QUINOXALINE DERIVATIVES

Abstract

The present invention relates to compounds according to general formula (I)

##STR00001##

which act as modulators of the glucocorticoid receptor and can be used in the treatment and/or prophylaxis of disorders which are at least partially mediated by the glucocorticoid receptor.

Claims

1. A compound according to general formula (I): ##STR00126## wherein R.sup.1 represents phenyl or 5 to 10-membered heteroaryl; R.sup.2 represents H; R.sup.3 and R.sup.4 independently of one another represent H; C.sub.1-10-alkyl; or together with the carbon atom joining them, form C.sub.3-10-cycloalkyl; A.sup.1, A.sup.2 and A.sup.3 corresponds to embodiment a, b, c, or d: TABLE-US-00015 embodiment A.sup.1 A.sup.2 A.sup.3 a C-R.sup.5 C-R.sup.6 C-R.sup.7 b C-R.sup.5 N C-R.sup.7 c C-R.sup.5 C-R.sup.6 N d N C-R.sup.6 C-R.sup.7 wherein R.sup.5 represents H; F; Cl; Br; I; C.sub.1-4-alkyl; C.sub.3-10-cycloalkyl; or O—C.sub.1-10-alkyl; R.sup.6 represents H; F; Cl; Br; I; C.sub.1-10-alkyl; C.sub.3-10-cycloalkyl; or O—C.sub.1-10-alkyl; R.sup.7 represents H; F; Cl; Br; I; C.sub.1-10-alkyl; C.sub.3-10-cycloalkyl; or O—C.sub.1-10-alkyl; A.sup.4 represents C or N; A.sup.5 represents O, N, N—R.sup.8 or C—R.sup.8, wherein R.sup.8 represents H; C.sub.1-10-alkyl; C.sub.3-10-cycloalkyl; 3 to 7 membered heterocycloalkyl; S(O).sub.2—C.sub.1-6-alkyl; or S(O).sub.2—C.sub.3-10-cycloalkyl, wherein C.sub.3-10-cycloalkyl, or 3 to 7 membered heterocycloalkyl, can optionally be bridged via C.sub.1-6-alkylene; A.sup.6 represents O, N, N—R.sup.9 or C—R.sup.9, wherein R.sup.9 represents H; C.sub.1-10-alkyl; C.sub.3-10-cycloalkyl; 3 to 7 membered heterocycloalkyl; S(O).sub.2—C.sub.1-6-alkyl; or S(O).sub.2—C.sub.3-10-cycloalkyl, wherein C.sub.3-10-cycloalkyl, or 3 to 7 membered heterocycloalkyl, can optionally be bridged via C.sub.1-6-alkylene; A.sup.1 represents O, N, N—R.sup.10 or C—R.sup.10, wherein R.sup.10 represents H; C.sub.1-10-alkyl; C.sub.3-10-cycloalkyl; 3 to 7 membered heterocycloalkyl; S(O).sub.2—C.sub.1-6-alkyl; or S(O).sub.2—C.sub.3-10-cycloalkyl, wherein C.sub.3-10-cycloalkyl, or 3 to 7 membered heterocycloalkyl can optionally be bridged via C.sub.1-6-alkylene; A.sup.8 represents C or N; wherein A.sup.4, A.sup.5, A.sup.6, A.sup.7 and A.sup.8 form a heteroaromatic system; and wherein if A.sup.4 represents C and each of A.sup.5, A.sup.6 and A.sup.8 represent N and A.sup.7 represents C—R.sup.10; then one of A.sup.1, A.sup.2 and A.sup.3 represents N; wherein C.sub.1-4-alkyl, C.sub.1-6-alkyl, C.sub.1-10-alkyl and C.sub.1-6-alkylene in each case independently from one another is linear or branched, saturated or unsaturated; wherein C.sub.1-4-alkyl, C.sub.1-6-alkyl, C.sub.1-10-alkyl, C.sub.1-6-alkylene, C.sub.3-10-cycloalkyl and 3 to 7 membered heterocycloalkyl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CN; C.sub.1-6-alkyl; CF.sub.3; CF.sub.2H; CFH.sub.2; CF.sub.2Cl; CFCl.sub.2; C(O)—C.sub.1-6-alkyl; C(O)—OH; C(O)—OC.sub.1-6-alkyl; C(O)—NH.sub.2; C(O)—N(H)(C.sub.1-6-alkyl); C(O)—N(C.sub.1-6-alkyl).sub.2; OH; ═O; OCF.sub.3; OCF.sub.2H; OCFH.sub.2; OCF.sub.2Cl; OCFCl.sub.2; O—C.sub.1-6-alkyl; O—C(O)—C.sub.1-6-alkyl; O—C(O)—O—C.sub.1-6-alkyl; O—(CO)—N(H)(C.sub.1-6-alkyl); O—C(O)—N(C.sub.1-6-alkyl).sub.2; O—S(O).sub.2—NH.sub.2; O—S(O).sub.2—N(H)(C.sub.1-6-alkyl); O—S(O).sub.2—N(C.sub.1-6-alkyl).sub.2; NH.sub.2; N(H)(C.sub.1-6-alkyl); N(C.sub.1-6-alkyl).sub.2; N(H)—C(O)—C.sub.1-6-alkyl; N(H)—C(O)—O—C.sub.1-6-alkyl; N(H)—C(O)—NH.sub.2; N(H)—C(O)—N(H)(C.sub.1-6-alkyl); N(H)—C(O)—N(C.sub.1-6-alkyl).sub.2; N(C.sub.1-6-alkyl)-C(O)—C.sub.1-6-alkyl; N(C.sub.1-6-alkyl)-C(O)—O—C.sub.1-6-alkyl; N(C.sub.1-6-alkyl)-C(O)—NH.sub.2; N(C.sub.1-6-alkyl)-C(O)—N(H)(C.sub.1-6-alkyl); N(C.sub.1-6-alkyl)-C(O)—N(C.sub.1-6-alkyl).sub.2; N(H)—S(O).sub.2OH; N(H)—S(O).sub.2—C.sub.1-6-alkyl; N(H)—S(O).sub.2—O—C.sub.1-6-alkyl; N(H)—S(O).sub.2—NH.sub.2; N(H)—S(O).sub.2—N(H)(C.sub.1-6-alkyl); N(H)—S(O).sub.2N(C.sub.1-6-alkyl).sub.2; N(C.sub.1-6-alkyl)-S(O).sub.2—OH; N(C.sub.1-6-alkyl)-S(O).sub.2-C.sub.1-6-alkyl; N(C.sub.1-6-alkyl)-S(O).sub.2—O—C.sub.1-6-alkyl; N(C.sub.1-6-alkyl)-S(O).sub.2—NH.sub.2; N(C.sub.1-6-alkyl)-S(O).sub.2—N(H)(C.sub.1-6-alkyl); N(C.sub.1-6-alkyl)-S(O).sub.2—N(C.sub.1-6-alkyl).sub.2; SCF.sub.3; SCF.sub.2H; SCFH.sub.2; S—C.sub.1-6-alkyl; S(O)—C.sub.1-6-alkyl; S(O).sub.2—C.sub.1-6-alkyl; S(O).sub.2—OH; S(O).sub.2—O—C.sub.1-6-alkyl; S(O).sub.2—NH.sub.2; S(O).sub.2—N(H)(C.sub.1-6-alkyl); S(O).sub.2—N(C.sub.1-6-alkyl).sub.2; C.sub.3-6-cycloalkyl; 3 to 7-membered heterocycloalkyl; phenyl; 5 or 6-membered heteroaryl; O—C.sub.3-6-cycloalkyl; O-(3 to 7-membered heterocycloalkyl); O-phenyl; O-(5 or 6-membered heteroaryl); C(O)—C.sub.3-6-cycloalkyl; C(O)-(3 to 7-membered heterocycloalkyl); C(O)-phenyl; C(O)-(5 or 6-membered heteroaryl); S(O).sub.2—(C.sub.3-6-cycloalkyl); S(O).sub.2-(3 to 7-membered heterocycloalkyl); S(O).sub.2-phenyl or S(O).sub.2-(5 or 6-membered heteroaryl); wherein phenyl, and 5 to 10-membered heteroaryl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CN; C.sub.1-6-alkyl; C.sub.1-6-alkenyl; C.sub.1-6-alkynyl; C.sub.1-6-alkynyl-C(H)(OH)CH.sub.3; C.sub.1-6-alkynyl-C(CH.sub.3).sub.2OH; CF.sub.3; CF.sub.2H; CFH.sub.2; CF.sub.2Cl; CFCl.sub.2; C.sub.1-6-alkylene-CF.sub.3; C.sub.1-6-alkylene-CF.sub.2H; C.sub.1-6-alkylene-CFH.sub.2; C.sub.1-6-alkylene-OH; C.sub.1-6-alkylene-OCH.sub.3; C(O)—C.sub.1-6-alkyl; C(O)—OH; C(O)—OC.sub.1-6-alkyl; C(O)—N(H)(OH); C(O)—NH.sub.2; C(O)—N(H)(C.sub.1-6-alkyl); C(O)—N(C.sub.1-6-alkyl).sub.2; OH; OCF.sub.3; OCF.sub.2H; OCFH.sub.2; OCF.sub.2Cl; OCFCl.sub.2; O—C.sub.1-6-alkyl; O—C.sub.3-6-cycloalkyl; O-(3 to 7-membered heterocycloalkyl); NH.sub.2; N(H)(C.sub.1-6-alkyl); N(C.sub.1-6-alkyl).sub.2; N(H)—C(O)—C.sub.1-6-alkyl; N(C.sub.1-6-alkyl)-C(O)—C.sub.1-6-alkyl; N(H)—C(O)—NH.sub.2; N(H)—C(O)—N(H)(C.sub.1-6-alkyl); N(H)—C(O)—N(C.sub.1-6-alkyl).sub.2; N(C.sub.1-6-alkyl)-C(O)—N(H)(C.sub.1-6-alkyl); N(C.sub.1-6-alkyl)-C(O)—N(C.sub.1-6-alkyl).sub.2; N(H)—S(O).sub.2—C.sub.1-6-alkyl; SCF.sub.3; S—C.sub.1-6-alkyl; S(O)—C.sub.1-6-alkyl; S(O).sub.2—C.sub.1-6-alkyl; S(O).sub.2—C.sub.3-6-cycloalkyl; S(O).sub.2—C.sub.1-6-alkylene-C.sub.3-6-cycloalkyl; S(O).sub.2—NH.sub.2; S(O).sub.2—N(H)(C.sub.1-6-alkyl); S(O).sub.2—N(C.sub.1-6-alkyl).sub.2; C.sub.3-6-cycloalkyl; C.sub.1-6-alkylene-C.sub.3-6-cycloalkyl; 3 to 7-membered heterocycloalkyl; C.sub.1-6-alkylene-(3 to 7-membered heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl; in the form of the free compound or a physiologically acceptable salt thereof.

2. The compound according to claim 1, wherein C.sub.1-4-alkyl, C.sub.1-6-alkyl, C.sub.1-10-alkyl, C.sub.1-6-alkylene, C.sub.3-10-cycloalkyl and 3 to 7 membered heterocycloalkyl in each case independently from one another are unsubstituted or mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; CN; C.sub.1-6-alkyl; CF.sub.3; CF.sub.2H; CFH.sub.2; CF.sub.2Cl; CFCl.sub.2; OH; ═O; OCF.sub.3; OCF.sub.2H; OCFH.sub.2; OCF.sub.2Cl; OCFCl.sub.2; O—C.sub.1-6-alkyl; C.sub.3-6-cycloalkyl; or 3 to 7-membered heterocycloalkyl; and/or phenyl, and 5 to 10-membered heteroaryl in each case independently from one another are unsubstituted or mono- or poly substituted with one or more substituents selected from F; Cl; Br; I; CN; C.sub.1-6-alkyl; C.sub.2-6-alkinyl, preferably —C≡C—CH.sub.3; CF.sub.3; CF.sub.2H; CFH.sub.2; CF.sub.2Cl; CFCl.sub.2; C.sub.1-6-alkylene-CF.sub.3; C.sub.1-6-alkylene-CF.sub.2H; C.sub.1-6-alkylene-CFH.sub.2; C(O)—C.sub.1-6-alkyl; C(O)—OH; C(O)—OC.sub.1-6-alkyl; OH; C.sub.1-6-alkylene-OH; OCF.sub.3; OCF.sub.2H; OCFH.sub.2; OCF.sub.2Cl; OCFCl.sub.2; O—C.sub.1-6-alkyl; O—C.sub.3-6-cycloalkyl; O-(3 to 7-membered heterocycloalkyl); SCF.sub.3; S—C.sub.1-6-alkyl; S(O)—C.sub.1-6-alkyl; S(O).sub.2—C.sub.1-6-alkyl; S(O).sub.2—C.sub.1-6-alkylene-C.sub.3-6-cycloalkyl; S(O).sub.2—NH.sub.2; S(O).sub.2—N(H)(C.sub.1-6-alkyl); S(O).sub.2—N(C.sub.1-6-alkyl).sub.2; C.sub.3-6-cycloalkyl; C.sub.1-6-alkylene-C.sub.3-6-cycloalkyl; 3 to 7-membered heterocycloalkyl; C.sub.1-6-alkylene-(3 to 7-membered heterocycloalkyl); phenyl or 5 or 6-membered heteroaryl.

3. The compound according to claim 1, wherein R.sup.1 represents phenyl or 5 to 10-membered heteroaryl which is selected from the group consisting of indolyl, indazolyl, pyridyl, preferably 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrazolyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, 2,4,5,6-tetrahydrocyclo-penta[c]pyrazolyl, benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indolizinyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl; and/or (i) R.sup.3 and R.sup.4, together with the carbon atom joining them, form C.sub.3-10-cycloalkyl; or (ii) R.sup.3 and R.sup.4 independently of one another represent H or C.sub.1-10-alkyl.

4. The compound according to claim 1, wherein R.sup.3 and R.sup.4, independently of one another represent H or —CH.sub.3; or (R.sup.3 and R.sup.4, together with the carbon atom joining them, form C.sub.3-10-cycloalkyl.

5. The compound according claim 4, wherein R.sup.3 and R.sup.4, together with the carbon atom joining them, form cyclobutyl.

6. The compound according to claim 1, wherein R.sup.1 represents (i) phenyl or 5 to 10-membered heteroaryl which is selected from the group consisting of indolyl, indazolyl, pyridyl, preferably 2-pyridyl, 3-pyridyl or 4-pyridyl, pyrazolyl, pyrazolopyrimidinyl, pyrrolopyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, furanyl, thienyl (thiophenyl), triazolyl, thiadiazolyl, 4,5,6,7-tetrahydro-2H-indazolyl, tetrahydrocyclo-penta[c]pyrazolyl, benzofuranyl, benzoimidazolyl, benzothienyl, benzothiadiazolyl, benzothiazolyl, benzotriazolyl, benzooxazolyl, benzooxadiazolyl, quinazolinyl, quinoxalinyl, carbazolyl, quinolinyl, dibenzofuranyl, dibenzothienyl, imidazothiazolyl, indolizinyl, isoquinolinyl, naphthyridinyl, oxazolyl, oxadiazolyl, phenazinyl, phenothiazinyl, phthalazinyl, purinyl, phenazinyl, tetrazolyl and triazinyl; or (ii) phenyl, unsubstituted or mono- or polysubstituted with one or more substituents selected from F; Cl; Br; I; —CH.sub.3; —CH.sub.2—CH.sub.3; O—CH.sub.3; —CF.sub.3; —C.sub.3-10-cycloalkyl; —CH.sub.2—C.sub.3-10-cycloalkyl; S(═O).sub.2—C.sub.3-10-cycloalkyl; S(═O).sub.2—CH.sub.2—C.sub.3-10-cycloalkyl; S(═O).sub.2—CH.sub.3; S(═O).sub.2—CH.sub.2—CH.sub.3; —CH.sub.2—CH.sub.2—O—CH.sub.2— (i.e. oxolanyl); —C═C—CH.sub.3; C(═O)—CH.sub.3; —CH═CH.sub.2; NH.sub.2; or —CH.sub.2—CH.sub.2—OH; or any of the following structure (II), (III), (IV), (V) or (VI), with the proviso that with respect to structures (II), (III), (IV) and (V) at least one of X and Z is a heteroatom: ##STR00127## wherein X represents N, N—R.sup.13 or C—R.sup.13; Z represents N, N—R.sup.13 or C—R.sup.13; R.sup.11, R.sup.12 and R.sup.13 represent, independently from one another, H; F; Cl; Br; I; CN; C.sub.1-10-alkyl; C.sub.3-10-cycloalkyl; 3 to 7 membered heterocycloalkyl; S(O)—(C.sub.1-10-alkyl); S(O)—(C.sub.3-10-cycloalkyl); S(O)-(3 to 7-membered heterocycloalkyl); S(O).sub.2—(C.sub.1-10-alkyl); S(O).sub.2—(C.sub.3-10-cycloalkyl); S(O).sub.2-(3 to 7-membered heterocycloalkyl); P(O)—(C.sub.1-10-alkyl).sub.2; P(O)(C.sub.1-10-alkyl)(C.sub.3-10-cycloalkyl); P(O)(C.sub.1-10-alkyl)(3 to 7-membered heterocycloalkyl); P(O)—(O—C.sub.1-10-alkyl).sub.2; P(O)(O—C.sub.1-10-alkyl)(O—C.sub.3-10-cycloalkyl); P(O)(O—C.sub.1-10-alkyl)(O-(3 to 7-membered heterocycloalkyl)); O—C.sub.1-10-alkyl; S—C.sub.1-10-alkyl; N(H)(C.sub.1-10-alkyl), N(C.sub.1-10-alkyl).sub.2; C(O)—C.sub.1-10-alkyl; C(O)—O—C.sub.1-10-alkyl; C(O)—NH.sub.2; C(O)—N(H)(C.sub.1-10-alkyl); C(O)—N(C.sub.1-10-alkyl).sub.2; O—C.sub.3-10-cycloalkyl; N(H)(C.sub.3-10-cycloalkyl), N(C.sub.1-10-alkyl)(C.sub.3-10-cycloalkyl); C(O)—C.sub.3-10-cycloalkyl; C(O)—O—C.sub.3-10-cycloalkyl; C(O)—N(H)(C.sub.3-10-cycloalkyl); C(O)—N(C.sub.1-10-alkyl)(C.sub.3-10-cycloalkyl); O-3 to 7-membered heterocycloalkyl; N(H)(3 to 7-membered heterocycloalkyl), N(C.sub.1-10-alkyl)(3 to 7-membered heterocycloalkyl); C(O)-3 to 7-membered heterocycloalkyl; C(O)—O-(3 to 7-membered heterocycloalkyl); C(O)—N(H)(3 to 7-membered heterocycloalkyl) or C(O)—N(C.sub.1-10-alkyl)(3 to 7-membered heterocycloalkyl); wherein C.sub.3-10-cycloalkyl and 3 to 7 membered heterocycloalkyl can optionally be bridged via C.sub.1-6-alkylene; and n represents 0, 1, 2 or 3; or wherein R.sup.11, R.sup.12 and R.sup.13 represent, independently from one another, F; Cl; Br; I; —CH.sub.3; O—CH.sub.3; —CF.sub.3; —C.sub.1-10-cycloalkyl; —CH.sub.2-C.sub.3-10-cycloalkyl; S(═O).sub.2—CH.sub.2-C.sub.3-10-cycloalkyl; S(═O).sub.2—CH.sub.3; —CH.sub.2—CH.sub.2—O—CH.sub.2— (i.e. oxolanyl); C≡C—CH.sub.3; C(═O)—CH.sub.3; —CH.sub.2—CH.sub.2—OH; and n represents 0, 1, 2 or 3.

7. The compound according to claim 1, wherein none of A.sup.1, A.sup.2 and A.sup.3 represents N, respectively; and/or R.sup.5, R.sup.6 and R.sup.7, independently from one another, represent CH.sub.3, F, Cl, CF.sub.3, or H.

8. The compound according to claim 1, wherein A.sup.7 does not represent C—R.sup.10; or none of A.sup.5, A.sup.6 and A.sup.7 represents C—R.sup.8, C—R.sup.9 or C—R.sup.10, respectively, and/or at most one of A.sup.5, A.sup.6 and A.sup.7 represents O; or at least one of A.sup.5, A.sup.6 and A.sup.7 represents C—R.sup.8, C—R.sup.9 or C—R.sup.10, respectively, and/or at most one of A.sup.5, A.sup.6 and A.sup.7 represents O; or at least one of A.sup.5, A.sup.6 and A.sup.7 represents N, respectively, and/or at most one of A.sup.5, A.sup.6 and A.sup.7 represents O; or at least one of A.sup.5, A.sup.6 and A.sup.7 represents N—R.sup.8, N—R.sup.9 or N—R.sup.10, respectively, and/or at most one of A.sup.5, A.sup.6 and A.sup.7 represents O; and/or R.sup.8, R.sup.9 and R.sup.10, independently from one another, represent S(O).sub.2—CH.sub.3, CH.sub.3, CH.sub.2CH.sub.3, F, CF.sub.3, CH.sub.2-cyclopropyl, or H.

9. The compound according to claim 1, wherein the definition of A.sup.5, A.sup.6 and A.sup.7 corresponds to embodiment e, f, g, h, i, j, k, l or m: TABLE-US-00016 embodiment A.sup.5 A.sup.6 A.sup.7 e N C-R.sup.9 C-R.sup.10 f C-R.sup.8 C-R.sup.9 C-R.sup.10 g N N C-R.sup.10 h N N N i N N N-R.sup.10 j C-R.sup.8 N N-R.sup.10 k N C-R.sup.9 N-R.sup.10 1 C-R.sup.8 N-R.sup.9 N m N C-R.sup.9 O

10. The compound according to claim 1, wherein the definition of A.sup.4, A.sup.5, A.sup.6, A.sup.7 and A.sup.8 corresponds to embodiment n, o, p, q, r, s, t, u, v, w, x or y: TABLE-US-00017 embodiment A.sup.4 A.sup.5 A.sup.6 A.sup.7 A.sup.8 n C N C-R.sup.9 C-R.sup.10 N o N N C-R.sup.9 C-R.sup.10 C p C C-R.sup.8 C-R.sup.9 C-R.sup.10 N q C N N C-R.sup.10 N r N N N C-R.sup.10 C s C N N N N t C N N N-R.sup.10 C u C C-R.sup.8 N N-R.sup.10 C v N N C-R.sup.9 N-R.sup.10 C w C N C-R.sup.9 N-R.sup.10 C x C C-R.sup.8 N-R.sup.9 N C y C N C-R.sup.9 O C

11. The compound according to claim 1 which is selected from the group consisting of: 1 7-fluoro-8-(3-fluoro-5-methylphenyl)-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 2 7,9-difluoro-1,4,4-trimethyl-8-(1H-pyrazol-3-yl)-5H-pyrrolo[1,2-a]quinoxaline 3 7,9-difluoro-8-(1H-indol-4-yl)-1,4,4-trimethyl-5H-pyrrolo[1,2-a]quinoxaline 4 7,9-difluoro-1,4,4-trimethyl-8-pyrazolo[1,5-a]pyrimidin-3-yl-5H-pyrrolo[1,2-a]quinoxaline 5 7,9-difluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-5H-imidazo[1,2-a]quinoxaline 6 7-fluoro-8-[2-methoxy-5-(trifluoromethyl)pyridin-3-yl]-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 7 7-fluoro-1,4,4,9-tetramethyl-8-[6-(trifluoromethyl)-1H-indol-4-yl]-5H-imidazo[1,2-a]quinoxaline 8 8-[1-(cyclopropylmethyl)indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 9 8-[1-(cyclopropylmethylsulfonyl)indol-4-yl]-7-fluoro-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 10 8-(1-cyclopropylindol-4-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 11 9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine 12 7,9-difluoro-1,4,4-trimethyl-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-5H-pyrrolo[1,2-a]quinoxaline 13 8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine 14 7-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 15 8-(5-chloro-2-methoxypyridin-3-yl)-7-fluoro-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 16 7-fluoro-8-[5-fluoro-3-(oxolan-3-yl)-1H-indol-7-yl]-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 17 7-fluoro-8-(5-fluoro-3-prop-1-ynyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-imidazo[1,2-a]quinoxaline 18 9-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine 19 7-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonylindazol-4-yl)-5H-imidazo[1,2-a]quinoxaline 20 7,9-difluoro-1,4,4-trimethyl-8-(1-methylsulfonylindazol-4-yl)-5H-pyrrolo[1,2-a]quinoxaline 21 1-[4-(7,9-difluoro-1,4,4-trimethyl-5H-pyrrolo[1,2-a]quinoxalin-8-yl)indol-1-yl]ethanone 22 8-(3-cyclopropyl-1H-indol-7-yl)-7,9-difluoro-4,4-dimethyl-5H-tetrazolo[1,5-a]quinoxaline 23 7-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-4,4-dimethyl-9-(trifluoromethyl)-5H-tetrazolo[1,5-a]quinoxaline 24 7-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-1,4,4,9-tetramethyl-5H-triazolo[4,5-c]quinoline 25 7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-triazolo[4,5-c]quinoline 26 2-[6-fluoro-4-(7-fluoro-1,4,4,9-tetramethyl-5H-triazolo[4,5-c]quinolin-8-yl)indol-1-yl]ethanol 27 8-fluoro-9-(6-fluoro-1-methylsulfonylindol-4-yl)-1,5,5,10-tetramethyl-6H-pyrazolo[1,5-c]quinazoline 28 8,10-difluoro-9-(6-fluoro-1-methylsulfonylindol-4-yl)-5,5-dimethyl-6H-pyrazolo[1,5-c]quinazoline 29 2-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-6,6,9-trimethyl-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine 29 3-fluoro-6,6,9-trimethyl-2-(3-methyl-1H-indol-7-yl)-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine 30 1,4,4,9-tetramethyl-8-(3-methyl-1H-indol-7-yl)-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine 32 6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-1,4,4,9-tetramethyl-5H-pyrazolo[4,3-c]quinoline 33 6-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonylindol-4-yl)-5H-pyrazolo[4,3-c]quinoline 34 6-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-1,4,4,9-tetramethyl-5H-pyrazolo[4,3-c]quinoline 35 7-fluoro-9-(6-fluoro-1-methylsulfonylindol-4-yl)-1,5,5,10-tetramethyl-6H-triazolo[1,5-c]quinazoline 36 7-fluoro-9-(6-fluoro-1-methylsulfonylindazol-4-yl)-1,5,5,10-tetramethyl-6H-triazolo[1,5-c]quinazoline 37 6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-1,9-dimethylspiro[5H-pyrazolo[4,3-c]quinoline-4,1-cyclobutane] 38 6-fluoro-1,9-dimethyl-8-(1-methylsulfonylindazol-4-yl)spiro[5H-pyrazolo[4,3-c]quinoline-4,1-cyclobutane] 39 6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,9-dimethylspiro[5H-pyrazolo[4,3-c]quinoline-4,1-cyclobutane] 40 1-ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-4,4,9-trimethyl-5H-pyrazolo[4,3-c]quinoline 41 1-ethyl-6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-4,4,9-trimethyl-5H-pyrazolo[4,3-c]quinoline 42 1-(cyclopropylmethyl)-6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-4,4,9-trimethyl-5H-pyrazolo[4,3-c]quinoline 43 1-(cyclopropylmethyl)-6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-pyrazolo[4,3-c]quinoline 44 1-(cyclopropylmethyl)-6-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-4,4,9-trimethyl-5H-pyrazolo[4,3-c]quinoline 45 7-fluoro-9-(6-fluoro-1-methylsulfonylindazol-4-yl)-5,5,10-trimethyl-6H-pyrazolo[1,5-c]quinazoline 46 7-fluoro-1,4,4,9-tetramethyl-8-(1-methylsulfonylindol-4-yl)-5H-pyrazolo[4,3-c]quinoline 47 6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-1,4,4,9-tetramethyl-5H-imidazo[4,5-c]quinoline 48 6-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-1,4,4,9-tetramethyl-5H-imidazo[4,5-c]quinoline 49 6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-1,4,4,9-tetramethyl-5H-imidazo[4,5-c]quinoline 50 7-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-1,3,4,4,9-pentamethyl-5H-pyrazolo[4,3-c]quinoline 51 6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-1,3,4,4,9-pentamethyl-5H-pyrazolo[4,3-c]quinoline 52 6,7-difluoro-8-(5-fluoro-3-methyl-1-indol-7-yl)-1,4,4-trimethyl-5H-pyrazolo[4,3-c]quinoline 53 6-fluoro-1,3,9-trimethyl-8-(1-methylsulfonylindol-4-yl)spiro[5H-pyrazolo[4,3-c]quinoline-4,1-cyclobutane] 54 6-fluoro-1,3,9-trimethyl-8-(1-methylsulfonylindazol-4-yl)spiro[5H-pyrazolo[4,3-c]quinoline-4,1-cyclobutane] 55 6-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4,9-trimethyl-2,5-dihydropyrazolo[4,3-c]quinoline 56 6-fluoro-1,3,9-trimethyl-8-(3-methyl-1H-indol-7-yl)spiro[5H-pyrazolo[4,3-c]quinoline-4,1-cyclobutane] 57 6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-4,4,9-trimethyl-2-methylsulfonyl-5H-pyrazolo[4,3-c]quinoline 58 6-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-4,4,9-trimethyl-2,5-dihydropyrazolo[4,3-c]quinoline 59 6-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-4,4,9-trimethyl-2,5-dihydropyrazolo[4,3-c]quinoline 60 8-(6-fluoro-1-methylsulfonylindazol-4-yl)-1,4,4,9-tetramethyl-5H-triazolo[4,5-c]quinoline 51 7-fluoro-8-(6-fluoro-1-methylsulfonylindol-4-yl)-4,4,9-trimethyl-5H-[1,3]oxazolo[4,5-c]quinoline 62 7-fluoro-8-(5-fluoro-3-methyl-1H-indol-7-yl)-4,4,9-trimethyl-5H-[1,3]oxazolo[4,5-c]quinoline and 63 7-fluoro-8-(6-fluoro-1-methylsulfonylindazol-4-yl)-4,4,9-trimethyl-5H-[1,3]oxazolo[4,5-c]quinoline in the form of the free compound or a physiologically acceptable salt thereof.

12. A pharmaceutical dosage form comprising a compound according to claim 1.

13. A pharmaceutical dosage form comprising a compound according to claim 11.

14. A method for the treatment and/or prophylaxis of pain and/or inflammation in a subject in need thereof, said method comprising administering to the subject an effective amount therefor of the compound according to claim 1.

15. A method for the treatment and/or prophylaxis of pain and/or inflammation in a subject in need thereof, said method comprising administering to the subject an effective amount therefor of the compound according to claim 11.

16. A method for the treatment and/or prophylaxis of inflammatory pain in a subject in need thereof, said method comprising administering to the subject an effective amount therefor of the compound according to claim 1.

17. A method for the treatment and/or prophylaxis of inflammatory pain in a subject in need thereof, said method comprising administering to the subject an effective amount therefor of the compound according to claim 11.

Description

EXAMPLES

[0127] The following abbreviations are used in the descriptions of the experiments:

[0128] AcOH=acetic acid; Ac=acetyl group; Ataphos=bis(di-tert-butyl(4 dimethylaminophenyl)phosphine)dichloropalladium(II); Ar=argon; BISPIN (or Bis-Pin)=bis(pinacolato)diborane; Cp*=Pentamethylcyclopentadienyl, dba=dibenzylideneacetone; DCM=dichloromethane; DIPEA=N,N-diisopropylethylamine; DMADMF=N,N-dimethylformamide dimethylacetal; DMAP=4-(dimethylamino)-pyridine; DMF=N,N-dimethylformamid; DMSO=dimethylsulfoxid; dppf=1,1′; bis(diphenylphosphanyl)ferrocene; EtOAc=ethyl acetate; EtOH=ethanol; h=hour; LDA=lithiumdiisopropylamide; LiHMDS=lithium bis(trimethylsilyl)amide; MeOH=methanol; min=minute; n-BuLi=n-butyllithium; pin=(pinacolato)borane; RT=room temperature; Rt=retention time; tert=tertiary; TEA=triethylamine; THF=tetrahydrofuran; p-TSA=para-toluene sulfonic acid; TMSCl=trimethylsilyl chloride; Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, X-Phos=2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0129] The intermediates in Table 1 are commercially available as the corresponding pinacolatoborane and/or as the corresponding boronic acid:

TABLE-US-00004 Name Structure (3-fluoro-5-methylphenyl)boronic acid Intermediate A1 [00006] embedded image 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrazole Intermediate A2 [00007] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-indole Intermediate A3 [00008] 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)pyrazolo[1,5-a]pyrimidine Intermediate A4 [00009] 2-methoxy-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-5-(trifluoromethyl) pyridine Intermediate A6 [00010] embedded image 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-6-(trifluoromethyl)-1H-indole Intermediate A7 [00011] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan- 2-yl)-1H-pyrrolo[2,3-b]pyridine Intermediate A12 [00012] 5-chloro-2-methoxy-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)pyridine Intermediate A15 [00013] embedded image

Synthesis of 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A5)

[0130] ##STR00014##

[0131] Step 1: To a stirring solution of 2-bromo-4-fluoro-6-nitrotoluene (4.69 g, 20 mmol, 1 eq) in 1,4-dioxane (25 ml) was slowly added N,N-dimethylformamide dimethylacetal (13.3 mL, 100 mmol, 5 eq) and pyrrolidine (1.47 mL, 20 mmol, 1 eq). The reaction mixture was then stirred for 18 h at 100° C. The reaction mixture was concentrated to a dark residue. To this residue were added AcOH (30 mL) and iron powder (11 g, 200 mmol, 10 eq) and then the reaction mixture was refluxed for 1 h. The reaction mixture was then cooled to RT and then filtered through a celite bed. The filtrate was neutralised by 50% sodium hydroxide solution and then extracted with EtOAc (2×100 mL). Combined organic layers was washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the crude which was purified by column chromatography to afford 4-bromo-6-fluoro-1H-indole (1.3 g, 30%) as brown liquid.

[0132] Step 2: To a stirring 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 1,4-dioxan (20 mL) was deoxygenated by Ar for 10 min. Pd.sub.2(dba).sub.3 (0.07 g, 0.07 mmol. 0.015 eq) and tricyclohexylphosphine (0.102 g, 0.36 mmol, 0.07 eq) was then added to the reaction mixture and again deoxygenated by Ar for 10 min. The reaction mixture was then stirred for 14 h at 110° C. The reaction mixture then cooled to RT and then filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude material which was purified by column chromatography to afford 6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.1 g, 82%) as light yellow solid.

Synthesis of 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A8)

[0133] ##STR00015##

[0134] Step 1: Sodium hydroxide (408 mg, 10.2 mmol, 4.0 eq.) was weighed out into a vial under nitrogen atmosphere, followed by the addition of DMSO (6.6 mL). The mixture was allowed to stir at ambient temperature for five minutes, before 4-bromo-1H-indole (500 mg, 2.6 mmol, 1.0 eq.) in DMSO (3.3 mL) was added. The mixture was stirred for 10 minutes, before the dropwise addition of (chloromethyl)cyclopropane (692 mg, 7.7 mmol, 3.0 eq.). The reaction mixture was then heated to 60° C. for 16 hours. Water and EtOAc were then added, the layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were washed with brine, dried over MgSO.sub.4 and the solvent was removed under reduced pressure to obtain a crude mixture of 4-bromo-1-(cyclopropylmethyl)-1H-indole (685 mg), which was used in the next step without further purification.

[0135] Step 2: 1-(cyclopropylmethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole was prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for intermediate A18, step 2. Yield: 814 mg, 77% over two steps.

Synthesis of 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A10)

[0136] ##STR00016##

[0137] Step 1: 4-Bromo-1H-indole (50 mg, 0.26 mmol, 1.0 eq), cyclopropyl boronic acid (48 mg, 0.59 mmol, 2.2 eq.), Na.sub.2CO.sub.3 (81 mg, 0.77 mol, 3.0 eq.), Cu(OAc).sub.2 (46 mg, 0.26 mmol, 1.0 eq.) and 2,2′-bipyridine (40 mg, 0.26 mmol, 1.0 eq.) were weighed out into a microwave vial, a stir bar was added and the vial was sealed. Then DCM (5.7 mL) was added, followed by purging the reaction mixture with oxygen. The reaction mixture was then stirred at ambient temperature for 22 days. Then, 10% NH.sub.4Cl solution was added, the layers were separated and the aqueous layer was repeatedly extracted with DCM. The combined organic layers were then washed with brined, dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The obtained residue was purified via silica gel chromatography to yield 39 mg (65%) of 4-bromo-1-cyclopropyl-1H-indole.

[0138] Step 2: 1-cyclopropyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole was prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for intermediate A18, step 2.

Synthesis of 5-fluoro-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A13)

[0139] ##STR00017##

[0140] Step 1: To a solution of 7-bromo-5-fluoro-3-methyl-1H-indole (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 atmosphere. Then the reaction mixture was stirred at the same temperature for 4 h. The reaction was quenched with saturated ammonium chloride solution at −60° C. Then the resulting mixture was extracted with EtOAc (2×100 mL), washed with brine solution and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography to afford 7-bromo-5-fluoro-3-methyl-1H-indole (0.3 g, 58%) as dense yellow liquid.

[0141] Step 2: To a solution of 7-bromo-5-fluoro-3-methyl-1H-indole (0.8 g, 3.669 mmol, 1 eq) in 1,4-dioxane (15.0 mL) were added KOAC (1.43 g, 14.67 mmol, 4 eq) and bispincolatediborane (1.12 g, 7.33 mmol, 2 eq). The solution was degassed with Ar for 20 min followed by addition of Pd.sub.2(dba).sub.3 (0.16 g, 0.183 mmol, 0.05 eq) and Cy.sub.3P (0.082 g, 0.293 mmol, 0.08 eq). The reaction mixture was refluxed for 16 h. After completion of reaction (monitored by TLC), solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography to afford 5-fluoro-3-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.7 g, 70%), as brown solid.

Synthesis of 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A14)

[0142] ##STR00018##

[0143] Step1: To a stirring solution of 4-bromo-6-fluoro-1H-indole (0.18 g, 0.841 mmol, 1 eq) in DMF (5 mL) was portion wise added sodium hydride (60%, 0.07 g, 1.68 mmol, 2 eq) at 0° C. The reaction mixture was then stirred for 30 min at RT. Methanesulfonylchloride (0.114 ml, 1.26 mmol, 1.5 eq) was then added to the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at RT. Reaction mixture was diluted with EtOAc (50 mL). Combined organic layers were washed with water (5×10 mL), brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. Crude product was purified by column chromatography to afford 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indole (0.1 g, 41%) as off-white solid.

[0144] Step2: To a stirring suspension of 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indole (1.2 g, 3.53 mmol, 1 eq), bis-pinacolatodiborane (1.79 g, 7.06 mmol, 2 eq) and potassium acetate (1.39 g, 10.62 mmol, 4 eq) in 1,4-dioxan (20 mL) was deoxygenated by Ar for 10 min. Pd.sub.2(dba).sub.3 (0.048 g, 0.052 mmol. 0.015 eq) and triclyclohexylphosphine (0.071 g, 0.25 mmol, 0.07 eq) was then added to the reaction mixture and again deoxygenated by Ar for 10 min. The reaction mixture was stirred for 14 h at 110° C. The reaction mixture was cooled to RT and then filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude product which was purified by column chromatography to afford 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.0 g, 80%) as light yellow solid.

Synthesis of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (intermediate A18)

[0145] ##STR00019##

[0146] Step 1: To a stirring solution of 4-bromo-1H-indazole (1.0 g, 5.07 mmol, 1 eq) in DMF (25 ml) was portion wise added sodium hydride (60%, 0.406 g, 10.152 mmol, 2 eq) at 0° C. The reaction mixture was stirred for 30 min at RT. Methanesulfonylchloride (0.59 mL, 7.6 mmol, 1.5 eq) was added to the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at RT. Reaction mixture was diluted with EtOAc (150 mL). Combined organic layers were washed with water (5×30 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. Crude product was purified by column chromatography (230-400 mesh silica gel 10% EtOAc/hexane; R.sub.f-value-0.5) to afford 4-bromo-1-(methylsulfonyl)-1H-indazole (0.95 g, 69%) as light yellow solid.

[0147] Step 2: To a stirring 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) was deoxygenated by Ar for 10 min. Pd(dppf)Cl.sub.2.DCM (0.141 g, 0.1727 mmol. 0.05 eq) was added to the reaction mixture and again deoxygenated by Ar for 10 min. The reaction mixture was stirred for 14 h at 110° C. The reaction mixture was cooled to RT and then filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude material which was purified by column chromatography (230-400 mesh silica gel, 10% EtOAc/hexane; R.sub.f-value-0.45) to afford 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.9 g, 85.4%) as off white solid.

[0148] The following intermediates were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for intermediate A18:

TABLE-US-00005 Intermediate Structure A9 [00020] embedded image

Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanone (intermediate A19)

[0149] ##STR00021##

[0150] Step 1: To a stirred solution of 4-bromo-1H-indole (0.5 g, 2.55 mmol, 1 eq) in THF (25 mL) was added sodium hydride (60%) (0.122 g, 3.06 mmol, 1.2 eq) at 0° C. and continued stirred at RT for 30 min. Acetyl chloride (0.02 mL, 3.06 mmol, 1.2 eq) was then added to the reaction mixture and again stirred for another 2 h. The reaction mixture was quenched with water and extracted with EtOAc (2×100 mL). Combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated to get the crude product which was purified by column chromatography to afford 1-(4-bromo-1H-indol-1-yl)ethanone (0.55 g, 91%) as brown liquid.

[0151] 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)diborane (0.707 g, 4.62 mmol, 2 eq) and potassium acetate (0.680 g, 6.93 mmol, 3 eq) in 1,4-dioxan (20 mL) was deoxygenated by Ar for 10 min. Pd.sub.2(dba).sub.3 (0.106 g, 0.1155 mmol, 0.08 eq) and Cy.sub.3P (0.052 g, 0.1848 mmol. 0.08 eq) was then added to the reaction mixture and reflux at 90° C. for another 16 h. The reaction mixture was cooled to RT and filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude material which was purified by column chromatography to afford 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanone (0.600 g, 92%) as brown liquid.

Synthesis of 1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanone (intermediate A20)

[0152] ##STR00022##

[0153] Step 1: To a stirring solution of 7-bromo-5-fluoroindole (7.0 g, 35.7 mmol, 1.0 eq.) in dimethylformamide (145 ml) was added powdered potassium hydroxide (3.0 g, 53.55 mmol, 1.5 eq.). The reaction mixture was then stirred for 30 min at room temperature. Iodine (10.0 g, 39.28 mmol, 1.1 eq.) was then added to the reaction mixture and and the resulting reaction mixture was then stirred for 2 h at room temperature. The reaction mixture was then diluted with ethyl acetate (1 L) and was washed with water (5×100 ml) followed by brine (100 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the crude product, which was purified by silica gel column chromatography (10% ethyl acetate/hexane; R.sub.f-value-0.4) to afford 7-bromo-3-iodo-1H-indole (8.5 g, 74%) as a brown solid.

[0154] Step 2: To a stirring solution of 7-bromo-3-iodo-1H-indole (8.5 g, 26.4 mmol, 1.0 eq.) in tetrahydrofuran (150 ml) was dropwise added LiHMDS (1.3 M, 101.5 ml, 132.3 mmol, 5.0 eq.) at −78° C. under an inert atmosphere. The reaction mixture was then stirred for 30 min at this temperature. MOMCl (8.44 g, 105.6 mmol, 4.0 eq) was then added to the reaction mixture at −78° C. The reaction mixture was then slowly allowed to reach room temperature and was then stirred for 16 h. The reaction mixture was quenches by the addition of a saturated solution of ammonium chloride (100 ml). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layers were washed with brine (100 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the crude product, which was purified by silica gel column chromatography (10% ethyl acetate/hexane; R.sub.f-value-0.5) to afford 7-bromo-3-iodo-1-(methoxymethyl)-1H-indole (9.0 g, 93%) as an off-white solid.

[0155] Step 3: A stirred suspension of 7-bromo-3-iodo-1-(methoxymethyl)-1H-indole (5.0 g, 13.66 mmol, 1.0 eq.), cyclopropylbronic acid (3.52 g, 40.98 mmol, 3.0 eq.) and K.sub.3PO.sub.4 (8.68 g, 40.98 mmol, 3.0 eq.) in 1,4-dioxane (100 ml) was deoxygenated with argon for 10 min. Pd(OAc).sub.2 (0.153 g, 0.683 mmol, 0.05 eq.) and xantphos (0.79 g, 1.366 mmol, 0.1 eq.) were then added to the reaction mixture, which was again deoxygenated for 10 min. The reaction mixture was then heated to 100° C. for 16 h. The reaction mixture was then cooled to room temperature and was filtered through a celite bed. The filtrate was concentrated under reduced pressure to get the crude material which was purified by silica gel column chromatography (10% ethyl acetate/hexane; R.sub.f-value-0.5) to afford 7-bromo-3-cyclopropyl-1-(methoxymethyl)-1H-indole (1.7 g, 44%) as an off-white solid.

[0156] Step 4: To a stirring solution of 7-bromo-3-cyclopropyl-1-(methoxymethyl)-1H-indole (2.2 g, 7.87 mmol, 1.0 eq.) in a mixture of methanol and water (3:1) (64 ml) was added oxalic acid (2.12 g, 23.57 mmol, 3.0 eq). The reaction mixture was then heated to 90° C. for 18 h. The reaction mixture was then cooled to room temperature and was concentrated under reduced pressure to get the crude residue, which was diluted with ethyl acetate (200 ml) and was washed with water (2×70 ml) and brine (70 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the crude product, which was purified by silica gel column chromatography (10% ethyl acetate/hexane; R.sub.f-value-0.55) to afford 7-bromo-3-cyclopropyl-1H-indole (1.3 g, 70%) as a colorless liquid.

[0157] Step 5: A stirring suspension of 7-bromo-3-cyclopropyl-1H-indole (1.35 g, 5.72 mmol, 1.0 eq.), bis-pinacolatodiborane (2.88 g, 11.44 mmol, 2.0 eq.) and potassium acetate (1.65 g, 17.16 mmol, 3.0 eq.) in 1,4-dioxane (67 ml) was deoxygenated by argon gas for 10 min. Pd.sub.2(dba).sub.3 (0.070 g, 0.085 mmol. 0.015 eq.) and triclyclohexylphosphine (0.12 g, 0.429 mmol, 0.075 eq.) were then added to the reaction mixture, which was again deoxygenated by argon for 10 min. The reaction mixture was then heated to 110° C. for 14 h. The reaction mixture was then cooled to room temperature and was filtered through a celite bed. The filtrate was concentrated under reduced pressure to get the crude material which was purified by column chromatography (20% ethyl acetate/hexane; R.sub.f-value-0.6) to afford 3-cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.5 g, 31%) as an off-white solid.

Synthesis of 2-(6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)ethanol (intermediate A21)

[0158] ##STR00023##

[0159] 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 RT for 30 min followed by addition of (2-bromoethoxy)(tert-butyl)dimethylsilane (1.17 g, 4.67 mmol, 2.0 eq) and reaction mixture was stirred at RT for 2 h. After completion of reaction (monitored by LCMS), reaction mixture was diluted with EtOAc (20 mL) and organic layer was washed with cold water (5×10 mL), brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. Crude product was purified by column chromatography to afford 4-bromo-1-(2-((tert-butyldimethylsilypoxy)ethyl)-6-fluoro-1H-indole (0.85 g, 98%) as brown liquid having (2-bromoethoxy)(tert-butyl)dimethylsilane as impurity.

[0160] Step 2: To a stirred solution of 4-bromo-1-(2-((tert-butyldimethylsilypoxy)ethyl)-6-fluoro-1H-indole (1.3 g, 3.49 mmol, 1 eq.) in THF (15 mL) was added TBAF (3.49 mL) (1M) at RT and the mixture was stirred for 16 h. After completion of reaction (monitored by LCMS & TLC), reaction mixture was diluted with EtOAc (20 mL) and organic layer was washed with cold water (5×10 mL), brine (10 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. Crude product was purified by column chromatography to afford 2-(4-bromo-6-fluoro-1H-indol-1-yl)ethanol (0.55 g, 61%) as brown liquid.

[0161] Step 3: To a stirred solution of 2-(4-bromo-6-fluoro-1H-indol-1-yl)ethanol (0.55 g, 2.13 mmol, 1 eq), bis(pinacolato)diborane (0.647 g, 2.55 mmol, 1.2 eq) and potassium acetate (0.626 g, 6.393 mmol, 3 eq) in 1,4-dioxan (20 mL) was deoxygenated by Ar for 10 min. PdCl.sub.2(dppf).DCM (0.173 g, 0.213 mmol. 0.1 eq) was then added to the reaction mixture and the mixture was stirred at 90° C. for 16 h. After completion of reaction (monitored by TLC), reaction mixture was filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude product which was used in next step without further purification.

Synthesis of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (intermediate A22)

[0162] ##STR00024##

[0163] Step 1: To a stirring solution of 4-bromo-1H-indole (1.0 g, 5.1 mmol, 1 eq) in DMF (20 ml) was portion wise added sodium hydride (60%, 0.245 g, 10.2 mmol, 2 eq) at 0° C. The reaction mixture was then stirred for 30 min at RT. Methanesulfonylchloride (0.584 ml, 7.6 mmol, 1.5 eq) then added to the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at RT. Reaction mixture was diluted with EtOAc (100 mL). Combined organic layers was washed with water (5×20 mL), brine (20 mL), dried over anhydrous Na.sub.2SO.sub.4 and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography to afford 4-bromo-1-(methylsulfonyl)-1H-indole (0.532 g, 38%) as off white solid.

[0164] Step 2: To a stirring suspension of 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-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-dioxan (10 Ll) was deoxygenated by Ar for 10 min. Pd.sub.2(dba).sub.3 (0.018 g, 0.019 mmol. 0.015 eq) and tricyclohexylphosphine (0.027 g, 0.094 mmol, 0.072 eq) was then added to the reaction mixture and again deoxygenated by Ar for 10 min. The reaction mixture was then stirred for 14 h at 110° C. The reaction mixture then cooled to RT and then filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude material which was purified by column chromatography to afford 1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.31 g, 73%) as off white solid.

Synthesis of 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (intermediate A23)

[0165] ##STR00025##

[0166] Step 1: To a stirring solution of 4-bromo-6-fluoro-1H-indazole (1.2 g, 5.58 mmol, 1 eq) in DMF (30 mL) was portion wise added sodium hydride (60%, 0.446 g, 11.16 mmol, 2 eq) at 0° C. The reaction mixture was then stirred for 30 min at RT. Methanesulfonylchloride (0.65 ml, 8.37 mmol, 1.5 eq) was added to the reaction mixture at 0° C. The reaction mixture was stirred for 2 h at RT. Reaction mixture was diluted with EtOAc (150 mL). Combined organic layers were washed with water (5×30 mL), brine (30 mL), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. Crude product was purified by column chromatography (230-400 mesh silica gel 10% EtOAc/hexane; R.sub.f-value-0.5) to afford 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indazole (1.3 g, 80%) as light yellow solid.

[0167] Step 2: To a stirring suspension of 4-bromo-6-fluoro-1-(methylsulfonyl)-1H-indazole (1.3, 4.43 mmol, 1 eq), bis(pinacolato)diborane (2.25 g, 8.87 mmol, 2 eq) and potassium acetate (1.3 g, 13.3 mmol, 3 eq) in 1,4-dioxane (45 mL) was deoxygenated by Ar for 10 min. Pd(dppf)Cl.sub.2DCM (0.18 g, 0.22 mmol. 0.05 eq) and was then added to the reaction mixture and again deoxygenated by Ar for 10 min. The reaction mixture was stirred for 14 h at 110° C. The reaction mixture was cooled to RT and then filtered through celite bed. Filtrate was concentrated under reduced pressure to get the crude material which was purified by column chromatography (230-400 mesh silica gel, 10% EtOAc/hexane; R.sub.f-value-0.45) to afford 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (1.1 g, 73%) as off white solid.

Synthesis of 8-bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (intermediate B1)

[0168] ##STR00026##

[0169] Step 1: To a solution of 4-fluoro-2-methyl-phenylamine (30 g, 0.239 mol) in DMF (450 ml) was added NBS (44.81 g, 0.251 mol) portionwise at −10° C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (1000 ml) and extracted with ethyl acetate (2×500 ml). The combined organic layers were washed with water (2×500 ml) and brine (250 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel; 10% ethyl acetate/hexane) to afford 2-bromo-4-fluoro-6-methyl-phenylamine (45 g, 92%) as a white solid.

[0170] Step 2: To the stirred suspension of 2-bromo-4-fluoro-6-methyl-phenylamine (40 g, 0.19 mol) in dry DMSO (600 ml) was added 2-amino-2-methyl-propionic acid (40.4 g, 0.39 mol) followed by K.sub.3PO.sub.4 (83.1 g, 0.39 mol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 30 min, then cuprous chloride (1.93 g, 0.019 mol) was added and reaction mixture was heated to 140° C. for 2 h. After completion of the reaction (monitored by TLC, 20% EA-Hexane, Rf 0.4), the reaction mixture was cooled to room temperature and filtered through celite and the celite bed was washed with ethyl acetate (500 ml). The resulting filtrate was poured into ice cold water (1 L). The resulting aqueous layer was extracted with ethyl acetate (2×250 ml). The combined organic layers were washed with water (2×500 ml) and brine (250 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel and 20% ethyl acetate/hexane as eluent) to afford 6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (25.8 g, 64%) as a brown solid.

[0171] Step 3: To a solution of 6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (8.6 g, 41.34 mmol, 1.0 eq.) in DMF (100 ml) was added NB S (8.83 g, 49.61 mmol, 1.2 eq.) portion wise at 0° C. The reaction mixture was gradually warmed to ambient temperature and was stirred for 3 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with ice water (500 ml) and was extracted with ethyl acetate (2×400 ml). The combined organic layers were washed with water (500 ml) and brine (400 ml) and were then dried over anhydrous Na.sub.2SO.sub.4. The solvent was evaporated under reduced pressure to get the crude compound which was purified by column chromatography (silica gel; 10% EA-Hexane) to afford 7-bromo-6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (6.2 g, 55%) as a light brown solid.

[0172] Step 4: P.sub.2S.sub.5 (5.56 g, 25.08 mmol, 1.2 eq.) was added to a mixture of acetonitrile and triethylamine (1:1, 80 ml) and was stirred for 15 min. Then, 7-bromo-6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (6.0 g, 20.90 mmol, 1.0 eq.) was added to the reaction mixture at 0° C. The reaction mixture was warmed to ambient temperature and was then refluxed for 1 h. The reaction mixture was diluted with water (250 ml) and extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (250 ml) and brine (250 ml) and were dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the crude material which was purified by column chromatography (silica gel 100-200 mesh, 10-15% EA/Hexane) to yield 7-bromo-6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2-thione (5.2 g, 82%) as alight yellow solid.

[0173] Step 5: To a solution of 7-bromo-6-fluoro-3,3,8-trimethyl-3,4-dihydro-1H-quinoxaline-2-thione (3.0 g, 9.90 mmol, 1.0 eq.) in THF (40 ml) were added propargylamine (6.3 ml, 99.0 mmol, 10.0 eq.) and HgCl.sub.2 (2.7 g, 9.90 mmol, 1.0 eq.) and the reaction mixture was heated to reflux for 16 h. After 16 h, HgCl.sub.2 (1.35 g, 0.5 eq.) was added to the reaction mixture and the reaction mixture was again heated to reflux for another 16 h. The reaction mixture was then diluted with ethyl acetate (300 ml), washed with water (150 ml) and brine (200 ml) and dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography (silica gel; 25-30% EA/Hexane) to yield 8-bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-imidazo[1,2-a]quinoxaline (2.1 g, 65%) as an off-white solid.

Synthesis of 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (intermediate B2)

[0174] ##STR00027##

[0175] Step 1: 4-Bromo-3,5-difluoro-phenylamine (5 g, 24.02 mmol) was treated with acetic anhydride (2.26 ml, 24.02 mmol) at 0° C. for 30 mins. After completion of the reaction as ensured from TLC, the reaction mixture was poured in ice water, the precipitated solids were filtered off and were washed washed thoroughly with water to afford N-(4-bromo-3,5-difluorophenyl)acetamide (5.3 g, 88%) as a solid.

[0176] Step 2: To a suspension of N-(4-bromo-3,5-difluorophenyfiacetamide (5.3 g, 21.19 mmol) in concentrated HNO.sub.3 at 0° C. (7.52 ml) was added concentrated H.sub.2SO.sub.4 (7.52 ml) dropwise. The reaction mixture was gradually warmed up to room temperature. After ensuring complete consumption of the starting material by TLC (2 h), the reaction mixture was poured into ice water, the precipitated solids were filtered off, washed thoroughly with water and were dried to afford N-(4-bromo-3,5-difluoro-2-nitrophenyfiacetamide (5.1 g, 82%) as a pale yellow solid.

[0177] Step 3: A solution of N-(4-bromo-3,5-difluoro-2-nitrophenyl)acetamide (500 mg, 1.69 mmol) in methanol (50 ml) was hydrogenated in a Parr shaker at 50 psi in the presence of 5% platinum on carbon (150 mg). After ensuring complete consumption of starting material by TLC (30 min), the reaction mixture was filtered through a bed of celite and the filtrate was then concentrated under reduced pressure to afford N-(2-amino-4-bromo-3,5-difluorophenyl)acetamide (430 mg, 96%) as a solid.

[0178] Step 4: To a solution of N-(2-amino-4-bromo-3,5-difluorophenyl)acetamide (380 mg, 1.433 mmol) in acetic acid (10 ml) was added 4-oxopentanal (144.4 mg, 1.433 mmol) and the mixture was heated to 120° C. for 10 minutes. After consumption of the starting material as evident from TLC (10 min), the reaction mixture was concentrated under reduced pressure and the residual crude material was purified using silica gel chromatography (elution with 4% ethyl acetate:hexane) to afford N-(4-bromo-3,5-difluoro-2-(2-methyl-1H-pyrrol-1-yl)phenyl)acetamide (268 mg, 57%) as a dark brown solid.

[0179] Step 5: N-(4-Bromo-3,5-difluoro-2-(2-methyl-1H-pyrrol-1-yl)phenyl)acetamide (420 mg, 1.276 mmol) was taken up in methanol (8 ml) and was treated with potassium carbonate (528.3 mg, 3.828 mmol). After completion of the reaction as ensured from TLC (16 h), the solids were filtered off and were washed thoroughly with methanol. The filtrate was concentrated under reduced pressure and was purified using silica gel chromatography (elution with 3% ethyl acetate:hexane) to afford 4-bromo-3,5-difluoro-2-(2-methyl-1H-pyrrol-1-yl)aniline (289 mg, 79%) as a solid.

[0180] Step 6: A solution of 4-bromo-3,5-difluoro-2-(2-methyl-1H-pyrrol-1-yl)aniline (300 mg, 1.044 mmol) in DCM (6 ml) at 0° C. was treated with acetone (0.092 ml, 1.253 mmol), followed by the addition of boron trifluoride etherate (0.088 ml, 0.626 mmol). After ensuring completion of the reaction by TLC (10 mins), the reaction mixture was quenched with saturated sodium bicarbonate solution. The organic part was separated and the aqueous part was extracted with additional DCM. The combined organic extracts were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The remains were purified using silica gel chromatography (elution with 2% ethyl acetate:hexane) to afford 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (270 mg, 79%) as a yellow solid.

Synthesis of 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (intermediate B3)

[0181] ##STR00028##

[0182] Step 1: To the stirred suspension of 2-bromo-4,6-difluoro-phenylamine (50 g, 0.24 mol) in dry DMSO (1 L) was added 2-amino-2-methyl-propionic acid (49.49 g, 0.48 mol) followed by K.sub.3PO.sub.4 (101.88 g, 0.48 mol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 30 min, then cuprous chloride (2.3 g, 0.024 mol) was added and reaction mixture was heated to 130° C. for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was cooled to room temperature and was filtered through celite, which was washed with ethyl acetate (1000 ml). The filtrate was poured into ice cold water and the resulting mixture was extracted with MTBE (3×1500 ml). The combined organic layers were washed with water (2×2500 ml) and brine (1 lit), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel; 30% EA/hexane) to afford 6,8-difluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (36 g, 71%) as a brown solid.

[0183] Step 2: To a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (10 g, 47.125 mmol) in DMF (120 ml) was added NB S (9.23 g, 51.837 mmol) portionwise at −10° C. The resulting reaction mixture was stirred at room temperature for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with ice water (500 ml) and extracted with MTBE (2×500 ml). The combined organic layers were washed with water (750 ml) followed by brine (400 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel; 20% EA-Hexane) to afford 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (10 g, 73%) as a light brown solid.

[0184] Step 3: P.sub.2S.sub.5 (6.86 g, 30.92 mmol, 1.2 eq.) was added to a mixture of acetonitrile and triethylamine (1:1, 100 ml) and the mixture was stirred for 15 min. Then, 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxalin-2-one (7.5 g, 25.77 mmol, 1.0 eq.) was added to the reaction mixture at 0° C. The reaction mixture was warmed to ambient temperature and was then refluxed for 3 h. The reaction mixture was diluted with water (250 ml) and was then extracted with ethyl acetate (2×300 ml). The combined organic layers were washed with water (250 ml) and brine (250 ml) and were dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the crude material which was purified by column chromatography (silica gel 100-200 mesh, 30% EA/Hexane) to yield 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxaline-2-thione (6.5 g, 21.17 mmol, 82%) as a yellow solid which was contaminated with the corresponding des-bromo compound (˜5-10%). The mixture was used as such in the next step without further purification.

[0185] Step 4: To a solution of 7-bromo-6,8-difluoro-3,3-dimethyl-3,4-dihydro-1H-quinoxaline-2-thione (6.0 g, 19.54 mmol, 1.0 eq.) in THF (100 ml) were added propargylamine (12 ml, 195.4 mmol, 10 eq.) and HgCl.sub.2 (5.2 g, 19.54 mmol, 1.0 eq.) and the reaction mixture was heated to reflux for 16 h. After 16 h, HgCl.sub.2 (2.6 g, 0.5 eq.) was again added to the reaction mixture and the mixture was heated to reflux for another 16 h. The reaction mixture was then diluted with ethyl acetate (500 ml), washed with water (200 ml) and brine (200 ml) and was dried over sodium sulfate. The solvent was evaporated under reduced pressure to get the crude product which was purified by column chromatography (silica gel; 30% EA/Hexane) and then triturated with DCM-hexane to yield 8-bromo-7,9-difluoro-1,4,4-trimethyl-4,5-dihydro-imidazo[1,2-a]quinoxaline (1.5 g, 23%) as a white solid.

Synthesis of 8-bromo-9-fluoro-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (intermediate B4)

[0186] ##STR00029##

[0187] Step 1: To a stirred solution of 3-Fluoro-pyridin-4-ylamine (13.0 g, 115.95 mmol) in ACN (270 ml) and added NB S (30.96 g, 173.93 mmol). The reaction was then heated to 80° C. for 4 h. The reaction mixture was concentrated and the obtained crude material was purified by flash column chromatography (20% Ethyl acetate/Hexane) to afford 3-bromo-5-fluoro-pyridin-4-ylamine (9.0 g, 41%) as an off-white solid.

[0188] Step 2: To a stirred solution of 3-bromo-5-fluoro-pyridin-4-ylamine (9.0 g, 47.12 mmol) and 2-amino-2-methyl-propionic acid (9.7 g, 94.24 mmol) in DMSO (170 ml) was added K.sub.3PO.sub.4 (20.0 g, 94.24 mmol). The reaction was degassed with argon for 30 minutes before the addition of CuCl (0.47 g, 4.71 mmol). The reaction mixture was heated to 130° C. for 16 h. The reaction mixture was then cooled to ambient temperature, was diluted with water and extracted with EtOAc (6×200 ml). The combined organic layers were dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated under reduced pressure. The residue was cooled and treated with crushed ice and stirred until solids formed. The solid was filtered off and was washed with cold water followed by n-hexane to afford 8-fluoro-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one (8.2 g, 89%).

[0189] Step 3: To a stirred solution of 8-fluoro-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one (8.2 g, 42.029 mmol) in toluene (90 ml) was added Lawesson's reagent (25.5 g, 63.044 mmol). The reaction was then heated to 120° C. for 7 h. The reaction mixture was concentrated under reduced pressure and the obtained crude material was purified by flash column chromatography (50% Ethyl acetate/Hexane, neutral Al.sub.2O.sub.3) to afford 8-fluoro-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]pyrazine-2-thione (6.5 g, 73%) as a yellow solid.

[0190] Step 4: To a stirred solution of 8-fluoro-3,3-dimethyl-3,4-dihydro-1H-pyrido[3,4-b]pyrazin-2-one (6.5 g, 30.7677 mmol) in n-butanol (117 ml) were added acetic acid hydrazide (9.117 g, 123.07 mmol) and acetic acid (11.7 ml) at room temperature. The reaction mixture was then heated to 140° C. for 16 h. The reaction mixture was concentrated under reduced pressure and the obtained crude material was purified by column chromatography (60% Ethyl acetate/Hexane, neutral Al.sub.2O.sub.3) to afford 9-fluoro-1,4,4-trimethyl-4,5-dihydro-2,3,5,7,9b-pentaaza-cyclopenta[a]naphthalene (2.5 g, 35%) as an off-white solid.

[0191] Step 5: To a stirred solution of 9-fluoro-1,4,4-trimethyl-4,5-dihydro-2,3,5,7,9b-pentaaza-cyclopenta[a]naphthalene (1.55 g, 6.652 mmol) in DMF (20 ml) was added dropwise a solution of N-Bromo succinimide (0.710 g, 3.99 mmol) in DMF (10 ml) at −30 C. After addition, the reaction temperature was slowly raised to room temperature and the mixture was stirred at room temperature for 16 h. The reaction was diluted with EtOAc, and was then washed with ice cold water. The organic layer was dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The obtained crude material was purified by column chromatography (50% Ethyl acetate/Hexane, neutral Al.sub.2O.sub.3) to afford 8-bromo-9-fluoro-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (415 mg, 20%) as an off-white solid.

Synthesis of 8-bromo-1,4,4,9-tetramethyl-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (intermediate B5)

[0192] ##STR00030##

[0193] Step 1: To the stirred solution of 4-methyl-3-nitro-pyridin-2-ylamine (25 g, 0.16 mol) in acetonitrile (500 ml) was added NB S (29.2 g, 0.16 mol) portionwise at room temperature. The resulting suspension was stirred at 80° C. for 2 h. After completion of the reaction (monitored by TLC, 20% EA-Hexane, Rf=0.5) the reaction mixture was concentrated. The obtained residue was diluted with ethyl acetate (500 ml) and was washed with water (3×250 ml). The organic layer was washed with water followed by brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 5-bromo-4-methyl-3-nitro-pyridin-2-ylamine (36 g, 94%) as a yellow solid.

[0194] Step 2: To the stirred solution of 5-bromo-4-methyl-3-nitro-pyridin-2-ylamine (43 g, 0.18 mol) in TFA:water (654 ml, 2:1) was added NaNO.sub.2 (25.5 g, 0.36 mol) portionwise at 0° C. The resulting suspension was stirred at 0° C. for 4 h. After completion of the reaction (monitored by TLC, 20% EA-Hexane, Rf=0.4), the reaction mixture was concentrated, the obtained residue was diluted with water (50 ml) and the solids were filtered off. The obtained solid was washed with MTBE and dried under vacuum to afford 5-bromo-4-methyl-3-nitro-pyridin-2-ol (40 g, 92%) as a yellow solid.

[0195] Step 3: To the stirred solution of 5-bromo-4-methyl-3-nitro-pyridin-2-ol (20 g, 85.829 mmol) in acetonitrile (400 ml) was added POBr.sub.3 (123 g, 429.145 mmol) portionwise at room temperature. The resulting suspension was heated to reflux for 16 hrs. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated. The obtained residue was diluted with ethyl acetate (500 ml) and was quenched with a saturated aqueous solution of NaHCO.sub.3. The organic layer was washed with water followed by brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 2,5-dibromo-4-methyl-3-nitro-pyridine (23 g, crude) as a brown solid. This crude material was used for the next step without further purification.

[0196] Step 4: To the stirred solution of 2,5-Dibromo-4-methyl-3-nitro-pyridine (43 g, 0.145 mol) in EtOH (860 ml) was added SnCl.sub.2.2 H.sub.2O (98.1 g, 0.435 mol) portionwise at room temperature. The resulting suspension was heated to reflux for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was concentrated, the obtained residue was diluted with ethyl acetate (900 ml) and washed with water (3×250 ml). The organic part was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude compound, which was triturated with MTBE-Hexane to afford 2,5-dibromo-4-methyl-pyridin-3-ylamine (20 g, 52%) as a brown solid.

[0197] Step 5: To the stirred suspension of 2,5-dibromo-4-methyl-pyridin-3-ylamine (5 g, 18.95 mmol) in dry DMA (100 ml) was added 2-amino-2-methyl-propionic acid (2.9 g, 28.425 mmol) followed by DBU (4.3 g, 28.425 mmol) at room temperature. The resulting reaction mixture was degassed with nitrogen for 30 minutes, then CuI (180 mg, 0.9475 mmol) was added and the reaction mixture was heated to 160° C. for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was cooled to room temperature and was filtered through celite. The celite bed was washed with ethyl acetate (100 ml). The resulting filtrate was poured into ice cold water. The resulting aqueous layer was extracted with MTBE (3×150 ml). The combined organic layers were washed with water (2×150 ml) and brine (100 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel and 30% ethyl acetate/hexane as eluent) to afford 7-romo-3,3,8-trimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (3.6 g, 70%) as a brown solid.

[0198] Step 6: To a solution of 7-bromo-3,3,8-trimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (2 g, 0.74 mmol) in toluene (25 ml) was added Lawesson's reagent (4.48 g, 1.05 mol) at RT and the reaction mixture was then heated to 120° C. for 2 h. After completion of the reaction (monitored by TLC in 20% EA-Hexane, Rf=0.5), the reaction mixture was concentrated and the obtained solid residue was quenched with sat. NaHCO.sub.3 solution (100 ml). The resulting mixture was extracted with ethyl acetate (3×150 ml), the combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated to afford the crude compound, which was purified by column chromatography (100-200 mesh silica gel and 20% ethyl acetate/hexane as eluent) to afford 7-bromo-3,3,8-trimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazine-2-thio ne (1.4 g, 66%) as a yellow solid.

[0199] Step 7: To a stirring solution of 7-bromo-3,3,8-trimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazine-2-thione (1.4 g, 0.491 mmol) in tetrahydrofuran (35 ml) was added dropwise hydrazine hydrate (0.7 ml, 1.47 mol) at 0° C. The reaction mixture was then stirred at room temperature for 16 h. Triethylamine (3.4 ml, 2.45 mol) followed by acetyl chloride (1.1 ml, 1.47 mol) were added successively to the reaction mixture dropwise at 0° C. and the resulting mixture was stirred for 2 h at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with water (50 ml) and was extracted with 10% MeOH-DCM (5×100 ml). The total organic part was washed by brine (100 ml), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford acetic acid (7-bromo-3,3,8-trimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ylidene)-hydrazide (1.3 g, 81%) as a yellow solid.

[0200] Step 8: Acetic acid (7-bromo-3,3,8-trimethyl-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-ylidene)-hydrazide (1.1 g, 3.37 mol) in a round bottom flask (25 ml) was cooled to −10° C., before the dropwise addition of phosphorus oxalylchloride (1.52 ml, 16.86 mmol) to the compound, followed by the dropwise addition of triethyl amine (0.47 ml, 3.37 mol). After the reaction mixture was stirred at −10° C. for 10 minutes and then 10 minutes at room temperature, the reaction was heated to reflux for 4 h. After completion of the reaction (monitored by LCMS), the reaction mixture was cooled to 0° C. and was quenched with crushed ice water (25 ml). The aqueous part was then basified using cold ammonium solution (25 ml) dropwise. The resulting basic aqueous layer was then extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the crude compound, which was purified by trituration using MTBE to afford 8-bromo-1,4,4,9-tetramethyl-4,5-dihydro-2,3,5,6,9b-pentaaza-cyclopenta[a]naphthalene (800 mg, 77%) as an off-white solid.

Synthesis of 8-bromo-7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (intermediate B6)

[0201] ##STR00031##

[0202] Step 1: To a stirred solution of 2-bromo-4,6-difluoroaniline (10.0 g, 48.076 mmol, 1.0 eq) and 2-aminoisobutyric acid (9.92 g, 96.152 mmol, 2.0 eq) in DMSO was added K.sub.3PO.sub.4 (20.41 g, 96.152 mmol, 2.0 eq) under a nitrogen atmosphere. The mixture was degassed for 10 minutes using nitrogen and then CuCl (0.476 g, 4.808 mmol, 0.1 eq) was added. The mixture was heated to 130° C. for 6 h (monitored by TLC). The reaction mixture was then cooled to room temperature and was filtered through a celite pad. The filtrate was diluted with EtOAc and washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated, the obtained crude material was purified via column chromatography (100-200 mesh silica gel, TLC system:EtOAc/hexane (3:7); R.sub.f=0.3) to give 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (5.1 g, 50%) as an off-white solid.

[0203] Step 2: PPh.sub.3 (3.70 g, 14.15 mmol, 2.5 eq) and DIAD (2.78 ml, 14.15 mmol, 2.5 eq) were added to a solution of 6,8-difluoro-3,3-dimethyl-3,4-dihydroquinoxalin-2(1H)-one (1.2 g, 5.66 mmol, 1.0 eq) in THF (40 ml) at 0° C. and the mixture was stirred for 30 minutes. Then the reaction mixture was allowed to warm to room temperature. TMSN.sub.3 (1.86 ml, 14.15 mmol, 2.5 eq) was added dropwise and the mixture was stirred for 14 h at room temperature. THF was removed under reduced pressure, the residue was diluted with EtOAc and washed with ice-cooled water. The extracted organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure to obtain the crude product, which was purified by column chromatography (100-200 mesh silica gel, TLC system:EtOAc/hexane (3:7); R.sub.f=0.35) to give 7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.75 g, 56%).

[0204] Step 3: To a stirred solution of 7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.700 g, 2.953 mmol, 1.0 eq) in DMF (200 ml) was added NBS (0.525 g, 2.953 mmol, 1.0 eq) portionwise at 0° C. and the reaction mixture was stirred at the same temperature for another hour (monitored by TLC). The reaction mixture was then quenched by adding water, causing precipitation. The solid was filtered off, was washed with water (3×10 ml) and then dried under vacuum to get 8-bromo-7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.66 g, 71%) as a white solid.

Synthesis of 8-bromo-7-fluoro-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-a]quinoxaline (intermediate B7)

[0205] ##STR00032##

[0206] Step 1: To a stirred solution of 2-bromo-4-fluoro-6-(trifluoromethyl)aniline (9.0 g, 35.02 mmol, 1.0 eq) and 2-aminoisobutyric acid (7.22 g, 70.04 mmol, 2.0 eq) in DMSO was added K.sub.3PO.sub.4 (14.86 g, 70.04 mmol, 2.0 eq) under nitrogen atmosphere. The mixture was degassed for 10 minutes (N.sub.2) and then CuCl (0.346 g, 3.502 mmol, 0.1 eq) was added. The mixture was heated to 130° C. for 6 h (monitored by TLC). The reaction mixture was then cooled to room temperature and filtered through a celite pad. The filtrate was diluted with EtOAc and was washed with water and brine. The organic layer was dried over Na.sub.2SO.sub.4 and concentrated, the obtained crude residue was purified by column chromatography (100-200 mesh silica gel, TLC system:EtOAc/hexane (3:7); R.sub.f=0.2) to give 6-fluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (4.5 g, 49%).

[0207] Step 2: PPh.sub.3 (3.0 g, 11.45 mmol, 2.5 eq) and DIAD (2.25 ml, 11.45 mmol, 2.5 eq) were added to a solution of 6-fluoro-3,3-dimethyl-8-(trifluoromethyl)-3,4-dihydroquinoxalin-2(1H)-one (1.2 g, 4.58 mmol, 1.0 eq) in THF (50 mL) at 0° C. and the mixture was stirred for 30 minutes. Then the reaction mixture was allowed to warm to room temperature. TMSN.sub.3 (1.5 ml, 11.45 mmol, 2.5 eq) was added dropwise and the mixture was stirred for 14 h at room temperature. THF was then removed under reduced pressure and the residue was diluted with EtOAc and was washed with ice-cooled water. The extracted organic layer was washed with brine, dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by column chromatography (100-200 mesh silica gel, TLC system:EtOAc/hexane (4:6); R.sub.f=0.45) to give 8-bromo-7-fluoro-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.75 g, 57%).

[0208] Step 3: To a stirred solution of 8-bromo-7-fluoro-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-alquinoxaline (0.750 g, 2.61 mmol, 1.0 eq) in DMF (50 ml) was added NBS (0.465 g, 2.61 mmol, 1.0 eq) portion-wise at 0° C. and the reaction mixture was stirred at the same temperature for another hour (monitored by TLC). The reaction mixture was then quenched by adding water, causing precipitation of a white solid. The solid was filtered off, was washed with water (3×10 ml) and then dried under vacuum to get 8-bromo-7-fluoro-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.620 g, 65%) as a white solid.

Synthesis of 8-bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-1,2,3]triazolo[4,5-c]quinoline (intermediate B8)

[0209] ##STR00033##

[0210] Step 1: Oven-dried glassware was used. CuCl (1.582 g, 15.98 mmol) was added to a solution of 3-fluoro-5-methylaniline (20 g, 160 mmol) and 2-methylbut-3-yn-2-yl acetate (43.2 g (70% pure), 240 mmol) in dry and degassed THF (250 mL). The mixture was stirred at 85° C. overnight. The reaction mixture was quenched with aqueous NH.sub.4Cl (500 mL) and diluted with EtOAc (250 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×200 mL). The combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. Filtration and in vacuo filtrate concentration gave the crude product. Purification by flash chromatography (220 g silica, gradient heptane/EtOAc, 1:0.fwdarw.19:1) afforded 7-fluoro-2,2,5-trimethyl-1,2-dihydroquinoline as a brown non-viscous oil (27.9 g (70% pure), 102 mmol, 63%).

[0211] Step 2: Heat gun dried glassware was used and the reaction was carried out under an inert atmosphere. A solution of 7-fluoro-2,2,5-trimethyl-1,2-dihydroquinoline (10 g (70% pure), 36.6 mmol) in dry Et.sub.2O (900 mL) was cooled to −78° C. Then, 1.6 M BuLi in hexanes (46 mL, 73.6 mmol) was slowly added and stirring was continued at the same temperature for 15 min and at −30° C. for another 15 min. The reaction mixture was re-cooled to −78° C. and a solution of Boc.sub.2O (17.5 g, 80 mmol) in dry Et.sub.2O (100 mL) was added dropwise. Then the reaction mixture was stirred at room temperature overnight Saturated aqueous NH.sub.4Cl (500 mL) was added to the suspension and the mixture was stirred until gas evolution ceased and a clear solution was obtained. The layers were separated and the aqueous layer was extracted with Et.sub.2O (3×50 mL). The organic layers were combined and washed with brine (250 mL) and dried over Na.sub.2SO.sub.4. Filtration followed by in vacuo concentration gave impure tert-butyl 7-fluoro-2,2,5-trimethylquinoline-1(2H)-cathoxylate as a brown oil (19.5 g).

[0212] Step 3: Heat gun dried glassware was used and the reaction was carried out under an inert atmosphere. To an ice-bath cooled solution of tert-butyl 7-fluoro-2,2,5-trimethylquinoline-1(2H)-carboxylate (18.8 g, max. 35.3 mmol) in dry THF (400 mL) was added dropwise 1 M BH.sub.3 in THF (210 mL, 210 mmol) while vigorously stirring. After complete addition, the mixture was allowed to warm up to room temperature and was stirred overnight. Then, the reaction mixture was cooled in an ice-bath and carefully oxidised by adding 1 M aqueous KOH (300 mL, 300 mmol), followed by 30% aqueous H.sub.2O.sub.2 (60 mL, 587 mmol). The mixture was stirred at room temperature for 3 h and was then diluted with water (300 mL) and EtOAc (200 mL). The aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine and dried over Na.sub.2SO.sub.4. Filtration and in vacuo filtrate concentration gave the crude product as a mixture of tert-butyl 7-fluoro-4-hydroxy-2,2,5-trimethyl-3,4-dihydroquinoline-1(2H)-carboxylate and tert-butyl 7-fluoro-3-hydroxy-2,2,5-trimethyl-3,4-dihydroquinoline-1(2H)-carboxylate as a brown oil (19.95 g). The isolated material was used as such without further purification.

[0213] Step 4: To a solution/suspension of a mixture of tert-butyl 7-fluoro-4-hydroxy-2,2,5-trimethyl-3,4-dihydroquinoline-1(2H)-calboxylate and tert-butyl 7-fluoro-3-hydroxy-2,2,5-trimethyl-3,4-dihydroquinoline-1(2H)-carboxy late (14.8 g, max. 26.3 mmol) in DCM (500 mL) was added PCC (6.02 g, 27.9 mmol). The obtained orange/brown suspension was stirred at room temperature for 2 h. An extra portion of PCC (1.51 g, 7.00 mmol) was added and stirring was continued overnight. Then, celite (ca. 50 g) was added and the reaction mixture was stirred at room temperature for 1 h. The black solid particles were filtered off over a silica column. The filter cake was washed with DCM (3×50 mL). Combined filtrates were in vacuo concentrated to obtain the crude product. Purification by flash chromatography (80 g silica, gradient heptane/EtOAc, 1:0.fwdarw.19:1) gave a pure batch (325 mg) and an impure batch (1.95 g) of tert-butyl 7-fluoro-2,2,5-trimethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate. The impure batch was repurified by flash chromatography (120 g silica, gradient heptane/EtOAc, 1:0.fwdarw.99:1, then heptane/EtOAc, 19:1) and gave another pure batch of tert-butyl 7-fluoro-2,2,5-trimethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1181 mg). Combining the pure batches gave tert-butyl 7-fluoro-2,2,5-trimethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate as an off-white solid (1.506 g, 4.90 mmol, 19% over three steps).

[0214] Step 5: To an ice-bath cooled solution of tert-butyl 7-fluoro-2,2,5-trimethyl-4-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (1.506 g, 4.90 mmol) in DCM (25 mL) was added a solution of TFA (20.64 mL, 269 mmol) in DCM (5 mL). After stirring the mixture at room temperature for 30 min, the reaction mixture was diluted with water (20 mL) and was cooled in an ice-bath. The acidic mixture was carefully alkalised with 2 M aqueous NaOH (135 mL) and saturated aqueous NaHCO.sub.3 to pH 8-9. The layers were separated using a phase separator. The aqueous layer was extracted with DCM (3×10 mL). The combined organic layers were in vacuo concentrated to isolate 7-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one as an orange solid (997 mg, 4.81 mmol, 98%).

[0215] Step 6: The conversion of 7-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one (911 mg, 4.40 mmol) was performed in 4 batches of 166 mg each (in 5 mL NMP each), 1 batch of 177 mg (in 5 mL NMP) and 1 batch of 70 mg (in 2.5 mL NMP). A typical procedure is shown below. Oven dried glassware was used. To a mixture of 7-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one (166 mg, 0.8 mmol), methylammonium acetate (365 mg, 4.0 mmol) and 4-nitrophenyl azide (171 mg, 1.04 mmol) was added dry NMP (5 mL) and after sealing, the vial was stirred at 80° C. for 90 h. The reaction mixture was cooled down to room temperature and combined with other reaction mixtures for work up. The obtained mixture was diluted with EtOAc (200 mL) and brine (1000 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3×100 mL). The combined organic layers were washed with brine (3×200 mL) and dried over Na.sub.2SO.sub.4. Filtration and in vacuo filtrate concentration gave the crude product. Purification by flash chromatography (120 g silica, EtOAc/heptane, 1:99.fwdarw.1:1) gave an impure batch of 7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinoline and the starting material 7-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one as a brownish solid (0.5 g, 2.41 mmol, 54% recovery). The impure batch of the target compound was purified further by flash chromatography (12 g silica, DCM followed by heptane/EtOAc, 19:1-1:1) and gave 7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinoline as a brownish solid (137 mg, 0.556 mmol, 12%).

[0216] Step 7: To an ice-bath cooled solution of 7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinoline (124 mg, 0.493 mmol) in dry DMF (7 mL) was added a solution of NBS (88 mg, 0.493 mmol) in dry DMF (2 mL) and the mixture was stirred at room temperature for 60 min. The reaction mixture was diluted with brine (150 mL) and EtOAc (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (4×20 mL). The combined organic layers were washed with brine (3×50 mL) and dried over Na.sub.2SO.sub.4. Filtration followed by in vacuo filtrate concentration gave the crude product. Purification by flash chromatography (12 g silica, gradient heptane/EtOAc, 20:1.fwdarw.1:1) gave 8-bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-[1,2,3]triazolo[4,5-c]quinoline as a salmon pink solid (150 mg, 0.461 mmol, 93%).

[0217] The following intermediates were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for intermediate B11:

TABLE-US-00006 Intermediate Structure B26 [00034] embedded image

Synthesis of 9-bromo-8-fluoro-1,5,5,10-tetramethyl-5,6-dihydropyrazolo[1,5-c]quinazoline (intermediate B9)

[0218] ##STR00035##

[0219] Step 1: In the glovebox stock solutions were prepared of 2-bromo-5-fluoro-3-methylaniline (1.20 g, 5.88 mmol) in degassed DMF (75 mL), 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.84 g, 8.82 mmol) in degassed DMF (75 mL) and Na.sub.2CO.sub.3 (1.25 g, 11.8 mmol) in degassed water (6 mL). These stock solutions were divided over 31 vials. Next, Pd(dppf)Cl.sub.2 (28 mg, 0.038 mmol) was added to each vial. The vials were capped, removed from the glovebox and stirred in the fume hood at 110° C. overnight. The 31 batches were combined, diluted with EtOAc (150 mL) and filtered through celite. The filter cake was rinsed with EtOAc (75 mL) and the combined filtrates were concentrated under reduced pressure. The crude product was co-evaporated with toluene (2×20 mL) and was then suspended in EtOAc (25 mL). The suspension was filtered through celite and the filter cake was rinsed with EtOAc (200 mL). The combined filtrate was concentrated under reduced pressure. Purification by flash chromatography (80 g silica, gradient DCM/(7M NH.sub.3 in MeOH), 1:0.fwdarw.95:5) afforded an impure batch of 5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline. The impure product was combined with other impure batches prepared in a similar fashion (starting with 25-200 mg of 5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline) and was purified further by preparative LC to afford pure 5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline (399 mg, 1.94 mmol, 23%).

[0220] Step 2: To an ice-bath cooled solution of 5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline (393 mg, 1.92 mmol) in dry DMF (24 mL) was added dropwise a solution of NB S (341 mg, 1.92 mmol) in dry DMF (8 mL). The mixture was stirred for 1 h and was then combined with another batch which was prepared in a similar fashion (starting from 50 mg (0.24 mmol) of 5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline). The mixture was diluted with brine (100 mL), EtOAc (100 mL) and water (25 mL), and the layers were separated. The aqueous phase was extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine (2×100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford crude 4-bromo-5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline (1.56 g).

[0221] Step 3: To a solution of 4-bromo-5-fluoro-3-methyl-2-(4-methyl-1H-pyrazol-5-yl)aniline (1.56 g, max. 2.16 mmol) in acetone (50 mL) was added p-TsOH H.sub.2O (41 mg, 0.22 mmol) and the solution was stirred at reflux temperature overnight. The mixture was diluted with brine (250 mL) and saturated aqueous NaHCO.sub.3 (50 mL), then the acetone was removed under reduced pressure. EtOAc (200 mL) was added and the layers were separated. The aqueous layer was extracted with EtOAc (2×150 mL) and the combined organic layer was washed with brine (3×150 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by flash chromatography (24 g silica, gradient heptane/EtOAc, 95:5.fwdarw.1:1) and co-evaporation with Et.sub.2O (4×20 mL) afforded 9-bromo-8-fluoro-1,5,5,10-tetramethyl-5,6-dihydropyrazolo[1,5-c]quinazoline (621 mg, 1.92 mmol, 89% over two steps).

Synthesis of 9-bromo-8,10-difluoro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline (intermediate B10)

[0222] ##STR00036##

[0223] Step 1: To a solution of 4-bromo-3,5-difluoroaniline (5 g, 24.0 mmol) in AcOH (60 mL) was added NIS (5.68 g, 25.2 mmol) and the mixture was stirred for 2 h. Then, the mixture was poured into water (300 mL) and was extracted with EtOAc (2×200 mL). The combined organic layers were washed with aqueous 1 M NaOH (200 mL), aqueous saturated Na.sub.2S.sub.2O.sub.3 (100 mL) and brine (300 mL). Next, the organic layers were dried over Na.sub.2SO.sub.4, concentrated under reduced pressure and co-evaporated with toluene (2×100 mL). Purification by flash chromatography (120 g silica, gradient heptane/EtOAc, 95:5.fwdarw.1:1) afforded a pure batch of 4-bromo-3,5-difluoro-2-iodoaniline (5.99 g, 17.9 mmol, 74%) and an impure batch. The impure batch was purified further by flash chromatography (40 g silica, gradient heptane/EtOAc 1:0.fwdarw.3:1) to afford 4-bromo-3,5-difluoro-2-iodoaniline (1.29 g, 3.86 mmol, 16%). Total yield of 4-bromo-3,5-difluoro-2-iodoaniline was 7.28 g (21.8 mmol, 90%).

[0224] Step 2: The reaction mixture was prepared in the glovebox. To a suspension of 4-bromo-3,5-difluoro-2-iodoaniline (1.5 g, 4.49 mmol), 1H-pyrazole-5-boronic acid (0.75 g, 6.74 mmol) and Na.sub.2CO.sub.3 (0.95 g, 8.98 mmol) in degassed DMF (105 mL) and degassed water (4.2 mL) was added Pd(dppf)Cl.sub.2 (0.66 g, 0.898 mmol). The mixture was removed from the glovebox and stirred at 110° C. for 3 h in a pre-heated oil-bath as an open inert system. The mixture was cooled down to room temperature and was diluted with EtOAc (250 mL). Brine (250 mL) and saturated aqueous NaHCO.sub.3 (100 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×250 mL). The combined organic layers were washed with 80% saturated brine (3×500 mL) and saturated brine (500 mL), dried over Na.sub.2SO.sub.4(s) and concentrated under reduced pressure to afford crude 4-bromo-3,5-difluoro-2-(1H-pyrazol-5-yl)aniline (2.11 g, max. 4.49 mmol).

[0225] Step 3: To a solution of two combined batches of crude 4-bromo-3,5-difluoro-2-(1H-pyrazol-5-yl)aniline (2.33 g, max. 4.94 mmol) in EtOH/acetone (50 mL, 1/1, v/v) was added p-TsOH H.sub.2O (94 mg, 0.49 mmol) and the solution was stirred at 50° C. for 30 min. The mixture was cooled down to room temperature. Brine (250 mL) and saturated aqueous NaHCO.sub.3 (50 mL) were added and the mixture was extracted with EtOAc (3×200 mL). The combined organic layers were washed with brine (500 mL), dried over Na.sub.2SO.sub.4(s) and concentrated under reduced pressure. Purification by flash chromatography (80 g silica, gradient heptane/EtOAc, 95:5.fwdarw.1:1) afforded impure 9-bromo-8,10-difluoro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline, which was further purified by preparative LC. The product containing fractions were combined and MeCN was removed under reduced pressure. The aqueous phase was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 9-bromo-8,10-difluoro-5,5-dimethyl-5,6-dihydropyrazolo[1,5-c]quinazoline (831 mg, 2.65 mmol, 53% over two steps).

Synthesis of 2-bromo-6,6,9-trimethyl-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine (intermediate B11)

[0226] ##STR00037##

[0227] Step 1: A suspension of 3-bromopyridin-2-amine (1 g, 5.78 mmol, 1 eq.) in dry DMSO (18 ml), 2-Amino-2-methyl-propionic acid (1.19 g, 11.56 mmol, 2 eq.) and K.sub.3PO.sub.4 (2.45 g, 11.56 mmol, 2 eq.) was degassed with argon for 10 min, before CuCl (0.078 g, 0.578 mmol, 0.1 eq) was added. The reaction mixture was then heated to 140° C. for 16 h. After completion of the reaction it was filtered through a celite bed, which was washed with ethyl acetate (100 ml). The filtrate was diluted with ethyl acetate (100 ml) and was washed with water (3×150 ml) and brine (200 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The crude residue was purified by column chromatography (100-200 mesh silica gel; 30% ethyl acetate/hexane; R.sub.f-value-0.5) to afford 2,2-dimethyl-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (0.5 g, 49%) as a brown solid.

[0228] Step 2: To a solution of 2,2-dimethyl-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one (0.5 g, 2.82 mmol, 1 eq.) in toluene (10 ml) was added Lawesson's reagent (1.71 g, 4.23 mmol, 1.5 eq.) at RT and the reaction mixture was then refluxed at 120° C. for 40 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO.sub.3 solution (50 ml) followed by extraction with ethyl acetate (3×50 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the crude residue which was purified by column chromatography (230-400 mesh silica gel; 20% ethyl acetate/hexane; R.sub.f-value-0.4) to afford 2,2-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-3 (2H)-thione (0.5 g, 91.9%) as a yellow solid.

[0229] Step 3: To a solution of 2,2-dimethyl-1,4-dihydropyrido[2,3-b]pyrazine-3(2H)-thione (6.5 g, 33.67 mmol, 1 eq.) in n-BuOH (120 ml) was added acetyl hydrazide (9.96 g, 134.71 mmol, 4 eq) followed by addition of acetic acid (12 ml) and then the reaction mixture was heated to 160° C. for 16 h in a sealed tube. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to get the crude material, which was purified by column chromatography (100-200 mesh silica gel; 5% methanol/dichloromethane; R.sub.f-value-0.3) to afford 6,6,9-trimethyl-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine (5 g, 70.1%) as an off-white solid.

[0230] Step 4: To the stirred solution of 6,6,9-trimethyl-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine (5 g, 23.25 mmol, 1 eq.) in DMF (60 ml) was added N-bromosuccinimide (4.5 g, 25.58 mmol, 1.1 eq) portionwise. The reaction mixture was allowed to warm to RT and was stirred for 2 h. The reaction mixture was quenched with ice, causing precipitation of a solid, which was filtered off, was dried under reduced pressure and was washed with pentane to afford 2-bromo-6,6,9-trimethyl-5,6-dihydropyrido[3,2-e][1,2,4]triazolo[4,3-a]pyrazine (3 g, 43.9%) as brown solid. The following intermediates were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for intermediate B11:

TABLE-US-00007 Intermediate Structure B12 [00038] embedded image

Synthesis of 8-bromo-1,4,4,9-tetramethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (intermediate B13)

[0231] ##STR00039##

[0232] Step 1: A mixture of 3-bromo-5-methylpyridin-4-amine (10 g, 53.47 mmol, 1 eq.), 2-amino-2-methyl-propionic acid (11 g, 106.95 mmol, 2 eq.) and K.sub.3PO.sub.4 (22.7 g, 106.95 mmol, 2 eq.) in dry DMSO (100 ml) was degassed with argon for 10 min before the addition of CuI (1 g, 5.347 mmol, 0.1 eq). The reaction mixture was then stirred at 140° C. for 16 h. After completion of the reaction it was filtered through a celite bed, which was washed with ethyl acetate (300 ml). The filtrate was diluted with ethyl acetate (300 ml) and was washed with water (3×500 ml) and brine (500 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated under reduced pressure. The obtained crude residue was purified by column chromatography (100-200 mesh silica gel; 30% ethyl acetate/hexane; R.sub.f-value-0.5) to afford 3,3,8-trimethyl-3,4-dihydropyrido[3,4-b]pyrazin-2(1H)-one (3 g, 29.4%) as a brown solid.

[0233] Step 2: To a solution of 3,3,8-trimethyl-3,4-dihydropyrido[3,4-b]pyrazin-2(1H)-one (1.5 g, 7.85 mmol, 1 eq.) in toluene (30 ml) was added Lawesson's reagent (4.76 g, 11.78 mmol, 1.5 eq.) at RT and the reaction mixture was then heated to 120° C. for 40 min. After completion of the reaction (monitored by TLC), the reaction mixture was quenched with sat. NaHCO.sub.3 solution (50 ml) followed by extraction with ethyl acetate (3×50 ml). The combined organic layers were washed with water (100 ml) and brine (100 ml), dried over anhydrous Na.sub.2SO.sub.4 and evaporated to get the crude material which was purified by column chromatography (230-400 mesh silica gel; 20% ethyl acetate/hexane; R.sub.f-value-0.4) to afford 3,3,8-trimethyl-3,4-dihydropyrido[3,4-b]pyrazine-2(1H)-thione (1 g, 61.7%) as a yellow solid.

[0234] Step 3: To a solution of 3,3,8-trimethyl-3,4-dihydropyrido[3,4-b]pyrazine-2(1H)-thione (1 g, 4.83 mmol, 1 eq) in THF (15 ml) was added hydrazine hydrate (1.5 ml) at RT. The reaction was then stirred at RT for 5 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to get the crude material, which was dissolved in triethylorthoacetate (15 ml). The resulting mixture was heated to 130° C. for 16 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to get the crude material, which was purified by column chromatography to afford 1,4,4,9-tetramethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (0.7 g, 63.6%) as a brown gum.

[0235] Step 4: To the stirred solution of 1,4,4,9-tetramethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (1.3 g, 5.67 mmol, 1 eq.) in DMF (15 ml) was added dropwise N-bromosuccinimide (1 g, 5.67 mmol, 1 eq) dissolved in DMF (5 ml) at 55° C. The reaction mixture was stirred at the same temperature for 2 h. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice and was extracted with EtOAc. The combined organic layers were washed water and brine, dried over Na.sub.2SO.sub.4, filtered and evaporated under reduced pressure to get the crude material, which was purified by column chromatography to afford 8-bromo-1,4,4,9-tetramethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (0.3 g, 17.6%) as a brown solid.

Synthesis of 8-bromo-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (intermediate B14)

[0236] ##STR00040##

[0237] Step 1: To a solution of 4-bromo-2-fluoro-5-methylaniline (5 g, 24.50 mmol) in AcOH (60 mL) was added NIS (5.51 g, 24.50 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was partially concentrated under reduced pressure to ˜10 mL and the remainder was poured into water (300 mL). The mixture was then extracted with EtOAc (2×200 mL). The combined organic layers were washed with aqueous 2 M NaOH (150 mL), saturated aqueous Na.sub.2S.sub.2O.sub.3 (300 mL) and brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by flash chromatography (120 g silica, gradient heptane/EtOAc, 95:5.fwdarw.85:15) afforded 4-bromo-6-fluoro-2-iodo-3-methylaniline (7.80 g, 23.6 mmol, 96%).

[0238] Step 2: The following procedure was repeated in three batches. In the glovebox was prepared a suspension of 4-bromo-6-fluoro-2-iodo-3-methylaniline (1.25 g, 3.79 mmol), 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1.18 g, 5.68 mmol) and Na.sub.2CO.sub.3 (1.21 g, 11.37 mmol) in DME (12.5 mL)/MeOH (6.25 mL). Pd(PPh.sub.3).sub.4 (0.44 g, 0.38 mmol) was added, and the vial was capped and removed from the glovebox. The mixture was then stirred at 150° C. for 45 minutes using microwave irradiation. The three batches were combined and water (75 mL), brine (75 mL) and EtOAc (150 mL) were added. The layers were separated and the aqueous phase was extracted with EtOAc (2×100 mL). The combined organic layers were washed with brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by flash chromatography (220 g silica, gradient heptane/EtOAc, 95:5.fwdarw.3:2) afforded 4-bromo-6-fluoro-3-methyl-2-(1-methyl-1H-pyrazol-5-yl)aniline (2.29 g, 8.06 mmol, 71%).

[0239] Step 3: A suspension of 4-bromo-6-fluoro-3-methyl-2-(1-methyl-1H-pyrazol-5-yl)aniline (2.29 g, 8.06 mmol), p-TSA (1.533 g, 8.06 mmol) and Na.sub.2SO.sub.4 (11.45 g, 81 mmol) in dry acetone (75 mL) was stirred at reflux overnight under a nitrogen atmosphere. The mixture was filtered through celite and the filter cake was washed with acetone (25 mL). The filtrates were combined and concentrated under reduced pressure. Purification by flash chromatography (220 g silica, gradient heptane/EtOAc, 9:1.fwdarw.3:2) afforded 8-bromo-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (965 mg, 2.98 mmol, 37%).

[0240] The following intermediates were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for intermediate B14:

TABLE-US-00008 Intermediate Structure Reagents B16 [00041] embedded image [00042] B17 [00043] [00044] B18 [00045] [00046] B19 [00047] [00048] B20 [00049] [00050] B22 [00051] [00052] B23 [00053] [00054] B24 [00055] [00056] B28 [00057] [00058]

Synthesis of 9-bromo-7-fluoro-1,5,5,10-tetramethyl-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline (intermediate B15)

[0241] ##STR00059##

[0242] Step 1: To a solution of 4-bromo-2-fluoro-5-methylaniline (15 g, 73.5 mmol) in AcOH (175 mL) was added NIS (16.5 g, 73.5 mmol) and the mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and the remainder was poured into H.sub.2O (500 mL), followed by extraction with EtOAc (3×250 mL). The combined organic layers were washed with aqueous 2 M NaOH (300 mL), saturated aqueous Na.sub.2S.sub.2O.sub.3 (300 mL) and brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was filtered over silica using heptane/EtOAc (4:1) as eluent. The product was further purified by crystallisation from hot heptane to afford 4-bromo-6-fluoro-2-iodo-3-methylaniline (21 g, 63.6 mmol, 86%).

[0243] Step 2: CuI (2.67 g, 14.00 mmol) was weighed out in the glovebox and was then added to a solution of 4-bromo-6-fluoro-2-iodo-3-methylaniline (15.4 g, 46.7 mmol) in degassed toluene (90 mL) in the fumehood. Pd(PPh.sub.3).sub.4 (2.70 g, 2.33 mmol), degassed Et.sub.3N (21.41 mL, 154 mmol) and degassed 1-(trimethylsilyl)-1-propyne (13.97 mL, 93 mmol) were added followed by the dropwise addition of degassed 1 M TBAF in THF (93 mL, 93 mmol). The mixture was stirred for 5 h before additional degassed 1-(trimethylsilyl)-1-propyne (13.97 mL, 93 mmol) was added followed by the dropwise addition of degassed 1 M TBAF in THF (93 mL, 93 mmol). Stirring was continued overnight. Aqueous 0.5 M HCl (500 mL) was added and the layers were separated. The aqueous phase was extracted with EtOAc (2×300 mL) and the combined organic layers were washed with saturated aqueous NaHCO.sub.3 (300 mL) and brine (300 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was coated on hydro-matrix and was purified by gravitational column chromatography (1 kg silica, heptane/EtOAc 1:0.fwdarw.99:1 (˜25 L) to afford impure product. The impure product was again coated on hydro-matrix and was purified in two batches by flash chromatography (440 g silica, heptane) which afforded 4-bromo-6-fluoro-3-methyl-2-(prop-1-yn-1-yl)aniline (6.10 g, 25.2 mmol, 54%).

[0244] Step 3: Cp*RuCl(PPh.sub.3).sub.2 (0.31 g, 0.38 mmol) was weighed in in the glovebox and was then added to a degassed solution of 4-bromo-6-fluoro-3-methyl-2-(prop-1-yn-1-yl)aniline (1.82 g, 7.51 mmol) and benzyl azide (0.938 mL, 7.51 mmol) in toluene (75 mL). The mixture was heated to 45° C. for 16 h and was then cooled down to room temperature and was concentrated under reduced pressure. Purification by flash chromatography (80 g silica, gradient heptane/EtOAc, 95:5.fwdarw.1:1) afforded 2-(1-benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-4-bromo-6-fluoro-3-methylaniline (1.92 g, 5.12 mmol, 68%).

[0245] Step 4: 2-(1-Benzyl-5-methyl-1H-1,2,3-triazol-4-yl)-4-bromo-6-fluoro-3-methylaniline (1.92 g, 5.12 mmol) was dissolved in MeOH (150 mL) by heating with a heatgun and the resulting solution was flushed with nitrogen for 5 min. Next, 10% Pd(C) (0.545 g, 0.512 mmol) was added, the atmosphere was replaced by H.sub.2 and the mixture was stirred overnight. The reaction mixture was filtered over celite (pre-rinsed with MeOH) and the filer cake was rinsed with MeOH (2×25 mL). The filtrates were combined and concentrated under reduced pressure to afford the product as its HBr-salt. The product was partitioned between EtOAc (100 mL), MeOH (5 mL), H.sub.2O (25 mL) and saturated aqueous NaHCO.sub.3 (50 mL). The layers were separated and the aqueous phase was extracted with EtOAc (50 mL). The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 6-fluoro-3-methyl-2-(5-methyl-1H-1,2,3-triazol-4-yl)aniline (1.0 g, 4.85 mmol, 95%).

[0246] Step 5: To a solution of crude 6-fluoro-3-methyl-2-(5-methyl-1H-1,2,3-triazol-4-yl)aniline (1.0 g, 4.85 mmol) in anhydrous MeCN (50 mL) was added NBS (0.863 g, 4.85 mmol) and the mixture was stirred for 1 h. Half saturated aqueous NaHCO.sub.3 (100 mL) and EtOAc (50 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×75 mL) and the combined organic layers were washed with brine (100 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford 4-bromo-6-fluoro-3-methyl-2-(4-methyl-1H-1,2,3-triazol-5-yl)aniline (1.46 g, max. 4.85 mmol).

[0247] Step 6: To a solution of crude 4-bromo-6-fluoro-3-methyl-2-(4-methyl-1H-1,2,3-triazol-5-yl)aniline (1.46 g, max. 4.85 mmol) in acetone (dried over 3 Å molsieves, 30 mL) was added Na.sub.2SO.sub.4 (17.3 g, 122 mmol) and p-TsOH.H.sub.2O (93 mg, 0.486 mmol) and the mixture was stirred for 30 min. The reaction mixture was poured into saturated aqueous NaHCO.sub.3 (50 mL). H.sub.2O (50 mL) and EtOAc (75 mL) were added and the layers were separated. The aqueous phase was extracted with EtOAc (2×75 mL) and the combined organic layers were washed with brine (150 mL), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. Purification by flash chromatography (24 g silica, gradient heptane/EtOAc 95:5.fwdarw.1:1) afforded 9-bromo-7-fluoro-1,5,5,10-tetramethyl-5,6-dihydro-[1,2,3]triazolo[1,5-c]quinazoline (1.32 g, 4.06 mmol, 79% (over 2 steps)).

Synthesis of 8-bromo-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-imidazo[4,5-c]quinoline (intermediate B21)

[0248] ##STR00060##

[0249] Step 1: To a solution of 8-fluoro-2,2,5-trimethyl-2,3-dihydro-1H-quinolin-4-one (this compound can be prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for 7-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one) (2.5 g, 12 mmol) in dry NMP (25 ml) were added molecular sieves (4 Å, 1 g) and methyl ammonium acetate (5.5 g, 60.3 mmol) followed by 4-nitrophenyl azide (2.5 g, 15.6 mmol) at RT and the reaction mixture was then heated to 80° C. for 3 days. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with MTBE (100 ml) nd was washed with water (70 ml) followed by brine (70 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4 and concentrated. The obtained crude residue was purified by column chromatography (silica gel, 100-200 mesh, 40% EtOAc in hexane as eluent) to afford 6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-imidazo[4,5-c]quinolone (10)(580 mg, 19.7%) as a brownish liquid.

[0250] Step 2: To a solution of 6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-imidazo[4,5-c]quinolone (100 mg, 0.407 mmol) in DMF (8 ml) was slowly added NBS (36.27 mg, 0.203 mmol) dissolved in DMF (2 ml) at 0° C. The resulting reaction mixture was stirred at 0° C. for 1 h. After completion of the reaction (monitored by LCMS), the reaction mixture was diluted with cold water (10 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with cold water (2×50 ml) followed by cold brine (20 ml), dried over anhydrous Na.sub.2SO.sub.4 and concentrated to afford the crude compound. Four batches (300 mg each) ware done in parallel and combined batches were purified by column chromatography (silica gel, 100-200 mesh, 1-1.5% MeOH in DCM as eluent) to afford 8-bromo-6-fluoro-1,4,4,9-tetramethyl-4,5-dihydro-1H-imidazo[4,5-c]quinolone (420 mg, 24.5%) as a brownish solid.

Synthesis of 8-bromo-6-fluoro-4,4,9-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline (intermediate B25)

[0251] ##STR00061##

[0252] Step 1: To an argon purged solution of 4-bromo-6-fluoro-2-iodo-3-methylaniline (40 g, 121.23 mmol) in Et.sub.3N:pyridine (1:1) (200 mL) was added 2-methyl-3-butyn-2-ol (17.6 mL, 181.85 mmol) and purging was continued for another 10 min, prior to the addition of CuI (1.15 g, 6.06 mmol), PPh.sub.3 (15.9 g, 60.62 mmol) and PdCl.sub.2(PPh.sub.3).sub.2 (4.25 g, 6.06 mmol) at RT. The resulting mixture was then heated to 90-95° C. for 20 h. The reaction was then quenched with brine (300 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated to get the crude product which was purified by column chromatography (silica gel:100-200 mesh) using 8-12% of EtOAc in pet-ether as eluent to afford 21 g (60%) of 4-(2-amino-5-bromo-3-fluoro-6-methylphenyl)-2-methylbut-3-yn-2-ol as a pale brown solid. (TLC system: 20% EtOAc in pet-ether, R.sub.f: 0.15).

[0253] Step 2: To a stirred solution of 4-(2-amino-5-bromo-3-fluoro-6-methylphenyl)-2-methylbut-3-yn-2-ol (21 g, 73.39 mmol) in 1,4-dioxane (210 mL) was added conc. HCl:water (1:1) (350 mL). The resulting mixture was then stirred at 120° C. for 20 h. The reaction mixture was cooled to RT, was diluted with EtOAc (500 mL) and ice-water (200 mL) and was then neutralized with solid NaHCO.sub.3. The organic layer was separated and the aqueous layer was re-extracted with EtOAc (3×200 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated. The crude product was purified by silica-gel chromatography (100-200 mesh) using 1.5% of EtOAc in pet-ether as an eluent to afford 5.7 g (37%) of 8-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one as a pale yellow solid (TLC system: 20% EtOAc in pet-ether, R.sub.f: 0.7).

[0254] Step 3: To a solution of 8-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one (5.7 g, 27.50 mmol) in DMF (40 mL) was added NBS (4.9 g, 27.50 mmol) in small portions at 0° C. and the mixture was stirred at 0-10° C. for 2 h. The reaction was monitored by LC-MS. After completion of the reaction, the reaction was diluted with cold water (100 ml), the precipitated solid was collected by filtration and was washed with water and dried to afford 7.9 g (99%) of 6-bromo-8-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one as a pale yellow solid (TLC system: 20% EtOAc in pet-ether, R.sub.f: 0.7).

[0255] Step 4: To a cold solution of 6-bromo-8-fluoro-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one (5 g, 17.47 mmol) in THF (50 mL) was added Bredereck's reagent (2.5 mL) at 0° C. The resulting mixture was stirred at reflux (Note: Another two more portions of Bredereck's reagent were added at intervals 18 h and 26 h) for 44 h. The reaction mixture was diluted with EtOAc (500 mL), washed with water (100 mL) and brine, dried over Na.sub.2SO.sub.4, and concentrated to give 6 g (crude) of (Z)-6-bromo-8-fluoro-3-(hydroxymethylene)-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one as a brown color gummy mass (TLC system: 10% EtOAc in pet-ether, R.sub.f: 0.5).

[0256] Step 5: To a cold solution of (Z)-6-bromo-8-fluoro-3-(hydroxymethylene)-2,2,5-trimethyl-2,3-dihydroquinolin-4(1H)-one (6 g, 19.10 mmol) in methanol (120 mL) was added hydrazine hydrate (9.3 mL, 191.00 mmol) at 0° C. and the reaction mixture was stirred at RT for 2 h. The reaction mass was quenched with sat. NaHCO.sub.3 solution, and extracted with EtOAc (3×500 mL). The combined organic layers were dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure (Note: Another 1 g reaction was carried out and was combined with the crude material for work up). The combined crude product was purified on silica-gel (100-200 mesh) using 15%-20% of EtOAc in pet-ether as an eluent to afford 2.4 g (44% over two steps) of 8-bromo-6-fluoro-4,4,9-trimethyl-4,5-dihydro-1H-pyrazolo[4,3-c]quinoline as a pale brown solid (TLC system: 20% EtOAc in pet-ether, R.sub.f: 0.2).

Synthesis of 8-bromo-7-fluoro-4,4,9-trimethyl-4,5-dihydro-oxazolo[4,5-c]quinoline (intermediate B27)

##STR00062##

[0257] Step 1: 4-Fluoro-2-methyl-6-nitro-phenylamine (50 g, 294.031 mmol) was treated with conc. HCl (80 ml) at 100° C. for 30 min. After that, the reaction mixture was allowed to cool to 0° C. before the dropwise addition of NaNO.sub.2 (24.34 g, 352.837 mmol) in water (120 ml) to the reaction mixture at 0° C. After 15 minutes of stirring, KI (73.218 g, 441.05 mmol) in water (120 ml) was added to the reaction mixture at 0° C. The reaction mixture was allowed to warm to room temperature and was then heated to 70° C. for 3 hours. After completion of the reaction (monitored by TLC, 20% EA-Hexane, Rf=0.7), the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford a crude residue, which was purified over column chromatography (using 100-200 mesh silica gel, eluted with 10% EA-Hexane) to afford 74 g (90%) of 5-fluoro-2-iodo-1-methyl-3-nitro-benzene as a yellow solid.

[0258] Step 2: To a stirred solution of 5-fluoro-2-iodo-1-methyl-3-nitro-benzene (40 g, 142.334 mmol) in TEA (400 ml) was added 2-methyl-but-3-yn-2-ol (27.844 ml, 284.667 mmol) at room temperature. The reaction mixture was degassed with N.sub.2 gas for 15 mins. After that, CuCl (769.79 mg, 5.693 mmol) followed by Pd(PPh.sub.3).sub.2Cl.sub.2 (1.998 g, 2.847 mmol) was added to the reaction mixture at RT. The reaction mixture was stirred for 16 hours at room temperature. After that, the reaction mixture was diluted with DCM (150 ml) and was stirred for 3 hours at reflux temperature. After completion of the reaction (monitored by TLC, 20% EA-Hexane, R.sub.f 0.5), the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na.sub.2SO.sub.4 and was concentrated to afford a crude residue, which was purified via column chromatography (using 100-200 mesh silica gel, eluted with 12% EA-Hexane) to afford 25 g (75%) of 4-(4-fluoro-2-methyl-6-nitro-phenyl)-2-methyl-but-3-yn-2-ol as a reddish liquid.

[0259] Step 3: To a stirred solution of 4-(4-fluoro-2-methyl-6-nitro-phenyl)-2-methyl-but-3-yn-2-ol (25 g, 105.383 mmol) in 10% H.sub.2O in MeOH (750 ml) was added NH.sub.4Cl (28.186 g, 526.94 mmol) followed by Zn dust (20.67 g, 316.149 mmol) at room temperature. The reaction mixture was then heated to reflux for 2 hours. After completion of the reaction (monitored by TLC, 20% EA-Hexane, R.sub.f 0.3), the reaction mixture was filtered through a celite bed, which was washed with ethyl acetate. The filtrate was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford 23 g of crude 4-(2-amino-4-fluoro-6-methyl-phenyl)-2-methyl-but-3-yn-2-ol as a dark brown solid. This crude material was carried on to the next step without further purification.

[0260] Step 4: A mixture of 4-(2-Amino-4-fluoro-6-methyl-phenyl)-2-methyl-but-3-yn-2-ol (23 g, 111.052 mmol) and 6N HCl (230 ml) was heated to 90° C. for 16 hours. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with sat. K.sub.2CO.sub.3 solution and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford a crude residue, which was purified via column chromatography (using 100-200 mesh, eluted with 10% EA-Hexane) to afford 15 g (68% over two steps) of 7-fluoro-2,2,5-trimethyl-2,3-dihydro-1H-quinolin-4-one.

[0261] Step 5: To a stirred solution of 7-fluoro-2,2,5-trimethyl-2,3-dihydro-1H-quinolin-4-one (2.5 g, 12.070 mmol) in THF (50 ml) was added KOtBu (1M in THF, 24.142 ml, 24.142 mmol) at room temperature. The reaction mixture was stirred for 30 minutes at room temperature. After that, isoamyl nitrite (2.424 ml, 18.105 mmol) was added to the reaction mixture dropwise at room temperature. The reaction mixture was stirred for 16 hours at room temperature. After completion of the reaction (monitored by LCMS), the reaction mixture was quenched with ice water and was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford 3.3 g of crude 7-fluoro-2,2,5-trimethyl-1,2-dihydro-quinoline-3,4-dione 3-oxime as a reddish brown liquid.

[0262] Step 6: To a stirred solution of 7-fluoro-2,2,5-trimethyl-1,2-dihydro-quinoline-3,4-dione 3-oxime (3.3 g, 13.968 mmol) in 10% H.sub.2O in MeOH (100 ml) was added NH.sub.4Cl (3.74 g, 69.84 mmol) followed by Zn dust (2.74 g, 41.905 mmol) at room temperature. The reaction mixture was stirred for 2 hours at room temperature. After completion of the reaction (monitored by TLC, 50% EA-Hexane, R.sub.f 0.3), the reaction mixture was filtered through a celite bed, which was washed with ethyl acetate. The filtrate was washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford 2.4 g of crude 3-amino-7-fluoro-2,2,5-trimethyl-2,3-dihydro-1H-quinolin-4-one, which was carried on to the next step without further purification.

[0263] Step 7: To a stirred solution of 3-amino-7-fluoro-2,2,5-trimethyl-2,3-dihydro-1H-quinolin-4-one (2.4 g, 10.798 mmol) in toluene (24 ml) was added methyl formate (4.66 ml, 75.587 mmol) at room temperature. The reaction mixture was then heated to 80° C. in a sealed tube for 16 hours. After completion of the reaction (monitored by TLC, 40% EA-Hexane, R.sub.f 0.5), the reaction mixture was concentrated to afford a crude residue, which was purified via column chromatography (using 100-200 mesh silica gel, eluted with 15% EA-Hexane) to afford 900 mg of N-(7-fluoro-2,2,5-trimethyl-4-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-formamide. LCMS of column purified material showed 50% of desired product in the obtained material, which was used as such in the next step.

[0264] Step 8: To a stirred solution of N-(7fluoro-2,2,5-trimethyl-4-oxo-1,2,3,4-tetrahydro-quinolin-3-yl)-formamide (800 mg, 3.196 mmol) in POCl.sub.3 (1.494 ml, 15.982 mmol) was added TEA (0.449 ml, 3.196 mmol) at room temperature. The reaction mixture was then heated to reflux for 4 hours. After completion of the reaction (monitored by TLC, 40% EA-hexane, R.sub.f 0.7), the reaction mixture was quenched with ice cold sat. NaHCO.sub.3 solution, followed by extraction with ethyl acetate. The combined organic layers were washed with brine, dried over Na.sub.2SO.sub.4 and concentrated to afford a crude residue, which was purified via column chromatography (using 100-200 mesh silica gel, eluted with 40% EA-Hexane) and later PREP-SFC to afford 300 mg (10.7% over four steps) of 7-fluoro-4,4,9-trimethyl-4,5-dihydrooxazolo[4,5-c]quinoline.

[0265] Step 9: To a stirred solution of 7-fluoro-4,4,9-trimethyl-4,5-dihydro-oxazolo[4,5-c]quinoline (745 mg, 3.207 mmol) in DMF (55 ml) was added NBS (485.16 mg, 2.725 mmol) in DMF (18 ml) portionwise at 0° C. The reaction was stirred for 1 hour at the same temperature. After completion of the reaction (monitored by TLC, 20% ea-hexane, Rf=0.5), the reaction mixture was quenched with saturated Na.sub.2S.sub.2O.sub.3 solution and was extracted with MTBE. The combined organic layers were washed with sat. NaHCO.sub.3 solution followed by brine and were then concentrated under reduced pressure to afford a crude residue, which was purified via flash chromatography (40 g silica column, eluted with 5% EA-Hexane solvent system) to afford 600 mg (60%) of 8-bromo-7-fluoro-4,4,9-trimethyl-4,5-dihydro-oxazolo[4,5-c]quinoline as a light brown solid.

Example 1: 7-fluoro-8-(3-fluoro-5-methylphenyl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline

[0266] ##STR00063##

[0267] Step 1: 8-Bromo-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (100 mg, 0.31 mmol, 1.0 eq.), (3-fluoro-5-methylphenyl)boronic acid (142 mg, 0.93 mmol, 3.0 eq.) and Pd(PtBu.sub.3).sub.2 (8 mg, 0.02 mmol, 0.05 eq.) were weighed out into a microwave vial, a stir bar was added, the vial was sealed and purged with nitrogen. Then, THF (2.0 mL) and 2M Na.sub.2CO.sub.3 solution (1.0 mL) were added, and the vial was slightly evacuated and backfilled/purged with nitrogen again. The reaction mixture was then heated to 60° C. for 48 hours and was then stirred for 48 hours at ambient temperature. Then, sat. NaHCO.sub.3 solution and EtOAc were added, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were then washed with brine, dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The obtained residue was purified via silica gel chromatography (using 4:1 EtOAc/cyclohexane as eluent) and later reverse phase HPLC to obtain 80 mg (73%) of 7-fluoro-8-(3-fluoro-5-methylphenyl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline. .sup.1H NMR (DMSO-d.sub.6) δ: 7.08-6.99 (m, 4H), 6.77 (d, 1H), 6.71 (d, 1H), 6.52 (s, 1H), 2.38 (s, 3H), 2.23 (d, 3H), 2.07 (s, 3H), 1.50-1.28 (m, 6H).

[0268] The following examples were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 1:

TABLE-US-00009 Example Inter- Yield Nr. Structure mediates % Data 2 [00064] embedded image A2, B2 8 [M + H].sup.+ (m/z): calc. for C.sub.17H.sub.16F.sub.2N.sub.4 + H: 315.1, found 315.1 3 [00065] A3, B2 41 .sup.1HNMR (DMSO-d.sub.6) δ: 11.21 (s, 1H), 7.46 (d, 1H), 7.38 (t, 1H), 7.22-7.14 (m, 1H), 7.03 (d, 1H), 6.74-6.68 (m, 1H), 6.53 (d, 1H), 6.22 (s, 1H), 5.97 (dd, 1H), 5.91 (d, 1H), 2.25 (d, 3H), 1.52-1.35 (m, 6H) 4 [00066] embedded image A4, B2 48 [M + H].sup.+ (m/z): calc. for C.sub.20H.sub.17F.sub.2N.sub.5 + H: 366.15 found: 366.1 5 [00067] A5, B3 72 [M + H].sup.+ (m/z): calc, for C.sub.21H.sub.17F.sub.3N.sub.4 + H: 383.15 found: 383.0 7 [00068] A7, B1 26 [M + H].sup.+ (m/z): calc. for C.sub.23H.sub.20F.sub.4N.sub.4 + H: 429.17 found 429.1 8 [00069] embedded image A8, B1 26 .sup.1H NMR (DMSO-d.sub.6) δ: 7.59-7.52 (m, 1H), 7.47 (d, 1H), 7.23 (dd, 1H), 6.98 (d, 1H), 6.82-6.71 (m, 2H), 6.48 (s, 1H), 6.09 (d, 1H), 4.09 (qd, 2H), 2.23 (d, 3H), 1.98 (s, 3H), 1.59-1.22 (m, 7H), 0.55 (ddd, 2H), 0.43 (hept, 2H) 9 [00070] A9, B1 68 .sup.1H NMR (DMSO-d.sub.6) δ: 7.90 (d, 1H), 7.60 (d, 1H), 7.46 (dd, 1H), 7.27 (d, 1H), 6.82- 6.75 (m, 2H), 6.58 (s, 1H), 6.45 (d, 1H), 3.60 (d, 2H), 2.23 (d,3H), 1.97 (s, 3H), 1.58- 1.28 (m, 6H), 0.83 (tt, 1H), 0.39-0.28 (m, 2H), −0.08 (dd, 2H) 10 [00071] embedded image A13, B1 62 .sup.1H NMR (DMSO-d.sub.6) δ: 7.60 (d, 1H), 7.34 (d, 1H), 7.27 (dd, 1H), 7.00 (d, 1H), 6.78 (s, 1H), 6.74 (d, 1H), 6.48 (s, 1H), 6.03 (d, 1H), 2.22 (d, 3H), 1.97 (s, 3H), 1.56-1.27 (m, 6H), 1.09 (tdd, 2H), 1.04-0.95 (m, 2H) 13 [00072] A14, B5 4 [M + H].sup.+ (m/z): calc, for C.sub.21H.sub.21FN.sub.6 + H: 377.19 found 377.3 21 [00073] embedded image A19, B2 19 .sup.1H NMR (DMSO-d.sub.6) δ: 8.44-8.38 (m, 1H), 7.91 (dd, 1H), 7.43 (td, 1H), 7.32 (d, 1H), 6.74 (dd, 1H), 6.63 (d, 1H), 6.53 (d, 1H), 6.00-5.95 (m, 1H), 5.91 (dd, 1H), 2.68 (d, 3H), 2.25 (d, 3H), 1.46 (s, 3H), 1.38 (s, 3H) 24 [00074] A14, B8 92 .sup.1H NMR (DMSO-d.sub.6) δ: 7.71-7.65 (m, 1H), 7.61 (dd, 1H), 7.26 (ddd, 1H), 6.75 (s, 1H), 6.67 (d, 1H), 6.58-6.42 (m, 1H), 4.10 (d, 3H), 3.56 (d, 3H), 2.22-2.12 (m, 3H), 1.54-1.44 (m, 6H) 25 [00075] embedded image A13, B8 78 .sup.1H NMR (DMSO-d.sub.6) δ: 10.61 (d, 1H), 7.26 (dd, 1H), 7.14 (dd, 1H), 6.88 (dd, 1H), 6.73- 6.59 (m, 2H), 4.13 (s, 3H), 2.26 (d, 3H), 2.13 (s, 3H), 1.55 (s, 3H), 1.45 (s, 3H) 26 [00076] A21, B8 80 .sup.1H NMR (DMSO-d.sub.6) δ: 7.42-7.33 (m, 2H), 6.88 (dd, 1H), 6.64 (d, 2H), 6.12 (d, 1H), 4.92 (t, 1H), 4.22 (q, 2H), 4.08 (s, 3H), 3.75 (q, 2H), 2.16 (s, 3H), 1.54-1.44 (m, 6H) 27 [00077] embedded image A14, B9 92 .sup.1H NMR (DMSO-d.sub.6) δ: 7.67 (dd, 1H), 7.62 (d, 1H), 7.34 (s, 1H), 7.24 (dd, 1H), 7.08 (s, 1H), 6.69 (d, 1H), 6.42 (d, 1H), 3.56 (s, 4H), 2.10-2.05 (m, 6H), 1.62 (m, 6H) 28 [00078] A14, B10 36 .sup.1H NMR (DMSO-d.sub.6) δ: 7.71-7.67 (m, 2H), 7.64 (d, 1H), 7.59 (d, 1H), 7.29 (dd, 1H), 6.62 (d, 1H), 6.57 (d, 1H), 6.52 (dd, 1H), 3.56 (s, 2H), 1.70 (d, 6H) 32 [00079] embedded image A14, B14 72 .sup.1H NMR (DMSO-d.sub.6) δ: 7.67-7.60 (m, 2H), 7.44 (s, 1H), 7.25 (dd, 1H), 7.04 (d, 1H), 6.58 (d, 1H), 5.95 (d, 1H), 3.83 (s, 3H), 3.53 (s, 3H), 2.16 (s, 3H), 1.45 (s, 6H) 33 [00080] A22, B14 46 [M + H].sup.+ (m/z): calc. for C.sub.23H.sub.23FN.sub.4O.sub.2S + H: 439.16 found 439.16 34 [00081] embedded image A23, B14 27 .sup.1H NMR (DMSO-d.sub.6) δ: 8.47 (d, 1H), 7.72- 7.66 (m, 1H), 7.48-7.42 (m, 2H), 7.14 (d, 1H), 6.06 (d, 1H), 3.88 (s, 3H), 3.56 (s, 3H), 2.21 (s, 3H), 1.46 (s, 6H) 35 [00082] A14, B15 64 .sup.1H NMR (DMSO-d.sub.6) δ: 7.69-7.62 (m, 2H), 7.26 (dd, 1H), 7.20 (d, 1H), 7.02 (d, 1H), 6.56 (dd, 1H), 3.56 (s, 3H), 2.43 (s, 3H), 2.16 (s, 3H), 1.89-1.65 (m, 7H) 36 [00083] embedded image A23, B15 54 .sup.1H NMR (DMSO-d.sub.6) δ: 8.45 (d, 1H), 7.74- 7.69 (m, 1H), 7.44 (dd, 1H), 7.30 (d, 1H), 7.10 (d, 1H), 3.56 (s, 3H), 2.46 (s, 3H), 2.21 (s, 3H), 1.79 (s, 6H) 56 [00084] A11, B24 69 .sup.1H NMR (DMSO-d.sub.6) δ: 10.49 (d, 1H), 7.48 (dd, 1H), 7.09-7.03 (m, 2H), 7.03-6.96 (m, 2H), 6.25 (d, 1H), 3.78 (s, 3H), 2.63- 2.31 (m, 7H), 2.29 (d, 3H), 2.06 (s, 3H), 1.95-1.78 (m, 2H) 61 [00085] embedded image A14, B27 73 .sup.1H NMR (DMSO-d.sub.6) δ: 8.38 (d, 1H), 7.64 (ddd, 1H), 7.58 (d, 1H), 7.09 (dd, 1H), 6.77 (s, 1H), 6.44-6.39 (m, 2H), 3.56 (d, 3H), 2.21 (s, 3H), 1.52 (s, 3H), 1.49 (s, 3H) 62 [00086] A13, B27 43 .sup.1H NMR (DMSO-d.sub.6) δ: 10.45 (d, 1H), 8.37 (s, 1H), 7.25-7.20 (m, 1H), 7.07 (dd, 1H), 6.74 (dd, 1H), 6.70 (s, 1H), 6.40 (d, 1H), 2.25 (d, 3H), 2.17 (s, 3H), 1.52 (s, 3H), 1.50 (s, 3H) 63 [00087] embedded image A23, B27 64 .sup.1H NMR (DMSO-d.sub.6) δ: 8.40 (s, 1H), 8.29 (d, 1H), 7.69 (ddd, 1H), 7.26 (dd, 1H), 6.87 (s, 1H), 6.44 (d, 1H), 3.58 (s, 3H), 2.25 (s, 3H), 1.53 (s, 3H), 1.50 (s, 3H)

Example 11: 9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine

[0269] ##STR00088##

[0270] Step 1: To a stirred solution of 8-bromo-9-fluoro-1,4,4-trimethyl-4,5-dihydro-2,3,5,7,9b-pentaaza-cyclopenta[a]naphthalene (100 mg, 0.3203 mmol) and 3-methyl-7-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (164.7 mg, 0.6407 mmol, 2 eq) in DMF (10 ml) was added 2M Na.sub.2CO.sub.3 solution (3.8 ml). The reaction mixture was degassed with argon for 30 minutes. Pd(PPh.sub.3).sub.4 (52 mg, 0.045 mmol) was added to the reaction mixture and the reaction mixture was heated to 120° C. for 16 h. The reaction mixture was filtered through a celite bed, which was afterwards washed with ethyl acetate. The filtrate was washed with ice cold water followed by brine. The organic layer was dried with anhydrous Na.sub.2SO.sub.4, filtered and concentrated. The obtained crude residue was purified by column chromatography (50% Ethyl acetate/Hexane, neutral alumina) to afford 9-fluoro-1,4,4-trimethyl-8-(3-methyl-1H-indol-7-yl)-4,5-dihydro-2,3,5,7,9b-pentaaza-cyclopenta[a]naphthalene (48 mg, 41%) as an off-white solid. .sup.1H NMR (DMSO-d.sub.6) δ: 10.82 (s, 1H), 8.30 (s, 1H), 7.58-7.56 (d, 1H), 7.51-7.49 (d, 1H), 7.22 (s, 1H), 7.14-7.10 (m, 2H), 2.64-2.61 (d, 3H), 2.30 (s, 3H), 1.56 (s, 6H).

Example 12: 7,9-difluoro-1,4,4-trimethyl-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline

[0271] ##STR00089##

[0272] Step 1: 8-Bromo-7,9-difluoro-1,4,4-trimethyl-5H-pyrrolo[1,2-a]quinoxaline (80 mg, 0.24 mmol, 1.0 eq.), 1H-pyrrolo[2,3-b]pyridin-4-ylboronic acid (119 mg, 0.73 mmol, 3.0 eq.) and Pd(PPh.sub.3).sub.4 (14 mg, 0.01 mmol, 0.05 eq.) were weighed out into a microwave vial, a stir bar was added, the vial was sealed and purged with nitrogen. Then, toluene (2.0 mL), 2M Na.sub.2CO.sub.3 solution (0.5 mL) and ethanol (0.3 mL) were added, and the vial was purged with nitrogen again. The reaction mixture was then heated to 90° C. for 16 hours. Then, DCM and water were added, and the resulting mixture was filtered through a hydrophobic frit. The organic layer was evaporated and the residue was purified via silica gel chromatography, reverse phase HPLC and finally recrystallization from EtOAc to yield 11 mg (12%) of 7,9-difluoro-1,4,4-trimethyl-8-(1H-pyrrolo[2,3-b]pyridin-4-yl)-4,5-dihydropyrrolo[1,2-a]quinoxaline. .sup.1H NMR (DMSO-d.sub.6) δ: 8.29 (d, 1H), 7.52 (t, 1H), 7.12 (d, 1H), 6.83-6.65 (m, 2H), 6.31 (d, 1H), 5.95 (dd, 2H), 2.26 (d, 3H), 1.42 (s, 6H)

[0273] The following examples were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 12:

TABLE-US-00010 Example Inter- Yield Nr. Structure mediates % Data 6 [00090] embedded image A6, B1 77 .sup.1H NMR (DMSO-d.sub.6) δ: 8.67 (dd, 1H), 8.15 (d, 1H), 6.79 (d, 1H), 6.71 (d, 1H), 6.62 (s, 1H), 3.96 (s, 3H), 2.22 (d, 3H), 2.03 (s, 3H), 1.52-1.28 (m, 6H) 14 [00091] A14, B1 36 .sup.1H NMR (DMSO-d.sub.6): δ 7.68-7.63 (m, 2H), 7.25 (d, 1H), 6.76 (d, 1H), 6.64 (s, 1H), 6.44 (s, 1H), 3.57 (s, 3H), 2.19 (s, 3H), 1.99 (s, 3H), 1.44-1.37 (m, 6H). 19 [00092] embedded image A18, B1 30 .sup.1H NMR (DMSO-d.sub.6) δ: 8.33 (s, 1H), 8.03 (d, 1H), 7.75 (dd, 1H), 7.44 (d, 1H), 6.89- 6.73 (m, 2H), 6.67 (s, 1H), 3.55 (s, 3H), 2.32- 2.23 (m, 3H), 2.01 (s, 3H), 1.58-1.29 (m, 6H) 20 [00093] A18, B2 50 .sup.1H NMR (DMSO-d.sub.6) δ: 8.47 (s, 1H), 8.05 (d, 1H), 7.80-7.70 (m, 1H), 7.50 (d, 1H), 6.82-6.74 (m, 2H), 6.04-5.96 (m, 1H), 5.92 (d, 1H), 3.55 (s, 3H), 2.27 (d, 3H), 1.43 (s, 6H) 60 [00094] embedded image A23, B26 63 .sup.1H NMR (DMSO-d.sub.6) δ: 7.62 (dd, 1H), 7.60 (d, 1H), 7.22 (dd, 1H), 7.09 (d, 1H), 6.85 (d, 1H), 6.46 (s, 1H), 4.14 (s, 3H), 3.54 (s, 3H), 2.23 (s, 3H), 1.49 (s, 6H)

Example 16: 7-fluoro-8-(5-fluoro-3-(tetrahydrofuran-3-yl)-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline

[0274] ##STR00095##

[0275] Step 1: 7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline was prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 23.

[0276] Step 2: To a stirred solution of 7-fluoro-8-(5-fluoro-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (1.6 g, 4.23 mmol, 1.0 eq) in DMF (40 ml) at 0° C. (40 ml) were added KOH (0.592 g, 10.58 mmol, 2.5 eq) and iodine (1.07 g, 4.23 mmol, 1.0 eq) and the resulting reaction mixture was stirred for 30 min at 0° C. The reaction mixture was diluted with EtOAc (800 ml), washed with aq. sodium metabisulfite (2×300 ml), water (4×300 ml) and brine (300 ml), dried (Na.sub.2SO.sub.4), filtered and concentrated under reduced pressure to afforded 7-fluoro-8-(5-fluoro-3-iodo-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (1.6 g, 75%). TLC system: 5% MeOH/DCM; R.sub.f: 0.3.

[0277] Step 3: A solution of 7-fluoro-8-(5-fluoro-3-iodo-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (1.5 g, 2.97 mmol, 1.0 eq.) in DMF (20 ml) was degassed with argon for 20 min followed by the addition of tetrabutylammonium chloride (0.82 g, 2.97 mmol, 1.0 eq.), NaOAc (0.732 g, 8.92 mmol, 3.0 eq.), Pd(OAc).sub.2 (0.066 g, 0.297 mmol, 0.1 eq.) and 2,5-dihydrofuran (2.19 ml, 29.76 mmol, 10 eq.). The reaction mixture was stirred at 50° C. for 48 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and the filtrate was concentrated to get the crude product, which was purified by prep-HPLC (10% MeOH/DCM; R.sub.f-value-0.3) to afford 8-(3-(2,3-dihydrofuran-3-yl)-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (0.35 g, 27%) as a white solid.

[0278] Step 4: A solution of 8-(3-(2,3-dihydrofuran-3-yl)-5-fluoro-1H-indol-7-yl)-7-fluoro-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (0.25 g, 0.56 mmol, 1.0 eq.) in ethanol (20 ml) was degassed with argon for 10 min followed by the addition of Pd/C (50 mg, 10 wt % loading) The reaction mixture was stirred at RT under hydrogen atmosphere for 3 h. After completion of the reaction (monitored by TLC), the reaction mixture was filtered through a celite bed and the filtrate was concentrated to afford 7-fluoro-8-(5-fluoro-3-(tetrahydrofuran-3-yl)-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (0.23 g, 91%) as a white solid.

[0279] .sup.1H NMR (DMSO-d.sub.6) δ: δ 10.75 (s, 1H), 7.38 (d, 1H), 7.22 (s, 1H), 6.88 (d, 1H), 6.74 (d, 2H), 6.57 (s, 1H) 4.12 (q, 1H), 3.91-3.96 (m, 1H), 3.82 (q, 1H), 3.55-3.66 (m, 2H), 2.33-2.37 (m, 1H), 2.23 (s, 3H), 2.00-2.07 (m, 1H), 1.94 (s, 3H), 1.46 (s, 3H), 1.37 (s, 3H).

Example 17: 7-fluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline

[0280] ##STR00096##

[0281] Step 1: A solution of 7-fluoro-8-(5-fluoro-3-iodo-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (0.26 g, 0.515 mmol, 1.0 eq) in THF and TEA (1:1) (10 ml) was deoxygenated with argon gas for 10 min in a sealed tube. Pd(PPh.sub.3).sub.2Cl.sub.2 (0.018 g, 0.025 mmol, 0.05 eq) and CuI (0.019 g, 0.103 mmol, 0.2 eq) were then added to the reaction mixture, which was again deoxygenated by argon gas for 10 min at −78° C. In a test tube propyne gas was condensed in TEA (3 ml) at −78° C. The volume rose to 5 ml. The condensed propyne gas was then instantly poured into the reaction mixture at −78° C. The reaction mixture was then stirred for 2 h at −78° C. and 14 h at room temperature. The reaction mixture was diluted with dichloromethane (50 ml). The organic layer was washed with water (2×20 ml) and brine (20 ml). The organic layer was dried over anhydrous Na.sub.2SO.sub.4, and concentrated under reduced pressure to get the crude material, which was purified by silica gel column chromatography (5% MeOH/DCM; R.sub.f-value-0.4) as well as by prep. HPLC to afford compound 7-fluoro-8-(5-fluoro-3-(prop-1-yn-1-yl)-1H-indol-7-yl)-1,4,4,9-tetramethyl-4,5-dihydroimidazo[1,2-a]quinoxaline (0.1 g, 47%) as an off-white solid.

[0282] .sup.1H NMR (DMSO-d.sub.6) δ: 11.27 (s, 1H), 7.57 (d, 1H), 7.26 (dd, 1H), 6.96-7.0 (bd, 1H), 6.74 (d, 2H), 6.59 (s, 1H), 2.23 (s, 3H), 2.08 (d, 3H), 1.94 (s, 3H), 1.44-1.38 (m, 6H).

Example 18: 9-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine

[0283] ##STR00097##

[0284] Step 1: 9-Fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine was prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 1.

[0285] Step 2: NaH (60% suspension in mineral oil, 10 mg, 0.25 mmol, 2.0 eq.) was suspended in DMF (2.9 mL) and the mixture was cooled to 0° C., followed by the addition of 9-fluoro-8-(6-fluoro-1H-indol-4-yl)-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine (45 mg, 0.13 mmol, 1.0 eq.). The resulting mixture was stirred for 15 minutes, followed by the addition of methanesulfonyl chloride (14 mg, 0.12 mmol, 1.0 eq.). The resulting mixture was stirred for 70 minutes at 0° C. Sat. NaHCO.sub.3 solution and EtOAc were then added, the layers were separated. The organic layer was washed with water and brine, was dried over MgSO.sub.4 and the solvent was removed under reduced pressure. The resulting residue was purified via silica gel chromatography and later reverse phase HPLC to give 6.3 mg (12%) of 9-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-1,4,4-trimethyl-4,5-dihydropyrido[3,4-e][1,2,4]triazolo[4,3-a]pyrazine.

[0286] [M+H].sup.+ (m/z): calc. for C.sub.20H.sub.18F.sub.2N.sub.6O.sub.2S+H: 444.12, found 445.2.

Example 22: 8-(3-cyclopropyl-1H-indol-7-yl)-7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline

[0287] ##STR00098##

[0288] Step 1: To a solution of 8-bromo-7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.250 g, 0.793 mmol, 1.0 eq) in dioxane (100 ml) were added K.sub.2CO.sub.3 (2M aqueous solution; 0.328 g, 2.38 mmol, 3.0 eq) and 3-cyclopropyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.254 g, 0.897 mmol, 1.1 eq). The solution was degassed with argon for 10 min followed by addition of Pd(PPh.sub.3).sub.4 (0.045 g, 0.0396 mmol, 0.05 eq). The reaction mixture was then heated for 15 h to 100° C. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to get the crude product, which was purified by preparative HPLC to afford 8-(3-cyclopropyl-1H-indol-7-yl)-7,9-difluoro-4,4-dimethyl-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.070 g, 23%) as a white solid.

[0289] .sup.1H NMR (DMSO-d.sub.6) δ: 10.66 (s, 1H), 7.68 (d, 1H), 7.57 (s, 1H), 7.12-7.04 (m, 3H), 6.72 (d, 1H), 1.96 (m, 1H), 1.68 (s, 6H), 0.86 (d, 2H), 0.63 (s, 2H).

[0290] The following examples were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 22:

TABLE-US-00011 Example Inter- Yield Nr. Structure Mediates % Data 31 [00099] embedded image A11, B13 43 .sup.1H NMR (DMSO-d.sub.6) δ: 10.6 (s, 1H), 7.91 (s, 1H), 7.54-7.52 (d, 1H), 7.24 (s, 1H), 7.10-7.06 (m, 2H), 6.99-6.98 (d, 1H), 2.53 (s, 3H), 2.29 (s, 3H), 2.03 (s, 3H), 1.52 (bs, 6H).

Example 23: 7-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-a]quinoxaline

[0291] ##STR00100##

[0292] Step 1: To a solution of 8-bromo-7-fluoro-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.3 g, 0.822 mmol, 1.0 eq) and 6-fluoro-1-(methylsulfonyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (0.334 g, 0.986 mmol, 1.2 eq) in a mixture of [t-amyl alcohol (5 ml)/1,4-dioxane (5 ml)/water (0.5 ml)] was added K.sub.2CO.sub.3 (0.340 g, 2.466 mmol, 3.0 eq). The solution was then degassed (N.sub.2) for 10 minutes followed by the addition of Ata-phos catalyst (bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II), 0.027 g, 0.0376 mmol, 0.05 eq). The reaction mixture was then heated at 100° C. for 16 h. After completion of the reaction (monitored by LCMS), the reaction mixture was filtered through a celite pad. The filtrate was concentrated under reduced pressure to get the crude product which was purified by preparative HPLC to afford 7-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-4,4-dimethyl-9-(trifluoromethyl)-4,5-dihydrotetrazolo[1,5-a]quinoxaline (0.035 g, 9%) as a white solid.

[0293] .sup.1H NMR (DMSO-d.sub.6) δ: 7.91 (s, 1H), 7.72 (d, 1H), 7.64 (d, 1H), 7.24 (dd, 1H), 7.19 (d, 1H), 6.60 (d, 1H), 3.60 (s, 3H), 1.71 (s, 3H), 1.64 (s, 3H).

[0294] The following examples were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 23:

TABLE-US-00012 Example Inter- Yield Nr. Structure Mediates % Data 15 [00101] embedded image A15, B1 42 .sup.1H NMR (DMSO-d.sub.6) δ: 8.30 (s, 1H), 7.96 (s, 1H), 6.82 (s, 1H), 6.72 (d, 1H), 3.85 (s, 3H), 2.42 (s, 3H), 2.03 (s, 3H), 1.44-1.46 (m, 6H). 29 [00102] A14, B11 74 .sup.1H NMR (DMSO-d.sub.6) δ: 7.73-7.71 (m, 1H), 7.69-7.68 (m, 1H), 7.65-7.63 (m, 1H), 7.56- 7.53 (m, 1H), 7.40-7.38 (m, 1H), 7.28-7.27 (m, 1H), 7.04 (s, 1H), 3.53 (s, 3H), 2.81 (s, 3H), 1.58 (s, 6H). 30 [00103] embedded image A11, B12 26 .sup.1H NMR (DMSO-d.sub.6) δ: 10.65 (s, 1H), 7.55- 7.53 (m, 1H), 7.36-7.33 (m, 1H), 7.24-7.21 (m, 1H), 7.15-7.14 (m, 2H), 7.10-7.06 (m, 1H), 2.67 (s, 3H), 2.29 (s, 3H), 1.59 (s, 6H).

Example 37: 6′-fluoro-8′-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-1′,9′-dimethyl-1′,5′-dihydrospiro[cyclobutane-1,4′-pyrazolo[4,3-c]quinoline]

[0295] ##STR00104##

[0296] Step 1: 8-bromo-6-fluoro-1,9-dimethyl-spiro[5H-pyrazolo[4,3-c]quinoline-4,1′-cyclobutane](50 mg, 0.15 mmol, 1.0 eq.), 6-fluoro-1-methylsulfonyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indole (76 mg, 0.22 mmol, 1.5 eq.), Pd.sub.2dba.sub.3 (14 mg, 0.015 mmol, 0.1 eq.) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (Xphos, 14 mg, 0.030 mmol, 0.2 eq.) were weighed out into a microwave vial under nitrogen. A stirr bar was added, the vial was sealed. Then, 1,4-dioxane (1.1 mL), 2-methylbutan-2-ol (1.1 mL) and 2M K.sub.2CO.sub.3 solution (0.3 mL) were added. Nitrogen gas was bubbled through the reaction mixture for two minutes. The reaction mixture was then heated to 60° C. for 21 hours. Then, DCM and water were added, and the resulting mixture was filtered through a hydrophobic frit. The organic layer was evaporated and the residue was purified via silica gel chromatography to yield 62 mg (89%) of 6′-fluoro-8′-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-1′,9′-dimethyl-1′,5′-dihydro spiro[cyclobutane-1,4′-pyrazolo[4,3-c]quinoline].

[0297] .sup.1H NMR (DMSO-d.sub.6) δ: 7.66 (s, 1H), 7.64 (dd, 1H), 7.62 (d, 1H), 7.27 (dd, 1H), 7.05 (d, 1H), 6.65-6.58 (m, 1H), 6.49 (d, 1H), 3.86 (s, 3H), 3.55 (s, 3H), 2.42 (d, 2H), 2.26 (s, 2H), 2.16 (s, 3H), 1.92-1.84 (m, 1H), 1.78 (dd, 1H).

[0298] The following examples were prepared in a similar manner (use of appropriate reagents and purification methods known to the person skilled in the art) as the synthesis described for example 37:

TABLE-US-00013 Example Inter- Yield Nr. Structure Mediates % Data 38 [00105] embedded image A18, B16 48 .sup.1H NMR (DMSO-d.sub.6) δ: 8.48 (d, 1H), 8.02- 7.93 (m, 1H), 7.74-7.68 (m, 1H), 7.67 (s, 1H), 7.45 (dd, 1H), 7.10 (d, 1H), 6.51 (d, 1H), 3.91-3.87 (m, 3H), 3.57-3.50 (m, 3H), 2.50-2.41 (m, 2H), 2.27 (d, 2H), 2.17 (s, 3H), 1.95-1.84 (m, 1H), 1.82-1.75 (m, 1H) 39 [00106] embedded image A13, B16 48 .sup.1H NMR (DMSO-d.sub.6) δ: 10.62 (d, 1H), 7.65 (s, 1H), 7.23 (dd, 1H), 7.16-7.12 (m, 1H), 7.04 (d, 1H), 6.89 (dd, 1H), 6.40 (d, 1H), 3.90 (s, 3H), 2.63-2.16 (m, 7H), 2.11 (s, 3H), 1.93-1.85 (m, 1H), 1.82-1.74 (m, 1H) 40 [00107] A23, B17 66 .sup.1H NMR (DMSO-d.sub.6) δ: 8.42 (d, 1H), 7.72- 7.66 (m, 1H), 7.51 (s, 1H), 7.47 (dd, 1H), 7.13 (d, 1H), 6.03 (d, 1H), 4.13-4.06 (m, 2H), 3.57 (s, 3H), 2.22 (s, 3H), 1.45 (s, 6H), 1.41 (t, 3H) 41 [00108] embedded image A14, B17 33 .sup.1H NMR (DMSO-d.sub.6) δ: 7.67-7.61 (m, 2H), 7.50 (d, 1H), 7.28 (dd, 1H), 7.04 (d, 1H), 6.54 (d, 1H), 5.94 (d, 1H), 4.10-4.03 (m, 2H), 3.55 (s, 3H), 2.17 (s, 3H), 1.45 (s, 6H), 1.39 (t, 3H) 42 [00109] A14, B18 92 .sup.1H NMR (DMSO-d.sub.6) δ: 7.87 (d, 1H), 7.65 (d, 1H), 7.51-7.44 (m, 2H), 7.29 (d, 1H), 6.99 (d, 1H), 6.45 (d, 1H), 5.89 (d, 1H), 3.98 (s, 2H), 3.50 (s, 3H), 1.45 (s, 7H), 0.43 (dd, 2H), 0.22 (t, 2H) 43 [00110] embedded image A13, B18 91 .sup.1H NMR (DMSO-d.sub.6) δ: 7.87 (d, 1H), 7.65 (d, 1H), 7.51-7.44 (m, 2H), 7.29 (d, 1H), 6.99 (d, 1H), 6.45 (d, 1H), 5.89 (d, 1H), 3.98 (s, 2H), 3.50 (s, 3H), 1.45 (s, 7H), 0.43 (dd, 2H), 0.22 (t, 2H) 44 [00111] A23, B18 quant. .sup.1H NMR (DMSO-d.sub.6) δ: 8.31 (d, 1H), 7.69 (ddd, 1H), 7.50 (s, 1H), 7.45 (dd, 1H), 7.12 (d, 1H), 6.03 (d, 1H), 3.99 (d, 2H), 3.56 (s, 3H), 2.23 (s, 3H), 1.46 (s, 7H), 1.16 (s, 1H), 0.47-0.41 (m, 2H), 0.30-0.24 (m, 2H) 45 [00112] embedded image A23, B19 90 .sup.1H NMR (DMSO-d.sub.6) δ: 8.33 (d, 1H), 7.73- 7.66 (m, 1H), 7.61 (d, 1H), 7.29 (dd, 1H), 7.15 (d, 1H), 6.93 (d, 1H), 6.71 (d, 1H), 3.55 (s, 3H), 2.27 (s, 3H), 1.71 (s, 6H 46 [00113] A22, B20 quant. .sup.1H NMR (DMSO-d.sub.6) δ: 7.90-7.86 (m, 1H), 7.59 (d, 1H), 7.47 (dd, 1H), 7.40 (s, 1H), 7.28 (d, 1H), 6.63 (d, 1H), 6.48 (d, 1H), 6.37 (s, 1H), 3.77 (s, 3H), 3.49 (s, 3H), 2.10 (s, 3H), 1.43 (s, 3H), 1.38 (s, 3H) 47 [00114] embedded image A14, B21 65 .sup.1H NMR (DMSO-d.sub.6) δ: 7.69 (s, 1H), 7.65- 7.59 (m, 2H), 7.23 (dd, 1H), 6.94 (d, 1H), 6.60 (dd, 1H), 5.90 (d, 1H), 3.72 (s, 3H), 3.54 (s, 3H), 2.15 (s, 3H), 1.43 (s, 6H) 48 [00115] A23, B21 57 .sup.1H NMR (DMSO-d.sub.6) δ: 8.46 (d, 1H), 7.70 (d, 1H), 7.67 (ddd, 1H), 7.40 (dd, 1H), 7.03 (d, 1H), 6.00 (d, 1H), 3.77 (s, 3H), 3.55 (s, 3H), 2.20 (s, 3H), 1.44 (s, 6H) 49 [00116] embedded image A13, B21 35 .sup.1H NMR (DMSO-d.sub.6) δ: 10.55 (d, 1H), 7.67 (s, 1H), 7.22 (ddd, 1H), 7.13 (dd, 1H), 6.93 (d, 1H), 6.86 (dd, 1H), 5.81 (d, 1H), 3.77 (s, 3H), 2.26 (d, 3H), 2.11 (s, 3H), 1.44 (s, 6H) 50 [00117] A23, B22 72 .sup.1H NMR (DMSO-d.sub.6) δ: 8.35 (d, 1H), 7.71 (ddd, 1H), 7.45 (dd, 1H), 6.64 (d, 1H), 6.43 (s, 1H), 3.70 (s, 3H), 3.57 (s, 3H), 2.23 (s, 3H), 2.14 (s, 3H), 1.43 (d, 6H) 51 [00118] embedded image A14, B28 91 .sup.1H NMR (DMSO-d.sub.6) δ: 7.66-7.61 (m, 2H), 7.25 (dd, 1H), 7.03 (d, 1H), 6.57 (dd, 1H), 5.81 (d, 1H), 3.72 (s, 3H), 3.54 (s, 3H), 2.25 (s, 3H), 2.13 (s, 3H), 1.48 (s, 6H) 52 [00119] A13, B23 96 .sup.1H NMR (DMSO-d.sub.6) δ: 10.75 (d, 1H), 7.46 (dd, 1H), 7.37 (s, 1H), 7.27 (dd, 1H), 7.17 (dd, 1H), 7.02 (dd, 1H), 6.47 (d, 1H), 4.07 (s, 3H), 2.26 (d, 3H), 1.52 (s, 6H) 53 [00120] embedded image A22, B24 62 .sup.1H NMR (DMSO-d.sub.6) δ: 7.87 (dt, 1H), 7.61 (d, 1H), 7.46 (dd, 1H), 7.30 (dd, 1H), 7.01 (d, 1H), 6.59 (dd, 1H), 6.34 (d, 1H), 3.72 (s, 3H), 3.49 (s, 3H), 2.59-2.30 (m, 7H), 2.10 (s, 3H), 1.95-1.76 (m, 2H) 54 [00121] A18, B24 62 .sup.1H NMR (DMSO-d.sub.6) δ: 8.46 (d, 1H), 7.99 (d, 1H), 7.70 (dd, 1H), 7.44 (d, 1H), 7.10 (d, 1H), 6.43 (d, 1H), 3.76 (s, 3H), 3.52 (s, 3H), 2.44 (s, 7H), 2.13 (s, 3H), 1.93-1.77 (m, 2H) 55 [00122] embedded image A13, B25 42 .sup.1H NMR (DMSO-d.sub.6) δ: 10.37 (s, 1H), 7.68 (s, 1H), 7.22-7.17 (m, 1H), 7.10-7.06 (m, 1H), 6.85 (d, 1H), 6.78-6.73 (m, 1H), 5.64 (s, 1H), 2.41-2.37 (m, 3H), 2.27-2.22 (m, 3H), 1.51 (s, 6H) 58 [00123] A14, B25 14 .sup.1H NMR (DMSO-d.sub.6) δ: 7.69 (s, 1H), 7.65- 7.56 (m, 2H), 7.11-7.07 (m, 1H), 6.87 (d, 1H), 6.43 (d, 1H), 5.73 (d, 1H), 3.54 (s, 3H), 2.42 (s, 3H), 1.53 (s, 3H), 1.49 (s, 3H) 59 [00124] embedded image A23, B25 23 .sup.1H NMR (DMSO-d.sub.6) δ: 7.62 (dd, 1H), 7.60 (d, 1H), 7.22 (dd, 1H), 7.09 (d, 1H), 6.85 (d, 1H), 6.46 (s, 1H), 4.14 (s, 3H), 3.54 (s, 3H), 2.23 (s, 3H), 1.49 (s, 6H)

Example 57: 6-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-4,4,9-trimethyl-2-(methylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline

[0299] ##STR00125##

[0300] Step 1: 6-fluoro-8-(6-fluoro-1-methylsulfonyl-indol-4-yl)-4,4,9-trimethyl-1,5-dihydropyrazolo[4,3-c]quinoline (40 mg, 0.09 mmol, 1.0 eq.) was dissolved in DCM (2.0 mL) followed by the addition of triethylamine (0.063 mL, 0.45 mmol, 5.0 eq.), and the reaction mixture was stirred for 5 minutes at ambient temperature. Then, methansulfonyl chloride (12 mg, 0.10 mmol, 1.1 eq.) was added and the reaction mixture was stirred for one hour, followed by the addition of another aliquot of methansulfonyl chloride (12 mg, 0.10 mmol, 1.1 eq.). The reaction mixture was then stirred at ambient temperature for 16 hours. DCM and water were added, and the resulting mixture was filtered through a hydrophobic frit. The organic part was evaporated and purified via silica gel column chromatography to yield 27 mg (57%) of 6-fluoro-8-(6-fluoro-1-(methylsulfonyl)-1H-indol-4-yl)-4,4,9-trimethyl-2-(methylsulfonyl)-4,5-dihydro-2H-pyrazolo[4,3-c]quinoline.

[0301] .sup.1H NMR (DMSO-d.sub.6) δ: 8.32-8.26 (m, 1H), 7.63 (dd, 1H), 7.60 (d, 1H), 7.12 (dd, 1H), 7.02 (d, 1H), 6.45 (d, 1H), 6.15-6.12 (m, 1H), 3.57-3.52 (m, 6H), 2.42 (s, 4H), 1.58 (s, 3H), 1.54 (s, 3H)

Biological Assays

Agonistic Mode of Action on the Glucocorticoid Receptor

[0302] The reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing a firefly luciferase gene under the control of the GR ligand binding domain fused to the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integrated into CHO cells. This cell line was established by stable transfection of CHO cells with a GAL4-UAS-Luciferase reporter construct. In a subsequent step the ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4 containing the DNA binding domain of GAL4 from pFA-AT2 was transfected. This fusion construct activated firefly luciferase expression under the control of a multimerized GAL4 upstream activation sequence (UAS). The signal of the emitted luminescence was recorded by the FLIPR.sup.TETRA. This allowed for specific detection of ligand-induced activation of the GR and therefore for 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.

[0303] The complete culture medium for the assay was: [0304] DMEM F-12 (1:1) MIXTURE (LONZA cat. No.: BE04-687F/U1) 500 mL [0305] 5 mL of 100 mM Sodium Pyruvate (LONZA cat. No.: BE12-115E) [0306] 25 mL of 7.5% Sodium Bicarbonate (LONZA cat. No. BE17-613E) [0307] 6.5 mL of 1 M Hepes (LONZA cat. No.: BE17-737E) [0308] 5 mL of 100× Penicillin/Streptomycin (LONZA cat. No. DE17-602E) [0309] 50 mL of Fetal Bovine Serum (Euroclone cat. No. ECS 0180L) [0310] 0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1) [0311] 0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)

[0312] Cryo-preserved CHO-Gal4/GR cells were suspended in complete medium and 5000 cells/25 μl/well were seeded into the wells of 384-well polystyrene assay plates (Thermo Scientific, cat. #4332) and cultured at 37° C., 5% CO.sub.2 and 95% humidity. After 24 hours growth medium was carefully removed and replaced by 30111 Opti-MEM (GIBCO, cat. #31985062) as assay buffer. To test the compounds an 8-point half-log compound dilution curve was generated in 100% DMSO starting from a 2 mM stock and compounds were then diluted 1:50 in Opti-MEM. 10111 of compounds were then added to the wells containing 30 μl Opti-MEM resulting in a final assay concentration range from 10 μM to 0.003 μM in 0.5% DMSO. Compounds were tested at 8 concentrations in quadruplicate data points. Cells were incubated for 6 hour with compounds and beclometasone (Sigma, cat. #Y0000351) as control compound at 37° C., 5% CO.sub.2 and 95% humidity in a total volume of 40 μl. Finally, cells were lysed with 20111 of Triton/Luciferin solution and the signal of the emitted luminescence was recorded at the FLIPR.sup.TETRA for 2 minutes.

[0313] The relative efficacy of a compound (% effect) was calculated based on the full effect of the agonist beclometasone:

% effect=((compound−min)/(max−min))×100 [0314] [min=Opti-MEM only, max=beclometasone]

[0315] To calculate EC.sub.50, max, min and slope factor for each compound a concentration response curve was fitted by plotting % effect versus compound concentration using a 4 parameter logistic equation:

y=A+(B−A)/(1+((10C)/x)D)

[A=min y, B=max y, C=logEC.sub.50, D=slope]

Antagonistic Mode of Action on the Glucocorticoid Receptor

[0316] The reporter cell line CHO-Gal4/GR consisted of a chinese hamster ovary (CHO) cell line (Leibniz Institute DSMZ—German Collection of Microorganisms and Cell Cultures GmbH: ACC-110) containing a firefly luciferase gene under the control of the GR ligand binding domain fused to the DNA binding domain (DBD) of GAL4 (GAL4 DBD-GR) stably integrated into CHO cells. This cell line was established by stable transfection of CHO cells with a GAL4-UAS-Luciferase reporter construct. In a subsequent step the ligand binding domain of the GR cloned into pIRES2-EGFP-GAL4 containing the DNA binding domain of GAL4 from pFA-AT2 was transfected. This fusion construct activated firefly luciferase expression under the control of a multimerized GAL4 upstream activation sequence (UAS). The signal of the emitted luminescence was recorded by the FLIPR.sup.TETRA. This allowed for specific detection of antagonistic properties of compounds by measuring the ligand-induced inhibition of beclometasone-activated GR. The GAL4/UAS reporter was premixed with a vector that constitutively expressed Renilla luciferase, which served as an internal positive control for transfection efficiency.

[0317] The complete culture medium for the assay was: [0318] DMEM F-12 (1:1) MIXTURE (LONZA cat. No.: BE04-687F/U1) 500 mL [0319] 5 mL of 100 mM Sodium Pyruvate (LONZA cat. No.: BE12-115E) [0320] 25 mL of 7.5% Sodium Bicarbonate (LONZA cat. No. BE17-613E) [0321] 6.5 mL of 1 M Hepes (LONZA cat. No.: BE17-737E) [0322] 5 mL of 100× Penicillin/Streptomycin (LONZA cat. No. DE17-602E) [0323] 50 mL of Fetal Bovine Serum (Euroclone cat. No. ECS 0180L) [0324] 0.25 mL of 10 mg/mL Puromycin (InvivoGen cat.: ant-pr-1) [0325] 0.5 mL of 100 mg/mL Zeocin (InvivoGen cat.: ant-zn-1)

[0326] Cryo-preserved CHO-Gal4/GR cells were suspended in complete medium and 5000 cells/25 μl/well were seeded into the wells of 384-well polystyrene assay plates (Thermo Scientific, cat. #4332) and cultured at 37° C., 5% CO.sub.2 and 95% humidity. After 24 hours growth medium was carefully removed and replaced by 20111 Opti-MEM (GIBCO, cat. #31985062) as assay buffer. For testing compounds an 8-point half-log compound dilution curve was generated in 100% DMSO starting from a 2 mM stock and compounds were then diluted 1:50 in Opti-MEM. To test the compounds in the antagonist mode 10111 of compounds were then added to the wells containing 20111 Opti-MEM and incubated for 10 min. After this pre-incubation 10111 of the reference agonist beclometasone (Sigma, cat. #Y0000351) at an EC.sub.50 of 2.5 nM were added resulting in a final assay concentration range from 10 μM to 0.003 μM in 0.5% DMSO in a total volume of 40 μl. Compounds were tested at 8 concentrations in quadruplicate data points. Cells were incubated for 6 hour with compounds and mifepristone as control compound (Sigma, cat. #M8046) at 37° C., 5% CO.sub.2 and 95% humidity. Finally, cells were lysed with 20111 of Triton/Luciferin solution and the signal of the emitted luminescence was recorded at the FLIPR.sup.TETRA for 2 minutes.

[0327] The relative efficacy of a compound (% effect) was calculated based on the full effect of the antagonist mifepristone:

% effect=((compound−min)/(max−min))x−100 [0328] [min=Opti-MEM only, max=mifepristone]

[0329] To calculate IC.sub.50, max, min and slope factor for each compound a concentration response curve was fitted by plotting % effect versus compound concentration using a 4 parameter logistic equation:

y=A+(B−A)/(1+((10C)/x)D) [0330] [A=min y, B=max y, C=loglCso, D=slope]

[0331] In Table 9 below, the IC.sub.50 or EC.sub.50 ranges of the Examples are summarized which were observed in the agonistic assay or the antagonistic assay described above.

TABLE-US-00014 TABLE 9 (A < 100 nM, B = 100 nM-1 μM, C = 1 μM-15 μM): Ex. # IC.sub.50 or EC.sub.50 1 A 2 B 3 A 4 C 5 A 6 A 7 B 8 A 9 A 10 B 11 A 12 A 13 C 14 B 15 A 16 B 17 B 18 C 19 B 20 B 21 B 22 B 23 A 24 A 25 A 26 A 27 A 28 B 29 B 30 B 31 B 32 A 33 A 34 A 35 B 36 B 37 A 38 A 39 A 40 B 41 A 42 C 43 C 44 C 45 C 46 A 47 B 48 B 49 A 50 A 51 B 52 A 53 B 54 A 55 B 56 A 57 B 58 B 59 B 60 A 61 B 62 B 63 C

QUINOXALINE DERIVATIVES

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Abstract

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