Macrocyclic kinase inhibitors
View Patent ↗Compounds having the formula are useful for inhibiting protein kinases. Also disclosed are methods of making the compounds, compositions containing the compounds, and methods of treatment using the compounds.
1. A compound of formula (I)
or a therapeutically acceptable salt thereof, wherein
is a single or double bond;
A is aryl, wherein the aryl is optionally substituted with one, two, or three substituents independently selected from the group consisting of alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkyl, cyano, halo, haloalkylsulfonyloxy, haloalkoxy, heteroarylalkoxy, heterocycle, heterocyclealkoxy, heterocycleoxyalkoxy, heterocycleoxyalkyl, heterocycleoxyalkynyl, heteroarylcarbonylalkoxy, haloalkyl, hydroxyalkenyl, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, hydroxy, nitro, NR a R b , (NR a R b )alkoxy, (NR a R b )alkyl, and (NR a R b )alkynyl;
R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, carboxy, cyano, halo, and nitro;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylsulfonyl, arylsulfonyl, halo, hydroxy, and NR a R b ;
or R 2 and R 3 , together with the atoms to which they are attached, form an epoxide;
X is N;
Y is selected from the group consisting of CH 2 , O, and NR z , wherein R z is selected from the group consisting of hydrogen and alkyl;
Z is O;
L 1 and L 2 are independently selected from the group consisting of a bond and alkylene;
R a and R b are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, and (NR c R d )alkylcarbonyl; and
R c and R d are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
2. A compound of formula (II)
or a therapeutically acceptable salt thereof, wherein
is a single or double bond;
R 1 is selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, carboxy, cyano, halo, and nitro;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxy, alkoxycarbonyl, alkyl, alkylsulfonyl, arylsulfonyl, halo, hydroxy, and NR a R b ;
or R 2 and R 3 , together with the atoms to which they are attached, form an epoxide;
R 4 is selected from the group consisting of alkoxy, alkyl, cyano, halo, heterocycleoxyalkoxy, heterocycleoxyalkyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, nitro, NR a R b , and (NR a R b )alkoxy;
R 5 is selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkylsulfanyl, arylsulfanyl, alkylsulfonyl, arylsulfonyl, carboxy, carboxyalkyl, haloalkylsulfonyloxy, heteroarylalkoxy, heteroarylcarbonylalkoxy, heterocycle, heterocyclealkoxy, heterocycleoxyalkyl, heterocycleoxyalkynyl, hydroxy, hydroxyalkoxy, hydroxyalkyl, hydroxyalkynyl, NR a R b , (NR a R b )alkoxy, (NR a R b )alkyl, (NR a R b )alkynyl, (NR a R b )carbonyl, (NR a R b )carbonylalkoxy, and (NR a R b )carbonylalkyl;
Y is selected from the group consisting of CH 2 , O, and NR z , wherein R z is selected from the group consisting of hydrogen and alkyl;
Z is O;
L 1 and L 2 are independently selected from the group consisting of a bond and alkylene;
R a and R b are independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, alkylsulfonyl, aryl, arylalkyl, arylsulfonyl, haloalkylcarbonyl, haloalkylsulfonyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylsulfonyl, and (NR c R d )alkylcarbonyl; and
R c and R d are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl.
3. The compound of claim 2 wherein
R 1 is selected from the group consisting of hydrogen and cyano;
R 2 and R 3 are independently selected from the group consisting of hydrogen, alkoxy, and hydroxy;
R 4 is halo;
R 5 is NR a R b ;
R a is hydrogen;
R b is heteroarylalkyl herein the heteroaryl portion of heteroalalkyl is pyridinyl;
is a single bond;
Y is O;
L 1 is CH 2 ; and
L 2 is CH 2 .
4. The compound of claim 1 wherein L 1 is CH 2 and L 2 is CH 2 .
5. The compound of claim 1 selected from the group consisting of
18-chloro-11,14-dihydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-2-one;
18-chloro-11,12,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-2-one;
18-chloro-12,13-dihydroxy-11,12,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-2-one;
17-chloro-10,13-dihydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one;
17-chloro-10,11,12,13-tetrahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one;
17-chloro-11,12-dihydroxy-10,11,12,13-tetrahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecin-2-one;
18-chloro-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(3-hydroxypropoxy)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(2,3-dihydroxypropoxy)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(2-hydroxyethoxy)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(2-methoxyethoxy)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-[2-(2-methoxyethoxy)ethoxy]-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-[2-(dimethylamino)ethoxy]-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-(2-piperidin-1-ylethoxy)-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-(2-pyrrolidin-1-ylethoxy)-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(2-morpholin-4-ylethoxy)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(3-morpholin-4-ylpropoxy)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-(pyridin-4-ylmethoxy)-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-(pyridin-3-ylmethoxy)-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-(pyridin-2-ylmethoxy)-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-(2-oxo-2-pyridin-2-ylethoxy)-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-[2-(1H-imidazol-1-yl)ethoxy]-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-isopropoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
17-amino-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
17-amino-18-chloro-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-[(pyridin-3-ylmethyl)amino]-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-[(pyridin-4-ylmethyl)amino]-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)pyridine-2-carboxamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)pyridine-4-carboxamide;
2-chloro-N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)isonicotinamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)pyridine-3-carboxamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)acetamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-2-(dimethylamino)acetamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-3-(cyclopentylamino)propanamide;
3-chloro-N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)propanamide
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-3-[cyclohexyl(methyl)amino]propanamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)methanesulfonamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-6-morpholin-4-ylpyridine-3-sulfonamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-2,2,2-trifluoroethanesulfonamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-4-fluorobenzenesulfonamide;
N-(18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl)-4-(trifluoromethoxy)benzenesulfonamide;
18-chloro-17-(3-hydroxyprop-1-ynyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-7-cyano-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecin-17-yl trifluoromethanesulfonate;
18-chloro-2-oxo-17-[3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl]-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(3-hydroxypropyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(2,3-dihydroxypropyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
17-allyl-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(3-hydroxy-3-methylbut-1-ynyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(3-hydroxybut-1-ynyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-[3-(diethylamino)prop-1-ynyl]-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-[3-(dimethylamino)prop-1-ynyl]-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(dimethylamino)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(diethylamino)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-2-oxo-17-piperidin-1-yl-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(isobutylamino)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
17-chloro-11,12-dihydroxy-2-oxo-2,3,10,11,12,13-hexahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecine-7-carbonitrile;
17-chloro-2-oxo-2,3,10,13-tetrahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecine-7-carbonitrile;
18-chloro-17-(methylamino)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
14-chloro-11-oxo-2,3,11,12,18,18a-hexahydro-1aH,10H-5,9-epiazenooxireno[1][9,15,1,3,6]benzodioxatriazacycloheptadecine-6-carbonitrile;
18-chloro-11,12-cis-dihydroxy-14-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(cis) 18-chloro-14-methyl-2-oxo-2,3,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-11,12-trans-dihydroxy-14-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(trans) 18-chloro-14-methyl-2-oxo-2,3,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-15-methyl-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,1,3,6,15-benzoxatetraazacycloheptadecine-7-carbonitrile;
(cis) 18-chloro-13-hydroxy-2-oxo-2,3,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-11,12,13-trihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-13-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(trans, trans) 18-chloro-11,12,13-trihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(cis, trans) 18-chloro-11,12,13-trihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-bromo-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-bromo-12,13dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
2-oxo-18-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
2-oxo-18-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-(3-hydroxypropyl)-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-(2-hydroxyethyl)-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-bromo-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-hydroxy-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-(2-hydroxyethyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-(3-hydroxypropyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
12,13-dihydroxy-18-(2-hydroxyethyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
12,13-dihydroxy-18-(3-hydroxypropyl)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-13-methoxy-2-oxo-2,3,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-11,12-dihydroxy-13-methoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-11,12-dihydroxy-13-methoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-13-ethoxy-11,12-cis-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(cis) 18-chloro-13-ethoxy-2-oxo-2,3,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-13-ethoxy-11,12-trans-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(cis) 18-nitro-2-oxo-2,3,13,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-ethoxy-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-(ethylamino)-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
17-(butylamino)-18-chloro-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
17-chloro-2-oxo-2,3,10,11,12,13-hexahydro-1H-8,4-epiazeno-9,14,1,3,6-benzodioxatriazacyclohexadecine-7-carbonitrile;
18-chloro-14-methyl-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-bromo-16-fluoro-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-bromo-16-fluoro-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
(cis) 19-chloro-2-oxo-2,3,10,11,14,15-hexahydro-1H-8,4-epiazeno-9,16,1,3,6-benzodioxatriazacyclooctadecine-7-carbonitrile;
(trans) 19-chloro-2-oxo-2,3,10,11,14,15-hexahydro-1H-8,4-epiazeno-9,16,1,3,6-benzodioxatriazacyclooctadecine-7-carbonitrile;
(12R,13S)-19-chloro-12,13-cis-dihydroxy-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,16,1,3-benzodioxadiazacyclooctadecine-7-carbonitrile;
(12R,13S)-19-chloro-12,13-trans-dihydroxy-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,16,1,3-benzodioxadiazacyclooctadecine-7-carbonitrile;
19-chloro-2-oxo-2,3,10,11,12,13,14,15-octahydro-1H-8,4-epiazeno-9,16,1,3,6-benzodioxatriazacyclooctadecine-7-carbonitrile;
18-methyl-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
16-bromo-18-methyl-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
16-bromo-18-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
16-(3-hydroxyprop-1-ynyl)-18-methyl-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-chloro-17-hydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-metheno-9,15,1,3-benzodioxadiazacycloheptadecine-7-carbonitrile;
11,12-cis-dihydroxy-18-nitro-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
11,12-trans-dihydroxy-18-nitro-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-ethoxy-12,13-dihydroxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-methoxy-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
2-oxo-18-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
12,13-dihydroxy-18-methoxy-2-oxo-2,3,11,12,13,14-hexahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile;
18-(2-hydroxyethoxy)-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile; and
18-[2-(dimethylamino)ethoxy]-2-oxo-2,3,11,14-tetrahydro-1H,10H-8,4-epiazeno-9,15,1,3,6-benzodioxatriazacycloheptadecine-7-carbonitrile.
6. A pharmaceutical composition comprising a compound of claim 1 or a therapeutically acceptable salt thereof, in combination with a therapeutically acceptable carrier.