75) (93.8 mg, 0.350 mmol, 2.0 eq.), Pd ₂ dba ₃ (16.0 mg, 0.018 mmol, 0.1 eq.) and X-Phos (16.9 mg, 0.036 mmol , 0.2 eq.). A magnetic stirring element was then added and the vessel was sealed. The vessel was then evacuated and backfilled with nitrogen three times, followed by the addition of 1,4-dioxane (1.3 ml), tert-amyl alcohol (1.3 ml) and 2 M K2CO3 (0.4 ml). The reaction mixture was then bubbled with nitrogen under sonication followed by heating to 60°C for four hours. The mixture was allowed to cool to ambient temperature, diluted with water and DCM, and filtered through a hydrophobic inlet filter. The organic layer was evaporated under reduced pressure to yield crude material, which was then purified by silica gel column chromatography and HPLC to yield 4-(6,7-difluoro-1,4,4,9-tetramethyl-4,5-dihydro[1, 2,4]triazolo[4,3-a]quinoxalin8-yl)-1H-indole-7-carbonitrile (Example 520) in 76% yield (54.0 mg) as a white solid.

1H NMR (DMSO^) δ: 12.20 (s, 1H), 7.72 (d, 1H), 7.57 (t, 1H), 7.22 (d, 1H), 6.90 (d, 1H), 6.36 (dd, 1H), 2.45 (s, 3H), 1.95 (s, 3H), 1.59 (s, 3H), 1.50 (s, 3H).

In the following tables. 3, 4 and 5 summarize how the remaining examples were obtained.

- 61 045285

Table 3

Etc. No. Intermediates Synthesis similar Yield (% mol) 'H-NMR 48 Int. connection-A-2 + Int. connection-B-9 Etc. 49 31% 1H NMR (400 MHz, DMSO-a ₆ , at 100°C): 7.68 (d, 1H), 7.63 (s, 1H), 7.24 (d, 1H, 1=10.16 Hz) , 7.11 (d, 1H), 6.57 (s, 1H), 6.26 (s, 1H), 3.48 (s, ZN), 2.69-2.67 (m, 2H), 2.53 (s, ZN), 1.57 (s, 6H), 0.54 (t, ZN). 53 Int. connection-A-23 + Int. connection-B-9 Etc. 49 15% 1H NMR (400 MHz, DMSO-a ₆ , at 100°C): 8.33 (s, 1H), 7.73 (d, 1H, 1=9.0 Hz), 7.4 (d, 1H) , 7.2 (d, 1H), 6.36 (s, 1H), 3.53 (s, ZN), 2.74-2.66 (m, 2H), 2.56 (s, ZN), 1.58 (s, 6H), 0.56 (t, ZN). 54 Int. connection-A-24 + Int. connection-E-S Etc. 49 40% 'H NMR (400 MHz, DMSO-a ₆ ): δ 7.44-7.38 (m, 2H), 7.24 (d, 1H), 7.0 (dd, 1H), 6.67 (s , 1H), 6.33 (d, 1H), 4.33 (t, 2H), 3.67 (t, 2H), 3.24 (s, ZN), 3.16 (s, ZN),2 .55 (s, ZN), 1.55 (s, 6N). 55 Int. connection-A-20 + Int. connection-E-S Etc. 49 63% 'H NMR (400 MHz, DMSO-a ₆ ): δ 7.40-7.39 (m, 2H), 7.23 (d, 1H), 7.0 (dd, 1H), 6.67 ( s, 1H), 6.33 (d, 1H), 4.9 (t, 1H), 4.22 (t, 2H), 3.74 (k, 2H), 3.17 (s, ZN), 2.56 (s, ZN), 1.55 (s, 6H). 56 Int. connection-A-2 + Int. connection-E-S Etc. 49 34% 'H NMR (400 MHz, DMSO-a ₆ ): δ 7.68-7.62 (m, 2H), 7.33-7.26 (m, 2H), 6.66 (s, 1H), 6 .69 (d, 1H), 3.56 (s, ZN), 3.18 (s, ZN), 2.57 (s, ZN), 1.55 (s, 6H). 57 Int. connection-A-12 + Int. connection-E-S Ex.49 33% 'H NMR (400 MHz, DMSO- _a6 ): δ 7.89 (d, 1H), 7.62 (d, 1H), 7.48 (d, 1H), 7.38 (d, 1H), 7.23 (d, 1H), 6.69 (d, 1H), 3.5 (s, ZN), 3.14 (s, ZN), 2.57 (s, ZN), 1.55 (s , 6H). 59 Int. connection-A-2 + Int. connection-V-P Etc. 49 20% 'H NMR (400 MHz, DMSO- _a6 ): δ 7.66 (dd, 1H), 7.63 (d, 1H), 7.31-7.36 (m, 1H), 7.19 (d , 1H), 6.55-6.56 (m, 2H), 3.56 (s, ZN), 2.18 (s, ZN), 1.95 (m, 1H), 1.50 (lat. , 6H), 1.08 (lat, 4H). 60 Int. connection-A-12 + Int. connection-VP Etc. 49 26% 'H NMR (400 MHz, DMSO- _a6 ): δ 7.88 (d, 1H), 7.62 (d, 1H), 7.46 (t, 1H), 7.33-7.35 (m , 1H), 7.16 (d, 1 = 10.4 Hz, 1H), 6.55 (d, 1H), 6.50 (s, 1H), 3.50 (s, ZN), 2.15 (s, ZN), 1.90 (m, 1H), 1.50 (lat, 6H), 1.07-1.11 (m, 4H). 61 Int. connection-A-20 + Int. connection-V-P Etc. 49 27% *H NMR (400 MHz, DMSO-a ₆ ): δ 7.38-7.40 (m, 2H), 7.15 (d, 1H), 6.96 (d, 1H), 6.46 (s , 1H), 6.16 (d, 1H), 4.90 (t, 1 = 5.2 Hz, 1H), 4.21 (t, 2H), 3.73 (k, 2H), 2.19 (s, ZN), 1.92 (m, 1H), 1.50 (lat, 6H), 1.07-1.12 (m, 4H). 62 Int. connection-A-15 + Int. connection-V-P Etc. 49 29% 'H NMR (400 MHz, DMSO-a ₆ ): δ 10.61 (s, 1H), 7.26 (dd, 1H), 7.15-7.18 (m, 2H), 6.93 (d , 1Н), 6.46 (s, 1Н), 2.25 (s, ЗН), 2,072.08 (m, 4Н), 1.51 (lat, 6Н), 1.09 (lat, 4Н) . 63 Int. Etc. 49 20% 'H NMR (400 MHz, DMSO-a ₆ ): δ 10.61 (s, 1H), 7.26 (dd, 1H), connection-A-2 + Int. connection-B-12 7.15-7.18 (m, 2H), 6.93 (d, 1H), 6.46 (s, 1H), 2.25 (s, ZN), 2.072.08 (m, 4H), 1 .51 (broad, 6H), 1.09 (broad, 4H). 64 Int. connection-A-22 + Int. connection-B-12 Etc. 49 26% 'H NMR (400 MHz, DMSO-a ₆ ): δ 7.88 (d, 1H), 7.62 (d, 1H), 7.46 (t, J = 8.0 Hz, 1H), 7. 33-7.35 (m, 1H), 7.16 (d, J = 10.4 Hz, 1H), 6.55 (d, 1H), 6.50 (s, 1H), 3.50 (s , ZN), 2.15 (s, ZN), 1.90 (m, 1N), 1.50 (lat, 6N), 1.07-1.11 (m, 4N). 65 Int. connection-A-20 + Int. connection-B-12 Etc. 49 27% 'H NMR (400 MHz, DMSO-a ₆ ): δ 7.38-7.40 (m, 2H), 7.15 (d, 1H), 6.96 (d, J = 10.0 Hz, 1H ), 6.46 (s, 1H), 6.16 (d, 1H), 4.90 (t, 1H), 4.21 (t, 2H), 3.73 (k, 2H), 2.19 (s, ZN), 1.92 (m, 1H), 1.50 (lat, 6H), 1.07-1.12 (m, 4H). 66 Int. connection-A-15 + Int. connection-B-12 Etc. 49 29% 'H NMR (400 MHz, DMSO-a ₆ ): δ 10.61 (s, 1H), 7.26 (dd, 1H), 7.15-7.18 (m, 2H), 6.93 (d , 1Н), 6.46 (s, 1Н), 2.25 (s, ЗН), 2,072.08 (m, 4Н), 1.51 (lat, 6Н), 1.09 (lat, 4Н) .

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Table 4

Etc. No. Intermediates Synthesis is analogical Yield (% mol) m/z [M+1] Ίΐ-NMR 300 Int. connection-B-7 + Intermediate connection-A43 Etc. 465 22% 'H NMR (DMSO-b/b) δ: 7.54 (m _s , 1H), 7.41 (d, 1H), 7.23 (dd, 1H), 7.13 (d, 1H), 7 .02 (d, 1H), 6.44 - 6.40 (m, 1H), 6.21 - 6.17 (m, 1H), 4.38 (t, 2H), 3.70 (t, 2H ), 3.25 (d, ZN), 2.50 (s, ZN), 2.03 (s, ZN), 1.55 1.51 (m, 6N) 304 Int. compound-B-7 + 1 -methyl-4 (4,4,5,5tetramethyl[1,3,2]dioxaborol an-2-yl)-1Nindazole Etc. 490 57% 'H NMR (DMSO-< ₇₆ ) δ: 7.86 (s, 1H), 7.68 (d, 1H), 7.49 (dd, 1H), 7.20 (d, 1H), 7. 16 (d, 1N), 6.51 (s, 1N), 4.10 (s, ZN), 2.52 (s, ZN), 2.04 (s, ZN), 1.53 (s, 6N ) 305 Int. connection-B-7 + Intermediate connection-A44 Etc. 465 88% 'H NMR (DMSO-b/b) δ: 7.61 (dd, 1H), 7.38 (d, 1H), 7.27 (dd, 1H), 7.11 (d, 1H), 7. 08 - 7.03 (m, 1Η), 6.42 (d, 1Η), 6.15 (dd, 1Η), 2.49 (s, ZN), 2.02 (s, ZN), 1.52 (s, 6H), 1.34 - 1.25 (m, W), 1.13 - 1.05 (m, 2H), 1.02-0.96 (m, 2H) 308 Int. connection-V-ZO + Intermediate connection-A12 Etc. 465 70% 'H NMR (DMSO-< ₇₆ ) δ: 7.91 (d, 1H), 7.66 (d, 1H), 7.48 (dd, 1H), 7.31 (d, 1H), 7. 15 (d, 1H), 6.55 (dd, 1H), 6.50 (d, 1H), 3.51 (s, ZN), 2.84 (s, 2H), 2.01 (s, ZN ), 1.75 - 1.34 (m, 6Η), 1.29 (t, ZN) 316 Int. connection-V-ZO + Intermediate connection-A15 Etc. 465 80% 'H NMR (DMSO-< ₇₆ ) δ: 10.59 (d, 1H), 7.27 (dd, 1H), 7.21 - 7.12 (m, 2H), 6.90 (d, 1H ), 6.45 (d, 1Η), 2.86 (s, 2Η), 2.27 (d, ZN), 1.98 (s, ZN), 1.69 - 1.39 (m, 6Η) , 1.29 (t, ZN) 322 Int. connection-V-ZO + Intermediate connection-A43 Etc. 465 66% 'H NMR (DMSO) δ: 7.53 (dd, 1H), 7.41 (d, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 7.01 (d, 1H), 6.41 (d, 1H), 6.16 (m _s , 1H), 4.37 (t, 2H), 3.70 (t, 2H), 3.25 (d, ZN), 2 .84 (s, 2N), 2.02 (s, ZN), 1.52 (s, 6N), 1.28 (t, ZN) 323 Int. connection-V-ZO + Intermediate connection-A2 Etc. 465 82% 'H NMR (DMSO-< ₇₆ ) δ: 7.69 - 7.67 (m, 1H), 7.66 (d, 1H), 7.27 (d, 1H), 7.19 (d, 1H ), 6.54 (d, 1H), 6.53 (dd, 1H), 3.56 (s, ZN), 2.83 (s, 2H), 2.03 (s, ZN), 1.74 - 1.33 (m, 6N), 1.28 (t, ZN)

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326 Int. connection-B-7 + Intermediate connection-A42 Etc. 490 62% 'H NMR (DMSO) δ: 7.60 (d, 1H), 7.44 (d, 1H), 7.27 (dd, 1H), 7.14 (d, 1H), 7.08 - 7, 04 (m, 1N), 6.51 - 6.30 (m, 2N), 6.27 (dd, 1N), 4.73 (td, 2N), 2.50 (s, ZN), 2.02 (s, ZN), 1.52 (s, 6H) 340 Int. connection-B-7 + Intermediate connection-A23 Etc. 465 77% 'H NMR (DMSO) δ: 8.47 - 8.43 (m, 1H), 7.72 (dd, 1H), 7.47 (dd, 1H), 7.29 (dd, 1H), 6, 63 (d, 1N), 3.57 (d, ZN), 2.54 (d, ZN), 2.08 (s, ZN), 1.53 (s, 6N) 349 Int. connection-B-7 + Intermediate connection-A45 Etc. 465 57% 'H NMR (DMSO-b/b) δ: 7.89 (d, 1H), 7.65 (d, 1H), 7.54 - 7.46 (m, 1H), 7.35 (d, 1H ), 7.17 (d, 1H), 6.66 (d, 1H), 6.51 (d, 1H), 6.07 (d, 2H), 2.50 (s, ZN), 2.01 (s, ZN), 1.58 (s, ZN), 1.48 (s, ZN) 350 Int. connection-B-7 + Intermediate connection-A47 Etc. 465 56% 'H NMR (DMSOA) δ: 7.90 ( _ms , 1H), 7.65 ( _ms , 1H), 7.47 ( _ms , 1H), 7.31 ( _ms , 1H), 7. 17 (m _s , 1H), 6.58 (m _s , 1H), 6.50 (t, 1H), 3.66 (m _s , 2H), 2.50 - 2.49 (m, ZN), 2.00 (s, ZN), 1.45 (s, 6N), 1.10 (m _s , ZN) 352 Int. compound-B-7 + 3-Methyl-1Nindazole-7boronic acid Etc. 465 20% 'H NMR (DMSO) δ: 12.56 (s, 1H), 7.74 (dd, 1H), 7.26 (dd, 1H), 7.20 - 7.12 (m, 2H), 6, 47 (d, 1H), 2.55 (s, ZN), 2.53 (s, ZN), 1.97 (s, ZN), 1.53 (s, 6H) 355 Int. compound-B-3O + 3-methyl-7(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indole Etc. 465 81% 'H NMR (DMSOCH) δ: 10.47 (d, 1H), 7.51 (d, 1H), 7.14 - 7.06 (m, ZH), 6.99 (d, 1H), 6, 40 (d, 1N), 2.93 - 2.78 (m, 2N), 2.29 (d, ZN), 1.96 (s, ZN), 1.67 1.43 (m, 6N), 1.28 (t, ZN) 366 Int. connection-B-7 + Intermediate connection-A30 Etc. 465 97% 'H NMR (DMSO-b/b) δ: 7.90 (d, 1H), 7.64 (d, 1H), 7.47 (dd, 1H), 7.31 (d, 1H), 7. 18 (d, 1H), 6.58 (d, 1H), 6.50 (d, 1H), 3.84 ( _ms , 1H), 2.50 (s, ZN), 2.00 (s, ZN), 1.64 - 1.42 (m, 6N), 1.23 (s, ZN), 1.22 (s, ZN) 374 Int. connection-V-ZO + Intermediate connection-A23 Etc. 465 85% 'H NMR (DMSO-b/b) δ: 8.42 (d, 1H), 7.75 - 7.70 (m, 1H), 7.49 - 7.44 (m, 1H), 7.29 (d, 1H), 6.62 (d, 1H), 3.57 (s, ZN), 2.94 - 2.80 (m, 2H), 2.10 - 2.06 (m, ZN), 1.67 - 1.42 (m, 6N), 1.30 (t, ZN) 375 Int. connection-B-7 + Intermediate connection-A46 Etc. 465 67% 'H NMR (DMSO) δ: 7.52 (d, 1H), 7.45 (d, 1H), 7.23 (dd, 1H), 7.13 (d, 1H), 7.02 (d, 1Н), 6.42 (d, 1Н), 6.20 - 6.13 (m, 1Н), 4.30 (t, 2Н), 2.65 (t, 2Н), 2.49 (d, ZN ), 2.21 (d, 6N), 2.03 (s, ZN), 1.57 - 1.48 (m, 6N) 378 Int. connection-B-7 + Intermediate connection-A22 Etc. 465 99% 'H NMR (DMSO-b/b) δ: 8.45 (s, 1H), 8.03 (d, 1H), 7.73 (dd, 1H), 7.46 (d, 1H), 7. 25 (d, 1N), 6.58 (d, 1N), 3.53 (s, ZN), 2.52 (d, ZN), 2.05 (s, ZN), 1.54 (s, 6N ) 389 Int. connection-V-ZO + Intermediate connection-A22 Etc. 465 96% 'H NMR (DMSO-b/b) δ: 8.41 (d, 1H), 8.02 (d, 1H), 7.73 (ddd, 1H), 7.46 (d, 1H), 7. 24 (d, 1H), 6.57 (d, 1H), 3.53 (d, ZN), 2.86 (s, 2H), 2.04 (s, ZN), 1.72 1.38 ( m, 6N), 1.30 (t, ZN) 391 Int. connection-B-7 + Intermediate connection-A48 Etc. 465 86% 'H NMR (DMSO) δ: 7.95 (dd, 1H), 7.66 (dd, 1H), 7.50 - 7.44 (m, 1H), 7.31 (d, 1H), 7. 18 (dd, 1H), 6.58 (dd, 1H), 6.50 (d, 1H), 3.15 ( _ms , 1H), 2.53 - 2.47 (m, ZN), 2, 01 (s, ZN), 1.53 (m, 6N), 1.33 - 1.25 (m, 2N), 1.15-1.07 (m, 2N) 464 Int. connection-B-9 + Intermediate connection-A20 Etc. 465 43% 'H NMR (DMSOCH) δ: 7.43 (d, 1H), 7.42 - 7.38 (m, 1H), 7.13 (d, 1H), 6.55 (d, 1H), 6. 28 - 6.18 (m, 1H), 4.23 (t, 2H), 3.76 (m _s , 2H), 2.67 (s, 2H), 2.54 (s, ZN), 1, 78 - 1.35 (m, 6N), 0.49 (t, ZN)

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467 Int. connection-B-45 + Intermediate connection-A23 Etc. 465 50% 'H NMR (DMSO) δ: 8.52 (s, 1H), 7.72 (dd, 1H), 7.52 (s, 1H), 7.29 (d, 1H), 6.64 (d, 1H), 3.57 (s, ZN), 2.65 (s, ZN), 2.02 (s, 1H), 1.80 (s, ZN), 1.19 (s, ZN), 0, 65 (s, 1H), 0.25 (s, 1H), -0.20 (d, 2H) 468 Int. compound-B-7 + indole-4 boronic acid Etc. 465 99% 'H NMR (DMSO) δ: 11.24 (s, 1H), 7.44 (d, 1H), 7.40 (t, 1H), 7.18 (t, 1H), 7.14 (d, 1H), 6.99 (d, 1H), 6.40 (d, 1H), 6.19 (dd, 1H), 2.50 (d, ZN), 2.03 (s, ZN), 1, 53 (s, 6H) 469 Int. compound-B-10 + indole-4 boronic acid Etc. 465 71% 'H NMR (DMSO-< ₇₆ ) δ: 11.19 (s, 1H), 7.44 (d, 1H), 7.37 (t, 1H), 7.23 - 7.15 (m, 2H ), 7.10 (d, 1H), 6.57 (d, 1H), 6.35 (t, 1H), 3.13 (s, ZN), 2.57 (s, ZN), 1.56 (s, 6H) 470 Int. connection-B-10 + Intermediate connection-A1 Etc. 465 75% 'H NMR (DMSO-< ₇₆ ) δ: 11.26 (s, 1H), 7.38 (t, 1H), 7.25 (d, 1H), 7.22 (dd, 1H), 6, 99 (dd, 1H), 6.64 (d, 1H), 6.35 (t, 1H), 3.16 (s, ZN), 2.57 (s, ZN), 1.56 (s, 6H ) 471 Int. connection-B-45 + Intermediate connection-A2 Etc. 465 67% 'H NMR (DMSO-oY δ: 7.69 - 7.63 (m, 2H), 7.47 7.23 (m, 1H), 7.19 (d, 1H), 6.69 - 6.64 (m, 1H), 6.56 (d, 1H), 3.54 (s, ZN), 2.61 (s, ZN), 2.08-1.82 (m, 1H), 1.79 ( s, ZN), 1.18 (s, ZN), 0.62 (s, 1N), 0.21 (s, 1N), -0.19 (d, 2N) 472 Int. compound-B-45 + 3-methyl-7(4,4,5,5tetramethyl-1,3,2 dioxaborolane-2- yl)-1H-indole Etc. 465 63% 'H NMR (DMSO- _b76 ) δ: 10.49 (s, 1H), 7.50 (d, 1H), 7.27 - 6.70 (m, 4H), 6.42 (d, 1H) , 2.64 (s, ZN), 2.30 (s, ZN), 2.04-1.86 (m, 1N), 1.79 (s, ZN), 1.19 (s, ZN), 0.55 (s, 1H), 0.06 (s, 1H), -0.14 - -0.34 (m, 2H) 473 Int. compound-B-10 + 4-(tetramethyl1,3,2dioxaborolan-2yl)-6(trifluoromethyl) Sh-indole Etc. 465 68% 'H NMR (DMSO- _b76 ) 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, ZN), 2.57 (s, ZN), 1.57 (s, 6H) 474 Int. connection-B-45 + Intermediate connection-A12 Etc. 465 45% 'H NMR (DMSO- _b76 ) δ: 7.89 (d, 1H), 7.64 (d, 1H), 7.48 (t, 1H), 7.36 (s, 1H), 7.15 (d, 1H), 6.67 (d, 1H), 6.51 (d, 1H), 3.49 (s, ZN), 3.35 (s, 1H), 2.61 (s, ZN) , 1.79 (s, ZN), 1.18 (s, ZN), 0.60 (s, 1H), 0.13 (s, 1H), -0.20 (s, 2H) 475 Int. connection-B-7 + Intermediate connection-A54 Etc. 465 91% 'H NMR (DMSO-^ ₆ ) δ: 7.16 (d, 1H), 7.15 (d, 1H), 6.48 (d, 1H), 7.72 (d, 1H), 7.55 (d, 1H), 6.52 (dd, 1H), 3.48 (s, ZN), 2.52 (s, ZN), 2.50 (s, ZN), 2.01 (s, ZN) , 1.73-1.17 (m, 6H) 476 Int. connection-B-10 + Intermediate connection-A54 Etc. 465 63% 'H NMR (DMSO-b7b) δ: 7.72 (m _s , 1H), 7.53 (d, 1H), 7.23 (t, 1H), 7.21 (d, 1H), 6.66 (d, 1H), 6.63 (dd, 1H), 3.47 (s, ZN), 3.16 (s, ZN), 2.58 (s, ZN), 2.53 (s, ZN) , 1.56 (s, 6H) 477 Int. compound-B-7 + 4-(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indole-6carbonitrile Etc. 465 67% ^1H NMR (DMSO-oU δ: 11.84 - 11.80 (m, 1H), 7.95 (d, 1H), 7.71 (t, 1H), 7.38 (d, 1H), 7 .20 (d, 1H), 6.50 (d, 1H), 6.34 (t, 1H), 2.51 (s, ZN), 2.02 (s, ZN), 1.55 - 1, 49 (m, 6N) 478 Int. connection-B-10 + Intermediate connection-A16 Etc. 465 48% 'H NMR (DMSO-b7 ₆ ) δ: 10.56 (d, W), 7.36 (dd, 1H), 7.22 (d, 1H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.64 (d, 1H), 3.18 (d, ZN), 2.57 (s, ZN), 1.92 (m _s , 1H), 1.56

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(s, 6H), 0.86 (m _s , 2H), 0.66 - 0.55 (m, 2H) 484 Int. connection-B-7 + Intermediate connection-A59 Etc. 465 24% 'H NMR (DMSO-< ₇₆ ) δ: 7.48 (dd, 1H), 7.38 (d, 1H), 7.25 (dd, 1H), 7.12 (d, 1H), 7. 06 - 7.00 (m, 1N), 6.42 (d, 1N), 6.18 (dd, 1N), 3.84 (s, ZN), 2.49 (s, ZN), 2.02 (s, ZN), 1.52 (s, 6H) 485 Int. connection-E-S + Intermediate connection-A59 Etc. 465 52% 'H NMR (DMSO-< ₇₆ ) δ: 7.47 (d, 1H), 7.35 (d, 1H), 7.25 (dd, 1H), 7.19 (d, 1H), 7. 14 (dd, 1H), 6.58 (d, 1H), 6.33 (dd, 1H), 3.83 (s, ZN), 3.12 (s, ZN), 2.57 (s, ZN ), 1.56 (s, 6H) 489 Int. compound-B-I + 7-fluoro-4-(4,4,5,5tetramethyl-1,3.2 dioxaborolan-2yl)-1H-indazole Etc. 465 36% 'H NMR (DMSO-A) δ: 8.06 (dd, 1H), 7.30 (d, 1H), 7.28 (d, 1H), 7.19 (dd, 1H), 6.69 ( s, 1H), 3.13 (s, ZN), 2.61 (s, ZN), 1.56 (s, 6H) 491 Int. connection-B-25 + Intermediate connection-A53 Etc. 465 57% 'H NMR (DMSO-< ₇₆ ) δ: 7.90 (d, 1H), 7.62 (d, 1H), 7.46 (t, 1H), 7.30 (d, 1H), 7. 17 (d, 1H), 6.58 (d, 1H), 6.50 (d, 1H), 3.61 (d, 2H), 2.50 (s, ZN), 2.01 (s, ZN ), 1.77 - 1.33 (m, 6H), 0.90 - 0.76 (m, 1H), 0.42 - 0.27 (m, 2H), -0.00 - -0.11 (m, 2H) 492 Int. connection-E-S + Intermediate connection-A66 Etc. 465 59% 'H NMR (DMSO-D,) δ: 8.22 - 8.18 (m, 1H), 7.88 (d, 1H), 7.69 (d, 1H), 7.32 (d, 1H) , 6.82 (dd, 1H), 6.77 (d, 1H), 3.64 (s, ZN), 3.18 (s, ZN), 2.58 (s, ZN), 1.57 ( s, 6H) 494 Int. compound -B-Y 7-fluoro-4-(4,4,5,5tetramethyl-1,3.2 dioxaborolan-2yl)-1H-indole Etc. 490 50% 'H NMR (DMSO-D,) δ: 11.69 (t, 1H), 7.44 (t, 1H), 7.20 (d, 1H), 7.09 - 6.98 (m, 2H) , 6.59 (d, 1N), 6.41 (m, 1N), 3.12 (s, ZN), 2.57 (s, ZN), 1.56 (s, 6N) 495 Int. compound -B-Y + 6-fluoro-4-(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indazole Etc. 465 22% 'H NMR (DMSO-D,) δ: 13.21 (s, 1H), 7.99 (s, 1H), 7.39 - 7.32 (m, 2H), 7.14 (dd, 1H) , 6.78 - 6.73 (m, 1H), 3.17 (s, ZN), 2.61 (s, ZN), 1.56 (s, 6H) 496 Int. compound-B-7 + 6-fluoro-4-(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indazole Etc. 465 51% 'H NMR (DMSO-D) δ: 13.28 (s, 1H), 7.89 (d, 1H), 7.41 - 7.34 (m, 1H), 7.26 (d, 1H) , 7.09 (dd, 1H), 6.55 (d, 1H), 2.53 (s, ZN), 2.07 (s, ZN), 1.53 (s, 6H) 497 Int. connection-B-7 + Intermediate connection-A68 Etc. 465 20% 'H NMR (DMSO-A) δ: 7.66 (dd, 1H), 7.63 (dd, 1H), 7.29 - 7.23 (m, 1H), 7.21 (d, 1H), 6.58 (d, 1H), 6.55 (d, 1H), 3.68 (d, 2H), 2.51 - 2.50 (m, ZN), 2.03 (s, ZN), 1 .53 (s, 6H), 0.86 (tt, 1H), 0.36 (d, 2H), -0.01 -0.06 (m, 2H) 502 Int. connection-B-51 + Intermediate connection-A12 Etc. 465 37% 'H NMR (DMSO-D) δ: 7.95 (m, 1H), 7.65 (d, 1H), 7.51 (dd, 1H), 7.34 (d, 1H), 6.55 (d, 1H), 6.45 (s, 1H), 3.52 (s, ZN), 2.44 (s, ZN), 1.98 (s, ZN), 1.63 (s, ZN) , 1.52 (s, ZN) 503 Int. connection-B-51 + Intermediate connection-A2 Etc. 465 70% 'H NMR (DMSO-D) δ: 7.73 (m, 1H), 7.66 (d, 1H), 7.35 (dd, 1H), 6.56 (d, 1H), 6.50 (s, 1H), 3.59 (s, ZN), 2.45 (s, ZN), 2.01 (s, ZN), 1.64 - 1.60 (m, ZN), 1.53 ( s, ZN), 504 Int. compound-B-7 + 4-(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indazole Etc. 465 13% 'H NMR (DMSO-D) δ: 7.88 (s, 1H), 7.58 (d, 1H), 7.45 (dd, 1H), 7.21 (d, 1H), 7.12 (d, 1H), 6.50 (d, 1H), 2.52 (s, ZN), 2.05 (s, ZN), 1.53 (s, 6H)

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505 Int. connection-E-S + Intermediate connection-A48 Etc. 465 62% 'H NMR (DMSO) δ: 7.94 (dt, 1H), 7.64 (d, 1H), 7.47 (dd, 1H), 7.38 (dd, 1H), 7.24 (d, 1H), 6.72 6.64 (m, 2H), 3.17 - 3.09 (m, 4H), 2.58 (s, ZN), 1.56 (s, 6H), 1.28 ( dd, 2H), 1.11 (dd, 2H) 506 Int. connection-B-7 + Intermediate connection-A69 Etc. 465 90% 'H NMR (DMSOCH) δ: 11.37 (t, W), 7.49 (dd, 1H), 7.45 (t, 1H), 7.17 (d, 1H), 7.03 (d, 1H), 6.47 (d, 1H), 6.20 (ddd, 1H), 2.49 (s, ZN), 2.03 (s, ZN), 1.52 (s, 6H) 507 Int. compound-B-7 + 4-(4,4,5,5tetramethyl-1,3,2dioxaborolan-2yl)-6(trifluoromethyl) 1H-indazole Etc. 465 35% 'H NMR (DMSO) δ: 8.06 (s, 1H), 7.98 (s, 1H), 7.41 (s, 1H), 7.29 (d, 1H), 6.57 (d, 1H), 2.54 (s, ZN), 2.04 (s, ZN), 1.53 (s, 6H) 508 Int. connection-B-51 + Intermediate connection-A15 Etc. 465 67% 'H NMR (DMSO-b7 ₆ ) δ: 10.70 (d, W), 7.33 (dd, 1H), 7.18 (dd, 1H), 6.97 (dd, 1H), 6.41 (s, 1H), 2.45 (s, ZN), 2.27 (s, ZN), 1.96 (s, ZN), 1.61 (s, ZN), 1.55 (s, ZN) 509 Int. connection-B-51 + Intermediate connection-A22 Etc. 465 39% 'H NMR (DMSO) δ: 8.46 (s, W), 8.08 (d, 1H), 7.77 (dd, 1H), 7.49 (d, 1H), 6.52 (s, 1N), 3.56 (s, ZN), 2.47 (s, ZN), 2.01 (s, ZN), 1.64 (s, ZN), 1.53 (s, ZN) 510 Int. connection-B-51 + Intermediate connection-A23 Etc. 465 4% 'H NMR (DMSO- _b76 ) δ: 8.47 (s, 1H), 7.81 - 7.75 (m, 1H), 7.54 (dd, 1H), 6.58 (s, 1H) , 3.60 (s, ZN), 2.48 (s, ZN), 2.04 (s, ZN), 1.58 (d, 6N) 511 Int. connection-E-S + Intermediate connection-A44 Etc. 465 20% 'H NMR (DMSO) δ: 7.60 (dd, 1H), 7.35 (d, 1H), 7.27 (dd, 1H), 7.21 - 7.13 (m, 2H), 6, 59 (d, 1N), 6.29 (dd, 1N), 3.48 (tg, W), 3.13 (s, ZN), 2.56 (s, ZN), 1.55 (s, 6N ), 1.09 (td, 2N), 1.02 - 0.96 (m, 2N) 512 Int. compound-B-38 + indole-4 boronic acid Etc. 465 52% 'H NMR (DMSO- _b76 ) δ: 11.27 (s, 1H), 7.49 (d, 1H), 7.40 (t, 1H), 7.21 (t, 1H), 7.01 (d, 1H), 6.77 (s, 1H), 6.14 (t, 1H), 2.45 (s, ZN), 1.97 (s, ZN), 1.60 (s, ZN) , 1.49 (s, ZN) 513 Int. connection-B-38 + int. compound -3methyl-7-(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indole Etc. 465 73% 'H NMR (DMSCM) δ: 10.59 (d, 1H), 7.57 (d, 1H), 7.17 - 7.08 (m, 2H), 7.05 (dd, 1H), 6, 78 (d, 1N), 2.47 (s, ZN), 2.30 (d, ZN), 1.93 (s, ZN), 1.56 (d, 6N) 514 Int. connection-B-38 + Intermediate connection-A15 Etc. 465 55% 'H NMR (DMSO- _b76 ) δ: 7.33 (dd, 1H), 7.19 (s, 1H), 6.99 (dd, 1H), 6.84 (d, 1H), 2.47 (s, ZN), 2.27 (d, ZN), 1.95 (s, ZN), 1.57 (s, ZN), 1.55 (s, ZN) 515 Int. connection-E-S + Intermediate connection-A71 Etc. 465 4% 396.1 517 Int. Comp.-B-7 7-fluoro-4-(4,4,5,5tetramethyl-1,3,2 dioxaborolan-2yl)-1H-indazole Etc. 465 46% 'H NMR (DMSOCH) δ: 7.99 (d, W), 7.28 (dd, 1H), 7.20 (d, 1H), 7.09 (dd, 1H), 6.50 (d, 1H), 2.52 (s, ZN), 2.03 (s, ZN), 1.53 (s, 6H) 521 Int. connection-B-38 + Intermediate connection-A73 Etc. 465 59% 'H NMR (DMSO) δ: 7.42 (dt, 1H), 7.38 (d, 1H), 6.99 (dd, 1H), 6.84 (d, 1H), 6.14 (d, 1N), 3.82 (d, ZN), 2.44 (s, ZN), 1.97 (s, ZN), 1.59 (s, ZN), 1.50 (s, ZN), 522 Int. connection-B-38 Etc. 55% 'H NMR (DMSO-b7 ₆ ) δ: 7.49 (d, 1H), 7.46 - 7.42 (m,

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+ Intermediate connection -A- 77 520 1H), 7.01 (d, 1H), 6.87 (d, 1H), 6.46 (d, 1H), 3.88 (s, ZN), 2.45 (s, ZN), 1, 97 (s, ZN), 1.58 (s, ZN), 1.49 (s, ZN) (MeO - hidden by water peak) 523 Int. connection-B-7 + Intermediate connection-A77 Etc. 520 87% 'H NMR (DMSOCH) δ: 7.49 (d, 1H), 7.42 - 7.38 (m, 1H), 7.16 (d, 1H), 6.96 (d, 1H), 6. 51 (d, 1H), 6.50 6.45 (m, 1H), 3.89 (s, ZN), 3.48 (s, ZN), 2.50 (s, ZN), 2.02 ( s, ZN), 1.52 (s, 6N) 524 Int. connection-E-S + Intermediate connection-A77 Etc. 465 86% 'H NMR (DMSO-A) δ: 7.47 (d, 1H), 7.42 - 7.38 (m, 1H), 7.24 (d, 1H), 7.03 (d, 1H), 6.69 (d, 1H), 6.60 (dd, 1H), 3.89 (s, ZN), 3.46 (s, ZN), 3.18 (s, ZN), 2.57 (s , ZN), 1.55 (s, 6N) 525 Int. connection-B-53 + Intermediate connection-A23 Etc. 465 41% 'H NMR (DMSO-A) δ: 8.48 (s, 1H), 7.78 (d, 1H), 7.54 (d, 1H), 6.58 (s, 1H), 3.60 ( s, ZN), 2.48 (d, ZN), 2.05 (s, ZN), 1.62 (s, ZN), 1.55 (s, ZN) 526 Int. connection-B-53 + Intermediate connection-A15 Etc. 465 61% 'H NMR (DMSO-A) δ: 10.72 - 10.68 (m, 1H), 7.33 (dd, 1H), 7.21 - 7.12 (m, W), 6.97 (dd , 1H), 6.41 (s, 1H), 2.45 (s, ZN), 2.27 (d, ZN), 1.96 (s, ZN), 1.61 (s, ZN), 1 .55 (s, ZN) 527 Int. connection-B-53 + Intermediate connection-A22 Etc. 465 73% 'H NMR (DMSO-D,) δ: 8.46 (s, 1H), 8.08 (d, 1H), 7.81 - 7.75 (m, 1H), 7.49 (d, 1H) , 6.53 (s, 1H), 3.56 (d, ZN), 2.47 (s, ZN), 2.01 (s, ZN), 1.65 (s, ZN), 1.53 ( s, ZN)

Table 5

Etc. No. Intermediates Synthesis similar Yield (% mol) Ίΐ-NMR 447 Intermediate, connection A2 + Intermediate. connection-B-38 Etc. 446 56% 'H NMR (400 MHz, DMSO- _a6 ): δ 7.72 (dd, 1H), 7.66 (d, 1H), 7.36 (dd, 1H), 6.93 (s, 1H), 6.58 (d, 1N), 3.59 (s, ZN), 2.45 (s, ZN), 1.97 (s, ZN), 1.57 (s, ZN), 1.50 (s , ZN). 449 Intermediate, connection A-20 + Intermediate. connection-B-38 Etc. 448 59% 'H NMR (DMSO-a ₆ ) δ= 7.46 (d, 1H), 7.41 (d, 1H), 6.98 (d, 1H), 6.85 (s, 1H), 6.13 (s, 1H), 4.92 (s, 1H), 4.22 (s, 2H), 3.74 (s, 2H), 2.44 (s, ZN), 1.97 (s, ZN) , 1.58 (s, ZN), 1.48 (s, ZN). 451 Intermediate, connection A-22 + Intermediate. connection-B-38 Etc. 448 54% 'H NMR (DMSO-a _b ) δ= 8.49 (s, 1H), 8.07 (d, 1H), 7.77 (t, 1H), 7.51 (d, 1H), 6.95 (s, 1H), 3.55 (s, ZN), 2.48 (s, ZN), 1.98 (s, ZN), 1.52-1.58 (m, 6H). 452 Intermediate, connection A-23 + Intermediate. connection-B-38 Etc. 448 58% 'H NMR (DMSO-a _b ) δ= 8.51 (S, 1H), 7.77 (d, 1H), 7.57 (d, 1H), 7.02 (s, 1H), 3.59 (s, ZN), 2.02 (s, ZN), 1.53-1.56 (m, 6N). (CH ₃ - hidden by DMSO peak) 453 Intermediate, connection A-2 + Intermediate. connection-B-41 Etc. 450 28% 'H NMR (DMSO-a _b ) δ= 7.66-7.64 (m, 2H), 7.29-7.26 (m, 1H), 7.18-7.16 (m, W), 6.58-6.56 (m, 2H), 4.84 (s, 1H), 4.55 (s, 2H), 3.56 (s, ZN), 1.52 (s, 6H). (CH ₃ - hidden by DMSO peak) 454 Intermediate, connection A-15 + Intermediate. connection-B-42 Etc. 450 54% Ή NMR (DMSO-a ₆ ) δ= 10.62 (s, W), 7.28-7.25 (m, 2H), 7.17 (s, 1H), 6.90-6.88 (m , 1H), 6.06 (s, 1H), 2.25 (s, ZN), 1.97 (s, ZN), 1.62-1.48 (m, 6H). (CH ₃ - hidden by DMSO peak) 456 Intermediate, connection A-12 + Intermediate. connection-B-42 Etc. 450 55% 'H NMR (DMSO-a ₆ ) δ= 7.91 (d, 1H), 7.65-7.64 (m, 1H), 7.49 (t, 1H), 7.31-7.29 ( m, 1H), 7.27 (s, 1H), 6.57-6.56 (m, 1H), 6.10 (s, 1H), 3.50 (s, ZN), 2.47 (s , ZN), 2.01 (s, ZN), 1.621.47 (m, 6N). 457 Intermediate, connection A-2 + Intermediate. Etc. 450 52% 'H NMR (DMSO-a ₆ ) δ= 7.68-7.65 (m, 2H), 7.31-7.27 (m, 2H), 6.56-6.55 (m, 1H), 6.15 (s, 1H), 3.56 (s, ZN), 2.03 (s,

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458 connection-B-42 Intermediate, connection A-22 + Intermediate. connection-B-42 Etc. 450 57% ZN), 1.59-1.48 (m, 6N). (CH ₃ - hidden by DMSO peak) 'H NMR (DMSO-a ₆ ) δ= 8.43 (s, 1H), 8.03 (d, 1H), 7.74 (t, 1H), 7.45 ( d, 1H), 7.35 (s, 1H), 6.17 (s, 1H), 3.53 (s, 3H), 2.04 (s, 3H), 1.55 (s, 6H). (CH ₃ - hidden by DMSO peak) 459 Intermediate, connection A-12 + Intermediate. connection-B-43 Etc. 455 40% 1H NMR (400 MHz, DMSO-ab): δ 7.90-7.88 (m, 1H), 7.59 (d, 1H), 7.45-7.41 (m, 1H), 7.33 -7.31 (m, 1H), 7.24-7.21 (m, 1H), 7.12-6.86 (m, 2H), 6.56-6.55 (m, 1H), 3 .50 (s, ZN), 1.54 (broad, 6N). (CH ₃ - hidden by DMSO peak) 460 Intermediate, connection A-8 + Intermediate. connection-B-43 Etc. 455 40% 1H NMR (400 MHz, DMSO-ab): δ 7.67-7.65 (m, 1H), 7.61 (d, 1H), 7.31-7.25 (m, 2H), 7.17 -6.91 (m, 2H), 6.56-6.55 (m, 1H), 3.75-3.69 (m, 2H), 1.61-1.54 (m, 6H), 1 .14-1.07 (m, ZN). (CH ₃ - hidden by DMSO peak) 461 Intermediate, connection A-47 + Intermediate. connection-B-43 Etc. 455 40% 1H NMR (400 MHz, DMSO-ab): δ 7.89 (d, 1H), 7.60 (d, 1H), 7.44-7.40 (m, W), 7.33-7.31 (m, 1H), 7.26-7.23 (m, 1H), 7.11-6.85 (m, 2H), 6.56-6.55 (m, 1H), 3.69-3 .63 (m, 2H), 1.54-1.50 (m, 6H), 1.14-1.05 (m, ZN). (CH ₃ - hidden by DMSO peak) 462 Intermediate, connection A-15 + Intermediate. connection-B-43 Etc. 455 40% 1H NMR (400 MHz, DMSO-ab): δ 10.57 (s, 1H), 7.28-7.22 (m, 2H), 7.14 (s, 1H), 7.08-6.82 (m, ZN), 2.25 (s, ZN), 1.551.48 (m, 6N). (CH ₃ - hidden by DMSO peak) 463 Intermediate, connection A-20 + Intermediate. connection-B-42 Etc. 450 43% 1H NMR (400 MHz, DMSO-ab): δ 7.42-7.39 (m, 2H), 7.28 (s, 1H), 6.93-6.91 (m, 1H), 6.16 -6.15 (m, 1H), 6.07 (m, 1H), 4.91 (t, 1H), 4.23 (t, 2H), 3.75-3.71 (m, 2H), 2.47 (s, ZN), 2.05 (s, ZN), 1.54 (s, 6H). 479 Intermediate, connection A-8 + Intermediate. connection-B-46 Etc. 481 37% 1H NMR (400 MHz, DMSO-ab): δ 7.66-7.64 (m, 2H), 7.247.21 (m, 1H), 7.06-7.03 (m, 1H), 6.57 -6.55 (m, 2H), 4.45-4.44 (m, 1H), 3.73-3.68 (m, 2H), 2.54 (s, ZN), 2.17-2 .15 (m, ZN), 1.60-1.47 (m, 6N), 1.14 (t, ZN). (CH ₃ - hidden by DMSO peak) 480 Intermediate, connection A-20 + Intermediate. connection-B-46 Etc. 481 52% 1H NMR (400 MHz, DMSO-ab): δ 7.43-7.41 (m, 2H), 7.047.02 (m, 1H), 6.92-6.89 (m, 1H), 6.51 (s, 1H), 6.23 (d, 1H), 4.89-4.86 (m, 1H), 4.23-4.21 (m, 2H), 4.17-4.16 (m , 1H), 3.75-3.71 (m, 2H), 2.56 (s, ZN), 2.17-2.16 (m, ZN), 1.54 (lat, 6H). 482 Intermediate, connection A-12 + Intermediate. connection-B-47 Etc. 455 20% 1H NMR (400 MHz, DMSO-ab): δ 7.90-7.88 (m, 1H), 7.62 (d, 1H), 7.47-7.45 (m, 1H), 7.39 -7.35 (m, 2H), 6.68 (d, 1H), 6.27 (s, 1H), 3.50 (s, ZN), 3.17 (s, ZN), 2.55 ( s, ZN), 1.57 (s, 6H). 486 Intermediate, connection A-2 + Intermediate. connection-B-46 Etc. 481 43% 1H NMR (400 MHz, DMSO-ab): δ 7.67-7.63 (m, 2H), 7.247.21 (m, 1H), 7.05-7.02 (m, 1H), 6.56 -6.55 (m, 2H), 4.41-4.39 (m, 1H), 3.53 (s, ZN), 2.54 (s, ZN), 2.17-2.16 (m , ZN), 1.611.47 (m, 6N). 487 Intermediate, connection A-15 + Intermediate. connection-B-46 Etc. 481 50% 1H NMR (400 MHz, DMSO-ab, 100°C): δ 10.29 (s, 1H), 7.27-7.25 (m, 1H), 7.14 (s, 1H), 7.00 -6.97 (m, 1H), 6.86-6.84 (m, 1H), 6.16 (s, 1H), 3.86-3.85 (m, 1H), 2.56 (s , ZN), 2.282.23 (m, 6N), 1.60 (s, 6N). 488 Intermediate, connection A-1 + Intermediate. connection-B-47 Etc. 483 29% 1H NMR (400 MHz, DMSO-ab): δ 11.28 (s, 1H), 7.38-7.37 (m, 2H), 7.22-7.19 (m, 1H), 6.99 -6.96 (m, 1H), 6.31 (s, 1H), 6.23 (s, 1H), 3.19 (s, ZN), 2.54 (s, ZN), 1.57 ( s, 6H). 493 Intermediate, connection A-43 + Intermediate. connection-B-47 Etc. 483 29% 1H NMR (400 MHz, DMSO-ab): δ 8.46 (s, 1H), 7.72-7.70 (m, 1H), 7.53 (s, 1H), 7.49-7.46 (m, 1H), 6.43 (s, 1H), 3.57 (s, ZN), 3.22 (s, ZN), 2.60 (s, ZN), 1.58 (s, 6H) . 498 Intermediate, connection A-2 + Intermediate. connection-B-49 Etc. 455 29% 1H NMR (400 MHz, DMSO-ab): δ 7.73-7.71 (m, 1H), 7.657.64 (m, 1H), 7.38-7.35 (m, 1H), 7.12 (s, 1H), 6.67-6.66 (m, 1H), 3.59 (s, ZN), 3.22 (s, ZN), 1.65 (s, ZN), 1.49 ( s, ZN). (CH ₃ - hidden by DMSO peak) 499 Intermediate, connection A-12 + Intermediate, connection B-49 Etc. 455 36% 1H NMR (400 MHz, DMSO-ab): δ 7.94-7.92 (m, 1H), 7.63 (d, 1H), 7.52-7.48 (m, 1H), 7.40 -7.38 (m, 1H), 7.05 (s, W), 6.66-6.65 (m, 1H), 3.53 (s, ZN), 3.18 (s, ZN), 1.65 (s, ZN), 1.49 (s, ZN). 501 Intermediate, connection A-23 + Intermediate, connection B-49 Etc. 500 39% 1H NMR (400 MHz, DMSO-ab): δ 8.53 (s, 1H), 7.78 (d, W), 7.55 (d, 1H), 7.23 (s, 1H), 3. 60 (s, ZN), 3.22 (s, ZN), 2.54 (s, ZN), 1.68 (s, ZN), 1.48 (s, ZN). 516 Intermediate, connection A-1 + Intermediate, connection-B-50 Etc. 500 44% 'H NMR (400 MHz, DMSO-a ₆ ): δ 11.33 (d, 1H), 7.51 (d, 1H), 7.36-7.39 (m, 1H), 7.28-32 (m, 1H), 7.02 (dd, 1H), 6.23 (d, 1H), 2.41 (s, 2H), 1.82 (s, ZN), 1.35 (s, ZN) . (CH ₃ hidden by DMSO peak) 519 Intermediate, connection A-23 + Intermediate, connection B-50 Etc. 518 17% 'H NMR (400 MHz, DMSO-a ₆ ): δ 8.65 (d, 1H), 7.83 (d, W), 7.59-7.67 (m, 2H), 3.62 (d , ZN), 2.49 (s, ZN), 1.83 (s, ZN), 1.37 (d,, ZN).

Example in table. 6 (below) was synthesized by standard chemical reactions that are known to one skilled in the art.

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Etc. No. Intermediates Exit (%) Ίΐ NMR 301 Demethylation at approx. 300 (DL-methionine) 19% 'H NMR (DMSO-b/b) δ: 7.53 (d, 1H), 7.42 (d, 1H), 7.22 (dd, 1H), 7.12 (d, 1H), 7. 01 (d, 1H), 6.42 (d, 1H), 6.20 - 6.16 (m, W), 4.91 (t, 1H), 4.27 (t, 2H), 3.77 (k, 2N), 2.50 (s, ZN), 2.04 (s, ZN), 1.55 - 1.51 (m, 6N)

Molecular structures and chemical names of the examples presented in Table. 3, 4, 5 and 6 are given in table. 7 below.

Etc. No. Structure Name 48 F < ί^ιΊ X XXO ^{N Sx} η 1 F 9-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1Ηindol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 53 F ^Ν ^=\ < ΧιΙ X ΧΧΧΧ ^χ ---Ν / Ν η 1 F 9-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline

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54 ζ \)--у--u\_~ζ ζ τ Χα 6-Fluoro-8-[6-fluoro-1-(2-methoxy-ethyl)-1H-indol-4yl]-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 55 F /Ν^Ζ 0^ BUT -X IT X=/ η 1 F 2-[6-Fluoro-4-(6-fluoro-9-methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1 N-indol1-yl]-EUN 56 ζχ* F 6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4yl)-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 57 Ν^/ Ο ^{Χ N} %?N^JLJLJt ζ° J Ύ Ύ Χ/Α / Η F 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1 methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline 59 /\ F / ^Ν ^\ FH ^Ν Ζ\ΛΖ,1 °\\// ⁰ || Ζρ N- ^S \ΗF 1 -Cyclopropyl-6-fluoro-8-(6-fluoro-1 methylsulfonyl-1 H-indol-4-yl)-9-methoxy-4,4dimethyl-5H-[1,2,4]triazolo[4,3 -a]quinoxaline 60 / ^Ν =\ <Ζ ΧΧ\^Χ\ ^ ⁷ ° X Ύ Τ Χν^ ⁴ / ^ι\τ ηχ Η 1 F 1-Cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-8- (1-methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline

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61 F 2-[4-(1-Cyclopropyl-6-fluoro-9-methoxy-4,4dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8yl)-6-fluoro-1H -indol-1-yl]-EtOH 62 Λκ F SOOOk 4 DUTg Ζ ν n n 1 F 1-Cyclopropyl-6-fluoro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-9-methoxy-4,4-dimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 63 Λκ F n^/ 1 ί^ιΊ ^Ν \χ JL °\^° ΤΤΧ/ ^Ν ^ ^χ Η 1 F 1 -Cyclopropyl-6-fluoro-8-(6-fluoro-1 methylsulfonyl-1 H-indol-4-yl)-4,4,9-trimethyl- 5H-[1,2,4]triazolo[4,3-a]quinoxaline 64 XT XjvC/'' ⁴ n 1 F 1 -Cyclopropyl-6-fluoro-4,4,9-trimethyl-8-(1 methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline 65 wik-. F 2-[4-(1-Cyclopropyl-6-fluoro-4,4,9-trimethyl-5H[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1H - indol-1-yl]-EtOH 66 Λκ f η 1 F 1 -Cyclopropyl-6-fluoro-8 -(5-fluoro-3-methyl-1Nindol-7-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline

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300 F 6-Φτορ-8-[ 1 -(2-methoxy-ethyl)-1 H-indol-4-yl] - 1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline 301 1 fl VvMvx Ϊ II 1 \ ⁿ η IF 2-[4-(6-Fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1 H-indol1-yl]-EUN 304 N/ . JI ^V '---N n 1 F 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indazol- 4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 305 N/ ^yCV F 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 308 jCjL ^Οχ ν° Av η 1 F 1 -Ethyl-6-fluoro-4,4,9-trimethyl-8-(1 methylsulfonyl-1H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline 316 n 1 F 1 -Ethyl-6-fluoro-8-(5-fluoro-3 -methyl-1 H-indol-7 -yl)- 4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline

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322 F 1 -Ethyl-6-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4yl]-4,4,9-trimethyl-5H-[1,2,4]triazolo [4, 3 a] quinoxaline 323 \F ν^Ζ I Χφ m η 1 F 1-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1Nindol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 326 F 8-[1 -(2,2-Difluoroethyl)-1 H-indol-4-yl]-6-fluoro- 1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline 340 XxX I Z Z'--\ z^ / ' Λ 6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 349 HfHch F 6-Fluoro-8-[1-(fluoromethylsulfonyl)-1H-indol-4yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 350 N--<। fZZ /\[Ίο XX M ηI F 8-[1-(Ethylsulfonyl)-1H-indol-4-yl]-6-fluoro- 1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline

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352 lX i XX Г ϊϊ\у “XX^r K~N η I F 6-Fluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol- 7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 355 l=L~ I χχ 1And and / N Η n 1 F 1 -Ethyl-6-fluoro-4,4,9-trimethyl-8-(3 -methyl-1Nindol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 366 F 6-Fluoro-8-[1-(isopropylsulfonyl)-1H-indol-4yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 374 \ F I XXXXXk °v° 4 Π X / ⁴ 7\ -Ν / ^Ν y η 1 F 1 -Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-4,4,9-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 375 F [2-[4-(6-Fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1 H-indol- 1 -yl]-ethyl]-dimethyl-amine 378 Ν^-Χ. ^ν Χ4 X Χ.Χ ΥΎΎ\Χλ ⁵ \ 7\ --Ν η 1 F 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline

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389 N--( i Al / \ 1 ] o ^N x Ax AA v A IjA 7X —-N η 1 F 1 -Ethyl-6-fluoro-4,4,9-trimethyl-8-(1 methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline 391 N—A i AAi / \ [ | O A/k A AAA v aAA η I F 8-[1-(Cyclopropylsulfonyl)-1H-indol-4-yl]-6fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 447 F M-^A i All ГхАхГхГхх °A° Jr ΧΧΧ/ ^Ν ^ ^χ / ^гА ηΑ A η 1 F 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1Nindol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 449 F N--AI Al ^HO \ / \ Г 1 A AAA \AA^fA^^^^F η 1 F 2-[4-(6,7-Difluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1Nindol-1-yl]-EUN 451 n^a I Aii ⁿ A ⁿ \J\AAA °a° AJA IA XX -N / NF H 1 F 6,7-Difluoro-1,4,4,9-tetramethyl-8-(1 methylsulfonyl-1H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline 452 F ^ν ί=Α 1 A|| ATI X/'C /X XX -XX -N / N γ^ F H 1 F 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline

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453 F / /ON /L ΝτςΜ 1 G ιΊ XX^/L/XJ-L V L ΎΎ W ¹ ' ⁴ n 1 F [6-Fluoro-8 -(6-fluoro-1-methylsulfonyl-1H-indol-4yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo [4,3a]quinoxaline- 9-yl]-MeOH 454 F M I ΓΗ n 1 Cl 6-Chloro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 456 Cl 6-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl1 H-indol-4-yl)-5H-[1,2,4]triazolo [4,3 - a] quinoxaline 457 F \ ω-·-m 6-Chloro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 458 YDL C.I. 6-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline 459 / F\ /F y, ^m F ^y \/\/A/\ °\/>° -JT ΎΎ KhZh -^^FF n 1 F 9-(Difluoromethyl)-6-fluoro-1,4,4-trimethyl-8-(1 methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline 460 9-(Difluoromethyl)-8-[1-(ethylsulfonyl)-b-fluoro1 H-indol-4-yl]-6-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline

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F / N—-f YP / \ T Г ] o ^N ^A Λ A. A \w 'X Tj\a ^Sv ^ and 1 F 461 /F\ /F N^—/ > / \ T Г ] 0 Already L\AL\A° | Ύ\Х^ж H F 9-(Difluoromethyl)-8-[ 1 -(ethylsulfonyl)-1 H-indole- 4-yl]-6-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 462 F / F\ ^F ^/N \ Y LH ^m ^Х\ЛХЛАА\ A XX X# NH η 1 F 9-(Difluoromethyl)-6-fluoro-8-(5-fluoro-3-methyl-1Nindol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3a] quinoxaline 463 > Cl 2-[4-(6-Chloro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1Nindol-1-yl]-EUN 464 ΛχΧθ. F 2-[4-(9-Ethyl-6-fluoro-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1Nindol-1-yl]-EUN 467 F Nt—< Y / \ I [ Ί °. OH. Λ AL Xo 4 IT A ⁴ N H 1 F 9-Cyclopropyl-6-fluoro-8-(6-fluoro-1 methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3-a ]quinoxaline

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468 i XX G? D -XU u/ ^H / 7\r η 1 F 6-Fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H[1,2,4]triazolo[4,3-a]quinoxaline 469 a=X < xx XT J J Xz η 1 F 6-Fluoro-8-(1H-indol-4-yl)-9-methoxy-1,4,4- trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 470 F /XX Χχ XT XJL/ ^H H 1 F 6-Fluoro-8-(6-fluoro-1 H-indol-4-yl)-9-methoxy-1,4,4- 1rimethyl-5H-[1,2,4]1riazolo[4,3-a]quinoxaline 471 F ^N ^=ri V XL / \ I [ I o ^N w /k A JX A w -X ХхХ\=Х ^x H 1 F 9-Cyclopropyl-6-fluoro-8-(6-fluoro-1 methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3-a ]quinoxaline 472 A T X ΎΥ^^ιΥί^ΐλ XYXX La N H h | F 9-Cyclopropyl-6-fluoro-1,4,4-trimethyl-8-(3 -methyl1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline 473 F F------1------F A JT ΪΎ Xy ^H HI F 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-[6(trifluoromethyl)-1 H-indol-4-yl]-5H[1,2,4]triazolo[4,3-a] quinoxaline

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474 N, J, JI % η 1 F 9-Cyclopropyl-6-fluoro-1,4,4-trimethyl-8-(1 methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline 475 Nt^YI [Z\ Lx/N, JL Lx 11 °\\χ>0 X YjXX ⁴ η 1 F 6-Fluoro-1,4,4,9-tetramethyl-8-(6-methyl-1 methylsulfonyl-1 H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a] quinoxaline 476 xxX η 1 F 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(6-methyl-1methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline 477 XXX ex η 1 F 4-(6-Fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1 H-indole6-carbonitrile 478 F λΥ < rji v-kAAsA ^\ 4 1/ L/^ Z Ν Y^ H H 1 F 8-(3-Cyclopropyl-5-fluoro-1H-indol-7-yl)-6-fluoro9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 479 F N^Y HN^ Y'Yl °y° XXX XX Z ^/ ^N^^Yr^ / η 1 F [8 - [1 -(Ethylsulfonyl)-6-fluoro-1H-indo l-4-yl]-6 fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a ]quinoxalin-9-yl]-methyl-amine

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480 F HN^ ^HO \ γ F 2-[6-Fluoro-4-(6-fluoro-1,4,4-trimethyl-9-methylamino5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1Nindol- 1 -il]-EYUN 482 .Ha Lr. —Oh oh 6-Chloro-9-methoxy-1,4,4-trimethyl-8-(1 methylsulfonyl-1 H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a]quinoxaline 484 i ιΡί DG ΎΎ HL DD η 1 F 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 485 Hi X z z-^\ 4h ^Z^ 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1Nindol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 486 F HN^ ^Ν γΛΠ d' t d u/ή / DD H 1 F [6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo [4,3a]quinoxaline- 9-yl]-methyl-amine 487 F ^===^ ^ΗΙ Ϊ^ f|l Χοι/ / H H 1 F [6-Fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline -9yl]-methyl-amine

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488 F Г Δ □Γ Ύ T ur Z Ί\Γ η 1 Cl 6-Chloro-8-(6-fluoro-1 H-indol-4-yl)-9-methoxy-1,4,4- 1rimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 489 r=( 7 flf ^N V^wxv4A 4 IJX/ ^NH WW -N N H 1 F 6-Fluoro-8-(7-fluoro-1H-indazol-4-yl)-9-methoxy- 1,4,4-trimethyl-5H-[1,2,4]1riazolo[4,3- a] quinoxaline 491 8-[1-(Cyclopropyl-methylsulfonyl)-1H-indol-4yl]-6-fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 492 F--F f [fS p V.Jn. D'n -XYYua Z η 1 F 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-[1 methylsulfonyl-b-(trifluoromethyl)-1 H-indol-4yl]-5H-[1,2,4]1riazolo[4, 3-a]quinoxaline 493 F 9^ rf I \ o vUaAa lUo 4 1 J 4 / ^x WZ\Z -n Z n η 1 Cl 6-Chloro-8-(6-fluoro-1-methylsulfonyl-1 H-indazole- 4-yl)-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 494 /=< A Vf ^F >T ΎΎ Xv ^NH HF 6-Fluoro-8-(7-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline

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495 F -X J J v=- / Z\ --N /N H I F 6-Φτορ-8-(6-φτορ-1 N-indazol-4-yl)-9-methoxy- 1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline 496 F i ιΓί 11 J V— / /N H 1 F 6-Fluoro-8-(6-fluoro-1H-indazol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 497 F ^N -=T i / \ II ° ^Ν ν^·\/\/ΐΧ\ ^z z° X^%2 8-[1-(Cyclopropyl-methylsulfonyl)-b-fluoro-1Nindol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H- [1,2,4]1riazolo[4,3-a]quinoxaline 498 F 9^ rX ^Ν νΧΛΛ iXo JT ΪΎ Xy ⁴ Z^N^XX^FH 1 F 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1Nindol-4-yl)-9-methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3- a]quinoxaline 499 π-- V V--°\ co--Q 6,7-Difluoro-9-methoxy-1,4,4-trimethyl-8-(1 methylsulfonyl-1H-indol-4-yl)-5H- [1,2,4]triazolo[4,3-a]quinoxaline 501 F , ^N =X 9^ Xn vMXz ιχ ₀ -D. IX X ^{z 4} / N ^F H 1 F 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3- a]quinoxaline

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502 Ν·--< ι / \ Γ Η ο ^N w A 44 4Α 4k \\^° XTXCw'' ⁴ n 1 Cl 6-Chloro-7-fluoro-1,4,4,9-tetramethyl-8-(1 methylsulfonyl-1 H-indol-4-yl)-5H[1,2,4]triazolo[4,3-a] quinoxaline 503 F / \ Γ Π 0 X ΤΥ \4Χ ^χ Ί\Γ Ί= Η 1 CI 6-Chloro-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1Nindol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 504 ι [44 ''ν-· ^,ι 4 ΤΧ Α Ν Η 1 F 6-Fluoro-8-(1H-indazol-4-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3-a]quinoxaline 505 A ( A ⁿ ^\4\YF4\ // ^ο Τ Ύ Τ W%=° ΧΑτ 4 F 8-[1-(Cyclopropylsulfonyl)-1H-indol-4-yl]-6fluoro-9-methoxy-1,4,4-trimethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 506 Cl ι Λ -У Ύ j Hu ⁿ η 1 F 8-(6-Chloro-1H-indol-4-yl)-6-fluoro-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 507 F F^l^F /A I CPU JT T j N η 1 F 6-Fluoro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)1H-indazol-4-yl]-5H-[1,2,4]triazolo[4,3- a] quinoxaline

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508 F ΧΧχΧΧ n 1 Cl 6-Chloro-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 509 ζχ Cl 6-Chloro-7-fluoro-1,4,4,9-tetramethyl-8-(1 methylsulfonyl-1 H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a] quinoxaline 510 F Ν^Ζ 1 Zll X "L J. 1 /\-N Ν f Η 1 Cl 6-Chloro-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 511 /X < χ Τ XX Χχ^ Ί\Γ Η 1 F 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-9methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3 - a] quinoxaline 512 λΥ ι ΓΖι X XX Χ/ ^ΝΗ Η 1 F 6,7-Difluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4,3-a]quinoxaline 513 λΖ ι Π ΖΧΧ Ζ/ Ν F Η η 1 F 6,7-Difluoro-1,4,4,9-tetramethyl-8-(3 -methyl-1Nindol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 514 6,7-Difluoro-8-(5-fluoro-3 -methyl-1 H-indol-7-yl)- 1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline

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F h | F 515 F η 1 F 6-Fluoro-8-(5-fluoro-1H-indol-7-yl)-9-methoxy-1,4,4- 1rimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 516 F , FF 1 / ^ν ^λ Jj XZ JL JL LLy™ / Ί\Γ ^F η 1 F 6,7-Difluoro-8-(6-fluoro-1 N-indol-4-yl)-1,4,4- 1rimethyl-9-(trifluoromethyl)-5H- [1,2,4]1riazolo[4,3-a]quinoxaline 517 /=f 1 fY 'ι τι Ύ ^x _NH \l II 1 \_ / Y^Y -N N ψ η 1 F 6-Fluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4,9tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 519 F , FF 1 ^N ^i \--- ^F 4^7ί / \ Г Г Π ° ⁿ ^J ⁿ ^XJ^A ii^o JT Ύ 1 U/ ^N \ / NF H 1 F 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)- 5H-[1,2,4]triazolo[4,3-a]quinoxaline 521 F 'Y 1 J Г ΪΎ U/ ^N_ h I F 6,7-Difluoro-8-(6-fluoro-1 -methyl-1 H-indol-4-yl)- 1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline

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522 F 6,7-Difluoro-8-(6-methoxy-1-methylsulfonyl-1Hindol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 523 / \ ί fl O η 1 F 6-Fluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline 524 X ΚΪΙ / \ 1 0. νχΑΑΛ X ΎΎ X/ ⁴ η 1 F 6-Fluoro-9-methoxy-8-(6-methoxy-1 methylsulfonyl-1 H-indol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3-a ]quinoxaline 525 F Νη—/ ι ΑΧ / \ [ ] 0 У ϊχύ ^Λ --Ν Ν CI η 1 F 7-Chloro-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1Nindazol-4-yl)-1,4,4,9-tetramethyl-5H- [1,2,4]triazolo[4,3-a]quinoxaline 526 F XXXX Ν Cl Η η 1 F 7-Chloro-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)- 1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline 527 ^Ν τ=χ ι Αχ X ΧχΧΧ ⁴ /X --Ν Ν CI Η 1 F 7-Chloro-6-fluoro-1,4,4,9-tetramethyl-8-(1 methylsulfonyl-1 H-indazol-4-yl)-5H[1,2,4]triazolo[4,3-a] 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: ACC110) containing the firefly luciferase gene under the control of the GR ligand-binding domain fused to DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR), stably integrated into CHO cells. This cell line was generated by stably transfecting CHO cells with the OAG4-uA8-luciferase reporter construct. In a subsequent step, the GR ligand binding domain cloned into pIRES2-EGFP-GAL4 containing the GAL4 DNA binding domain from pFA-AT2 was transfected. This fusion construct activated firefly luciferase expression under the control of a multimerized upstream GAL4 transcriptional activating sequence (UAS). The emitted luminescence signal was detected using FLIPR ^tetra . This allowed the specific detection of ligand-induced GR activation and thus the identification of 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 the assay was as follows:

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DMEM F-12 MIX (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. No.: ant-pr-1)

0.5 ml 100 mg/ml Zeocin (InvivoGen Cat. No.: ant-zn-1)

Low-temperature preserved CHO-Gal4/GR cells were suspended in complete medium and 5000 cells/25 μl/well were seeded into wells of 384-well polystyrene assay plates (Thermo Scientific, cat. no. 4332) and cultured at 37°C, 5 % CO ₂ and humidity 95%. After 24 h, the culture medium was carefully removed and replaced with 30 μl of Opti-MEM (GIBCO, cat. no. 31985062) as assay buffer. To test compounds, an 8-point semi-log compound dilution curve was generated in 100% DMSO starting with a 2 mM stock solution and then the compounds were diluted 1:50 in Opti-MEM. 10 μL of compounds were then added to wells containing 30 μL of OptiMEM, resulting in a final test concentration range of 10 μM to 0.003 μM in 0.5% DMSO. Compounds were tested at 8 concentrations across four replicate data points. Cells were incubated for 6 hours with compounds and beclomethasone (Sigma, cat. no. Y0000351) as a 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 Triton/luciferin solution, and the emitted luminescence signal was recorded using FLIPR ^tetra for 2 min.

Relative compound potency (% effect) was calculated based on the total effect of the agonist beclomethasone:

% effect = ((connection - min)/(max - min)) x 100

[min=Opti-MEM only, max=beclomethasone]

To calculate the EC5o, maximum, minimum, and slope for each compound, a 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, B=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: ACC110) containing the firefly luciferase gene under the control of the GR ligand-binding domain fused to DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR), stably integrated into CHO cells. This cell line was generated by stably transfecting CHO cells with a GAL4-UAS-luciferase reporter construct. In a subsequent step, the GR ligand binding domain cloned into pIRES2-EGFP-GAL4 containing the GAL4 DNA binding domain from pFA-AT2 was transfected. This fusion construct activated firefly luciferase expression under the control of a multimerized upstream GAL4 transcriptional activating sequence (UAS). The emitted luminescence signal was detected using FLIPR ^tetra . This allowed us to specifically detect the antagonistic properties of the compounds by measuring ligand-induced GR inhibition activated by beclomethasone. 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 the assay was as follows:

DMEM F-12 MIX (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. No.: ant-pr-1)

0.5 ml 100 mg/ml Zeocin (InvivoGen Cat. No.: ant-zn-1)

Low-temperature preserved CHO-Gal4/GR cells were suspended in complete medium and 5000 cells/25 μl/well were seeded into wells of 384-well polystyrene assay plates (Thermo Scientific, cat. no. 4332) and cultured at 37°C, 5 % CO ₂ and humidity 95%. After 24 h, the culture medium was carefully removed and replaced with 20 μl of Opti-MEM (GIBCO, cat. no. 31985062) as assay buffer. To test compounds, an 8-point semi-log dilution curve of the compound was prepared in 100% DMSO, starting with a 2 mM stock solution, and then the compounds were diluted in Opti-MEM at a ratio of 1:50. For testing compounds in antagonist mode 10 µl

- 88 045285 compounds were then added to wells containing 20 µl Opti-MEM and incubated for 10 min. Following this pre-incubation, 10 μL of the reference agonist beclomethasone (Sigma, Cat. No. Y0000351) was added at an EC50 of 2.5 nM, resulting in a final test concentration range of 10 μM to 0.003 μM in 0.5% DMSO for a total volume of 40 μL. Compounds were tested at 8 concentrations across four replicate data points. Cells were incubated for 6 hours with compounds and mifepristone control (Sigma, cat. no. 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 using FLIPR ^tetra for 2 min.

Relative compound potency (% effect) was calculated based on the total effect of the mifepristone antagonist:

% effect = ((connection - min)/(max - min)) x -100

[min=Opti-MEM only, max=mifepristone]

To calculate the _IC50 , maximum, minimum, and slope for each compound, a 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=logICso, O=slope]

In table 7 below summarizes the IC ₅₀ or EC ₅₀ ranges in the examples that were observed in the agonist assay or antagonist assay described above.

(A < 100 nM; B = 100 nM-1 µM; C = 1 µM-15 µM; n.d. = not determined)

Table 7

38 A 449 IN 489 IN 48 A 450 A 490 IN 49 IN 451 IN 491 A 53 IN 452 A 492 IN 54 IN 453 A 493 IN 55 V 454 A 494 IN 56 V 455 A 495 V

- 89 045285

57 IN 456 A 496 IN 58 IN 457 A 497 A 59 WITH 458 IN 498 A 60 n.d. 459 A 499 IN 61 WITH 460 A 500 IN 62 V 461 IN 501 IN 63 V 462 A 502 A 64 With 463 A 503 WITH 65 With 464 IN 504 V 66 V 465 A 505 V 300 V 466 IN 506 V 301 V 467 IN 507 V 304 V 468 A 508 V 305 A 469 IN 509 V 308 A 470 IN 510 A 316 IN 471 A 511 IN 322 n.d. 472 IN 512 A 323 IN 473 IN 513 IN 326 IN 474 IN 514 A 340 V 475 V 515 IN 349 V 476 V 516 A 350 A 477 V 517 IN 352 IN 478 A 518 IN 355 V 479 IN 519 IN 366 With 480 V 520 V 374 n.d. 481 V 521 A 375 IN 482 V 522 IN 378 With 483 A 523 V 389 n.d. 484 A 524 V 391 A 485 IN 525 A 446 A 486 V 526 A 447 A 487 A 527 IN 448 A 488 A

Claims (15)

1. Compound of general formula (II) or (III) Where R ¹ represents C _1-10 alkyl or C _3-10 cycloalkyl; R ² represents CN; C _1-10 alkyl; C _3-10 cycloalkyl; O-C _1-10 alkyl; N(H)(C _1-10 alkyl) or N(C _1-10 alkyl) ₂ ; R ³ represents H; F; Cl; Br or I; R ⁴ represents F or Cl; R ⁵ and R ⁶ are, independently of each other, unsubstituted C _1-4 alkyl; X represents N or NR ⁷ ; Z is N, NR ⁷ or CR ⁹ ; - 90 045285 provided that where X represents NR ⁷ , Z represents N or CR ⁹ ; when X is N, Z is NR ⁷ ; R ⁷ represents H or LR ⁸ ; Where L represents bond; S(O) or S(O) ₂ ; R ⁸ represents C _1-10 alkyl or C ₃ . ₁₀ cycloalkyl; where C ₃ . ₁₀ cycloalkyl may optionally be connected through a ^^alkylene bridge; R ⁹ and R ¹⁰ are independently of each other H; C ₁ . ₁₀ αlkyl or C _3-10 cycloalkyl; R ¹¹ represents F; Cl; Br; I; CN; C _1-10 alkyl or O-C _1-10 alkyl; n is 0, 1 or 2; where C _1-10 alkyl, C _1-4 alkyl and C ₁ . ₆ alkylene in each case, independently of each other, are linear or branched and saturated; where C _1-10 alkyl, C ₁ . ₄ alkyl and C ₃ . ₁₀ cycloalkyl is in each case independently of one another unsubstituted, mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CF ₃ ; CF2H; CFH2; HE; =O; OC ₁ . ₆ αlkylα; NH2; N(H)(C ₁ . ₆ alkyl); or N(C ₁ . ₆ alkyl) ₂ ; in the form of the free compound or a physiologically acceptable salt thereof. 2. A compound according to claim 1, wherein R ⁵ and R ⁶ are both CH ₃ . 3. A compound according to any of the preceding claims, wherein X is NR ⁷ and Z is N or CR ⁹ . 4. The connection according to any of the previous paragraphs, where R ¹ represents C ₁ . ₆ αlkyl or C ₃ . ₆ cycloalkyl. 5. The connection according to any of the previous paragraphs, where R ² represents CN; C ₁ . ₆ alkyl; C ₃ . ₆ cycloalkyl; O-C ₁ . ₆ αlkyl or N(H)(C ₁ . ₆ -alkyl). 6. The compound according to any of the previous paragraphs, where R ³ represents H; F or Cl. 7. The compound according to any of the previous paragraphs, where R ⁷ represents H. 8. A compound according to any one of claims 1 to 6, where R ⁷ represents LR ⁸ ; where R ⁸ represents C ₁ . ₆ αlkyl or C ₃ . ₆ cycloalkyl; where C ₃ . ₆ cycloalkyl may optionally be connected via C ₁ . ₄ αalkylene bridge. 9. The compound according to any of the previous paragraphs, where R ⁹ represents H. 10. The compound according to any of the previous paragraphs, where R ¹⁰ represents H; C ₁ . ₆ alkyl or C ₃ . ₆ cycloalkyl. 11. The connection according to any of the previous paragraphs, where R ¹¹ represents F; Cl; Br; I; CN; C ₁ . ₆ αlkyl or O-Cl. ₆ alkyl. 12. A compound according to any of the previous paragraphs, selected from the group consisting of: 38 8-(3-Cyclopropyl-5-fluoro-1H-indol-7-yl)-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3а ]quinoxaline 48 9-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4, 3 a]quinoxaline 49 9-Ethyl-6-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a] quinoxaline 53 9-Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indazol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo [4 ,3-a] quinoxaline 54 6-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 55 2-[6-Fluoro-4-(6-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl) -1Nindol-1-yl]-EtOH 56 6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4 ,3-a]quinoxaline 57 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 58 8-[1-(2,2-Difluoroethyl)-6-fluoro-1H-indol-4-yl]-6-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1, 2,4]triazolo[4,3-a]quinoxaline 59 1-Cyclopropyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-9-methoxy-4,4-dimethyl-5H[1,2,4]triazolo[4 ,3-a]quinoxaline 60 1-Cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3- a] quinoxaline 61 2-[4-(1-Cyclopropyl-6-fluoro-9-methoxy-4,4-dimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)6- fluoro-III-indol-1 -yl] -EtOH 62 1-Cyclopropyl-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-9-methoxy-4,4-dimethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline 63 1-Cyclopropyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline - 91 045285 64 1 -Cyclopropyl-6-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3 a]quinoxaline 65 2-[4-(1-Cyclopropyl-6-fluoro-4,4,9-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro1 H-indol-1-yl]-EtOH 66 1 -Cyclopropyl-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4, 3 a]quinoxaline 300 6-Fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline 301 2-[4-(6-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol-1yl ]-EtOH 304 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 305 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 308 1-Ethyl-6-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 316 1-Ethyl-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline 322 1-Ethyl-6-fluoro-8-[1-(2-methoxy-ethyl)-1H-indol-4-yl]-4,4,9-trimethyl-5H-[1,2,4]triazolo[ 4,3a]quinoxaline 323 1 -Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo[4, 3 a]quinoxaline 326 8-[1-(2,2-Difluoroethyl)-1H-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[ 4,3a]quinoxaline 340 6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 a ]quinoxaline 349 6-Fluoro-8-[1-(fluoromethylsulfonyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3а] quinoxaline 350 8-[1-(Ethylsulfonyl)-1H-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 352 6-Fluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 355 1-Ethyl-6-fluoro-4,4,9-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3-a] quinoxaline 366 6-Fluoro-8-[1 -(isopropylsulfonyl)-1H-indol-4-yl]-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 374 1 -Ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-4,4,9-trimethyl-5H-[1,2,4]triazolo [4, 3-a] quinoxaline 375 [2-[4-(6-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol- 1yl]ethyl]dimethylamine 378 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 389 1-Ethyl-6-fluoro-4,4,9-trimethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 391 8-[1 -(Cyclopropylsulfonyl)-III-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3 a]quinoxaline 446 8-[1-(Ethylsulfonyl)-6-fluoro-III-indol-4-yl]-6,7-difluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[ 4,3a]quinoxaline 447 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4, 3a]quinoxaline 448 6,7-Difluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 449 2-[4-(6,7-Difluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro -SH-indol-1 yl]-EtOH 450 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline9-carbonitrile 451 6,7-Difluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 452 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo [4, 3-a] quinoxaline 453 [6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline -9-yl]-MeOH 454 6-Chloro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a]quinoxaline 455 9-(Difluoromethyl)-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4 ,3-a]quinoxaline 456 6-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triαzolo[4,3-α]chi- 92 045285 noxaline 457 6-Chloro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a] quinoxaline 458 6-Chloro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 459 9-(Difluoromethyl)-6-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo [4,3- a] quinoxaline 460 9-(Difluoromethyl)-8-[1 -(ethylsulfonyl)-b-fluoro-1 H-indol-4-yl]-6-fluoro-1,4,4-trimethyl-5H[1,2,4] triazolo[4,3-a]quinoxaline 461 9-(Difluoromethyl)-8-[1 -(ethylsulfonyl)-III-indol-4-yl]-6-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline 462 9-(Difluoromethyl)-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[ 4.3 a]quinoxaline 463 2-[4-(6-Chloro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro-1H -indol-1yl]-EtOH 464 2-[4-(9-Ethyl-6-fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-6-fluoro1 H-indol-1-yl]-EtOH 465 6-Fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 466 9-(Difluoromethyl)-6-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indazol-7-yl)-5H-[1,2,4]triazolo[4,3a] quinoxaline 467 9-Cyclopropyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl5H-[1,2,4]triazolo[4,3 - a] quinoxaline 468 6-Fluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 469 6-Fluoro-8-(1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 470 6-Fluoro-8-(6-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 471 9-Cyclopropyl-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H[1,2,4]triazolo[4,3 -a]quinoxaline 472 9-Cyclopropyl-6-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 473 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-[1,2,4]triazolo[4,3a] quinoxaline 474 9-Cyclopropyl-6-fluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a] quinoxaline 475 6-Fluoro-1,4,4,9-tetramethyl-8-(6-methyl-1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a] quinoxaline 476 6-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 477 4-(6-Fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indol-6-carbonitrile 478 8-(3-Cyclopropyl-5-fluoro-1H-indol-7-yl)-6-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo [4, 3-a] quinoxaline 479 [8-[1 -(Ethylsulfonyl)-6-fluoro-1H-indol-4-yl]-6-Fluoro-1,4,4-trimethyl-5H-[1,2,4]triazolo[4, 3a]quinoxalin-9-yl]-methylamine 480 2-[6-Fluoro-4-(6-fluoro-1,4,4-trimethyl-9-methylamino-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl) 1 H-indol-1-yl]-EtOH 481 [8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-1,4,4-Ίrimethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-9yl ]methylamine 482 6-Chloro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a]quinoxaline 483 6-Chloro-8-(6-fluoro-1-methylsulfonyl-1 H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo [4 ,3-a] quinoxaline 484 6-Fluoro-1,4,4,9-tetramethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a]quinoxaline 485 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-(1-methyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3-a] quinoxaline 486 [6-Fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline -9-yl]methylamine 487 [6-Fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a ]quinoxalin-9yl]methylamine 488 6-Chloro-8-(6-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 489 6-Fluoro-8-(7-fluoro-1H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 490 6-Fluoro-8-(7-fluoro-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 491 8-[1 -(Cyclopropyl-methylsulfonyl)-1H-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3- a] quinoxaline 492 6-Fluoro-9-methoxy-1,4,4-trimethyl-8-[1-methylsulfonyl-6-(trifluoromethyl)-1 H-indol-4-yl] -5H- 93 045285 [1,2,4]triazolo[4,3-a]quinoxaline 493 6-Chloro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo [4, 3-a] quinoxaline 494 6-Fluoro-8-(7-fluoro-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 495 6-Fluoro-8-(6-fluoro-1H-indazol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 496 6-Fluoro-8-(6-fluoro-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 497 8-[1-(Cyclopropyl-methylsulfonyl)-6-fluoro-III-indol-4-yl]-6-fluoro-1,4,4,9-tetramethyl5H-[1,2,4]triazolo[4, 3-a]quinoxaline 498 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo [ 4,3-a]quinoxaline 499 6,7-Difluoro-9-methoxy-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo [4,3a ]quinoxaline 500 6,7-Difluoro-1,4,4-trimethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-9-(trifluoromethyl)-5H-[1,2,4]triazolo [4, 3-a] quinoxaline 501 6,7-Difluoro-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 502 6-Chloro-7-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonyl-1H-indol-4-yl)-5H-[1,2,4]triazolo[4,3a ]quinoxaline 503 6-Chloro-7-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[ 4,3-a]quinoxaline 504 6-Fluoro-8-(1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 505 8-[1 -(Cyclopropylsulfonyl)-III-indol-4-yl]-6-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3- a]quinoxaline 506 8-(6-Chloro-1H-indol-4-yl)-6-fluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 507 6-Fluoro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indazol-4-yl]-5H-[1,2,4]triazolo[4,3a]quinoxaline 508 6-Chloro-7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[ 4,3a]quinoxaline 509 6-Chloro-7-fluoro-1,4,4,9-tetramethyl-8 -(1-methylsulfonyl-1 H-indazol-4-yl)-5H-[1,2,4]triazolo [4,3a ]quinoxaline 510 6-Chloro-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 511 8-(1-Cyclopropyl-1H-indol-4-yl)-6-fluoro-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3a]quinoxaline 512 6,7-Difluoro-8-(1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 513 6,7-Difluoro-1,4,4,9-tetramethyl-8-(3-methyl-1H-indol-7-yl)-5H-[1,2,4]triazolo[4,3-a] quinoxaline 514 6,7-Difluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4, 3a]quinoxaline 515 6-Fluoro-8-(5-fluoro-1H-indol-7-yl)-9-methoxy-1,4,4-trimethyl-5H-[1,2,4]triazolo[4,3-a] quinoxaline 516 6,7-Difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H-[1,2,4]triazolo[4, 3a]quinoxaline 517 6-Fluoro-8-(7-fluoro-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxaline 518 6,7-difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)-5H[1,2,4]triazolo [4,3-a]quinoxaline 519 6,7-Difluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4-trimethyl-9-(trifluoromethyl)5H-[1,2,4]triazolo [4,3-a]quinoxaline 520 4-(6,7-Difluoro-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3-a]quinoxalin-8-yl)-1H-indole-7carbonitrile 521 6,7-Difluoro-8-(6-fluoro-1-methyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4, 3a]quinoxaline 522 6,7-Difluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4, 3-a]quinoxaline 523 6-Fluoro-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[4,3a] quinoxaline 524 6-Fluoro-9-methoxy-8-(6-methoxy-1-methylsulfonyl-1H-indol-4-yl)-1,4,4-Ίrimethyl-5H-[1,2,4]triazolo[4, 3-a] quinoxaline 525 7-Chloro-6-fluoro-8-(6-fluoro-1-methylsulfonyl-1H-indazol-4-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo [ 4,3-a]quinoxaline 526 7-Chloro-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-[1,2,4]triazolo[ 4,3a]quinoxaline 527 7-Chloro-6-fluoro-1,4,4,9-tetramethyl-8 -(1-methylsulfonyl-1H-indazol-4-yl)-5H-[1,2,4]triazolo [4,3а ]quinoxaline - 94 045285 in the form of a free compound or a physiologically acceptable salt thereof. 13. A dosage form containing a compound according to any one of claims 1 to 12 and one or more pharmaceutical excipients. 14. Use of a compound according to any one of claims 1 to 12 for the treatment and/or prevention of pain and/or inflammation. 15. Use according to claim 14 for the treatment and/or prevention of inflammatory pain.