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COMPOUNDS AND COMPOSITIONS FOR THE TREATMENT OF CYSTIC FIBROSIS

20210292324 · 2021-09-23

    Inventors

    Cpc classification

    International classification

    Abstract

    The present invention relates to compounds of Formula (Ia) or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof. It further discloses a pharmaceutical composition comprising the compounds of Formula (Ia) and the use of compounds of Formula (Ib), in particular to modulate CFTR protein or ABC protein activities.

    ##STR00001##

    Claims

    1. A compound of Formula (Ia): ##STR00144## or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof wherein: Z is selected from the group consisting of C═O, SO.sub.2 or CONR.sup.i; R.sup.i is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, and heterocycloalkyl; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are independently selected from the group consisting of CR.sup.ii and N, with the proviso that the number of nitrogen atoms in the ring is comprised from 0 to 2; each R.sup.ii is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-aryl, O-heteroaryl, COR.sup.viii, COOR.sup.viii, CONHR.sup.c, CONR.sup.dR.sup.e, OH, O—C.sub.1-6alkyl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-haloC.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, CN, NO.sub.2, NHR.sup.c, NR.sup.dR.sup.e, N(R.sup.e)COR.sup.c, N(R.sup.e)COOR.sup.c, N(R.sup.x)CONR.sup.ixR.sup.x, N(R.sup.x)SO.sub.2R.sup.xi, SO.sub.2R.sup.xi, SO.sub.2NHR.sup.c, SO.sub.2NR.sup.dR.sup.e, halogen, and hydroxy-C.sub.1-6alkyl; A.sub.1 and A.sub.4 are CR.sup.iiiR.sup.iv, A.sub.2 and A.sub.3 are selected from a bond and CR.sup.iiiR.sup.iv; R.sup.iii and R.sup.iv are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, haloC.sub.1-6alkyl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, CONR.sup.ixR.sup.x, OH, O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, CN, halogen, NR.sup.ixR.sup.x, N(R.sup.ix)COR.sup.viii, or R.sup.iii and R.sup.iv form a C.sub.3-C.sub.6 cycloalkyl with the C to which they are linked; or, when A.sub.3 is a bond, two groups R.sup.iv on A.sub.1 and A.sub.2, or on A.sub.1 and A.sub.4 are linked together to form a ring and thus the moiety ##STR00145## represents one of the structures selected from the group consisting of: ##STR00146## wherein R.sup.a and R.sup.b are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, halogen, OH, O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, B is selected from the group consisting of: ##STR00147## wherein Y and W are independently selected from the group consisting of O, S, CR.sup.v, CR.sup.vR.sup.vi, N, and NR.sup.vii, wherein R.sup.v and R.sup.vi are selected form the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O—C.sub.1-6alkyl, O—C.sub.1-6alkylaryl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-haloC.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, C.sub.1-6alkyl-O-aryl, C.sub.1-6alkyl-O-heteroaryl, hydroxy-C.sub.1-6alkyl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, and CONR.sup.xR.sup.x; R.sup.vii is selected form the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.2-6alkyl-O—C.sub.1-6alkyl, C.sub.2-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.2-6alkyl-O-heterocycloalkyl, C.sub.2-6alkyl-O-aryl, and C.sub.2-6alkyl-O-heteroaryl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, CONR.sup.ixR.sup.x, OH, O—C.sub.1-6alkyl, O—C.sub.1-6alkylaryl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-heteroaryl, O-aryl, O-haloC.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, C.sub.1-6alkyl-O-aryl, C.sub.1-6alkyl-O-heteroaryl, hydroxy-C.sub.1-6alkyl, CN, NO.sub.2, NR.sup.ixR.sup.x, N(R.sup.x)COR.sup.viii, N(R.sup.x)COOR.sup.viii, N(R.sup.x)CONR.sup.ix, R.sup.x, N(R.sup.x)SO.sub.2R.sup.xi, SO.sub.2R.sup.xi, SO.sub.2NR.sup.ixR.sup.x, and halogen; R.sup.viii is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, and C.sub.1-6alkyl-O-heterocycloalkyl; R.sup.ix is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.x is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-6alkyl-O—C.sub.2-6alkyl, and hydroxy-C.sub.2-6alkyl; R.sup.xi is selected from the group consisting of C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.c is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.2-6alkyl-O—C.sub.1-6alkyl, and C.sub.2-6alkyl-O-heterocycloalkyl; R.sup.d is selected from the group consisting of C.sub.1-6alkyl, haloC.sub.1-6alkyl, aryl, and heteroaryl; R.sup.e is selected from the group consisting of C.sub.1-6alkyl, haloC.sub.1-6alkyl, aryl, heteroaryl, C.sub.1-6alkyl-O—C.sub.2-6alkyl, and hydroxy-C.sub.2-6alkyl; provided that at least one of R.sup.iii or R.sup.iv of at least one of A.sub.1, A.sub.2, A.sub.3 or A.sub.4 is not H and that, when Z is C═O, A.sub.1 is not CH(C.sub.1-6alkyl) when A.sub.4 is CH.sub.2 or A.sub.1 is not CH.sub.2 when A.sub.4 is CH(C.sub.1-6alkyl).

    2. The compound of Formula (Ia) according to claim 1 wherein Z is C═O; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are CR.sup.ii; each R.sup.ii is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, COR.sup.viii, COOR.sup.viii, CONHR.sup.c, CONR.sup.dR.sup.e, OH, O—C.sub.1-6alkyl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-haloC.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, CN, NO.sub.2, NHR.sup.c, NR.sup.dR.sup.e, SO.sub.2R.sup.xi, SO.sub.2NHR.sup.c, SO.sub.2NR.sup.dR.sup.e, halogen, and hydroxy-C.sub.1-6alkyl; R.sup.iii and R.sup.iv are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, haloC.sub.1-6alkyl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, CONR.sup.ixR.sup.x, OH, O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, CN, halogen.

    3. The compound of Formula (Ia) according to claim 1 wherein R.sup.iii and R.sup.iv are independently selected from the group consisting of hydrogen and C.sub.1-6alkyl, haloC.sub.1-6alkyl, OH, O—C.sub.1-6alkyl, halogen or, when A.sub.3 is a bond, two groups R.sup.iv on A.sub.1 and A.sub.2, are linked together to form a ring and thus the moiety ##STR00148## represents: ##STR00149##

    4. The compound of Formula (Ia) according to claim 1 wherein R.sup.iii and R.sup.iv are independently selected from the group consisting of hydrogen and methyl.

    5. The compound of Formula (Ia) according to claim 1, selected from the group consisting of: TABLE-US-00004 040 (2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11- yl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone 041 (1H-indol-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)methanone 042 (5-bromofuran-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)methanone 047 [5-(trifluoromethyl)-1H-pyrazol-3-yl]-(4,4,8-trimethyl-3,5-dihydro-1H- pyrido[4,3-b]indol-2-yl)methanone 053 (4-fluoro-2-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3- yl)methanone 055 (4-fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3- yl)methanone 077 (6-fluoro-4,4,9-trimethyl-3,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 079 (7R,10S)-or (7S,10R)-(4-fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3- yl)methanone 080 (7S,10R)-or (7R,10S)-4-fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3- yl)methanone 105 rac-(6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 108 ®-(fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 109 (S)-(6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 112 (6-fluoro-3,3,9-trimethyl-4,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 113 [(S)-6,9-difluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 114 [®-6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-(1H- indol-2-yl)methanone 115 [(S)-8-methoxy-6-fluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone 117 [®-8-methoxy-6-fluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone 121 (6-fluoro-3-isopropyl-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)-(5-methyl-1H-pyrazol-3-yl)methanone 122 (6,9-difluoro-8-methoxy-spiro[4,5-dihydro-3H-pyrido[4,3-b]indole-1,1′- cyclopropane-2-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 123 (6,9-difluoro-1,3-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5- methyl-1H-pyrazol-3-yl)methanone 124 (6,9-difluoro-8-methoxy-spiro[4,5-dihydro-1H-pyrido[4,3-b]indole-3,1′- cyclopropane-2-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 125 [6-(dimethylamino)-1H-indol-2-yl]-(8-methylspiro[3,5-dihydro-1H- pyrido[4,3-b]indole-4,1′-cyclopropane]-2-yl)methanone 126 (4-ethyl-6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5- methyl-1H-pyrazol-3-yl)methanone 127 6-fluoro-9-methyl-2-(5-methyl-1H-pyrazole-3-carbonyl)-1,3,4,5- tetrahydropyrido[4,3-b]indole-3-carboxylic acid 128 [6-(dimethylamino)-1H-indol-2-yl]-[8-methyl-1-(trifluoromethyl)-1,3,4,5- tetrahydropyrido[4,3-b]indol-2-yl]methanone 129 (6-fluoro-8-methoxy-1,4-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)-(5-methyl-1H-pyrazol-3-yl)methanone 130 (6-fluoro-4-methoxy-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)- (5-methyl-1H-pyrazol-3-yl)methanone 131 6-fluoro-4,9-dimethyl-2-(5-methyl-1H-pyrazole-3-carbonyl)-3,5-dihydro- 1H-pyrido[4,3-b]indole-4-carboxylic acid 132 (4,4-difluoro-8-methoxy-3,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-(5- methyl-1H-pyrazol-3-yl)methanone 133 (3,6-dimethyl-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12- tetraen-4-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 134 (6,6-dimethyl-4,8,12-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12- tetraen-4-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 135 2-(5-bromofuran-2-carbonyl)-8-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indole-4-carboxylic acid

    6. A pharmaceutical composition comprising a compound of Formula (Ia) according to claim1 and a pharmaceutically acceptable carrier, stabilizer, diluent or excipient thereof.

    7. A compound of Formula (Ia) according to any of claim 1 for the use as a medicament.

    8. A compound of Formula (Ib) ##STR00150## or pharmaceutically acceptable salts, hydrates, solvates, clathrates, polymorphs, stereoisomers thereof or a pharmaceutical composition according to claim 6, for the use to potentiate CFTR protein or ABC protein activities wherein: Z is selected from the group consisting of C═O, SO.sub.2 or CONR.sup.i; R.sup.i is selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, and heterocycloalkyl; X.sub.1, X.sub.2, X.sub.3 and X.sub.4 are independently selected from the group consisting of CR.sup.ii and N, with the proviso that the number of nitrogen atoms in the ring is comprised from 0 to 2; each R.sup.ii is independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O-aryl, O-heteroaryl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, CONR.sup.ixR.sup.x, OH, O—C.sub.1-6alkyl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-haloC.sub.1-6 alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, CN, NO.sub.2, NR.sup.ixR.sup.x, N(R.sup.x)COR.sup.viii, N(R.sup.x)COOR.sup.viii, N(R.sup.x)CONR.sup.ixR.sup.x, N(R.sup.x)SO.sub.2R.sup.xi, SO.sub.2R.sup.xi, SO.sub.2NR.sup.ixR.sup.x, halogen, and hydroxy-C.sub.l-6alkyl; A.sub.1 and A.sub.4 are CR.sup.iiiR.sup.iv, A.sub.2 and A.sub.3 are selected from a bond and CR.sup.iiiR.sup.iv; R.sup.iii and R.sup.iv are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, haloC.sub.1-6alkyl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, CONR.sup.ixR.sup.x, OH, O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, CN, halogen, NR.sup.ixR.sup.x, N(R.sup.ix)COR.sup.viii, or R.sup.iii and R.sup.iv form a C.sub.3-C.sub.6 cycloalkyl with the C to which they are linked; or when A.sub.3 is a bond, two groups R.sup.iv on A.sub.1 and A.sub.2, or on A.sub.1 and A.sub.4 are linked together to form a ring and thus the moiety ##STR00151## represents one of the structures selected from the group consisting of: ##STR00152## wherein R.sup.a and R.sup.b are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, halogen, OH, O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl; B is selected from the group consisting of: ##STR00153## wherein Y and W are independently selected from the group consisting of O, S, CR.sup.v, CR.sup.vR.sup.vi, N, and NR.sup.vii, wherein R.sup.y and R.sup.vi are selected form the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, O—C.sub.1-6alkyl, O—C.sub.1-6alkylaryl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-haloC.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, C.sub.1-6alkyl-O-aryl, C.sub.1-6alkyl-O-heteroaryl, hydroxy-C.sub.1-6alkyl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, and CONR.sup.ixR.sup.x; R.sup.vii is selected form the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.2-6alkyl-O—C.sub.1-6alkyl, C.sub.2-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.2-6alkyl-O-heterocycloalkyl, C.sub.2-6alkyl-O-aryl, and C.sub.2-6alkyl-O-heteroaryl; R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 and R.sub.10 are independently selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, COR.sup.viii, COOR.sup.viii, CONHR.sup.viii, CONR.sup.ixR.sup.x, OH, O—C.sub.1-6alkyl, O—C.sub.1-6alkylaryl, O—C.sub.3-6cycloalkyl, O-heterocycloalkyl, O-heteroaryl, O-aryl, O-haloC.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, C.sub.1-6alkyl-O—C.sub.3-6cycloalkyl, C.sub.1-6alkyl-O-heterocycloalkyl, C.sub.1-6alkyl-O-aryl, C.sub.1-6alkyl-O-heteroaryl, hydroxy-C.sub.1-6alkyl, CN, NO.sub.2, NR.sup.ixR.sup.x, N(R.sup.x)COR.sup.viii, N(R.sup.x)COOR.sup.viii, N(R.sup.x)CONR.sup.ixR.sup.x, N(R.sup.x)SO.sub.2RR.sup.xi, SO.sub.2R.sup.xi, SO.sub.2NR.sup.ixR.sup.x, and halogen; R.sup.viii is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-6alkyl-O—C.sub.1-6alkyl, and C.sub.1-6alkyl-O-heterocycloalkyl; R.sup.ix is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, and heteroaryl; R.sup.x is selected from the group consisting of hydrogen, C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C.sub.1-6alkyl-O—C.sub.2-6alkyl, and hydroxy-C.sub.2-6alkyl; R.sup.xi is selected from the group consisting of C.sub.1-6alkyl, haloC.sub.1-6alkyl, C.sub.3-6cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.

    9. The compound of Formula (Ib) according to claim 8, for the use in the treatment of a disease selected from the group consisting of cystic fibrosis, chronic obstructive pulmonary disease, chronic constipation, and dry eye syndrome.

    10. The compound of Formula (Ib) according to claim 8, for the use in the treatment of cystic fibrosis.

    11. The compound of Formula (Ib) according to claim 8 selected from the group consisting of: TABLE-US-00005 001 (6-Dimethylamino-1H-indol-2-yl)-(1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2- yl)-methanone 002 (1-Phenyl-1H-pyrazol-4-yl)-(1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)- methanone 003 (8-Methoxy-1,3,4,5-tetrahydro-pyrido[4,3-b]indol-2-yl)-(5-trifluoromethyl- 1H-pyrazol-3-yl)-methanone 004 1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl-[5-(trifluoromethyl)-1H-pyrazol-3- yl]methanone 005 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 006 (5-methyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol- 2-yl)methanone 007 (5-isopropyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 008 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1H-pyrazol-3- yl)methanone 009 [6-(dimethylamino)-1H-indol-2-yl]-(8-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 010 1H-indol-2-yl-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)methanone 011 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[2-(trifluoromethyl)- 1H-imidazol-4-yl]methanone 012 (3,5-dimethyl-1H-pyrazol-4-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 013 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-phenyl-1H-pyrazol- 3-yl)methanone 014 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1-phenylpyrazol-4- yl)methanone 015 (5-isopropyl-1H-pyrazol-3-yl)-(8-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 016 (8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-methyl-1H- pyrazol-3-yl)methanone 017 (8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1-phenylpyrazol-4- yl)methanone 018 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[1-methyl-5- (trifluoromethyl)pyrazol-3-yl]methanone 019 (5-isopropyl-1H-pyrazol-3-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)methanone 021 [6-(dimethylamino)-1H-indol-2-yl]-(8-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 022 2-(5-bromo-2-furoyl)-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole 023 (5-bromo-2-furyl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)methanone 024 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-2- furyl]methanone 025 (4-bromo-2-furyl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)methanone 026 (8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1H-pyrazol-3- yl)methanone 027 (8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-phenyl-1H- pyrazol-3-yl)methanone 028 (8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[2-(trifluoromethyl)- 1H-imidazol-4-yl]methanone 029 (5-bromo-2-furyl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone 030 2-furyl-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone 031 (5-tert-butyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 032 1H-indol-2-yl(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone 033 (5-cyclopropyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 034 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[3-(trifluoromethyl)- 1H-pyrazol-4-yl]methanone 035 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-2- pyridyl]methanone 036 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[6-(trifluoromethyl)- 1H-indol-2-yl]methanone 037 (8-isopropyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 038 (6-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 039 (8-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H- pyrazol-3-yl]methanone 040 (2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11-yl)(5- (trifluoromethyl)-1H-pyrazol-3-yl)methanone 041 (1H-indol-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)methanone 042 (5-bromofuran-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)methanone 043 (8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[6-(trifluoromethyl)-2- pyridyl]methanone 044 (6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 045 [8-(trifluoromethoxy)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 046 (8-bromo-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H- pyrazol-3-yl]methanone 047 [5-(trifluoromethyl)-1H-pyrazol-3-yl]-(4,4,8-trimethyl-3,5-dihydro-1H- pyrido[4,3-b]indol-2-yl)methanone 048 [5-(trifluoromethyl)-1H-pyrazol-3-yl]-[8-(trifluoromethyl)-1,3,4,5- tetrahydropyrido[4,3-b]indol-2-yl]methanone 049 (6,8-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 050 (6-fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H- pyrazol-3-yl]methanone 051 (6-fluoro-8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 052 (8-methylsulfonyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 053 (4-fluoro-2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol- 11-yl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone 054 (9-fluoro-6-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 055 (4-fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol- 11-yl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone 056 (6,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 057 2-[5-(trifluoromethyl)-1H-pyrazole-3-carbonyl]-1,3,4,5-tetrahydropyrido[4,3- b]indole-8-carbonitrile 058 (9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 059 (7-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 060 (6,8-difluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 061 (6-bromo-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 063 (6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1H-indol-2- yl)methanone 077 (6-fluoro-4,4,9-trimethyl-3,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 079 (7R,10S)-or (7S,10R)-(4-fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3- yl)methanone 080 (7S,10R)-or (7R,10S)-4-fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3- yl)methanone 081 (6,9-difluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)- 1H-pyrazol-3-yl]methanone 082 [6-fluoro-8-(trifluoromethyl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 086 (6-fluoro-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 087 [6-fluoro-9-(trifluoromethyl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 088 (6-chloro-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 092 (6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[2- (trifluoromethyl)thiazol-4-yl]methanone 093 (4-bromo-3-pyridyl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 094 (3-bromo-4-pyridyl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 095 (5-bromo-2-methoxy-3-pyridyl)-(6-fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3-b]indol-2-yl)methanone 096 (6-bromo-1H-indazol-4-yl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 097 [2-amino-4-(trifluoromethyl)thiazol-5-yl]-(6-fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3-b]indol-2-yl)methanone 098 [3-(4-bromophenyl)-5-methyl-isoxazol-4-yl]-(6-fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3-b]indol-2-yl)methanone 104 3-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carbonyl)-1H- pyrazole-5-carboxylic acid 105 rac-(6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 106 rac-(6-fluoro-1,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 107 8-methoxy-N-(5-methyl-1H-pyrazol-3-yl)-1,3,4,5-tetrahydropyrido[4,3- b]indole-2-carboxamide 108 (R)-(6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 109 (S)-(6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 112 (6-fluoro-3,3,9-trimethyl-4,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 113 [(S)-6,9-difluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5- (trifluoromethyl)-1H-pyrazol-3-yl]methanone 114 [(R)-6-fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-(1H- indol-2-yl)methanone 115 [(S)-8-methoxy-6-fluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone 116 rac-(6-fluoro-1-methyl-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl)-(5 (trifluoromethyl)-1H-pyrazol-3-yl)methanone 117 [(R)-8-methoxy-6-fluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2- yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone 119 (8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(3-methyl-1-propyl- pyrazol-4-yl)methanone 120 [2-(dimethylamino)-4-pyridyl]-(8-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indol-2-yl)methanone 121 (6-fluoro-3-isopropyl-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)- (5-methyl-1H-pyrazol-3-yl)methanone 122 (6,9-difluoro-8-methoxy-spiro[4,5-dihydro-3H-pyrido[4,3-b]indole-1,1′- cyclopropane-2-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 123 (6,9-difluoro-1,3-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5- methyl-1H-pyrazol-3-yl)methanone 124 (6,9-difluoro-8-methoxy-spiro[4,5-dihydro-1H-pyrido[4,3-b]indole-3,1′- cyclopropane-2-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 125 [6-(dimethylamino)-1H-indol-2-yl]-(8-methylspiro[3,5-dihydro-1H- pyrido[4,3-b]indole-4,1′-cyclopropane]-2-yl)methanone 126 (4-ethyl-6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5- methyl-1H-pyrazol-3-yl)methanone 127 6-fluoro-9-methyl-2-(5-methyl-1H-pyrazole-3-carbonyl)-1,3,4,5- tetrahydropyrido[4,3-b]indole-3-c arboxylic acid 128 [6-(dimethylamino)-1H-indol-2-yl]-[8-methyl-1-(trifluoromethyl)-1,3,4,5- tetrahydropyrido[4,3-b]indol-2-yl]methanone 129 (6-fluoro-8-methoxy-1,4-dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)- (5-methyl-1H-pyrazol-3-yl)methanone 130 (6-fluoro-4-methoxy-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5- methyl-1H-pyrazol-3-yl)methanone 131 6-fluoro-4,9-dimethyl-2-(5-methyl-1H-pyrazole-3-carbonyl)-3,5-dihydro-1H- pyrido[4,3-b]indole-4-carboxylic acid 132 (4,4-difluoro-8-methoxy-3,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-(5-methyl- 1H-pyrazol-3-yl)methanone 133 (3,6-dimethyl-4,8,10-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraen- 4-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 134 (6,6-dimethyl-4,8,12-triazatricyclo[7.4.0.02,7]trideca-1(9),2(7),10,12-tetraen- 4-yl)-(5-methyl-1H-pyrazol-3-yl)methanone 135 2-(5-bromofuran-2-carbonyl)-8-methoxy-1,3,4,5-tetrahydropyrido[4,3- b]indole-4-carboxylic acid

    Description

    PREPARATIONS AND EXAMPLES

    [0150] The compounds exemplified in this invention may be prepared from readily available starting materials using the following general methods and procedures for example exemplified in Michael B. Smith—March's Advanced Organic Chemistry: reactions, mechanisms, and structure—7th Edition, John Wiley & Sons Inc., 2013.

    [0151] It is well known to one of ordinary skill in the art that transformation of a chemical function into another may require that one or more reactive centers in the compound containing this function be protected in order to avoid undesired side reactions. Protection of such reactive centers, and subsequent de-protection at the end of the synthetic transformations, can be accomplished following standard procedures described, for instance, in Peter G. M. Wuts—Green's Protective Groups in Organic Synthesis, Fifth Edition, John Wiley & Sons Inc., 2014.

    [0152] It will be appreciated that where typical or preferred experimental conditions (i.e. reaction temperatures, time, moles of reagents, solvents, etc.) are given, other experimental conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by the person skilled in the art, using routine optimization procedures.

    [0153] The synthesis of a compound of Formula (Ia) and (Ib), according to the synthetic processes described below, can be conducted in a stepwise manner, whereby each intermediate is isolated and purified by standard purification techniques such as, for example, column chromatography, before carrying out the subsequent reaction. Alternatively, two or more steps of the synthetic sequence can be carried out in a so-called “one-pot” procedure, as known in the art, whereby only the compound resulting from the two or more steps is isolated and purified.

    [0154] The compounds of (Ia) and (Ib), prepared with the methods described herein below, may be treated or purified by conventional techniques or means for example by filtration, distillation, chromatography, recrystallization and combination thereof.

    [0155] The salts of compounds of (Ia) and (Ib) may be prepared by reacting a basic compound with the desired acid in solution, or by reacting an acidic compound with the desired base in solution.

    [0156] With the aim of better illustrating the present invention, the syntheses of example compounds reported in Table 1 are provided.

    General Procedures

    [0157] ##STR00014##

    General Procedure 1 (GP1)

    [0158] ##STR00015##

    [0159] [Int-1.1] (2-Bromo-5-methyl-phenyl) hydrazine hydrochloride: 2-Bromo-5-methyl-aniline (1.5 g, 1 eq., 8.15 mmol) was added at 0° C. to a vigorously stirred aqueous solution of HCl 36% (2.9 mL). To the so-obtained suspension, a solution of sodium nitrite (1.1 g, 1.9 eq., 15.8 mmol) in water (1.8 mL) and a solution of tin chloride (4.5 g, 2.4 eq., 19.8 mmol) in HCl 6M (8.2 mL) were added. The reaction mixture was stirred at room temperature for 24 h, and basified with NaOH 12 M. The aqueous phase was extracted with Et.sub.2O (3×20 mL); the combined organic extracts were dried over Na.sub.2SO.sub.4, and filtered. To obtain the hydrazine hydrochloride a saturated solution of HCl in Et.sub.2O was added. The salt was filtered and washed with Et.sub.2O, obtaining a white solid (1.7 g, 89%): .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.16 (bs, 3H), 7.80 (bs, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.93 (d, J=1.8 Hz, 1H), 6.76 (dd, J=8.1, 1.8 Hz, 1H), 2.28 (s, 3H). UPLC-MS: t.sub.R=1.81 min (method A); MS (ESI) m/z calcd for C.sub.7H10BrN.sub.2 (M+H).sup.+: 201.0, found: 201.2.

    Procedures 2

    General Procedure 2a (GP2a)

    [0160] ##STR00016##

    [0161] [Int-2.1] 6-Bromo-9-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride: To a solution of [Int-1.1] (1 g, eq., 4.21 mmol) and Cert-butyl 4-oxopiperidine-1-carboxylate (0.8 g, 1 eq., 4.21 mmol) in EtOH (15 mL), HCl 36% (4 mL)was added. The reaction mixture was heated at 80° C. and stirred for 16 h. The suspension was filtered and washed with Et.sub.2O to furnish the title compound as brown solid (0.6 g, 50%): .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.27 (s, 1H), 9.21 (bs, 2H), 7.17 (d, J=7.7 Hz, 1H), 6.72 (dd, J=7.7, 0.9 Hz, 1H), 4.55 (s, 2H),3.44 (t, J=6.1 Hz, 2H), 3.04 (t, J=6.1 Hz, 2H), 2.50 (s, 3H). UPLC-MS: t.sub.R=1.57 min (method A); MS (ESI) m/z calcd for C.sub.12H.sub.14BrN.sub.2 (M+H).sup.+: 365.0.0, found: 265.3.

    General Procedure 2b (GP2b)

    [0162] ##STR00017##

    [0163] [Int-2.2] 6-Fluoro-9-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride: A solution of [Int-1.2] (0.5 g, 2.83 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.564 g, 2.83 mmol) in EtOH (5 mL) was stirred at room temperature, until the formation of hydrazone intermediate. 2,4,6-Trichloro-1,3,5-triazine (0.208 g, 1.13 mmol) was added and reaction mixture was heated to 90 ° C. for 8h. The reaction mixture was cooled to room temperature and the obtained precipitate was filtered and washed with cold EtOH. The crude product was obtained as a light orange solid (0.65 g, 95%). UPLC-MS: t.sub.R=1.31 min (method A); MS (ESI) m/z calcd for C.sub.12H.sub.14FN.sub.2 (M+H).sup.+: 205.1, found: 205.8.

    General Procedure 2c (GP2c)

    [0164] ##STR00018##

    [0165] [Int-2.3] 8-(Trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole: 4-Trifluoromethylphenyl hydrazine (0.5 g, 2.84 mmol) and 4-oxopiperidine-1-carboxylate (0.4 g, 2.84 mmol) were dissolved in EtOH (15 mL) and the reaction mixture was stirred at room temperature for 30 min, until the complete formation of hydrazone. Solvent was removed under reduced pressure and the crude mixture was dissolved in AcOH (25 mL) following by addition of trifluoroborate diethyletherate (0.7 mL, 5.68 mmol). The reaction was stirred at 90° C. for 16 h. The solvent was removed and the crude mixture was poured into 2M aq.NaOH (15 mL) and extracted with DCM (2×10 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the crude product as brown solid, which was used in the next step without any further purification. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 7.68 (s, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.27 (d, J=8.6 Hz, 1H), 3.88 (d, J=4.9 Hz, 2H), 3.02 (q, J=5.5 Hz, 2H), 2.70 (t, J=5.7 Hz, 2H). UPLC-MS: t.sub.R=1.59 min (method A); MS (ESI) m/z calcd for C.sub.12H.sub.12F.sub.3N.sub.2 (M+H).sup.+: 241.1, found: 242.1.

    Procedures 3

    General Procedure 3a (GP3a)

    [0166] [001] [6-(Dimethylamino)-1H-indol-2-yl]-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: 6-(Dimethylamino)-1H-indole-2-carboxylic acid (0.02 g, 1 eq., 0.12 mmol), HATU (0.05 g, 1.1 eq., 0.13 mmol) and DIPEA (0.04 mL, 2 eq., 0.24 mmol) were dissolved in DMF (2 mL) and stirred at room temperature for 10 min. 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole (0.03 g, 1 eq., 0.12 mmol) was added and the reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with 2M aq. HCl (10 mL) and the aqueous phase was extracted with EtOAc (2×10 mL). The combined extracts were washed sequentially with water (15 mL) and brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the crude product. The title compound was obtained after preparative LC-MS, as a white solid (0.01 g, 34%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.11 (s, 1H), 10.97 (s, 1H), 7.46 (dd, J=8.1, 4.8 Hz, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.10-7.02 (m, 1H), 6.97 (t, J=7.5 Hz, 1H), 6.87 (s, 1H), 6.75 (dd, J=8.9, 2.3 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 4.94 (s, 2H), 4.12 (d, J=5.9 Hz, 2H), 2.98 (s, 2H), 2.92 (s, 6H). UPLC-MS: t.sub.R=2.27 min (method A); MS (ESI) m/z calcd for C.sub.22H.sub.23N.sub.40 (M+H).sup.+: 359.2, found: 359.3.

    General Procedure 3b (GP3b)

    [0167] [004] 1,3,4,5-Tetrahydropyrido[4,3-b]indol-2-yl-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: To a solution of 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (20 mg, 0.12 mmol) in DCM (1 ml), DMF (cat.) and oxalyl chloride (20 μL, 0.24 mmol) were added at 0° C. under N.sub.2 atmosphere, and the reaction mixture was stirred at room temperature for 30 min. The solvent was removed under reduced pressure. Toluene (3mL) was added and solvent evaporated again. The obtained acyl chloride was added to a solution of 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.02 g, 1 eq., 0.12 mmol) and Et.sub.3N (0.03 mL, 2 eq., 0.24 mmol) in DCM (2 mL) cooled to 0° C. The reaction mixture was stirred at room temperature for 16 h, and quenched with aq. 2M HCl (10 mL). The aqueous phase was extracted with DCM (2×10 mL, and the combined extracts were washed with water (15 mL),brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the crude product, which was purified by flash chromatography eluting with cyclohexane/EtOAc (8:2) to give the pure title compound as white solid (0.02 g, 45%). .sup.1H NMR (400 MHz, DMSO-d.sub.6 ): δ 14.39 (s, 1H), 10.99 (s, 1H), 7.54-7.40 (m, 1H), 7.37-7.17 (m, 2H), 7.11-6.87 (m, 2H), 4.86 (d, J=31.0 Hz, 2H), 4.20-3.73 (m, 2H), 2.95 (d, J=33.2 Hz, 2H). UPLC-MS: t.sub.R=2.27 min (method A); MS (ESI) m/z calcd for C.sub.16H.sub.14F.sub.3N.sub.4O (M+H).sup.+: 335.1, found: 335.3.

    General Procedure 3c (GP3c)

    [0168] [029] (5-bromo-2-furyl)-(1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)methanone: 5-Bromofuran-2-carboxylic acid (0.06 g, 1 eq., 0.32 mmol), 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole (0.06 g, 1 eq., 0.32 mmol), Et.sub.3N (0.09 mL, 2 eq., 0.64 mmol) and EDC.Math.HCl (0.07 g, 1.1 eq., 0.38 mmol) were dissolved in DCM (2 mL) and stirred at room temperature for 16 h. The reaction was quenched with aq. 2M HCl (10 mL) and the aqueous phase was extracted with EtOAc (2×10 mL). The combined extracts were washed with water (15 mL), brine (15 mL), dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo to afford the crude product, which was purified by flash chromatography eluting with DCM/EtOAc (0 to 20%) to give the pure title compound as white solid (0.02 g, 20%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.96 (s, 1H), 7.43 (d, J=7.7 Hz, 1H), 7.37-7.24 (m, 1H), 7.14 (d, J=3.5 Hz, 1H), 7.05 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.01-6.93 (m, 1H), 6.81 (d, J=3.5 Hz, 1H), 4.81 (bs, 2H), 3.99 (t, J=5.7 Hz, 2H), 2.94 (bs, 2H). UPLC-MS: t.sub.R=2.17 min (method A); MS (ESI) m/z calcd for C.sub.16H.sub.14BrN.sub.2O.sub.2 (M+H).sup.+: 345.0, found: 345.6.

    Synthesis of Substituted Phenyl-Hydrazines

    [0169] ##STR00019##

    [0170] [Int-1.2] (2-Fluoro-5-methyl-phenyl) hydrazine hydrochloride: Following GP1, the title compound was obtained from 2-fluoro-5-methyl-aniline, as crude product as a light brown powder in a quantitative yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.02 (s, 3H), 8.81 (s, 1H), 6.97 (dd, J=8.6, 2.2 Hz, 1H), 6.91 (dd, J=12.0, 8.1 Hz, 1H), 6.50 (ddd, J=7.5, 4.6, 2.1 Hz, 1H), 2.23 (s, 3H). UPLC-MS: t.sub.R=1.39 min (Method A); MS (ESI) m/z calcd for C.sub.7H.sub.10FN.sub.2 (M+H).sup.+: 141.1, found: 141.3.

    ##STR00020##

    [0171] [Int-1.3] (2-Fluoro-4-methoxy-phenyl) hydrazine hydrochloride: Following GP1, the title compound was obtained from 2-fluoro-3-methoxy-aniline, as a light pink powder in 51% yield. UPLC-MS: t.sub.R=1.42 min (Method A); MS (ESI) m/z calcd for C.sub.7H.sub.10FN.sub.2O (M+H).sup.+: 157.1, found: 157.3

    ##STR00021##

    [0172] [Int-1.4] (2-Fluoro-5-(trifluoromethyl)phenyl)hydrazine hydrochloride: Following GP1, the title compound was obtained from 2-fluoro-5-(trifuoromethyl)aniline, as a light pink powder in 15% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.49 (br s, 3H), 8.68 (s, 1H), 7.62 (dd, J=7.9, 2.2 Hz, 1H), 7.43 (dd, J=11.2, 8.5 Hz, 1H), 7.36-7.29 (m, 1H). UPLC-MS: t.sub.R=1.37 min (Method A); MS (ESI) m/z calcd for C.sub.7H.sub.7F.sub.4N.sub.2 (M+H).sup.+: 195.0, found: 195.2

    ##STR00022##

    [0173] [Int-1.5] (2-Fluoro-4-(trifluoromethyl)phenyl)hydrazine hydrochloride: Following GP1, the title compound was obtained from 2-fluoro-3-(trifuoromethyl)aniline, as a light brown powder in 66% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.49 (br s, 3H), 8.87 (s, 1H), 7.64 (dd, J=11.7, 2.0 Hz, 1H), 7.57 (dd, J=8.5, 2.0 Hz, 1H), 7.31 (t, J=8.5 Hz, 1H). UPLC-MS: t.sub.R=1.42 min (Method A); MS (ESI) m/z calcd for C.sub.7H.sub.7F.sub.4N.sub.2 (M+H).sup.+: 195.0, found: 195.6

    Synthesis of Substituted Tetrahydro-γ-Carbolines

    [0174] ##STR00023##

    [0175] [Int-2.5] 6,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from (2,4-dimethylphenyl)hydrazine, and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 47% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.81 (s, 1H), 7.01 (s, 1H), 6.71 (s, 1H), 4.15 (s, 2H), 2.93 (t, J=6.0 Hz, 2H), 2.39 (s, 3H), 2.32 (s, 3H). UPLC-MS: t.sub.R=1.52 min (Method A); MS (ESI) m/z calcd for C.sub.13H.sub.17N.sub.2 (M+H).sup.+: 201.1, found: 201.3.

    ##STR00024##

    [0176] [Int-2.6] 6-Fluoro-8-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride: Following GP2a, the title compound was obtained from (2-fluoro-4-methyl-phenyl)hydrazine, and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 63% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.46 (s, 1H), 7.08 (s, 1H), 6.79 (d, J=12.4 Hz, 1H), 4.27 (s, 2H), 3.47 (t, J=6.1 Hz, 2H), 3.00 (t, J=6.0 Hz, 2H), 2.37 (s, 3H). UPLC-MS: t.sub.R=1.44 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.4FN.sub.2 (M+H).sup.+: 205.1, found: 205.2.

    ##STR00025##

    [0177] [Int-2.7] 6,9-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from (2,5 dimethylphenyl)hydrazine, and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 47% yield. UPLC-MS: t.sub.R=1.47 min (Method A); MS (ESI) m/z calcd for C.sub.13H.sub.17N.sub.2 (M+H).sup.+: 201.1, found: 201.3.

    ##STR00026##

    [0178] [Int-2.8] 9-Fluoro-6-methyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride: Following GP2a, the title compound was obtained from (5-fluoro-2-methyl-phenyl)hydrazine hydrochloride, and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 26% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.35 (s, 1H), 6.87-6.80 (m, 1H), 6.68 (dd, J=10.8, 7.9 Hz, 1H), 4.38 (s, 2H), 3.46 (t, J=6.1 Hz, 2H), 3.03 (t, J=6.2 Hz, 2H), 2.40 (s, 3H).UPLC-MS: t.sub.R=1.44 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.14FN .sub.2 (M+H).sup.+: 205.1, found: 205.3.

    ##STR00027##

    [0179] [Int-2.9] 6,8-Difluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from (2,4-difluoro-phenyl)hydrazine hydrochloride, and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 51% yield: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (s, 1H), 9.28 (s, 2H), 7.19 (dd, J=9.4, 2.2 Hz, 1H), 6.98 (ddd, J=11.7, 9.8, 2.3 Hz, 1H), 4.26 (s, 2H), 3.46 (t, J=6.1 Hz, 2H), 3.03 (t, J=6.1 Hz, 2H). UPLC-MS: t.sub.R=1.35 min (Method A); MS (ESI) m/z calcd for C.sub.11H.sub.11F.sub.2N.sub.2 (M+H).sup.+: 209.1, found: 209.3.

    ##STR00028##

    [0180] [Int-2.11] 2-Methyl-5,6,7,8,9,10-hexahydro-7,10-epimino cyclohepta[b]indole hydrochloride: Following GP2a, the title compound was obtained from 4-tolyl hydrazine and tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate, as a white solid in 36% yield. UPLC-MS: t.sub.R=1.48 min (Method A); MS (ESI) m/z calcd for C.sub.14H.sub.17N.sub.2 (M+H).sup.+: 212.1, found: 212.2.

    ##STR00029##

    [0181] [Int-2.12] 4-Fluoro-2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride: Following GP2a, the title compound was obtained from (2-fluoro-4-methyl-phenyl)hydrazine hydrochloride and tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate, as a white solid in 36% yield. UPLC-M S: t.sub.R=1.55 min (Method A); MS (ESI) m/z calcd for C.sub.14H.sub.16FN.sub.2 (M+H).sup.+: 231.1, found: 231.2.

    ##STR00030##

    [0182] [Int-2.13] 4-Fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole hydrochloride: Following GP2a, the title compound was obtained from [Int-1.2] and tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate, as a white solid in 37% yield. UPLC-MS: t.sub.R=1.56 min (Method A); MS (ESI) m/z calcd for C.sub.14H.sub.16FN.sub.2 (M+H).sup.+: 231.1, found: 231.3.

    ##STR00031##

    [0183] [Int-2.14] 6-Fluoro-4,4,9-trimethyl-1,2,3,5-tetrahydropyrido[4,3-b]indole hydrochloride: Following GP2a, the title compound was obtained from [Int-1.2] and tert-butyl 3,3-dimethyl-4-oxo-piperidine-1-carboxylate, as a brown solid in 34% yield. UPLC-MS: t.sub.R=1.49 min (Method A); MS (ESI) m/z calcd for C.sub.14H.sub.18FN.sub.2 (M+H).sup.+: 233.1, found: 233.1.

    ##STR00032##

    [0184] [Int-2.17] 6,9-Difluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from (2,5-difluorophenyl)hydrazine and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 22% yield. UPLC-MS: t.sub.R=1.69 min (Method A); MS (ESI) m/z calcd for C.sub.11H.sub.11F.sub.2N.sub.2 (M+H).sup.+: 209.1, found: 209.5.

    ##STR00033##

    [0185] [Int-2.18] Mixture of 6-Fluoro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride and 6-Chloro-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride: Following GP2a, a mixture of the title compounds was obtained from [Int-1.3] and Cert-butyl 4-oxopiperidine-1-carboxylate, as brown solid in 39% total yield. UPLC-MS: t.sup.R1 =1.39 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.13ClN.sub.2O (M+H).sup.+: 237.1, found: 237.4; t.sub.R2=1.52 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.14FN.sub.2O (M+H).sup.+: 221.1, found: 221.8.

    ##STR00034##

    [0186] [Int-2.20] 6-Fluoro-9-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride: Following GP2a, the title compound was obtained from [Int-1.4] and tert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 21% yield. UPLC-MS: t.sub.R=1.41 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.11F.sub.4N.sub.2 (M+H).sup.+: 259.1, found: 259.1.

    ##STR00035##

    [0187] [Int-2.21] 6-Fluoro-8-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride: Following GP2a, the title compound was obtained from [Int-1.5] and Cert-butyl 4-oxopiperidine-1-carboxylate, as a brown solid in 32% yield: UPLC-MS: t.sub.R=1.41 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.11F.sub.4N.sub.2 (M+H).sup.+: 259.1, found: 259.1.

    ##STR00036##

    [0188] [Int-2.22] 8-Isopropyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from (4-isopropylphenyl)hydrazine and tert-butyl 4-oxopiperidine-1-carboxylate, as a white solid in 42% yield. UPLC-MS: t.sub.R=1.67 min (Method A); MS (ESI) m/z calcd for C.sub.14H.sub.19N.sub.2 (M+H).sup.+: 215.1, found: 215.2.

    ##STR00037##

    [0189] [Int-2.23] 6-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from o-tolylhydrazine and Cert-butyl 4-oxopiperidine-1-carboxylate, as a white solid in 42% yield. UPLC-MS: t.sub.R=1.31 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.15N.sub.2 (M+H).sup.+: 187.1, found: 187.2.

    ##STR00038##

    [0190] [Int-2.24] Mixture of 7-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride and 9-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride: Following GP2a, a mixture of the title compounds was obtained from (3-methylphenyl) hydrazine and tert-butyl 4-oxopiperidine-1-carboxylate, as a white solid in 50% total yield. UPLC-MS: t.sub.R1=1.27 min, t.sub.R2=1.31 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.15N.sub.2 (M+H).sup.+: 187.1, found: 187.1.

    ##STR00039##

    [0191] [Int-2.25] 8-Bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole hydrochloride: Following GP2a, the title compound was obtained from (4-bromophenyl)hydrazine hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate, after purification by trituration with chilled ethanol, as an off-white solid in 16% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.38 (s, 1H), 9.24 (br s, 2H), 7.69 (d, J=1.9 Hz, 1H), 7.32 (d, J=8.6 Hz, 1H), 7.20 (dd, J=8.6, 1.9 Hz, 1H), 4.28 (s, 2H), 3.46 (t, J=6.1 Hz, 2H), 3.03 (t, J=6.1 Hz, 2H); UPLC-MS: t.sub.R=1.48 min (generic method); MS (ESI) m/z calcd for C.sub.11H.sub.12BrN.sub.2 (M+H).sup.+: 251.0, found: 251.1.

    ##STR00040##

    [0192] [Int-2.26] 8-(Trifluoromethoxy)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2a, the title compound was obtained from (4-trifluoromethoxy)hydrazine hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate, after purification by trituration with chilled ethanol as the solvent. The solid was partitioned between EtOAc (50 mL) and sat. aq. NaHCO.sub.3 (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced pressure. The resultant residue was purified by silica gel flash-column chromatography, with DCM/MeOH (9:1) as the eluent, to yield the title compound as a yellow solid in 8% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.11 (s, 1H), 7.41-7.23 (m, 2H), 6.97 (dd, J=8.9, 2.3 Hz, 1H), 3.94 (s, 2H), 3.12 (t, J=5.8 Hz, 2H), 2.76 (t, J=5.8 Hz, 2H); UPLC-MS: t.sub.R=1.64 min (generic method); MS (ESI) m/z calcd for C.sub.12H.sub.12F.sub.3N.sub.2O (M+H).sup.+: 257.1, found: 257.2.

    ##STR00041##

    [0193] [Int-2.27] 6-Fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b] indole: Following GP2a, the title compound was obtained from (2-fluorophenyl)hydrazine hydrochloride and tert-butyl 4-oxopiperidine-1-carboxylate, after purification by trituration with chilled ethanol as the solvent. The solid was partitioned between EtOAc (50 mL) and sat. aq. NaHCO.sub.3 (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced pressure. The resultant residue was purified by silica gel flash-column chromatography, with DCM/MeOH/Et.sub.3N (9:1:0.1) as the eluent, to yield the title compound as an off-white solid in 5% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.25 (s, 1H), 7.16 (d, J=7.7 Hz, 1H), 6.96-6.77 (m, 1H), 3.94 (s, 2H), 3.11 (t, J=5.8 Hz, 2H), 2.75 (t, J=5.8 Hz, 2H); UPLC-MS: t.sub.R=1.25 min (generic method); MS (ESI) m/z calcd for C.sub.11H.sub.12FN.sub.2 (M+H).sup.+: 191.1, found: 191.1.

    ##STR00042##

    [0194] [Int-2.28] 8-Methylsulfonyl-2,3,4,5-tetrahydro-1H-pyrido [4,3-b]indole hydrochloride: Following GP2c, the title compound was obtained from (4-methylsulfonylphenyl)hydrazine hydrochloride and piperidin-4-one hydrochloride, after purification by trituration with DCM as the solvent, as a yellow solid in a quantitative yield. UPLC-MS: t.sub.R=1.08 min (generic method); MS (ESI) m/z calcd for C.sub.12H.sub.15N.sub.2O.sub.2S (M+H).sup.+: 251.1, found: 251.1.

    ##STR00043##

    [0195] [Int-2.29] 2,3,4,5-Tetrahydro-1H-pyrido[4,3-b]indole-8-carbonitrile hydrochloride: Following GP2c, the title compound was obtained from 4-hydrazinobenzonitrile hydrochloride and piperidin-4-one hydrochloride, after purification by trituration with chilled ethanol as the solvent, as a yellow solid in 73% yield. UPLC-MS: t.sub.R=1.10 min (generic method); MS (ESI) m/z calcd for C.sub.12H.sub.12N.sub.3 (M+H).sup.+: 198.1, found: 198.1.

    ##STR00044##

    [0196] [Int-2.30] 2-Benzyl-4,4,8-trimethyl-3,5-dihydro-1H-pyrido [4,3-b]indole: Following GP2a, the title compound was obtained from p-tolylhydrazine and 1-benzyl-3,3-dimethyl-piperidin-4-one, after purification by trituration with chilled ethanol as the solvent. The solid was partitioned between EtOAc (50 mL) and sat. aq. NaHCO.sub.3 (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced pressure. The resultant residue was purified by silica gel flash-column chromatography, with DCM/MeOH (95:5) as the eluent, to yield the title compound as a yellow oil in 16% yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.64 (s, 1H), 7.45-7.31 (m, 4H), 7.30-7.23 (m, 1H), 7.14 (d, J=8.2 Hz, 1H), 7.02 (br s, 1H), 6.81 (dd, J=8.2, 1.6 Hz, 1H), 3.72 (s, 2H), 3.51 (s, 2H), 2.45 (s, 2H), 2.31 (s, 3H), 1.26 (s, 6H); UPLC-MS: t.sub.R=1.82 min (apolar method); MS (ESI) m/z calcd for C.sub.21H.sub.25N.sub.2 (M+H).sup.+: 305.2, found: 305.3.

    ##STR00045##

    [0197] [Int-2.31] 4,4,8-Trimethyl-1,2,3,5-tetrahydropyrido[4,3-b] indole: To a solution of [Int-2.30] (0.1 g, 0,33 mmol) in EtOH (5 mL) were added NH.sub.4HCO.sub.2 (0.208 g, 3.30 mmol) and Pd/C (0.010 g), and the resultant mixture stirred at room temperature for 4 h. The suspension was filtered through a pad of celite and the filtrate evaporated under reduced pressure. The resultant residue was partitioned between EtOAc (50 mL) and sat. aq. NaHCO.sub.3 (50 mL). The organic phase was separated, washed with brine (50 mL), dried over anhydrous Na.sub.2SO.sub.4, filtered and the solvent evaporated under reduced pressure to yield the title compound as a yellow solid in a quantitative yield. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.57 (s, 1H), 7.14 (d, J=8.1 Hz, 1H), 7.06 (br s, 1H), 6.81 (dd, J=8.1, 1.6 Hz, 1H), 3.79 (s, 2H), 2.71 (s, 2H), 2.33 (s, 3H), 1.24 (s, 6H); UPLC-MS: t.sub.R=1.50 min (generic method); MS (ESI) m/z calcd for C.sub.14H.sub.19N.sub.2 (M+H).sup.+: 215.2, found: 215.2.

    ##STR00046##

    [0198] [Int-2.32] (R/S)-6-Fluoro-3,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.2] and tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 29% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.03 (bs), 6.64 (dd, J=11.3, 7.6 Hz, 1H), 6.57 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 4.17 (dd, J=14.8, 1.1 Hz, 1H), 4.08 (app-dt, J=14.8, 1.8, 1.8 Hz, 1H), 2.89 (m, 1H), 2.67 (ddd, J=17.5, 3.5, 1.5 Hz, 1H), 2.34 (m, 1H), 2.44 (s, 3H), 1.18 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.46 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17FN.sub.2O (M+H).sup.+: 218.27; found: 219.4.

    ##STR00047##

    [0199] [Int-2.33] (R/S)-6-Fluoro-1,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.2] and tert-butyl 2-methyl-4-oxo-piperidine-1-carboxylate, a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated Purification by neutral alumina column chromatography with DCM/MeOH:NH.sub.3 (95:5:0.1) gave the title compound as a brown resin with a 6% yield: .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.06 (bs), 6.66 (dd, J=11.1, 7.6 Hz, 1H), 6.58-6.61 (m, 1H), 4.39 (q, J=6.5 Hz, 1H), 3.10 (ddd, J=13.1, 10.2, 4.9 Hz, 1H), 2.97 (ddd, J=12.8, 6.1, 2.2Hz, 1H), 2.66 (m, 1H), 2.56 (ddd, J=16.0, 4.8, 2.0 Hz, 1H), 2.50 (s, 3H), 1.37 (d, J=6.5 Hz, 3H). UPLC-MS: t.sub.R=1.46 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17FN.sub.2O (M+H).sup.+: 218.27; found: 219.4.

    ##STR00048##

    [0200] [Int-2.34] (R)-6-Fluoro-3,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.2] and tert-butyl (R)-2-methyl-4-oxo-piperidine-1-carboxylate, a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 28% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.03 (bs), 6.64 (dd, J=11.3, 7.6 Hz, 1H), 6.57 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 4.17 (dd, J=14.8, 1.1 Hz, 1H), 4.08 (app-dt, J=14.8, 1.8, 1.8 Hz, 1H), 2.89 (m, 1H), 2.67 (ddd, J=17.5, 3.5, 1.5 Hz, 1H), 2.34 (m, 1H), 2.44 (s, 3H), 1.18 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.46 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17FN.sub.2O (M+H).sup.+: 218.27; found: 219.4.

    ##STR00049##

    [0201] [Int-2.35] (S)-6-fluoro-3,9-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.2] and tert-butyl (S)-2-methyl-4-oxo-piperidine-1-carboxylate, a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated. After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 28% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.03 (bs), 6.64 (dd, J=11.3, 7.6 Hz, 1H), 6.57 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 4.17 (dd, J=14.8, 1.1 Hz, 1H), 4.08 (app-dt, J=14.8, 1.8, 1.8 Hz, 1H), 2.89 (m, 1H), 2.67 (ddd, J=17.5, 3.5, 1.5 Hz, 1H), 2.34 (m, 1H), 2.44 (s, 3H), 1.18 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.46 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17FN.sub.2O (M+H).sup.+: 218.27; found: 219.4.

    ##STR00050##

    [0202] [Int-2.36] 6-Fluoro-3,3,9-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.2] and tert-butyl 2,2-dimethyl-4-oxo-piperidine-1-carboxylate, the title compound was obtained after purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1), as a brown solid with a 15% yield. .sup.1H-NMR (400 MHz, CDCl.sub.3) δ 8.28 (bs, 1H), 6.62-6.72 (m, 2H), 4.28 (s, 2H), 2.52 (s, 2H), 2.35 (s, 3H), 1.42 (s, 6H). UPLC-MS: t.sub.R=1.46 min (Method A); MS (ESI) m/z calcd for C.sub.14H.sub.17FN.sub.2 (M+H).sup.+: 233.3; found: 233.5.

    ##STR00051##

    [0203] [Int-2.37] (S)-6,9-Difluoro-3-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2c, using (2,5-difluorophenyl)hydrazine hydrochloride and tert-butyl (S)-methyl-4-oxo-piperidine-1-carboxylate, a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 23% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.40 (bs, 1H), 6.75 (ddd, J=12.1, 8.5, 3.6 Hz, 1H), 6.61 (ddd, J=11.7, 8.5, 3.2 Hz, 1H), 3.99 (d, J=15.6 Hz, 1H), 3.94 (app-dt, J=15.1, 1.9, 1.9 Hz, 1H), 2.92 (m, 1H), 2.69 (ddd, J=16.3, 3.7, 1.6 Hz, 1H), 2.34 (app-dt, J=16.2, 2.0, 2.0 Hz, 1H), 1.18 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.29 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.12F2N.sub.2 (M+H).sup.+: 223.1; found: 223.4.

    ##STR00052##

    [0204] [Int-2.38] (R/S)-6,9-Difluoro-1-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2c, using (2,5-difluorophenyl)hydrazine hydrochloride and tert-butyl (S)-methyl-4-oxo-piperidine-1-carboxylate, a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated Purification by neutral alumina column chromatography with DCM/MeOH:NH.sub.3 (95:5:0.1) gave the title compound as a brown resin with a 6% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.06 (bs), 6.66 (dd, J=11.1, 7.6 Hz, 1H), 6.58-6.61 (m, 1H), 4.39 (q, J=6.5 Hz, 1H), 3.10 (ddd, J=13.1, 10.2, 4.9 Hz, 1H), 2.97 (ddd, J=12.8, 6.1, 2.2Hz, 1H), 2.66 (m, 1H), 2.56 (ddd, J=16.0, 4.8, 2.0 Hz, 1H), 2.50 (s, 3H), 1.37 (d, J=6.5 Hz, 3H). UPLC-MS: t.sub.R=1.46 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17FN.sub.2O (M+H).sup.+: 218.27; found: 219.4.

    ##STR00053##

    [0205] [Int-2.39] (R)-6,9-Difluoro-3-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2c, using (2,5-difluorophenyl)hydrazine hydrochloride and tert-butyl (R)-methyl-4-oxo-piperidine-1-carboxylate, a 8:2 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 23% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.40 (bs, 1H), 6.75 (ddd, J=12.1, 8.5, 3.6 Hz, 1H), 6.61 (ddd, J=11.7, 8.5, 3.2 Hz, 1H), 3.99 (d, J=15.6 Hz, 1H), 3.94 (app-dt, J=15.1, 1.9, 1.9 Hz, 1H), 2.92 (m, 1H), 2.69 (ddd, J=16.3, 3.7, 1.6 Hz, 1H), 2.34 (app-dt, J=16.2, 2.0, 2.0 Hz, 1H), 1.18 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.29 min (Method A); MS (ESI) m/z calcd for C.sub.12H.sub.12F.sub.2N.sub.2 (M+H).sup.+: 223.1; found: 223.4.

    ##STR00054##

    [0206] [Int-2.40] (S)-6-Fluoro-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.3] and tert-butyl (S)-methyl-4-oxo-piperidine-1-carboxylate, a 7:3 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 18% yield. .sup.1H-NMR (400 MHz, DMSO-d6) □ 10.90 (bs), 6.66 (d, J=2.2 Hz, 1H), 6.50 (dd, J=12.8, 2.1 Hz, 1H), 3.87 (d, J=14.5 Hz, 1H), 3.80 (d, J=13.8 Hz, 1H), 3.73 (s, 3H), 3.16 (m, 1H), 2.92 (m, 1H), 2.66 (m, 1H), 2.32 (m, 1H), 1.19 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.28 min (Method A); MS (ESI) m/z calcd for C.sub.13H.sub.15FN.sub.2O (M+H).sup.+: 235.27; found: 235.4.

    ##STR00055##

    [0207] [Int-2.41] (R/S)-6-Fluoro-1-methyl-6-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.3] and tert-butyl (S)-methyl-4-oxo-piperidine-1-carboxylate a 7:3 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated Purification by neutral alumina column chromatography with DCM/MeOH:NH.sub.3 (95:5:0.1) gave the title compound as a brown solid with a 6% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 10.94 (bs), 6.71 (d, J=2.1 Hz, 1H), 6.51 (dd, J=12.8, 2.1 Hz, 1H), 4.03 (q, J=6.5 Hz, 1H), 3.73 (s, 3H), 3.17 (m, 1H), 3.11 (app-dt, J=12.5, 5.0, 5.0 Hz, 1H), 2.84 (ddd, J=12.3, 7.5, 5.2 Hz, 1H), 2.61 (app-dtd, J=16.6, 5.1, 5.1, 1.2 Hz, 1H), 1.36 (d, J=6.5 Hz, 3H). UPLC-MS: t.sub.R=1.28 min (Method A); MS (ESI) m/z calcd for C.sub.13H.sub.15FN.sub.2O (M+H).sup.+: 235.27; found: 235.4.

    ##STR00056##

    [0208] [Int-2.42] (3R)-6-Fluoro-8-methoxy-3-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP2b, using [Int-1.3] and tert-butyl (2R)-methyl-4-oxo-piperidine-1-carboxylate, a 7:3 mixture of regioisomers was afforded. Hydrochloride salt was removed with sat. aq. NaHCO.sub.3, and aqueous layer was exctracted with EtOAc (3×20mL). Organics were dried over Na.sub.2SO.sub.4, filtered, and evaporated After purification by neutral alumina chromatography with DCM/MeOH/NH.sub.3 (95:5:0.1) the title compound was obtained as a brown solid with a 18% yield. .sup.1H-NMR (400 MHz, DMSO-d6) δ 10.90 (bs), 6.66 (d, J=2.2 Hz, 1H), 6.50 (dd, J=12.8, 2.1 Hz, 1H), 3.87 (d, J=14.5 Hz, 1H), 3.80 (d, J=13.8 Hz, 1H), 3.73 (s, 3H), 3.16 (m, 1H), 2.92 (m, 1H), 2.66 (m, 1H), 2.32 (m, 1H), 1.19 (d, J=6.3 Hz, 3H). UPLC-MS: t.sub.R=1.28 min (Method A); MS (ESI) m/z calcd for C.sub.13H.sub.15FN.sub.2O (M+H).sup.+: 235.27; found: 235.4.

    Synthesis of Final Compounds

    [0209] [002] (1-Phenyl-1-H-pyrazol-4-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3b, the title compound was obtained from 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.060 g, 0.32 mmol) and 1-phenylpyrazole-4-carboxylic acid (0.030 g, 0.32 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.030 g, 26%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.95 (s, 1H), 8.89 (s, 1H), 8.07 (s, 1H), 7.98-7.88 (m, 2H), 7.54 (dd, J=8.6, 7.3 Hz, 2H), 7.45 (d, J=7.8 Hz, 1H), 7.42-7.33 (m, 1H), 7.30 (d, J=8.0 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.96 (s, 1H), 5.00-4.70 (m, 2H), 4.09-3.93 (m, 2H), 3.07-2.83 (m, 2H). UPLC-MS: t.sub.R=2.12 min (Method A); MS (ESI) m/z calcd for C.sub.21H.sub.19N.sub.4O (M+H).sup.+: 343.1, found: 343.2.

    [0210] [003] (8-Methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.20 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.055 g, 76%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.38 (s, 1H), 10.79 (s, 1H), 7.42-7.08 (m, 2H), 7.14-6.83 (m, 1H), 6.68 (dd, J=8.6, 2.4 Hz, 1H), 5.02-4.63 (m, 2H), 4.12-3.84 (m, 2H), 3.84-3.56 (m, 3H), 3.11-2.72 (m, 2H); UPLC-MS: t.sub.R=2.00 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O.sub.2 (M+H).sup.+: 365.1, found: 365.1.

    [0211] [005] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]mathanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.030 g, 40%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.37 (s, 1H), 10.82 (s, 17H), 7.37-6.96 (m, 3H) 6.87 (s, 3H), 4.92-4.69 (m, 2H), 4.10-3.77 (m, 2H), 3.04-2.71 (m, 2H), 2.43-2.25 (m, 3H); UPLC-MS: t.sub.R=2.21 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O (M+H).sup.+: 349.1, found: 349.1.

    [0212] [006] (5-Methyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (0.032 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (1:1) as the eluent, as an off-white solid (0.031 g, 49%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.86 (s, 1H), 10.75 (s, 1H), 7.29-6.97 (m, 2H), 6.91-6.76 (m, 1H), 6.60-6.20 (m, 1H), 4.90 (app-d, J=130.5 Hz, 2H), 4.19 (s, 1H), 3.98 (s, 1H), 2.99-2.67 (m, 2H), 2.41-2.30 (m, 3H), 2.31-2.21 (m, 3H); UPLC-MS: t.sub.R=1.82 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.19N.sub.4O (M+H).sup.+: 295.2, found: 295.1.

    [0213] [007] (5-Isopropyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 5-isopropyl-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (4:6) as the eluent, as a white solid (0.037 g, 54%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.91 (s, 1H), 10.75 (s, 1H), 7.28-6.95 (m, 2H), 6.93-6.75 (m, 1H), 6.62-6.20 (m, 1H), 4.93 (app-d, J=150.3 Hz, 2H), 4.21 (s, 1H), 3.98 (s, 1H), 3.19-2.69 (m, 3H), 2.35 (app-d, J=13.1 Hz, 3H), 1.31-1.02 (m, 6H); UPLC-MS: t.sub.R=2.06 min (generic method); MS (ESI) m/z calcd for C.sub.19H.sub.23N.sub.4O (M+H).sup.+: 323.2, found: 323.2.

    [0214] [008] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 1H-pyrazole-3-carboxylic acid (0.022 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (4:6) as the eluent, as an off-white solid (0.022 g, 37%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 5 13.22 (s, 1H), 10.78 (s, 1H), 8.02-7.44 (m, 1H), 7.37-6.96 (m, 2H), 6.96-6.77 (m, 1H), 6.74-6.45 (m, 1H), 4.93 (app-d, J=123.2 Hz, 2H), 4.19 (s, 1H), 4.01 (s, 1H), 3.06-2.72 (m, 2H), 2.36 (app-d, J=16.1 Hz, 3H); UPLC-MS: t.sub.R=1.75 min (generic method); MS (ESI) m/z calcd for C.sub.16H.sub.17N.sub.4O (M+H).sup.+: 281.1, found: 281.1.

    [0215] [009] [6-(Dimethylamino)-1H-indol-2-yl]-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 6-(dimethylamino)-1H-indole-2-carboxylic acid (0.048 g, 0.20 mmol) , after purification by silica gel flash-column chromatography with DCM/EtOAc (4:6) as the eluent, as an off-white solid (0.020 g, 33%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.09 (s, 1H), 10.80 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.22 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.91-6.80 (m, 2H), 6.74 (dd, J=8.9, 2.2 Hz, 1H), 6.63 (d, J=2.1 Hz, 1H), 4.91 (br s, 2H), 4.09 (s, 2H), 2.99-2.90 (m, 2H), 2.91 (s, 6H), 2.35 (s, 3H); UPLC-MS: t.sub.R=2.44 min (generic method); MS (ESI) m/z calcd for C.sub.23H.sub.25N.sub.4O (M+H).sup.+: 373.2, found: 373.1.

    [0216] [010] 1H-Indol-2-yl-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 1H-indole-2-carboxylic acid (0.032 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.025 g, 35%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.61 (s, 1H), 10.82 (s, 1H), 7.66 (d, J=7.9 Hz, 1H), 7.46-7.43 (m, 1H), 7.27-7.13 (m, 3H), 7.07 (ddd, J=7.9, 6.9, 1.0 Hz, 1H), 6.97 (br s, 1H), 6.91-6.83 (m, 1H), 4.92 (br s, 2H), 4.06 (s, 2H), 2.96 (s, 2H), 2.35 (s, 3H); UPLC-MS: t.sub.R=2.41 min (generic method); MS (ESI) m/z calcd for C.sub.21H.sub.20N.sub.3O (M+H).sup.+: 330.2, found: 330.1.

    [0217] [011] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[2-(trifluoromethyl)-1H-imidazol-4-yl]-methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 2-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/MeOH (95:5) as the eluent, as a white solid (0.052 g, 78%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.10 (br s, 1H), 10.77 (s, 1H), 7.91 (br s, 1H), 7.33-6.95 (m, 2H), 6.86 (d, J=8.2 Hz, 1H), 5.34-4.53 (m, 2H), 4.52-3.64 (m, 2H), 2.90 (br s, 2H), 2.36 (s, 3H); UPLC-MS: t.sub.R=2.00 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O (M+H).sup.+: 349.1, found: 349.1.

    [0218] [012] (3,5-Dimethyl-1H-pyrazol-4-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 3,5-dimethyl-1H-pyrazole-4-carboxylic acid (0.028 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/MeOH (95:5) as the eluent, as a white solid (0.010 g, 13%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.43 (s, 1H), 10.74 (s, 1H), 7.16 (app-d, J=8.2 Hz, 2H), 6.85 (dd, J=8.0, 1.7 Hz, 1H), 4.61 (br s, 2H), 3.83 (br s, 2H), 2.79 (br s, 2H), 2.33 (s, 3H), 2.16 (s, 3H), 2.08 (s, 3H); UPLC-MS: t.sub.R=1.72 min (generic method); MS (ESI) m/z calcd for C.sub.18H.sub.21N.sub.4O (M+H).sup.+: 309.2, found: 309.2.

    [0219] [013] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-phenyl-1H-pyrazol-3-yl)-methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 5-phenyl-1H-pyrazole-3-carboxylic acid (0.038 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (7:3) as the eluent, as a white solid (0.040 g, 38%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.79-13.27 (m, 1H), 10.78 (s, 1H), 8.01-7.69 (m, 2H), 7.57-7.31 (m, 3H), 7.31-7.11 (m, 2H), 7.12-6.97 (m, 1H), 6.96-6.79 (m, 1H), 5.29-4.50 (m, 2H), 4.40-3.76 (m, 2H), 3.04-2.78 (m, 2H), 2.35 (app-d, J=20.7 Hz, 3H); UPLC-MS: t.sub.R=2.19 min (generic method); MS (ESI) m/z calcd for C.sub.22H.sub.21N.sub.4O (M+H).sup.+: 357.2, found: 357.2.

    [0220] [014] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1-phenylpyrazol-4-yl)methanone: Following GP3a, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.037 g, 0.20 mmol) and 1-phenylpyrazole-4-carboxylic acid (0.038 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (7:3) as the eluent, as a white solid (0.065 g, 69%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.80 (s, 1H), 8.89 (s, 1H), 8.07 (s, 1H), 7.98-7.87 (m, 2H), 7.59-7.48 (m, 2H), 7.42-7.31 (m, 1H), 7.23 (s, 1H), 7.18 (d, J=8.2 Hz, 1H), 6.86 (d, J=8.2 Hz, 1H), 4.83 (app-d, J=44.9 Hz, 2H), 3.98 (app-t, J=5.7 Hz, 2H), 2.92 (app-d, J=24.3 Hz, 2H), 2.35 (s, 3H); UPLC-MS: t.sub.R=2.28 min (generic method); MS (ESI) m/z calcd for C.sub.22H.sub.21N.sub.4O (M+H).sup.+: 357.2, found: 357.2.

    [0221] [015] (5-Isopropyl-1H-pyrazol-3-yl)-(8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3a, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.20 mmol) and 5-isopropyl-1H-pyrazole-3-carboxylic acid (0.031 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (7:3) as the eluent, as a pink solid (0.052 g, 78%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.94 (s, 1H), 10.73 (s, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.88 (app-d, J=93.7 Hz, 1H), 6.69 (dd, J=8.8, 2.4 Hz, 1H), 6.60-6.31 (m, 1H), 4.94 (app-d, J=144.9 Hz, 2H), 4.29-4.15 (m, 1H), 4.08-3.87 (m, 1H), 3.78 (s, 3H), 3.14-2.81 (m, 3H), 1.26 (d, J=6.8 Hz, 6H); UPLC-MS: t.sub.R=1.85 min (generic method); MS (ESI) m/z calcd for C.sub.19H.sub.23N.sub.4O.sub.2 (M+H).sup.+: 339.1, found: 339.2.

    [0222] [016] (8-Methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-methyl-1H-pyrazol-3-yl)-methanone: Following GP3a, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.20 mmol) and 5-methyl-1H-pyrazole-3-carboxylic acid (0.25 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/MeOH (95:5) as the eluent, as an off-white solid (0.058 g, 95%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.86 (s, 1H), 10.72 (s, 1H), 7.18 (d, J=8.6 Hz, 1H), 6.87 (app-d, J=89.3 Hz, 1H), 6.72-6.61 (m, 1H), 6.57-6.27 (m, 1H), 4.90 (app-d, J=124.2 Hz, 2H), 4.18 (s, 1H), 3.97 (s, 1H), 3.90-3.56 (m, 3H), 2.99-2.72 (m, 2H), 2.34-2.11 (m, 3H); UPLC-MS: t.sub.R=1.61 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.19N.sub.4O.sub.2 (M+H).sup.+: 311.1, found: 311.1.

    [0223] [017] (8-Methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1-phenylpyrazol-4-yl)methanone: Following general procedure 3a, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.040 g, 0.20 mmol) and 1-phenylpyrazole-4-carboxylic acid (0.038 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (7:3) as the eluent, as a white solid (0.065 g, 92%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.77 (s, 1H), 8.89 (s, 1H), 8.08 (s, 1H), 7.98-7.88 (m, 2H), 7.54 (dd, J=8.6, 7.3 Hz, 2H), 7.42-7.31 (m, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.99 (s, 1H), 6.68 (dd, J=8.7, 2.4 Hz, 1H), 4.83 (app-d, J=42.1 Hz, 2H), 3.98 (app-t, J=5.7 Hz, 2H), 3.75 (s, 3H), 3.12-2.73 (s, 2H); UPLC-MS: t.sub.R=2.06 min (generic method); MS (ESI) m/z calcd for C.sub.22H.sub.21N.sub.4O.sub.2 (M+H).sup.+: 373.2, found: 373.1.

    [0224] [018] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[1-methyl-5-(trifluoromethyl)pyrazol-3-yl]methanone: To a solution of 5-trifluoromethyl-1H-pyrazole-3-carboxylic acid (0.150 g, 0.8 mmol) in THF (4 mL) and DMF (4 mL) under nitrogen atmosphere, NaH (60% dispersion in mineral oil, 0.067 g, 1.68 mmol) was added at 0° C. Mixture was stirred for 10 min and MeI (60 μL, 0.96 mmol) was added, stirring for other 3 h at room temperature. Mixture was quenched with aqueous HCl 1M until pH 4-5. The aqueous layer was extracted with EtOAc (3×20mL). Collected organic layers were washed with water (10 mL) and brine (10 mL), dried with Na.sub.2SO.sub.4, filtered and solvent evaporated to afford a crud product which was used in the next step without any further purification. Following GP3c the obtained carboxylic acid was coupled with 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. The title compound was obtained, after purification by silica gel flash-column chromatography with DCM/EtOAc (75:15) as the eluent, as a white solid (0.097 g, 18% overall). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.78 (s, 1H), 7.27-7.08 (m, 3H), 6.86 (app-t, J=8.7 Hz, 1H), 4.85 (app-d, J=69.3 Hz, 2H), 4.08 (t, J=5.9 Hz, 1H), 4.05 (s, 3H), 3.99 (t, J=5.6 Hz, 1H), 2.94-2.76 (m, 2H), 2.35 (app-d, J=14.9 Hz, 3H). UPLC-MS: t.sub.R=2.31 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.18F.sub.3N.sub.4O (M+H).sup.+: 363.1, found: 363.2.

    [0225] [019] (5-Isopropyl-1H-pyrazol-3-yl)-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3b, the title compound was obtained from 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.033 g, 0.19 mmol) and 5-isopropyl-1H-pyrazole-3-carboxylic acid (0.03 g, 0.19 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.013 g, 23%). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.92 (s, 1H), 10.90 (s, 1H), 7.44 (d, J=7.8 Hz, 1H), 7.30 (d, J=7.9 Hz, 1H), 7.09-6.88 (m, 2H), 6.41-6.30 (m, 1H), 5.20-5.11 (m, 1H), 4.83-4.71 (m, 1H), 4.29-4.19 (m, 1H), 4.00-3.95 (m, 1H), 3.05-2.94 (m, 1H), 2.94-2.82 (m, 2H), 1.24 (d, J=6.7 Hz, 6H). UPLC-MS: t.sub.R=1.91 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.21N.sub.4O (M+H).sup.+: 309.2, found: 309.2.

    [0226] [021] [6-(Dimethylamino)-1H-indol-2-yl]-(8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3c, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.12 mmol) and 6-(dimethylamino)-1H-indole-2-carboxylic acid (0.025 g, 0.12 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (50:50) as the eluent, as a white solid (0.023 g, 50%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.09 (s, 1H), 10.76 (s, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 6.96 (d, J=2.4 Hz, 1H), 6.85 (s, 1H), 6.73 (dd, J=8.9, 2.3 Hz, 1H), 6.66 (dd, J=8.7, 2.4 Hz, 1H), 6.63 (d, J=2.2 Hz, 1H), 4.89 (bs, 2H), 4.05 (s, 2H), 3.74 (s, 3H), 2.93 (bs, 2H), 2.90 (s, 6H). UPLC-MS: t.sub.R=2.17 min (Method A); MS (ESI) m/z calcd for C.sub.23H.sub.25N.sub.4O.sub.2 (M+H).sup.+: 389.2, found: 389.2.

    [0227] [022] 2-(5-Bromo-2-furoyl)-8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole: Following GP3c, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.063 g, 0.26 mmol) and 5-bromofuran-2-carboxylic acid (0.050 g, 0.26 mmol), after purification by silica gel flash-column chromatography with cyclohexane/EtOAc (8:2) as the eluent, as an off-white solid (0.076 g, 77%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.77 (s, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.14 (d, J=3.6 Hz, 1H), 6.95 (br s, 1H), 6.80 (d, J=3.5 Hz, 1H), 6.68 (dd, J=8.7, 2.5 Hz, 1H), 4.77 (br s, 2H), 3.97 (app-t, J=5.6 Hz, 2H), 3.75 (s, 3H), 2.90 (br s, 2H); UPLC-MS: t.sub.R=2.07 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.16BrN.sub.2O.sub.3 (M+H).sup.+: 375.0, found: 375.1.

    [0228] [023] (5-Bromo-2-furyl)-(8-methyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol) and 5-bromofuran-2-carboxylic acid (0.052 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (90:10) as the eluent, as a white solid (0.058 g, 60%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.80 (s, 1H), 7.26-7.15 (m, 2H), 7.13 (d, J=3.5 Hz, 1H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 6.79 (d, J=3.5 Hz, 1H), 4.78 (bs, 2H), 3.97 (t, J=5.7 Hz, 2H), 2.90 (bs, 2H), 2.35 (s, 3H). UPLC-MS: t.sub.R=2.30 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16BrN.sub.2O.sub.2 (M+H).sup.+: 359.0, found: 359.0.

    [0229] [024] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-2-furyl]-methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol)and 5-trifluoromethyl-2-carboxylic acid (0.048 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (90:10) as the eluent, as a white solid (0.078 g, 83%). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.83 (s, 1H), 7.43 (dq, J=3.7, 1.2 Hz, 1H), 7.35-7.07 (m, 3H), 6.88 (dd, J=8.2, 1.6 Hz, 1H), 4.81 (app-d, J=40.3 Hz, 2H), 3.98 (s, 2H), 3.10-2.80 (m, 2H), 2.36 (s, 3H).UPLC-MS: t.sub.R=2.41 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.16F.sub.3N2O.sub.2 (M+H).sup.+: 349.1, found: 349.1.

    [0230] [025] (4-Bromo-2-furyl)-(8-methyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol) and 4-bromofuran-2-carboxylic acid (0.051 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (90:10) as the eluent, as a white solid (0.068 g, 70%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.81 (s, 1H), 8.14 (d, J=0.8 Hz, 1H), 7.28 (s, 1H), 7.21 (s, 1H), 7.19 (d, J=8.2 Hz, 1H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 5.04-4.57 (m, 2H), 3.97 (t, J=5.7 Hz, 2H), 2.91 (bs, 2H), 2.36 (s, 3H). UPLC-MS: t.sub.R=2.31 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16BrN2O.sub.2 (M+H).sup.+: 359.0, found: 359.0.

    [0231] [026] (8-Methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(1H-pyrazol-3-yl)methanone: Following GP3c, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.070 g, 0.35 mmol) and 1H-pyrazole-3-carboxylic acid (0.039 g, 0.35 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (55:45) as the eluent, as a white solid (0.030 g, 30%). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.21 (s, 1H), 10.74 (s, 1H), 7.82 (s, 1H), 7.18 (d, J=8.6 Hz, 1H), 7.07-6.72 (m, 1H), 6.72-6.53 (m, 2H), 5.19-4.66 (m, 2H), 4.16 (s, 1H), 4.07-3.93 (m, 1H), 3.74 (app-d, J=18.0 Hz, 3H), 3.01-2.75 (m, 2H). UPLC-MS: t.sub.R=1.52 min (Method A); MS (ESI) m/z calcd for C.sub.16H.sub.17N.sub.4O.sub.2 (M+H).sup.+: 297.1, found: 297.2.

    [0232] [027] (8-Methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-phenyl-1H-pyrazol-3-yl)-methanone: Following GP3c, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.030 g, 0.15 mmol) and 5-phenyl-1H-pyrazole-3-carboxylic acid (0.028 g, 0.15 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (50:50) as the eluent, as a white solid (0.016 g, 29%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 13.66 (s, 1H), 10.76 (s, 1H), 7.84 (app-d, J=7.5 Hz, 2H), 7.47 (app-t, J=7.6 Hz, 2H), 7.42-7.32 (m, 1H), 7.19 (d, J=8.6 Hz, 1H), 7.08 (s, 1H), 7.04-6.76 (m, 1H), 6.73-6.59 (m, 1H), 5.22-4.60 (m, 2H), 4.39-3.92 (m, 2H), 3.74 (app-d, J=23.1 Hz, 3H), 2.91 (app-d, J=28.6 Hz, 2H). UPLC-MS: t.sub.R=2.00 min (Method A); MS (ESI) m/z calcd for C.sub.22H.sub.21N.sub.4O.sub.2 (M+H).sup.+: 373.2, found: 373.2.

    [0233] [028] (8-Methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[2-(trifluoromethyl)-1H-imidazol-4-yl]methanone: Following GP3c, the title compound was obtained from 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.030 g, 0.15 mmol) and 2-(trifluoromethyl)-1H-imidazole-4-carboxylic acid (0.027 g, 0.15 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (60:40) as the eluent, as a white solid (0.022 g, 40%). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.10 (s, 1H), 10.74 (s, 1H), 7.90 (s, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.07-6.73 (m, 1H), 6.67 (dd, J=8.7, 2.4 Hz, 1H), 5.28-4.60 (m, 2H), 4.42-3.85 (m, 2H), 3.75 (s, 3H), 3.03-2.77 (m, 2H). UPLC-MS: t.sub.R=1.69 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O.sub.2 (M+H).sup.+: 365.1, found: 365.1.

    [0234] [030] 2-Furyl-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol)and furan-2-carboxylic acid (0.030 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (90:10) as the eluent, as a white solid (0.058 g, 76%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.80 (s, 1H), 7.88 (dd, J=1.8, 0.8 Hz, 1H), 7.23-7.14 (m, 2H), 7.08 (d, J=3.3 Hz, 1H), 6.86 (dd, J=8.2, 1.7 Hz, 1H), 6.66 (dd, J=3.5, 1.8 Hz, 1H), 4.80 (bs, 2H), 3.99 (t, J=5.3 Hz, 2H), 2.90 (bs, 2H), 2.35 (s, 3H). UPLC-MS: t.sub.R=2.07 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.17N.sub.2O.sub.2 (M+H).sup.+: 281.1, found: 281.1.

    [0235] [031] (5-tert-Butyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3c, the title compound was obtained from 8-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol)and 5-tert-Butyl-1H-pyrazole-3-carboxylic acid (0.045 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.046 g, 51%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.96 (s, 1H), 10.76 (s, 1H), 7.29-7.01 (m, 2H), 6.94-6.82 (m, 1H), 6.42-6.28 (m, 1H), 5.16 (bs, 1H), 4.75 (bs, 1H), 4.29-4.15 (m, 1H), 4.02-3.95 (m, 1H), 2.98-2.79 (m, 2H), 2.43-2.29 (m, 3H), 1.31 (s, 9H). UPLC-MS: t.sub.R=2.16 min (Method A); MS (ESI) m/z calcd for C.sub.20H.sub.25N.sub.4O (M+H).sup.+: 337.2, found: 337.2.

    [0236] [032] 1H-Indol-2-yl-(1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3a, the title compound was obtained from 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.31 mmol) and 1H-Indole-2-carboxylic acid (0.053 g, 0.31 mmol), after purification by preparative LC/MS, as a white solid (0.021 g, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.62 (s, 1H), 10.98 (s, 1H), 7.66 (dt, J=8.0, 1.0 Hz, 1H), 7.48-7.40 (m, 2H), 7.32 (d, J=8.0 Hz, 1H), 7.20 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.14-7.01 (m, 2H), 6.98 (d, J=5.4 Hz, 2H), 4.95 (s, 2H), 4.12 (d, J=6.9 Hz, 2H), 3.00 (s, 2H). UPLC-MS: t.sub.R=2.24 min (Method A); MS (ESI) m/z calcd for C.sub.20H.sub.18N.sub.3O (M+H).sup.+: 316.1, found: 316.3.

    [0237] [033] (5-Cyclopropyl-1H-pyrazol-3-yl)-(8-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3c, the title compound was obtained from 8-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol) and 5-Cyclopropyl-1H-pyrazole-3-carboxylic acid (0.041 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.042 g, 48%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 12.98 (d, J=38.2 Hz, 1H), 10.76 (s, 1H), 7.33-6.99 (m, 2H), 6.94-6.77 (m, 1H), 6.40-6.17 (m, 1H), 5.07 (s, 1H), 4.74 (s, 1H), 4.24-4.10 (m, 1H), 3.99-3.87 (m, 1H), 3.01-2.76 (m, 2H), 2.45-2.33 (m, 3H), 1.99-1.87 (m, 1H), 1.02-0.88 (m, 2H), 0.80-0.66 (m, 2H). UPLC-MS: t.sub.R=1.98 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.21N.sub.4O (M+H).sup.+: 321.2, found: 321.3.

    [0238] [034] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[3-(trifluoromethyl)-1H-pyrazol-4-yl]-methanone: Following GP3c, the title compound was obtained from 8-Methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.06 g, 0.27 mmol) and 3-(Trifluoromethyl)-1H-pyrazole-4-carboxylic acid (0.049 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (75:25) as the eluent, as a white solid (0.036 g, 39%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 13.95 (s, 1H), 10.79 (s, 1H), 8.38-8.21 (m, 1H), 7.33-6.98 (m, 2H), 7.01-6.73 (m, 1H), 4.81-4.67 (m, 1H), 4.61-4.47 (m, 1H), 4.11-3.89 (m, 1H), 3.75-3.59 (m, 1H), 2.97-2.75 (m, 2H), 2.45-2.19 (m, 3H). UPLC-MS: t.sub.R=1.97 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O (M+H).sup.+: 349.1, found: 349.1.

    [0239] [035] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-2-pyridyl]-methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol)and 5-(trifluoromethyl)pyridine-2-carboxylic acid (0.051 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (90:10) as the eluent, as a white solid (0.069 g, 71%). .sup.1H-NMR showed the presence of conformers. Major conformer: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.80 (s, 1H), 9.07-9.03 (m, 1H), 8.41-8.37 (m, 1H), 7.87 (dt, J=8.2, 0.8 Hz, 1H), 7.28-7.24 (m, 1H), 7.20 (d, J=8.2 Hz, 1H), 6.88 (dd, J=8.2, 1.6 Hz, 1H), 4.83 (s, 1H), 3.66 (t, J=5.7 Hz, 2H), 2.84 (t, J=5.7 Hz, 2H), 2.38 (s, 3H); Minor conformer: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 10.81 (s, 1H), 9.09-9.00 (m, 1H), 8.37-8.32 (m, 1H), 7.81 (dt, J=8.2, 0.8 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 7.00 (d, J=1.6 Hz, 1H), 6.83 (dd, J=8.3, 1.6 Hz, 1H), 4.55 (t, J=1.4 Hz, 2H), 4.06 (t, J=5.8 Hz, 2H), 2.91 (t, J=5.8 Hz, 2H), 2.28 (s, 3H). UPLC-MS: t.sub.R=2.30 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17F.sub.3N.sub.3O (M+H).sup.+: 360.1, found: 360.2.

    [0240] [036] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[6-(trifluoromethyl)-1H-indol-2-yl]methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.27 mmol) and 6-(trifluoromethyl)-1H-indole-2-carboxylic acid (0.061 g, 0.27 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (90:10) as the eluent, as a white solid (0.078 g, 73%). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 12.11 (s, 1H), 10.83 (s, 1H), 7.88 (d, J=8.4 Hz, 1H), 7.76 (s, 1H), 7.36 (dd, J=8.5, 1.6 Hz, 1H), 7.29-7.15 (m, 2H), 7.10 (bs, 1H), 6.87 (d, J=8.2 Hz, 1H), 5.25-4.56 (m, 2H), 4.10 (s, 2H), 2.97 (bs, 2H), 2.35 (s, 3H). UPLC-MS: t.sub.R=2.63 min (Method A); MS (ESI) m/z calcd for C.sub.22H.sub.19F3N30 (M+H).sup.+: 398.1, found: 398.2.

    [0241] [037] (8-Isopropyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-methanone: Following GP3c, the title compound was obtained from [Int-2.22] (0.060 g, 0.24 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.047 g, 0.26 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.056 g, 62%). .sup.1H-NMR showed the presence of conformers. .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.38 (s, 1H), 10.82 (s, 1H), 7.37-7.14 (m, 3H), 6.95 (d, J=8.2 Hz, 1H), 4.83 (app-d, J=27.1 Hz, 2H), 3.96 (app-d, J=33.3 Hz, 2H), 3.08-2.81 (m, 3H), 1.31-1.20 (m, 6H). UPLC-MS: t.sub.R=2.43 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.20F.sub.3N.sub.4O (M+H).sup.+: 377.2, found: 377.2.

    [0242] [038] (6-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]-methanone: Following GP3c, the title compound was obtained from [Int-2.23] (0.06 g, 0.27 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.053 g, 0.30 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (85:15) as the eluent, as a white solid (0.040 g, 42%). .sup.1H-NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.39 (s, 1H), 10.90 (s, 1H), 7.50-7.08 (m, 2H), 7.11-6.64 (m, 2H), 4.84 (app-d, J=30.8 Hz, 2H), 3.99 (app-d, J=38.2 Hz, 2H), 2.96 (app-d, J=31.2 Hz, 2H), 2.44 (s, 3H). UPLC-MS: t.sub.R=2.19 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O (M+H).sup.+: 349.2, Found: 349.2.

    [0243] [039] (8-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, the title compound was obtained from 8-fluoro-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.050 g, 0.26 mmol)and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.047 g, 0.26 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.012 g, 13%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.39 (s, 1H), 11.10 (s, 1H), 7.38-7.12 (m, 3H), 6.88 (s, 1H), 4.96-4.72 (m, 2H), 4.16-3.84 (m, 2H), 3.05-2.85 (m, 2H). UPLC-MS: t.sub.R=2.08 min (Method A); MS (ESI) m/z calcd for C.sub.16H.sub.13F.sub.4N.sub.4O (M+H).sup.+: 353.2, found: 353.2.

    [0244] [040] (2-Methyl-5,6,7,8,9,10-hexahydro-7,10-epimino cyclohepta [b]indol-11-yl) (5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3b, the title compound was obtained from [Int-2.11] (0.070 g, 0.28 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.061 g, 0.34 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (70:30) as the eluent, as a white solid (0.070 g, 67%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.35 (s, 1H), 10.80 (app-d, J=8.5 Hz, 1H), 7,32 and 7.01 (s, 1H), 7.28 (s, 1H), 7.16 (dd, J=8.2, 4.1 Hz, 1H), 6.85 (d, J=8.3 Hz, 1H), 5.81-5.47 (m, 1H), 4.95 (app-d, J=42.0 Hz, 1H), 3.51-3.33 (m, 1H), 2.71 (t, J=16.5 Hz, 1H), 2.37 (app-d, J=10.0 Hz, 3H), 2.34-2.17 (m, 1H), 2.15-1.87 (m, 2H), 1.74 (s, 1H). UPLC-MS: t.sub.R=2.28 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.18F.sub.3N.sub.4O (M+H).sup.+: 375.1, found: 375.2.

    [0245] [041] (1H-Indol-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11-yl)methanone: Following GP3c, the title compound was obtained from [Int-2.11] (0.100 g, 0.40 mmol) and 1H-indole-2-carboxylic acid (0.065 g, 0.40 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.072 g, 49%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.79-11.20 (m, 1H), 10.79 (s, 1H), 7.72-7.49 (m, 1H), 7.50-7.36 (m, 1H), 7.32 (s, 1H), 7.25-7.13 (m, 2H), 7.11-6.94 (m, 1H), 6.93-6.72 (m, 1H), 5.98-5.32 (m, 1H), 5.32-4.75 (m, 1H), 3.53-3.41 (m, 2H), 3.07-2.64 (m, 1H), 2.38 (s, 3H), 2.36-2.16 (m, 1H), 2.16-1.86 (m, 2H), 1.81-1.67 (m, 1H). UPLC-MS: t.sub.R=2.44 min (Method A); MS (ESI) m/z calcd for C.sub.23H.sub.22N.sub.3O (M+H).sup.+: 356.2, found: 356.2.

    [0246] [042] (5-Bromofuran-2-yl)(2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11-yl)methanone: Following GP3c, the title compound was obtained from [Int-2.11] (0.070 g, 0.28 mmol)and 5-bromofuran-2-carboxylic acid (0.053 g, 0282 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.053 g, 49%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.77 (s, 1H), 7.29 (s, 1H), 7.21-6.92 (m, 2H), 6.84 (dd, J=8.2, 1.6 Hz, 1H), 6.80-6.65 (m, 1H), 5.91-5.49 (m, 1H), 5.01 (d, J=27.0 Hz, 1H), 2.83-2.58 (m, 1H), 2.37 (s, 3H), 2.32-2.10 (m, 2H), 2.04-1.84 (m, 2H), 1.81-1.64 (m, 1H). UPLC-MS: t.sub.R=2.40 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.13BrN.sub.2O.sub.2 (M+H).sup.+: 385.0, found: 385.7.

    [0247] [043] (8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[6-(trifluoromethyl)-2-pyridyl]methanone: Following GP3c, the title compound was obtained from 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole hydrochloride (0.056 g, 0.30 mmol) and 6-(trifluoromethyl)pyridine-2-carboxylic acid (0.057 g, 0.30 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.055 g, 12%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 10.81 (d, J=8.2 Hz, 1H), 8.25 (dt, J=12.6, 7.7 Hz, 1H), 8.03 (dd, J=7.7, 3.9 Hz, 1H), 7.94 (dd, J=28.2, 7.8 Hz, 1H), 7.26 (s, 1H), 7.19 (dd, J=13.8, 8.1 Hz, 1H), 6.88 (dt, J=21.4, 10.5 Hz, 1H), 4.92-4.71 (m, 1H), 4.64-4.37 (m, 1H), 4.22-3.97 (m, 1H), 3.69-3.60 (m, 1H), 2.58-2.45 (m, 1H), 2.37 (s, 3H), 2.33-2.21 (m, 1H). UPLC-MS: t.sub.R=2.30 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17F.sub.3N.sub.3O (M+H).sup.+: 360.1, found: 360.2.

    [0248] [044] (6-Fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, the title compound was obtained from [Int-2.2] (0.1 g, 0.42 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.076 g, 0.42 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.031 g, 20%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.42 (s, 1H), 11.39 (s, 1H), 7.20 (s, 1H), 6.73 (t, J=9.6 Hz, 1H), 6.66 (s, 1H), 5.09 (d, J=35.3 Hz, 2H), 4.25-3.84 (m, 2H), 2.93 (d, J=31.2 Hz, 2H), 2.55 (s, 3H). UPLC-MS: t.sub.R=2.22 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15F.sub.4N.sub.4O (M+H).sup.+: 367.2, found: 367.3.

    [0249] [045] [8-(Trifluoromethoxy)-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.26] (0.051 g, 0.20 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (7:3) as the eluent, as a white solid (0.072 g, 88%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.38 (s, 1H), 11.29 (s, 1H), 7.51 (s, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.25 (d, J=39.2 Hz, 1H), 7.01 (d, J=8.7 Hz, 1H), 4.86 (app-d, J=35.4 Hz, 2H), 3.98 (app-d, J=34.4 Hz, 2H), 2.96 (app-d, J=38.7 Hz, 2H); UPLC-MS: t.sub.R=2.33 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.13F.sub.6N.sub.4O.sub.2 (M+H).sup.+: 419.1, found: 419.2.

    [0250] [046] (8-Bromo-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.25] (0.05 g, 0.2 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.2 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (7:3) as the eluent, as a white solid (0.068 g, 92%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.37 (s, 1H), 11.21 (s, 1H), 7.70 (s, .sup.1H), 7.35-7.09 (m, 3H), 4.84 (app-d, J=38.0 Hz, 2H), 3.97 (app-d, J=36.1 Hz, 2H), 2.94 (app-d, J=35.8 Hz, 2H); UPLC-MS: t.sub.R=2.26 min (generic method); MS (ESI) m/z calcd for C.sub.16H.sub.13BrF.sub.3N.sub.4O (M+H).sup.+: 413.0, found: 413.1.

    [0251] [047] [5-(Trifluoromethyl)-1H-pyrazol-3-yl]-(4,4,8-trimethyl-3,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)methanone: Following general procedure 3a, the title compound was obtained from [Int-2.31] (0.043 g, 0.20 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (9:1) as the eluent, as an off-white solid (0.032 g, 58%). .sup.1H NMR showed the presence of conformers: .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.39 (s, 1H), 10.85 (s, 1H), 7.39-7.03 (m, 3H), 6.87 (app-d, J=8.4 Hz, 1H), 5.01-4.64 (m, 2H), 3.96-3.45 (m, 2H), 2.44-2.23 (m, 3H), 1.33 (s, 3H), 1.24 (s, 3H); UPLC-MS: t.sub.R=2.35 min (generic method); MS (ESI) m/z calcd for C.sub.19H.sub.20F.sub.3N.sub.4O (M+H).sup.+: 377.2, found: 377.2.

    [0252] [048] [5-(trifluoromethyl)-1H-pyrazol-3-yl]-[8-(trifluoromethyl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]methanone: Following GP3c, the title compound was obtained from [Int-2.3] (0.1 g, 0.42 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.075 g, 0.42 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (80:20) as the eluent, as a white solid (0.038 g, 22%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.38 (s, 1H), 11.48 (d, J=6.3 Hz, 1H), 7.93 (s, 1H), 7.50 (t, J=6.8 Hz, 1H), 7.42-7.10 (m, 2H), 4.92 (d, J=36.6 Hz, 2H), 4.00 (d, J=32.1 Hz, 2H), 2.98 (d, J=35.7 Hz, 2H). UPLC-MS: t.sub.R=2.26 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.13F.sub.6N.sub.4O (M+H).sup.+: 403.1, found: 403.3.

    [0253] [049] (6,8-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, the title compound was obtained from [Int-2.5] (0.085 g, 0.36 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.065 g, 0.36 mmol), after purification by preparative LC/MS, as a white solid (0.031 g, 24%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.39 (s, 1H), 10.76 (s, 1H), 7.23 (d, J=29.1 Hz, 1H), 7.05 (d, J=16.4 Hz, 1H), 6.69 (s, 1H), 4.81 (d, J=30.4 Hz, 2H), 3.98 (d, J=37.0 Hz, 2H), 2.94 (d, J=30.5 Hz, 2H), 2.39 (s, 3H), 2.33 (d, J=10.9 Hz, 3H). UPLC-MS: t.sub.R=2.31 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.18F.sub.3N.sub.4O (M+H).sup.+: 363.1, found: 363.2.

    [0254] [050] (6-Fluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.27] (0.038 g, 0.20 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by silica gel flash-column chromatography with DCM/EtOAc (8:2) as the eluent, as a white solid (0.052 g, 92%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.38 (s, 1H), 11.46 (s, 1H), 7.37-7.12 (m, 2H), 7.04-6.74 (m, 2H), 4.85 (app-d, J=32.5 Hz, 2H), 3.98 (app-d, J=36.6 Hz, 2H), 2.95 (app-d, J=36.5 Hz, 2H); UPLC-MS: t.sub.R=2.12 min (generic method); MS (ESI) m/z calcd for C.sub.16H.sub.13F.sub.4N.sub.4O (M+H).sup.+: 353.1, found: 353.1.

    [0255] [051] (6-Fluoro-8-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, the title compound was obtained from [Int-2.6] (0.147 g, 0.61 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.110 g, 0.61 mmol), after purification by preparative LC/MS, as a white solid (0.015 g, 6%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.39 (s, 1H), 11.31 (s, 1H), 7.24 (d, J=30.2 Hz, 1H), 7.08 (d, J=12.7 Hz, 1H), 6.74 (d, J=12.3 Hz, 1H), 4.82 (d, J=31.7 Hz, 2H), 3.98 (d, J=34.1 Hz, 2H), 2.94 (d, J=34.6 Hz, 2H), 2.37 (d, J=8.5 Hz, 3H). UPLC-MS: LR =2.24 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15F.sub.4N.sub.4O (M+H).sup.+: 367.1, found: 367.2.

    [0256] [052] (8-Methylsulfonyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, the title compound was obtained from [Int-2.28] (0.068 g, 0.24 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.043 g, 0.24 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (50:50) as the eluent, as a white solid in (0.031 g, 31%): .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.40 (s, 1H), 11.63 (s, 1H), 8.14 (d, J=1.7 Hz, 1H), 7.62-7.56 (m, 1H), 7.56-7.49 (m, 1H), 7.29 (d, J=61.9 Hz, 1H), 4.94 (d, J=38.4 Hz, 2H), 4.02 (tq, J=12.6, 6.6, 5.9 Hz, 2H), 3.21-3.10 (m, 3H), 3.00 (d, J=38.3 Hz, 2H). UPLC-MS: t.sub.R=1.71 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O.sub.3S (M+H).sup.+: 413.1, found: 413.2.

    [0257] [053] (4-Fluoro-2-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b] indol-11-yl) (5-(trifluoromethyl) -1H-pyrazol-3-yl)methanone: Following GP3c, the title compound was obtained from [Int-2.12] (0.134 g, 0.50 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.090 g, 0.50 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 80%) as the eluent, as a white solid (0.063 g, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.38 (s, 1H), 11.28 (d, J=6.1 Hz, 1H), 7.24 (d, J=47.6 Hz, 1H), 7.08 (d, J=44.0 Hz, 1H), 6.70 (d, J=12.6 Hz, 1H), 5.80-5.58 (m, 1H), 4.98 (d, J=26.8 Hz, 1H), 3.42 (d, J=4.7 Hz, 1H), 2.72 (t, J=15.8 Hz, 1H), 2.44-2.22 (m, 4H), 2.16-2.00 (m, 1H), 1.94 (dt, J=21.3, 10.7 Hz, 1H), 1.76 (d, J=18.0 Hz, 1H). UPLC-MS: t.sub.R=2.32 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 393.1, found: 393.2.

    [0258] [054] (9-Fluoro-6-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, the title compound was obtained from [Int-2.8] (0.090 g, 0.37 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.067 g, 0.37 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 80%) as the eluent, as a white solid (0.041 g, 13%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.41 (s, .sup.1H). 11.21 (s, 1H), 7.21 (s, 1H), 6.79 (s, 1H), 6.70-6.55 (m, 1H), 4.90 (s, 2H), 3.99 (d, J=33.1 Hz, 2H), 2.96 (d, J=31.0 Hz, 2H), 2.40 (s, 3H). UPLC-MS: t.sub.R=2.21 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15F.sub.4N.sub.4O (M+H).sup.+: 367.1, found: 367.2.

    [0259] [055] (4-Fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11-yl)(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.13] (0.200 g, 0.75 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.135 g, 0.75 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 80%) as the eluent, as a white solid (0.056 g, 5%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.40 (s, 1H), 11.41 (d, J=12.5 Hz, 1H), 7.18 (d, J=110.2 Hz, 1H), 6.80-6.57 (m, 2H), 5.98-5.61 (m, 1H), 4.97 (d, J=26.9 Hz, 1H), 3.51-3.37 (m, 1H), 2.73 (t, J=15.2 Hz, 1H), 2.57 (s, 1H), 2.41-2.26 (m, 3H), 2.16-1.95 (m, 2H), 1.76 (d, J=8.1 Hz, 1H). UPLC-MS: t.sub.R=2.29 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 393.1, found: 393.2.

    [0260] [056] (6,9-Dimethyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.7] (0.069 g, 0.29 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.052 g, 0.29 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 90%) as the eluent, as a white solid (0.032g, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.46 (s, 1H), 10.82 (s, 1H), 7.18 (s, 1H), 6.71 (d, J=7.2 Hz, 1H), 6.62 (d, J=8.6 Hz, 1H), 5.09 (d, J=35.8 Hz, 2H), 4.25-3.70 (m, 2H), 2.94 (d, J=26.5 Hz, 2H), 2.55 (s, 2H), 2.37 (s, 4H). UPLC-MS: t.sub.R=2.25 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.18F.sub.3N.sub.4O (M+H).sup.+: 363.1, found: 363.2.

    [0261] [057] 2-[5-(Trifluoromethyl)-1H-pyrazole-3-carbonyl]-1,3,4, 5-tetrahydropyrido[4,3-b]indole-8-carbonitrile: Following GP3a, the title compound was obtained from [Int-2.29] (0.039 g, 0.20 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.036 g, 0.20 mmol), after purification by preparative LC-MS, as a white solid (0.012 g, 20%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.38 (s, 1H), 11.62 (s, 1H), 8.09 (s, 1H), 7.56-7.35 (m, 2H), 7.25 (app-d, J=36.1 Hz, 1H), 4.89 (app-d, J=35.9 Hz, 2H), 3.98 (app-d, J=36.7 Hz, 2H), 2.97 (app-d, J=37.1 Hz, 2H); UPLC-MS: t.sub.R=1.92 min (generic method); MS (ESI) m/z calcd for C.sub.17H.sub.13F3N.sub.5O (M+H).sup.+: 360.1, found: 360.2.

    [0262] [058] (9-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, a mixture of regioisomer [058] and [059] was obtained from [Int-2.24] (0.2 g, 1.07 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.212 g, 1.18 mmol). The title compound was obtained, as pure isomer, after purification by preparative LC/MS, as a white solid (0.006 g, 7%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.36 (s, 1H), 10.92 (s, 1H), 7.24-7.03 (m, 2H), 6.90 (s, 1H), 6.70 (s, 1H), 5.24 -4.96 (m, 2H), 4.11-3.81 (m, 2H), 3.04-2.80 (m, 2H), 2.58 and 2.46 (s, 3H). NOESY-2D: strong dipolar coupling between multiplet at 5.24-4.96 ppm and singlet at 5.58ppm. UPLC-MS: t.sub.R=2.13 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16F.sub.3N.sub.4O (M+H).sup.+: 349.1, found: 349.1.

    [0263] [059] (7-Methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3c, a mixture of regioisomer [058] and [059] was obtained from [Int-2.24] (0.200 g, 1.07 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.212 g, 1.18 mmol). The title compound was obtained, after purification by preparative LC/MS, as a pure isomer, as a white solid (0.006 g, 7%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 14.31 (s, 1H), 10.80 (s, 1H), 7.39-7.27 (m, 1H), 7.20 (s, 1H), 7.09 (s, 1H), 6.79 (d, J=12.3 Hz, 1H), 4.97-4.69 (m, 2H), 4.11-3.81 (m, 2H), 3.01-2.81 (m, 2H), 2.37 (s, 3H). UPLC-MS: t.sub.R=2.17 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16F3N.sub.4O (M+H).sup.+: 349.1, found: 349.1.

    [0264] [060] (6,8-Difluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.9] (0.100 g, 0.41 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.074 g, 0.41 mmol), after purification by preparative LC/MS, as a white solid (0.049 g, 32%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.59 (s, 1H), 7.27 (s, 1H), 7.22 (dd, J=9.4, 2.3 Hz, 1H), 6.92 (t, J=10.7 Hz, 1H), 4.83 (d, J=36.4 Hz, 2H), 4.07-3.85 (m, 2H), 3.08-2.84 (m, 2H). UPLC-MS: t.sub.R=2.23 min (Method A); MS (ESI) m/z calcd for C.sub.16H.sub.12F.sub.5N.sub.4O (M+H).sup.+: 371.1, found: 371.2.

    [0265] [061] (6-Bromo-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.1] (0.250g, 0.83 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.149 g, 0.83 mmol), after purification by preparative LC/MS, as a white solid (0.110 g, 31%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.14 (s, 1H), 7.21 (s, 1H), 7.12 (d, J=7.7 Hz, 1H), 6.77-6.60 (m, 1H), 5.09 (d, J=38.0 Hz, 2H), 3.96 (d, J=34.0 Hz, 2H), 2.96 (d, J=27.8 Hz, 2H), 2.61-2.36 (m, 3H). UPLC-MS: t.sub.R=2.44 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15BrF.sub.3N.sub.4O (M+H).sup.+: 428.2, found: 428.9.

    [0266] [063] (6-Fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-(1H-indol-2-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.094 g, 0.46 mmol) and 1H-indole-2-carboxylic acid (0.074 g, 0.46 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.046 g, 29%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.62 (bs, 1H), 11.39 (bs, 1H), 7.66 (dt, J=8.0, 0.8 Hz, 1H), 7.51-7.41 (m, 1H), 7.21 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.07 (ddd, J=8.0, 7.0, 1.0 Hz, 1H), 6.99-6.90 (m, 1H), 6.73 (dd, J=11.2, 7.9 Hz, 1H), 6.65 (t, J=6.3 Hz, 1H), 5.32-4.96 (m, 2H), 4.17-4.06 (m, 2H), 3.10-2.87 (m, 2H), 2.52 (s, 3H). UPLC-MS: t.sub.R=2.46 min (Method A); MS (ESI) m/z calcd for C.sub.21H.sub.19FN.sub.3O (M+H).sup.+: 348.1, found: 348.2.

    [0267] [077] (6-Fluoro-4,4,9-trimethyl-3,5-dihydro-1H-pyrido[4,3-b]indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-methanone: Following GP3a, the title compound was obtained from [Int-2.14] (0.3 g, 1.28 mmol)and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.253 g, 1.40 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.045 g, 9%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.42 (s, 1H), 11.34 (s, 1H), 7.15 (d, J=28.0 Hz, 1H), 6.73 (t, J=9.6 Hz, 1H), 6.63 (br s, 1H), 5.11 (br s, 2H), 3.77-3.72 (m, 2H), 2.50-2.048 (m, 3H), 1.37 (s, 3H), 1.28 (s, 3H). UPLC-MS: t.sub.R=2.32 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.19F.sub.4N.sub.4O (M+H).sup.+: 395.1, found: 395.4.

    [0268] [079] (7R,10S)- or (7S,10R)-4-Fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-methanone: The title compound was obtained from compound [055] by means of semi-preparative chiral separation (Column: ChiralPak AD, 250×4.6mm, 10 μm; mobile phase: n-Heptane-EtOH (75:25); Flow Rate: 1.0 mL/min; UV: 268nm) as a white powder (0.023 g, 28%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.41 (s, 1H), 11.41 (d, J=12.5 Hz, 1H), 7.18 (d, J=110.2 Hz, 1H), 6.79-6.57 (m, 2H), 5.98-5.61 (m, 1H), 4.97 (d, J=26.9 Hz, 1H), 3.51-3.37 (m, 1H), 2.73 (t, J=14.8 Hz, 1H), 2.57 (s, 1H), 2.41-2.26 (m, 3H), 2.16-1.95 (m, 2H), 1.76 (d, J=8.1 Hz, 1H). UPLC-MS: t.sub.R=2.01 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 393.1, found: 393.4.

    [0269] [080] (7S,10R)- or (7R,10S)-4-Fluoro-1-methyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indol-11-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-methanone: The title compound was obtained from compound [055] by means of semi-preparative chiral separation (Column: ChiralPak AD, 250×4.6mm, 10 μm; mobile phase: n-Heptane-EtOH (75:25); Flow Rate: 1.0 mL/min; UV: 268nm) as a white powder (0.024 g, 28%). .sup.1H NMR (400 MHz, DMSO-d6): δ 14.40 (s, 1H), 11.41 (d, J=12.5 Hz, 1H), 7.18 (d, J=110.2 Hz, 1H), 6.80-6.57 (m, 2H), 5.98-5.61 (m, 1H), 4.97 (d, J=26.9 Hz, 1H), 3.51-3.37 (m, 1H), 2.73 (t, J=15.2 Hz, 1H), 2.57 (s, 1H), 2.41-2.26 (m, 3H), 2.16-1.95 (m, 2H), 1.76 (d, J=8.1 Hz, 1H). UPLC-MS: t.sub.R=2.02 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 393.1, found: 393.4.

    [0270] [081] (6,9-Difluoro-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.17] (0.100 g, 0.41 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.081 g, 0.45 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 30%) as the eluent, as a white solid (0.020 g, 13%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.39 (s, 1H), 11.78 (s, 1H), 7.20 (s, 1H), 6.85 (t, J=8.6 Hz, 1H), 6.75-6.68 (m, 1H), 5.01-4.84 (m, 2H), 4.00-3.95 (m, 2H), 3.00-2.95 (m, 2H). UPLC-MS: t.sub.R=2.32 min (Method A); MS (ESI) m/z calcd for C.sub.16H.sub.12F.sub.5N.sub.4O (M+H).sup.+: 371.1, found: 371.3.

    [0271] [082] (6-Fluoro-8-(trifluoromethyl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.21] (0.150 g, 0.51 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.101 g, 0.56 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.012 g, 6%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 14.38 (s, 1H), 12.01 (s, 1H), 7.85 (s, 1H), 7.39-7.10 (m, 2H), 5.08-4.81 (m, 2H), 4.10-3.89 (m, 2H), 3.12-2.89 (m, 2H). UPLC-MS: t.sub.R=2.06 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.12F.sub.7N.sub.4O (M+H).sup.+: 421.1, found: 421.5.

    [0272] [086] (6-Fluoro-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-methanone: Following GP3a, the title compound was obtained from [Int-2.18] (0.150 g, 0.58 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.115 g, 0.64 mmol), after purification by preparative LC-MS, as a white solid (0.056 g, 25%). .sup.1H NMR (400 MHz, DMSO-d6): δ 14.39 (br s, 1H), 11.25 (s, 1H), 7.28-7.17 (m, 1H), 6.92-6.80 (m, 1H), 6.59 (dd, J=12.8, 2.1 Hz, 1H), 4.87-4.76 (m, 2H), 4.08-3.88 (m, 2H), 3.77 (d, J=7.8 Hz, 3H), 3.03-2.83 (m, 2H). UPLC-MS: t.sub.R=1.86 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15F.sub.4N.sub.4O.sub.2 (M+H).sup.+: 383.1, found: 383.2.

    [0273] [087] (6-Fluoro-9-(trifluoromethyl)-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)-methanone: Following GP3a, the title compound was obtained from [Int-2.20] (0.5 g, 1.70 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.335 g, 1.86 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.023 g, 7%). .sup.1H NMR (400 MHz, DMSO-d6): δ 14.39 (br s, 1H), 12.20 (s, 1H), 7.41 (br s, 1H), 7.23-7.02 (m, 1H), 7.08 (t, J=9.3 Hz, 1H), 4.85 (s, 2H), 4.13-3.84 (m, 2H), 3.10-3.01 (m, 2H). UPLC-MS: t.sub.R=2.03 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.12F.sub.7N.sub.4O (M+H).sup.+: 421.1, found: 421.3.

    [0274] [088] (6-Chloro-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.18] (0.150 g, 0.58 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.115 g, 0.64 mmol), after purification by preparative LC-MS, as a by-product of compound [086], as a white solid (0.020 g, 18%). .sup.1H NMR (400 MHz, DMSO-d6): δ 14.37 (br s, 1H), 11.14 (s, 1H), 7.28-7.17 (m, 1H), 7.09-6.97 (m, 1H), 6.80 (d, J=2.2 Hz, 1H), 4.89-4.75 (m, 2H), 4.07-3.89 (m, 2H), 3.78 (s, 3H), 3.05-2.85 (m, 2H). UPLC-MS: t.sub.R=2.13 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15ClF.sub.3N.sub.4O (M+H).sup.+: 399.1, found: 399.9.

    [0275] [092] (6-Fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indol-2-yl)-(2-(trifluoromethyl)thiazol-4-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 2-(trifluoromethyl)thiazole-4-carboxylic acid (0.063 g, 0.32 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 30%) as the eluent, as a white solid (0.033 g, 30%). .sup.1H NMR (400 MHz, DMSO-d.sub.6): δ 11.36 (s, 1H), 8.63 (d, J=10.6 Hz, 1H), 6.78-6.58 (m, 2H), 5.20-5.07 (m, 2H), 4.03 3.83 (m, 2H), 2.91 (t, J=5.2 Hz, 2H), 2.56-2.35 (m, 3H). UPLC-MS: t.sub.R=2.08 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.14F.sub.4N.sub.3OS (M+H).sup.+: 384.1, found: 384.5.

    [0276] [093] (4-Bromo-3-pyridyl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 4-bromopyridine-3-carboxylic acid (0.064 g, 0.32 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 60%) as the eluent, as a white solid (0.037 g, 33%). .sup.1H NMR (400 MHz, DMSO-d6): δ 11.39-11.35 (m, 1H), 8.67-8.59 (m, 1H), 8.52 (dd, J=8.1, 5.4 Hz, 1H), 7.88-7.66 (m, 1H), 6.77-6.55 (m, 1H), 6.71-6.66 (m, 1H), 5.26-4.95 (m, 2H), 3.54 (tt, J=5.9, 2.5 Hz, 2H), 2.98-2.77 (m, 2H), 2.57 (s, 3H). UPLC-MS: t.sub.R=1.95 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.16BrFN.sub.3O (M+H).sup.+: 388.0, found: 389.2.

    [0277] [094] (3-Bromo-4-pyridyl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 3-bromopyridine-4-carboxylic acid (0.064 g, 0.32 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.037 g, 33%). .sup.1H NMR (400 MHz, DMSO-d6): δ 11.40-11.35 (m, 1H), 8.89-8.82 (m, 1H), 8.66 (dd, J=9.1, 4.8 Hz, 1H), 7.56-7.41 (m, 1H), 6.79-6.55 (m, 1H), 6.71-6.66 (m, 1H), 5.26-4.98 (m, 2H), 3.50 (q, J=5.8 Hz, 2H), 2.81 (t, J=5.9 Hz, 2H), 2.57 (s, 3H). UPLC-MS: t.sub.R=1.99 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.16BrFN.sub.3O (M+H).sup.+: 388.0, found: 389.5.

    [0278] [095] (5-Bromo-2-methoxy-3-pyridyl)-(6-fluoro-9-methyl-1,3, 4,5-tetrahydropyrido[4,3-b]indol-2-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 5-bromo-2-methoxy-pyridine-3-carboxylic acid (0.074 g, 0.32 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 30%) as the eluent, as a white solid (0.017 g, 14%). .sup.1H NMR (400 MHz, DMSO-d6): δ 11.37-11.31 (m, 1H), 8.40 (t, J=2.8 Hz, 1H), 8.02-7.93 (m, 1H), 6.74 (dd, J=11.2, 7.9 Hz, 1H), 6.71-6.65 (m, 1H), 5.10-4.58 (m, 2H), 3.91 (s, 3H), 3.52 (d, J=6.8 Hz, 2H), 2.94-2.71 (m, 2H), 2.55 (s, 3H). UPLC-MS: t.sub.R=2.29 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.18BrFN.sub.3O.sub.2 (M+H).sup.+: 418.0, found: 419.7.

    [0279] [097] (2-Amino-4-(trifluoromethyl)thiazol-5-yl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 2-amino-4-(trifluoromethyl)thiazole-5-carboxylic acid (0.068 g, 0.32 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 40%) as the eluent, as a white solid (0.021 g, 18%). .sup.1H NMR (400 MHz, DMSO-d6): δ 11.35 (s, 1H), 7.72 (s, 2H), 6.73 (dd, J=11.2, 7.9 Hz, 1H), 6.65 (dd, J=8.0, 4.7 Hz, 1H), 5.15-4.65 (m, 2H), 3.95-3.65 (m, 2H), 2.83 (t, J=5.8 Hz, 2H), 2.52 (s, 3H). UPLC-MS: t.sub.R=1.98 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.15F.sub.4N.sub.4OS (M+H).sup.+: 399.1, found: 399.0.

    [0280] [098] (3-(4-Bromophenyl)-5-methyl-isoxazol-4-yl)-(6-fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-methanone: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 3-(4-bromophenyl)-5-methyl-isoxazole-4-carboxylic acid (0.090 g, 0.32 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 30%) as the eluent, as a white solid (0.022 g, 16%). .sup.1H NMR (400 MHz, DMSO-d6): δ 11.28-11.19 (m, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 1H), 7.34 (q, J=8.4 Hz, 2H), 6.78-6.52 (m, 1H), 6.70-6.61 (m, 1H), 5.07 (br s, 2H), 3.56 (br s, 2H), 2.85 (br s, 2H), 2.17 (s, 3H), 1.40 (s, 3H). UPLC-MS: t.sub.R=2.43 min (Method A); MS (ESI) m/z calcd for C.sub.23H.sub.20BrFN302 (M+H).sup.+: 468.1, found: 469.5.

    [0281] [104] 3-(6-Fluoro-9-methyl-1,3,4,5-tetrahydropyrido[4,3-b] indole-2-carbonyl)-1H-pyrazole-5-carboxylic acid: Following GP3a, the title compound was obtained from [Int-2.2] (0.070 g, 0.29 mmol) and 1H-pyrazole-3,5-dicarboxylic acid (0.091 g, 0.58 mmol), after purification by preparative LC/MS, as a white solid (0.012 g, 12%). .sup.1H NMR (400 MHz, DMSO-d6): δ 11.37-11.30 (m, 1H), 6.76-6.57 (m, 3H), 5.43-4.17 (m, 2H), 5.08-3.95 (m, 2H), 2.95-2.78 (m, 2H), 2.55 (s, 3H). UPLC-MS: t.sub.R=1.40 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.16FN.sub.4O.sub.3 (M+H).sup.+: 343.1, found: 343.2.

    [0282] [105] rac-(6-Fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl) methanone: Following GP3a, the title compound was obtained from [Int-2.32] (0.070 g, 0.27 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.048 g, 0.27 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.049 g, 47%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.37 (bs), 11.36 (bs), 7.18 (bs), 6.73 (dd, J=11.2, 8.0 Hz, 1H), 6.66 (m, 1H), 4.48-5.57 (m, 3H), 3.13 (m, 1H), 2.69 (s, 3H), 2.65 (m, 1H), 2.34 (m, 1H), 1.26 (d, J=6.8 Hz, 3H). UPLC-MS: t.sub.R=2.58 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 381.1, found: 381.3.

    [0283] [106] rac-(6-Fluoro-1,9-dimethyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl] methanone: Following GP3a, the title compound was obtained from [Int-2.33] (0.090 g, 0.35 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.062 g, 035 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.060 g, 45%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.38 (bs), 11.41 (bs), 7.18 (bs), 6.75 (dd, J=11.1, 7.9 Hz, 1H), 6.68 (dd, J=8.2, 5 Hz, 1H), 5.99 (q, J=6.6 Hz, 1H), 4.15 (m, 1H), 3.71 (ddd, J=14.1, 11.9, 4.4 Hz), 3.13 (ddd, J=17.1, 11.9, 6.0 Hz, 1H), 2.82 (dd, J=16.5, 4.2 Hz, 1H), 2.58 (s, 3H), 1.56 (d, J=6.5 Hz, 3H). UPLC-MS: t.sub.R=2.58 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.17F.sub.9N.sub.4 (M+H).sup.+: 381.1, found: 381.3.

    [0284] [107] 8-Methoxy-N-(5-methyl-1H-pyrazol-3-yl)-1,3,4,5-tetrahydropyrido[4,3-b]indole-2-carboxamide: To a solution of 5-methyl-1H-pyrazol-3-amine (0.026 g, 0.26 mmol) in DMF (2.0 mL), DIPEA (90 μL, 0.52 mmol) and carbonyldiimidazole (0.046 g, 0.26 mmol) were added. After 1 h stirring, 8-methoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.054 g, 0.26 mmol) was added, and mixture stirred at room temperature for 12h and at 60° C. for 4h. EtOAc (20 mL) was added and organic layer was washed with water, aq. sat. NH.sub.4Cl (15mL) and brine (20 mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in vacuo. Flash chromatography purification, eluting with cyclohexane/EtOAc (50:50) gave the pure title compound as pale yellow solid (0.012 g, 14%). .sup.1H NMR (400 MHz, DMSO-d.sub.6) δ 11.76 (s, 1H), 10.67 (s, 1H), 8.90 (s, 1H), 7.17 (d, J=8.7 Hz, 1H), 6.88 (d, J=2.4 Hz, 1H), 6.67 (dd, J=24.4, 8.7 Hz, 1H), 6.07 (s, 1H), 4.60 (s, 2H), 3.79 (t, J=5.7 Hz, 2H), 3.75 (s, 3H), 2.77 (t, J=5.7 Hz, 2H), 2.16 (s, 3H). UPLC-MS: t.sub.R=1.59 min (method A); MS (ESI) m/z calcd for C.sub.17H.sub.20N.sub.5O.sub.2 (M+H).sup.+: 326.2, found: 326.2.

    [0285] [108] (R)-(6-Fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl] methanone: Following GP3a, the title compound was obtained from [Int-2.34] (0.070 g, 0.27 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.048 g, 0.27 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.049 g, 47%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.37 (bs), 11.36 (bs), 7.18 (bs), 6.73 (dd, J=11.2, 8.0 Hz, 1H), 6.66 (m, 1H), 4.48-5.57 (m, 3H), 3.13 (m, 1H), 2.69 (s, 3H), 2.65 (m, 1H), 2.34 (m, 1H), 1.26 (d, J=6.8 Hz, 3H). UPLC-MS: t.sub.R=2.58 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.14F.sub.4N.sub.4O (M+H).sup.+: 381.1, found: 381.3. Chiral analysis: t.sub.R=112.7min; e.e.=97.3%

    [0286] [109] (S)-(6-Fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)-[5-(trifluoromethyl)-1H-pyrazol-3-yl] methanone: Following GP3a, the title compound was obtained from [Int-2.35] (0.070 g, 0.27 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.048 g, 0.27 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.049 g, 47%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.37 (bs), 11.36 (bs), 7.18 (bs), 6.73 (dd, J=11.2, 8.0 Hz, 1H), 6.66 (m, 1H), 4.48-5.57 (m, 3H), 3.13 (m, 1H), 2.69 (s, 3H), 2.65 (m, 1H), 2.34 (m, 1H), 1.26 (d, J=6.8 Hz, 3H). UPLC-MS: t.sub.R=2.58 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 381.1, found: 381.3. Chiral analysis: t.sub.R=104.39min; e.e.=78.0%.

    [0287] [112] (6-Fluoro-3,3,9-trimethyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl)-(5-(trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.36] (0.045 g, 0.19 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.080 g, 0.44 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.016 g, 20%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.29 (bs, 1H), 11.38 (bs, 1H), 7.14 (s, 1H), 6.70 (dd, J=11.3, 7.8 Hz, 1H), 6.59 (ddd, J=7.8, 4.7, 0.6 Hz, 1H), 5.0 (s, 2H), 2.96 (s, 2H), 2.30 (s, 3H), 1.59 (s, 6H). UPLC-MS: t.sub.R=2.45 min (Method A); MS (ESI) m/z calcd for C.sub.19H.sub.19F.sub.4N.sub.4O (M+H).sup.+: 394.4, found: 394.5.

    [0288] [113] [(S)-6,9-Difluoro-3-methyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl] methanone: Following GP3a, the title compound was obtained from [Int-2.37] (0.024 g, 0.108 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.022 g, 0.12 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.021 g, 46%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.37 (bs, 1H), 11.76 (s, 1H), 7.16 (bs, 1H), 6.84 (ddd, J=11.8, 8.8, 3.5 Hz, 1H), 6.71 (m, 1H), 4.30-5.43 (m, 3H), 3.12 (m, 1H), 2.68 (m, 1H), 1.26 (d, J=6.7 Hz, 3H). UPLC-MS: t.sub.R=2.17 min (Method A); MS (ESI) m/z calcd for C.sub.17H.sub.14F.sub.5N.sub.4O (M+H).sup.+: 384.1, found: 385.4.

    [0289] [114] [(R)-6-Fluoro-3,9-dimethyl-1,3,4,5-tetrahydropyrido [4,3-b]indol-2-yl]-(1H-indol-2-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.34] (0.025 g, 0.114 mmol) and indole 2-carboxylic acid (0.02 g, 0.13 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.036 g, 87%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 11.35 (s, 1H), 7.64 (dd, J=8.0, 1.0 Hz, 1H), 7.44 (dd, J=8.2, 1.0 Hz, 1H), 7.20 (ddd, J=8.2, 7.0, 1.2 Hz, 1H), 7.06 (ddd, J=8.0, 7.0, 1.0 Hz, 1H) 6.91 (d, J=1.3 Hz, 1H), 6.73 (dd, J=11.2, 8.0 Hz, 1H), 6.65 (dd, J=7.9, 4.7 Hz, 1H), 5.60 (d, J=16.2 Hz, 1H), 5.22 (m, 1H), 4.68 (m, 1H), 3.23 (m, 1H), 2.70 (d, J=16.5 Hz, 1H), 2.53, (s, 3H), 1.28 (d, J=6.8 Hz, 3H). UPLC-MS: t.sub.R=2.40 min (Method A); MS (ESI) m/z calcd for C.sub.22H.sub.21FN.sub.3O (M+H).sup.+: 362.2, found: 362.5.

    [0290] [115] [(S)-8-Methoxy-6-fluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.40] (0.018 g, 0.076 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.015 g, 0.085 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.011 g, 39%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.40 (bs, 1H), 11.23 (bs, 1H), 7.20 (bs, 1H), 6.87 (bs, 1H), 6.58 (dd, J=12.8, 2.1 Hz, 1H), 4.17-5.33 (m, 3H), 3.77 (s, 3H), 3.11 (m, 1H), 2.61 (m, 1H), 1.24 (d, J=6.7 Hz, 3H). UPLC-MS: t.sub.R=2.11 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 397.1, found: 397.4. Chiral analysis: t.sub.R=9.60 min; e.e.=>99.5%

    [0291] [116] rac-(6-Fluoro-1-methyl-8-methoxy-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl)-(5 (trifluoromethyl)-1H-pyrazol-3-yl)methanone: Following GP3a, the title compound was obtained from [Int-2.41] (0.018 g, 0.076 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.015 g, 0.085 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid as a mixture of rotamers (major/minor 0.72:0.28) (0.014 g, 46%). .sup.1H-NMR (400 MHz, DMSO-d6) of major rotamer: δ 14.38 (bs, 1H), 11.24 (bs, 1H), 7.17 (bs, 1H), 6.86 (bs, 1H), 6.59 (bd, J=13.1 Hz, 1H), 5.68 (q, J=6.6 Hz, 1H), 4.17 (m, 1H), 3.78 (s, 3H), 3.60 (m, 1H), 3.14 (m, 1H), 2.77 (m, 1H), 1.52 (d, J=6.7 Hz, 3H). UPLC-MS: t.sub.R=2.11 min (Method A); MS (ESI) m/z calcd for C18H1F4N.sub.4O (M+H).sup.+: 397.1, found: 397.4.

    [0292] [117] [(R)-8-Methoxy-6-fluoro-3-methyl-1,3,4,5-tetrahydropyrido[4,3-b]indol-2-yl]-[5-(trifluoromethyl)-1H-pyrazol-3-yl]methanone: Following GP3a, the title compound was obtained from [Int-2.42] (0.018 g, 0.076 mmol) and 5-(trifluoromethyl)-1H-pyrazole-3-carboxylic acid (0.015 g, 0.085 mmol), after purification by silica gel flash-column chromatography with Cyclohexane/EtOAc (0 to 50%) as the eluent, as a white solid (0.011 g, 39%). .sup.1H-NMR (400 MHz, DMSO-d6) δ 14.40 (bs, 1H), 11.23 (bs, 1H), 7.20 (bs, 1H), 6.87 (bs, 1H), 6.58 (dd, J=12.8, 2.1 Hz, 1H), 4.17-5.33 (m, 3H), 3.77 (s, 3H), 3.11 (m, 1H), 2.61 (m, 1H), 1.24 (d, J=6.7 Hz, 3H). UPLC-MS: t.sub.R=2.11 min (Method A); MS (ESI) m/z calcd for C.sub.18H.sub.17F.sub.4N.sub.4O (M+H).sup.+: 397.1, found: 397.4. Chiral analysis: t.sub.R=14.04 min; e.e.=98.6%.

    Biological Data

    [0293] Activity in terms of EC50 of the compounds of the invention is illustrated in Table 1.

    TABLE-US-00003 TABLE 1 # Compound structure Substance Name Substance Formula Activity 001 [00057]embedded image (6-Dimethylamino-1H-indol-2- yl)-(1,3,4,5-tetrahydro- pyrido[4,3-b]indol-2-yl)- methanone C22 H22 N4 O +++ 002 [00058]embedded image (1-Phenyl-1H-pyrazol-4-yl)- (1,3,4,5-tetrahydro- pyrido[4,3-b]indol-2-yl)- methanone C21 H18 N4 O + 003 [00059]embedded image (8-Methoxy-1,3,4,5- tetrahydro-pyrido[4,3- b]indol-2-yl)-(5- trifluoromethyl-1H-pyrazol- 3-yl)-methanone C17 H15 F3 N4 O2 +++ 004 [00060]embedded image 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl-[5- (trifluoromethyl)-1H pyrazol-3-yl]methanone C16 H13 F3 N4 O +++ 005 [00061]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H15 F3 N4 O +++ 006 [00062]embedded image (5-methyl-1H-pyrazol-3-yl)- (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C17 H18 N4 O + 007 [00063]embedded image (5-isopropyl-1H-pyrazol-3- yl)-(8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C19 H22 N4 O + 008 [00064]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(1H-pyrazol-3- yl)methanone C16 H16 N4 O + 009 [00065]embedded image [6-(dimethylamino)-1H-indol- 2-yl]-(8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C23 H24 N4 O +++ 010 [00066]embedded image 1H-indol-2-yl-(8-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C21 H19 N3 O +++ 011 [00067]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[2- (trifluoromethyl)-1H- imidazol-4-yl]methanone C17 H15 F3 N4 O + 012 [00068]embedded image (3,5-dimethyl-1H-pyrazol-4 yl)-(8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C18 H20 N4 O + 013 [00069]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(5-phenyl-1H- pyrazol-3-yl)methanone C22 H20 N4 O +++ 014 [00070]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(1- phenylpyrazol-4-yl)methanone C22 H20 N4 O + 015 [00071]embedded image (5-isopropyl-1H-pyrazol-3- yl)-(8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C19 H22 N4 O2 + 016 [00072]embedded image (8-methoxy-1,3,4,5- tetrahydropyriao[4,3- b]indol-2-yl)-(5-methyl-1H- pyrazol-3-yl)methanone C17 H18 N4 O2 + 017 [00073]embedded image (8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(1- phenylpyrazol-4-yl)methanone C22 H20 N4 O2 + 018 [00074]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[1-methyl-5- (trifluoromethyl)pyrazol 3- yl]methanone C18 H17 F3 N4 O + 019 [00075]embedded image (5-isopropyl-1H-pyrazol-3- yl)-(1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C18 H20 N4 O + 021 [00076]embedded image [6-(dimethylamino)-1H-indol- 2-yl]-(8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C23 H24 N4 O2 +++ 022 [00077]embedded image 2-(5-bromo-2-furoyl)-8- methoxy-2,3,4,5-tetrahydro- 1H-pyrido[4,3-b]indole C17 H15 Br N2 O3 + 023 [00078]embedded image (5-bromo-2-furyl)-(8-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C17 H15 Br N2 O2 + 024 [00079]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-2- furyl]methanone C18 H15 F3 N2 O2 +++ 025 [00080]embedded image (4-bromo-2-furyl)-(8-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C17 H15 Br N2 O2 + 026 [00081]embedded image (8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(1H-pyrazol-3- yl)methanone C16 H16 N4 O2 + 027 [00082]embedded image (8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(5-phenyl-1H- pyrazol-3-yl)methanone C22 H20 N4 O2 +++ 028 [00083]embedded image (8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[2- (trifluoromethyl)-1H- imidazol-4-yl]methanone C17 H15 F3 N4 O2 + 029 [00084]embedded image (5-bromo-2-furyl)-(1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C16 H13 Br N2 O2 ++ 030 [00085]embedded image 2-furyl-(8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C17 H16 N2 O2 + 031 [00086]embedded image (5-tert-butyl-1H-pyrazol-3- yl)-(8-methyl-1,3,4,5- tetrahydropyriao[4,3- b]indol-2-yl)methanone C20 H24 N4 O ++ 032 [00087]embedded image 1H-indol-2-yl(1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C20 H17 N3 O +++ 033 [00088]embedded image (5-cyclopropyl-1H-pyrazol-3- yl)-(8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C19 H20 N4 O + 034 [00089]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[3- (trifluoromethyl)-1H- pyrazol-4-yl]methanone C17 H15 F3 N4 O + 035 [00090]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-2- pyridyl]methanone C19 H16 F3 N3 O + 036 [00091]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[6- (trifluoromethyl)-1H-indol- 2-yl]methanone C22 H18 F3 N3 O +++ 037 [00092]embedded image (8-isopropyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H pyrazol-3-yl]methanone C19 H19 F3 N4 O ++ 038 [00093]embedded image (6-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H15 F3 N4 O ++ 039 [00094]embedded image (8-fluoro-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C16 H12 F4 N4 O +++ 040 [00095]embedded image (2-methyl-5,6,7,8,9,10- hexahydro-7,10- epiminocyclohepta[b]indol- 11-yl)(5-(trifluoromethyl)- 1H-pyrazol-3-yl)methanone C19 H17 F3 N4 O + 041 [00096]embedded image (1H-indol-2-yl)(2-methyl- 5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol- 11-yl)methanone C23 H21 N3 O +++ 042 [00097]embedded image (5-bromofuran-2-yl)-(2- methyl-5,6,7,8,9,10- hexahydro-7,10- epiminocyclohepta[b]indol- 11-yl)methanone C19 H17 Br N2 O2 +++ 043 [00098]embedded image (8-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[6- (trifluoromethyl)-2- pyridyl]methanone C19 H16 F3 N3 O + 044 [00099]embedded image (6-fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H14 F4 N4 O +++ 045 [00100]embedded image [8-(trifluoromethoxy)- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H12 F 6 N4 O2 +++ 046 [00101]embedded image (8-bromo-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C16 H12 Br F3 N4 O +++ 047 [00102]embedded image [5-(trifluoromethyl)-1H- pyrazol-3-yl]-(4,4,8- trimethyl-3,5-dihydro-1H- pyrido[4,3-b]indol-2- yl)methanone C19 H19 F3 N4 O +++ 048 [00103]embedded image [5-(trifluoromethyl)-1H- pyrazol-3-yl]-[8- (trifluoromethyl)-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]methanone C17 H12 F6 N4 O +++ 049 [00104]embedded image (6,8-dimethyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H17 F3 N4 O +++ 050 [00105]embedded image (6-fluoro-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C16 H12 F4 N4 O +++ 051 [00106]embedded image (6-fluoro-8-methyl-1,3,4,5- tetrahydropyriao[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 Hi4 F4 N4 O +++ 052 [00107]embedded image (8-methylsulfonyl-1,3,4,5- tetrahydropyriao[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H15 F3 N4 O3 S + 053 [00108]embedded image (4-fluoro-2-methyl- 5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol- 11-yl)-(5-(trifluoromethyl)- 1H-pyrazol-3-yl)methanone C19 H16 F4 N4 O + 054 [00109]embedded image (9-fluoro-6-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 Hi4 F4 N4 O +++ 055 [00110]embedded image (4-fluoro-1-methyl- 5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol- 11-yl)(5-(trifluoromethyl)- 1H-pyrazol-3-yl)methanone C19 H16 F4 N4 O ++ 056 [00111]embedded image (6,9-dimethyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H17 F3 N4 O ++ 057 [00112]embedded image 2-[5-(trifluoromethyl)-1H- pyrazole-3-carbonyl]- 1,3,4,5- tetrahydropyrido[4,3- b]-indole-8-carbonitrile C17 H12 F3 N5 O ++ 058 [00113]embedded image (9-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 Hi 5 F3 N4 O +++ 059 [00114]embedded image (7-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H15 F3 N4 O +++ 060 [00115]embedded image (6,8-difluoro-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C16 H11 F5 N4 O +++ 061 [00116]embedded image (6-bromo-9-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H14 Br F3 N4 O ++ 063 [00117]embedded image (6-fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(1H-indol-2- yl)methanone C21 H18 F N3 O +++ 077 [00118]embedded image (6-fluoro-4,4,9-trimethyl- 3,5-dihydro-1H-pyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C19 H18 F4 N4 O +++ 079 [00119]embedded image (7R,10S)- or (7S,10R)-(4- fluoro-1-methyl- 5,6,7,8,9,10-hcxahydro-7,10- epiminocyclohepta[b]indol- 11-yl)-(5-(trifluoromethyl)- 1H-pyrazol-3-yl)methanone C19 H16 F4 N4 O + 080 [00120]embedded image (7S,10R)- or (7R,10S)-4- fluoro-1-methyl- 5,6,7,8,9,10-hexahydro-7,10- epiminocyclohepta[b]indol- 11-yl)-(5-(trifluoromethyl)- 1H-pyrazol-3-yl)methanone C19 H16 F4 N4 O +++ 081 [00121]embedded image (6,9-difluoro-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C16 H11 F5 N4 O +++ 082 [00122]embedded image [6-fluoro-8- (trifluoromethyl)-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H11 F7 N4 O +++ 086 [00123]embedded image (6-fluoro-8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H14 F4 N4 O2 +++ 087 [00124]embedded image [6-fluoro-9- (trifluoromethyl)-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H11 F7 N4 O +++ 088 [00125]embedded image (6-chloro-8-methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H14 C1F3 N4 O2 +++ 092 [00126]embedded image (6-fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[2- (trifluoromethyl)thiazol-4- yl]methanone C17 H13 F4 N3 O S +++ 093 [00127]embedded image (4-bromo-3-pyridyl)-(6- fluoro-9-methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C18 H15 Br F N3 O + 094 [00128]embedded image (3-bromo-4-pyridyl)-(6- fluoro-9-raethyl-1,3,4,5- tetrahydropyriao[4,3- b]indol-2-yl)methanone C18 H15 Br F N3 O + 095 [00129]embedded image (5-bromo-2-methoxy-3- pyridyl)-(6-fluoro-9-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C19 H17 Br F N3 O2 + 097 [00130]embedded image [2-amino-4- (trifluoromethyl)thiazol-5- yl]-(6-fluoro-9-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C17 H14 F4 N4 O S + 098 [00131]embedded image [3-(4-bromophenyl)-5-methyl- isoxazol-4-yl]-(6-fluoro-9- methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)methanone C23 H19 Br F N3 O2 + 104 [00132]embedded image 3-(6-fluoro-9-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indole-2-carbonyl)-1H- pyrazole-5-carboxylic acid C17 H15 F N4 O3 + 105 [00133]embedded image rac-(6-fluoro-3,9-dimethyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H16 F4 N4 O +++ 106 [00134]embedded image rac-(6-fluoro-1,9-dimethyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H16 F4 N4 O +++ 107 [00135]embedded image 8-methoxy-N-(5-methyl-1H- pyrazol-3-yl)-1,3,4,5- tetrahydropyrido[4,3- b]indole-2-carboxamide C17 H19 N5 O2 + 108 [00136]embedded image (R)-(6-fluoro-3,9-dimethyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H16 F4 N4 O +++ 109 [00137]embedded image (S)-(6-fluoro-3,9-dimethyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 Hi 6 F4 N4 O +++ 112 [00138]embedded image (6-fluoro-3,3,9-trimethyl- 4,5-dihydro-1H-pyrido[4,3- b]indol-2-yl)-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C19 H18 F4 N4 O ++ 113 [00139]embedded image [(S)-6,9-difluoro-3-methyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C17 H13 F5 N4 O +++ 114 [00140]embedded image [(R)-6-fluoro-3,9-dimethyl- 1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-(1H-indol-2- yl)methanone C22 H20 F N3 O ++ 115 [00141]embedded image [(S)-8-methoxy-6-fluoro-3- methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H16 F4 N4 O2 +++ 116 [00142]embedded image rac-(6-fluoro-1-methyl-8- methoxy-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl)-(5 (trifluoromethyl)-1H- pyrazol-3-yl)methanone C18 H16 F4 N4 O2 +++ 117 [00143]embedded image [(R)-8-methoxy-6-fluoro-3- methyl-1,3,4,5- tetrahydropyrido[4,3- b]indol-2-yl]-[5- (trifluoromethyl)-1H- pyrazol-3-yl]methanone C18 H16 F4 N4 O2 +++