IP Library › Granted Patent US 9,056,874
Granted Patent B2
US 9,056,874 · App. 13/826,725 · Granted Jun 16, 2015

Complement pathway modulators and uses thereof

Inventors: Christopher Michael Adams (Somerville, MA); Charles Babu (Arlington, TX); Michael Paul Capparelli (Cambridge, MA); Jian Ding (Bedford, MA); Takeru Ehara (Arlington, MA); Keith Jendza (Boston, MA); Nan Ji (Arlington, MA); Rajeshri Ganesh Karki (Somerville, MA); Toshio Kawanami (Boston, MA); Liang Xue (Arlington, TX); Nello Mainolfi (Boston, MA); James J. Powers (Waltham, MA); Michael H. Serrano-Wu (Belmont, MA); Chun Zhang (Waltham, MA)
Assignee: NOVARTIS AG
C07D491/048C07D403/06A61K31/4184C07D413/06A61K31/423C07D403/14C07D401/14A61K31/4439A61K45/06C07D403/08C07D403/04C07D413/14C07D487/04
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Quick Facts
Patent No.
US 9,056,874
App. No.
13/826,725
Granted
Jun 16, 2015
Kind
B2
Abstract

The present invention provides a compound of formula I: a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

Claims (347)

1. A compound, or salt or a tautomer thereof, according to Formula (I):

Wherein

is a single or double bond;

X is N;

Y is N(H);

one occurrence of R is cyano and the other occurrence of R is hydrogen or R 4 ;

R 1 is halogen, hydroxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, S(O) p C 1 -C 6 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl or OCH 2 C(O)R 7 ;

p is 0, 1, or 2;

R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 6 alkyl or halogen;

R 3 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 C(O)R 7 , phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups, and wherein the alkyl and haloalkyl is optionally substituted with 0 or 1 hydroxy groups;

R 4 is 0, 1, or 2 substitutents independently selected at each occurrence from halogen and C 1 -C 6 alkyl;

R 5 is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S;

or R 3 and R 5 taken in combination form a divalent —CH 2 —CH 2 — or —CH 2 —N(H)— group;

R 6 is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, [CR A 2 ] n R 7 , [CR A 2 ] n C(O)R 7 , O[CR A 2 ] n R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, (CH 2 ) n R 9 , O(CH 2 ) n R 9 , C(O)R 7 , N(H)[CR A 2 ] n R 7 , O[CR A 2 ] n C(O)R 7 , N(H)[CR A 2 ] n C(O)R 7 or tetrazolyl;

or CR 5 R 6 , taken in combination, form a divalent carbonyl group, a divalent ═CH 2 group or cyclopropyl which cyclopropyl is optionally substituted by CO 2 H or CH 2 OH;

n is 1, 2, 3 or 4;

R A is independently selected at each occurrence from hydrogen, halogen or C 1 -C 4 alkyl;

R 7 is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino;

R 8 is hydrogen or halogen; and

R 9 is a 5 member heteroaryl having 1 to 4 ring heteroatoms selected from N, O or S and optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups.

2. A compound, or salt or a tautomer thereof, according to Formula (I):

Wherein

is a single or double bond;

X is N;

Y is N(H);

one occurrence of R is cyano and the other occurrence of R is hydrogen or R 4 ;

R 1 is halogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, C 3 -C 6 cycloalkylC 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, S(O) p C 1 -C 6 alkyl, CH 2 NHC(O)C 1 -C 4 alkyl or OCH 2 C(O)R 7 ;

p is 0, 1, or 2;

R 2 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 6 alkyl or halogen;

R 3 is hydrogen, halogen, cyano, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, CH 2 C(O)R 7 , phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S, wherein the phenyl or heteroaryl is optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups, and wherein the alkyl and haloalkyl is optionally substituted with 0 or 1 hydroxy groups;

R 4 is 0, 1, or 2 substitutents independently selected at each occurrence from halogen and C 1 -C 6 alkyl;

R 5 is hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, phenyl or 5 or 6 member heteroaryl having 1, 2 or 3 ring heteroatoms independently selected from N, O or S;

or R 3 and R 5 taken in combination form a divalent CH 2 —CH 2 — group;

R 6 is hydrogen, hydroxy, amino, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 alkoxyC 1 -C 6 alkoxy, mono- and di-C 1 -C 4 alkylamino, amino C 1 -C 6 alkylamino, CH 2 R 7 , NHC(O)C 1 -C 6 alkyl, NHS(O 2 )C 1 -C 6 alkyl, C(O)NH 2 , CO 2 H, OCR A 2 C(O)R 7 or N(H)CR A 2 C(O)R 7 ;

or CR 5 R 6 , taken in combination, form a divalent carbonyl group or a divalent ═CH 2 group;

R A is independently selected at each occurrence from hydrogen or C 1 -C 4 alkyl; and

R 7 is hydroxy, C 1 -C 4 alkoxy, amino or mono- and di-C 1 -C 4 alkylamino.

3. The compound of claim 1 , or salt or tautomer thereof, according to Formula (Ia):

4. The compound of claim 1 , or salt or tautomer thereof, wherein R 4 is absent.

5. The compound of claim 1 , or salt or tautomer thereof, wherein R 3 is hydrogen, chloro or phenyl.

6. The compound of claim 1 , or salt or tautomer thereof, wherein R 3 is hydrogen.

7. The compound of claim 1 , or a salt or tautomer thereof, wherein R 2 is methyl.

8. The compound of claim 1 , or a salt or tautomer thereof, wherein R 1 is halogen, C 1 -C 4 alkyl, vinyl, cyclopropyl, C 1 -C 4 alkoxy, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkoxy, cyclopropylC 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy or S(O) 2 C 1 -C 4 alkyl.

9. The compound of claim 1 , or a salt or tautomer thereof, wherein R 1 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyclopropyl, bromo or difluoromethoxy.

10. The compound of claim 1 , or a salt or tautomer thereof, wherein R 5 is hydrogen, methyl, ethyl cyclopropyl or trifluoromethyl.

11. The compound of claim 1 , or a salt or tautomer thereof, wherein R 6 is hydrogen, hydroxy, methoxy, amino, mono- and di-methylamino or CH 2 R 7 ; and

R 7 is hydroxy, amino, N(H)CH 3 or N(CH 3 ) 2 .

12. The compound of claim 1 , or a salt or tautomer thereof, wherein R 5 is methyl or trifluoromethyl;

R 6 is hydroxy, methoxy, amino, methylamino or CH 2 R 7 ; and

R 7 is hydroxy, amino, N(H)CH 3 or N(CH 3 ) 2 .

13. The compound of claim 1 , or a salt or tautomer thereof, wherein R 8 is hydrogen.

14. The compound of claim 1 , or a salt or tautomer thereof, wherein R 8 is fluorine.

15. The compound of claim 1 , or a salt or tautomer thereof, in which

one occurrence of R is cyano and the other occurrence of R is hydrogen;

R 1 is methyl, hydroxyl or methoxy;

R 2 is methyl;

R 3 is hydrogen, chloro or phenyl;

R 4 is absent;

R 5 is hydrogen, methyl, ethyl or trifluoromethyl;

R 6 is amino, CO 2 H, (CH 2 ) n C(O)R 7 or (CH 2 ) n -tetrazolyl; and

n is 1, 2, or 3.

16. The compound of claim 1 , or a salt or tautomer thereof, which compound is selected from the group consisting of

(±)-2-(((2-aminoethyl)amino)(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)(methylamino)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+) and (−)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+) or (−)-2-(1-(3-chloro-5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-(difluoromethoxy)-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(hydroxy(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-hydroxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-methoxy-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-2,2,2-trifluoro-1-(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(amino(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(amino(7-methyl-5-(methylsulfonyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-( 2 H 3 ) methoxy-7-methyl-1H indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-isopropoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-(2-methoxyethoxy)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((7-fluoro-5-methoxy-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((7-chloro-5-( 2 H 3 )methoxy-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile; and

(±)-2-((5-((1-methoxypropan-2-yl)oxy)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(hydroxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5-ethoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-ethoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(hydroxy(5-isopropoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(hydroxy(5-isopropoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((7-chloro-5-( 2 H 3 )methoxy-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile;

2-(5-methoxy-7-methyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethoxy-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethoxy-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-hydroxy-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-hydroxy-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-hydroxy-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)propyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-hydroxy-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)propyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-(cyclopropylmethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-(cyclopropylmethoxy)-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5-isopropoxy-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(cyclopropyl(methoxy)(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(cyclopropyl(methoxy)(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(( 2 H 3 )methyl(methoxy)(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(( 2 H 3 )methyl(methoxy)(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-( 2 H 3 )methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-( 2 H 3 )methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile;

(−)-2-((3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-6-carbonitrile;

(−)-2-(1-(3-Chloro-5-methoxy-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(3-chloro-5-methoxy-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(methoxy(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indol-5-yl)oxy)acetamide;

(±)-2-((4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-hydroxyethyl)-7-methyl-1H-indol-5-yl)oxy)acetic acid;

(+)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethoxy-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethoxy-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)ethyl)-benzo[d]imidazole-5-carbonitrile;

(+)-2-(2,2,2-trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-Methyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate;

(+)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid;

(−)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetic acid;

(+)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-amino-2,2,2-trifluoro-1-(5-isopropoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(dimethylamino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(amino(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(amino(5-isopropoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((dimethylamino)(5-methoxy-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(2-amino-1-(5-ethoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5-ethoxy-7-methyl-1H-indol-4-yl)-2-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile

2-((5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-(aminomethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

N-((4-((5-cyano-1H-benzo[d]imidazol-2-yl)methyl)-7-methyl-1H-indol-5-yl)methyl)acetamide;

2-((5,7-dimethyl-1H-indol-4-yl)methyl)-7-fluoro-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-chloro-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-vinyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-methoxymethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5,7-dimethyl-1H-indol-4-yl)methyl)-4-methyl-1H-benzo[d]imidazole-5-carbonitrile;

2-((5,7-dimethyl-1H-indol-4-yl)methyl)-6-fluoro-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-ethyl-7-methyl-1H-indol-4-yl)methyl)-6-fluoro-1H-benzo[d]imidazole-5-carbonitrile;

6-chloro-2-((5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5,7-dimethyl-1H-indol-4-yl)methyl)-6-methoxy-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile;

(−)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)benzo[d]imidazole-5-carbonitrile;

(+)-2-(hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(hydroxy(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5-(ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-(ethoxymethyl)-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(hydroxy(5-(isobutyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(hydroxy(5-(isobutyl)-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(hydroxy(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(hydroxy(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5-chloro-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-chloro-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-bromo-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)-4-methyl-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)-4-methyl-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-cyclopropyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-6-fluoro-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5,7-dimethyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-cyano-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1H-indol-4-yl)methoxy)acetic acid;

(+)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5-isobutyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5,7-dimethyl-1H-indol-4-yl)(ethoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5,7-dimethyl-1H-indol-4-yl)(2-methoxyethoxy)methyl)benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5,7-dimethyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-(5-ethyl-7-methyl-1H-indole-4-carbonyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-hydroxy-1-(7-methyl-5-propyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-hydroxy-1-(5-isobutyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-hydroxy-1-(5-isobutyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-chloro-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-chloro-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-bromo-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-bromo-7-methyl-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-hydroxypropyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(cyclopropyl(5,7-dimethyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5,7-dimethyl-1H-indol-4-yl)(hydroxy)(phenyl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(2,2,2-trifluoro-1-hydroxy-1-(5-(hydroxymethyl)-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-4-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-hydroxyethyl)-N,7-dimethyl-1H-indole-5-carboxamide;

(±)-2-(1-hydroxy-1-(7-methyl-5-(trifluoromethyl)-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-isobutyl-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-isobutyl-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((3-bromo-5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((3-chloro-5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((3-chloro-5-ethyl-7-methyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-3-(trifluoromethyl)-1H-indol-4-yl)-1-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(hydroxy(3,5,7-trimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((3-cyano-5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((3-cyano-5-ethyl-7-methyl-1H-indol-4-yl)(methoxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-ethyl-7-methyl-3-(2,2,2-trifluoro-1-hydroxyethyl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(5-hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(5-hydroxy-6,8-dimethyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(6-ethyl-5-hydroxy-8-methyl-1,3,4,5-tetrahydrobenzo[cd]indol-5-yl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(amino(5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(amino(5,7-dimethyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(amino(5-ethyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(amino(5-isopropyl-7-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5,7-dimethyl-1H-indol-4-yl)(methylamino)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-N-((5-cyano-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1H-indol-4-yl)methyl)methanesulfonamide;

(±)-N-((5-cyano-1H-benzo[d]imidazol-2-yl)(5,7-dimethyl-1H-indol-4-yl)methyl)acetamide;

(+)-2-(1-amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5,7-dimethyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-isopropyl-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-(methylamino)ethyl)-1H-benzo[d]imidazole-6-carbonitrile;

(±)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-1-(dimethylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-bromo-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-bromo-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-bromo-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-bromo-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-amino-1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoro-1-(methylamino)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5,7-dimethyl-1H-indol-4-yl)-2-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(5-ethyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethoxy)acetic acid;

2-((7-chloro-5-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((7-ethyl-5-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((7-bromo-5-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((7-(hydroxymethyl)-5-methyl-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-(1-(5-ethyl-7-methyl-1H-indol-4-yl)vinyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)vinyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5-ethyl-7-methyl-3-(1H-pyrazol-5-yl)-1H-indol-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5-ethyl-7-methyl-3-phenyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5,7-dimethyl-3-phenyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5,7-dimethyl-3-phenyl-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5,7-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5,7-dimethyl-3-(1-methyl-1H-pyrazol-4-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-((5,7-dimethyl-3-(pyridin-3-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-((5,7-dimethyl-3-(pyridin-3-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((5,7-dimethyl-3-(1H-pyrazol-5-yl)-1H-indol-4-yl)(hydroxy)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

2-(2-(5-methoxy-7-methyl-1H-indol-4-yl)propan-2-yl)-1H-benzo[d]imidazole-5-carbonitrile;

2-((5,7-dimethylindolin-4-yl)methyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-methoxy-1-(5-methoxy-7-methylindolin-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-methoxy-1-(5-methoxy-7-methylindolin-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate;

(−)-ethyl 2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)acetate;

(±)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethoxy)-2-fluoroacetic acid;

(±)-2-(2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)-1-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(6-methoxy-8-methyl-5-(trifluoromethyl)-1,3,4,5-tetrahydropyrrolo[4,3,2-de]isoquinolin-5-yl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-((2-aminoethypamino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-((2-aminoethypamino)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5-cyano-1H-benzo[d]imidazol-2-yl)-1-(5-cyclopropyl-7-methyl-1H-indol-4-yl)-2,2,2-trifluoroethoxy)acetic acid;

(+)-2-(1-amino-1-(5-bromo-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(−)-2-(1-amino-1-(5-bromo-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-amino-1-(6-fluoro-5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(6-fluoro-5-methoxy-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-6-carbonitrile;

(−)-2-(1-( 2 H 3 )methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(+)-2-(1-( 2 H 3 )methoxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(2,2,2-trifluoro-1-((2-hydroxyethyl)amino)-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-((1-(5-cyano-1H-benzo[d]imidazol-2-yl)-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)amino)acetic acid;

(+) or (−)-2-(1-amino-2,2,2-trifluoro-1-(5-hydroxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-6-carbonitrile;

(±)-2-(5-cyano-1H-benzo[d]imidazol-2-yl)-2-(5-methoxy-7-methyl-1H-indol-4-yl)cyclopropanecarboxylic acid;

(±)-3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)propanoic acid;

(±)-2-(3-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)propyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-4-(5-cyano-1H-benzo[d]imidazol-2-yl)-4-(5-methoxy-7-methyl-1H-indol-4-yl)butanoic acid;

(±)-3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)-2-methylpropanoic acid

(±)-2-(3-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)-2-methylpropyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(4-hydroxy-1-(5-methoxy-7-methyl-1H-indol-4-yl)-3-methylbutyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-2-(1-(5-methoxy-7-methyl-1H-indol-4-yl)-2-(2H-tetrazol-5-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile;

(±)-4-(5-cyano-1H-benzo[d]imidazol-2-yl)-4-(5-methoxy-7-methyl-1H-indol-4-yl)pentanoic acid;

(±)-3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methyl-1H-indol-4-yl)butanoic acid;

(±)-5-(5-cyano-1H-benzo[d]imidazol-2-yl)-5-(5-methoxy-7-methyl-1H-indol-4-yl)pentanoic acid; and

(±)-2-(1-(6-fluoro-5-methoxy-7-methyl-1H-indol-4-yl)-1-methoxyethyl)-1H-benzo[d]imidazole-5-carbonitrile;

and salts, stereoisomers, racemates and tautomers thereof.

17. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers and a therapeutically effective amount of a compound of claim 1 .

18. A pharmaceutical combination, comprising a therapeutically effective amount of the compound according to claim 1 and a second therapeutically active agent.

19. The compound of claim 2 , or salt or tautomer thereof, according to Formula (Ia):

20. The compound of claim 2 , or salt or tautomer thereof, wherein R 4 is absent.

21. The compound of claim 2 , or salt or tautomer thereof, wherein R 3 is hydrogen, chloro or phenyl.

22. The compound of claim 2 , or salt or tautomer thereof, wherein R 3 is hydrogen.

23. The compound of claim 2 , or a salt or tautomer thereof, wherein R 2 is methyl.

24. The compound of claim 2 , or a salt or tautomer thereof, wherein R 1 is halogen, C 1 -C 4 alkyl, vinyl, cyclopropyl, C 1 -C 4 alkoxy, hydroxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkoxy, cyclopropylC 1 -C 4 alkoxy, haloC 1 -C 4 alkoxy or S(O) 2 C 1 -C 4 alkyl.

25. The compound of claim 2 , or a salt or tautomer thereof, wherein R 1 is C 1 -C 4 alkyl, C 1 -C 4 alkoxy, cyclopropyl, bromo or difluoromethoxy.

26. The compound of claim 2 , or a salt or tautomer thereof, wherein R 5 is hydrogen, methyl, ethyl cyclopropyl or trifluoromethyl.

27. The compound of claim 2 , or a salt or tautomer thereof, wherein R 6 is hydrogen, hydroxy, methoxy, amino, mono- and di-methylamino or CH 2 R 7 ; and R 7 is hydroxy, amino, N(H)CH 3 or N(CH 3 ) 2 .

28. The compound of claim 2 , or a salt or tautomer thereof, wherein R 5 is methyl or trifluoromethyl;

R 6 is hydroxy, methoxy, amino, methylamino or CH 2 R 7 ; and

R 7 is hydroxy, amino, N(H)CH 3 or N(CH 3 ) 2 .

29. The compound of claim 1 , or a salt or tautomer thereof, which is (−)-2-(1-amino-2,2,2-trifluoro-1-(5-methoxy-7-methyl-1H-indol-4-yl)ethyl)-1H-benzo[d]imidazole-5-carbonitrile.

Assignments (4)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2013
From: ADAMS, CHRISTOPHER MICHAEL; CAPPARELLI, MICHAEL PAUL; DING, JIAN; EHARA, TAKERU; JENDZA, KEITH; JI, NAN; KARKI, RAJESHRI GANESH; KAWANAMI, TOSHIO; MAINOLFI, NELLO; POWERS, JAMES J.; SERRANO-WU, MICHAEL H.; ZHANG, CHUN
To: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
Reel/Frame 031476/0350 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2013
From: NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
To: NOVARTIS AG
Reel/Frame 031476/0516 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2013
From: BABU, CHARLES; XUE, LIANG
To: ALCON RESEARCH, LTD.
Reel/Frame 031476/0569 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 25, 2013
From: ALCON RESEARCH, LTD.
To: NOVARTIS AG
Reel/Frame 031476/0771 →
Continuity (2)
Provisional Application 61642798 · May 4, 2012
Related Publication 20130296377A1 · Nov 7, 2013