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US 6,441,017 B1Granted
Inhibitors of prenyl-protein transferase
AssigneeMerck & Co., Inc.
InventorsIan M. Bell, Douglas C. Beshore, Steven N. Gallicchio, C. Blair Zartman
Life of this patent
Estimating the term…
Abstract
The present invention is directed to macrocyclic compounds which inhibit prenyl-protein transferase (FTase) and the prenylation of the oncogene protein Ras. The invention is further directed to chemothera-peutic compositions containing the compounds of this invention and methods for inhibiting prenyl-protein transferase and the prenylation of the oncogene protein Ras.
Claims26
A compound of the formula A:
- wherein
- X1 is (C(R1a)2)nA1(C(R1a)2)nA2;
- X2 is (C(R1b)2)pA3(C(R1b)2)p;
- X3 is (C(R1c)2)qA4(C(R1c)2)q;
- R1a, R1b and R1c are independentlys elected from:
- a) hydrogen;
- b) unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, R10O—, R6aS(O)m, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, —C(O)NR6R7, R10C(O)NR10—, (R10)2NC(O) NR10—, R10C(O)—, —N(R10)2, R10OC(O)—, or R10OC(O)NR10—;
- and
- c) unsubstituted or substituted C1-C6 alkyl, wherein one or more of the substituents on the substituted C1-C6 alkyl is selected from unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C3-C10 cycloalkyl, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, R10O—, R6aS(O)m, R10C(O)NR10—, (R10)2NC(O)NR10—, R10C(O)—, —C(O)NR6R7, R10OC(O)—, —N(R10)2, R10OC(O)NR10—, and halo;
- A1, A3 and A4 are independently selected from
- a) a bond,
- b) —C(═O)—,
- c) —HC═CH—,
- d) —C≡C—,
- e) O,
- f) NR10,
- g) NR10C(O),
- h) C(O)NR10,
- i) OC(O)NR10,
- j) NR10C(O)O,
- k) S(═O)m,
- l) C(O)O, and
- m) OC(O);
- A2 is selected from
- a) a bond,
- b) —C(═O)—,
- c) NR10C(O),
- d) S(═O)m, and
- e) OC(O);
- R2 is independently selected from:
- a) hydrogen,
- b) CN,
- c) NO2,
- d) halogen,
- e) aryl, unsubstituted or substituted,
- f) heterocycle, unsubstituted or substituted:
- g) C1-C6 alkyl, unsubstituted or substituted,
- h) OR10,
- i) N3,
- j) R6aS(O)m,
- k) C3-C10 cycloalkyl, umsubstituted or substituted,
- l) C2-C6 alkenyl, unsubstituted or substituted,
- m) C2-C6 alkynyl, unsubstituted or substituted,
- n) (R10)2NC(O)NR10—,
- o) R10C(O)—,
- p) R10C(O)NR10—,
- q) R10OC(O)—,
- r) —N(R10)2,
- s) R10OC(O)NR10—, and
- t) —(C1-C6 alkyl)NR10C(O)R13;
- R3 is independently seleted from:
- H, CN, NO2, halo, unsubstituted or substituted C1-C6 alkyl, N3, oxido, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle, unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted aralkyl, unsubstituted or substituted beterocyclylalkyl, C1-C6 perfluoroalkyl, CF3O—, CF3CH2—, unsubstituted or substituted C3-C10 cycioalkyl, OR10, NR6R7, OR6, —C(O)R10, —O(C1-C6 alkyl)OR10, —S(O)mR6a, —C(O)NR6R7, —NHC(O)R10, —(C1-C6 alkyl)OR10, and —(C1-C6 alkyl)C(O)R10;
- R4 and R5 are independently selected from:
- H, OR10, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstitiuted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, unsubstituted or substituted heterocycle,
- wherein the substituted group is substituted with one or more of:
- 1) aryl or heterocycle, unsubstituted or substituted with:
- a) C1-C6 alkyl,
- b) (CH2)nOR6,
- c) (CH2)nNR6R7,
- d) halogen,
- e) CN,
- f) aryl or heteroaryl,
- g) perfludro-C1-C4 alkyl,
- h) S(O)mR6a,
- 2) C3-C6 cycloalkyl,
- 3) OR6,
- 4) S(O)mR6a,
- 15) N3,
- 16) halo, and
- 17) perfluoro, C1-4-alkyl;
- or
- R4 and R5 are attached to the same C atom and are combined to form —(CH2)u— wherein one of the carbon atoms is optionally replaced by a m selected from:
- O, S(O)m, —NC(O)—, and —N(COR10)—;
- and any of R4 and R5 are optionally attached to the same carbon atom;
- R6, R7 and R7a are independently selected from:
- H, C1-C6 alkyl, C3-C6 cycloalkyl, heterocycle, aryl, aralkyl, aroyl, heteraroyl, arylsulfonyl, heteroarylsulfony, C1-C4 perfluoroalkyl, unsubstituted or substituted with one or two substituents selected from:
- a) C1-C6 alkoxy,
- b) substituted or unsubstituted aryl or substituted or unsubstituted heterocycle,
- c) halogen,
- d) HO,
- g) —S(O)mR6a, or
- h) N(R10)2;
- or
- R6 and R7 may be joined in a ring;
- R7 and R7a may be joined in a ring;
- R6a is selected from
- a) C3-6 cycloakyl, heterocycle, aryl, unsubstituted or substituted with one or more of the following:
- 1) C1-4 alkoxy,
- 2) aryl or heterocycle,
- 3) halogen,
- 4) HO,
- 6) SO2R6a,
- 7) N(R10)2;
- and
- b) C1-C6 alkyl, unsubstituted or substituted with one or more of the following:
- 1) —C(R10)2C1-4 alkoxy,
- 2) aryl or heterocyle,
- 3) —C(R10)2 halogen,
- 4) —C(R10)2OH,
- 6) —C(R10)2SO2R6a, and
- 7) —C(R10)2N(R10)2;
- R8 is independently selected from
- a) hydrogen,
- b) unsubstituted or substituted C2-C6 alkenyl, unsubstituted or substituted C2-C6 alkynyl, unsubstituted or substituted C3-C6 cycloalkyl, unsubstituted or substituted C1-C4 perfluoroalkyl, F, Cl, Br, R10O—, CN, R6aS(O)m—, C(O)NR6R7, R10(C(O)NR10—, NO2, (R10)2NC(O)NR10—, R10C(O)—, R10OC(O)—, R10OC(O)NR10—, N3, or —N(R10)2, and
- c) C1-C6 alkyl, unsubstituted or substituted by C1-C4 perfluoroalkyl, F, Cl, Br, R10O—, R6aS(O)m—, R10C(O)NR10—, CN, —C(O)NR6R7, (R10)2NC(O)NR10—, R10C(O)—, R10C(O)—, N3, —N(R10)2, and R10OC(O)NR10—;
- R9 is independently selected from
- 1) H, unsubstituted or substituted C1-C6 alkyl, unsubstituted or substituted C2-C8 alkenyl, unsubstituted or substituted C2-C8 alkynyl, unsubstituted or substituted aryl, and unsubstituted or substituted heterocyele, wherein the substituted group is substituted with one or more of:
- a) C1-C6 alkyl, unsubstituted or substituted,
- b) (CH2)nOR6,
- c) (CH2)nNR6R7,
- d) halogen,
- e) CN,
- f) aryl, unsubstituted or substituted,
- g) heterocycle, unsubstituted or substituted,
- h) perfluoro-C1-C4 alkyl,
- i) S(O)mR6a,
- j) N(R10)2,
- k) NR10C(O)R11,
- l) NR10OC(O)R11N(R10)2,
- 2) C3-C6 cycloalkyl,
- 3) S(O)1-2R6a,
- 8) —(C1-C6 alkyl)NR10C(O)R13;
- R10 is independently selected from
- a) hydrogen,
- b) unsubstituted or substituted C1-C6 alkyl,
- c) unsubstituted or substituted C3-C6 cycloalkyl,
- d) 2,2,2-trifluoroethyl,
- e) unsubstituted or substituted heteroaryl,
- f) unsubstituted or substituted aralkyl,
- g) unsubstituted or substituted aryl, and
- h) unsubstituted or substituted heterocyclylalkyl;
- R11 is independently selected from
- a) unsubstituted or substituted C1-C6 alkyl,
- b) unsubstituted or substituted aralkyl,
- c) unsubstituted or substituted heterocycle,
- d) unsubstituted or substituted aryl, and
- e) unsubstituted or substituted heterocyclylaekyl;
- R13 is independently selected from
- a) H,
- b) unsubstituted or substituted C1-C6 alkyl,
- c) unsubstituted or substituted C2-C6 alkenyl,
- d) unsubstituted or substituted C2-C6 alkynyl,
- e) unsubstituted or substituted aryl,
- f) unsubstituted or substituted heterocycle,
- g) aralkyl, unsubstituted or substituted,
- h) heterocyclylalkyl, unsubstituted or substituted,
- i) CF3,
- j) CF3O—,
- k) CF3CH2—,
- l) C3-C10 cycloalkyl, unsubstituted or substituted,
- m) OR10,
- n) —C(O)R10,
- o) —O(C1-C6 alkyl)OR10,
- p) —C(O)NR6R7,
- q) —(C1-C6 alkyl)OR10, and
- r) —(C1-C6 alkyl)C(O)R10;
- G1 and G2 are independently selected from oxygen or H2;
- V is aryl;
- W is a 5-membered heterocycle;
- Y1 and Y2 are independently selected from
- a) a bond,
- b) C1-C8 alkyl,
- c) C2-C8 alkenyl,
- d) C2-C8 alkynyl,
- e) C3-C20 cycyloalkyl,
- f) aryl, and
- g) heterocycle;
- Z1 and Z2 are independently selected from
- a) a bond,
- b) O,
- c) C(O),
- d) S(O)m,
- e) C(O)NR10,
- f) (C(R1a)2)n,
- g) (C(R1a)2)nO,
- h) O(C(R1a)2)n, and
- i) NR10;
- m is 0, 1 or 2;
- n is 0, 1, 2, 3, 4, 5 or 6;
- p is 0, 1, 2, 3, 4, 5 or 6;
- q is 0, 1, 2, 3, 4, 5 or 6;
- r is 0 to 5, provided that r is 0 when V is a bond;
- s is 0, 1, 2, 3 or 4;
- provided that s is 0 when W is a bond;
- t is 0, 1, 2, 3 or 4;
- provided that t is 0 when Y1 is a bond;
- u is 4 or 5;
- v is 0, 1, 2,3 or 4;
- and
- w is 0, 1, 2, 3 or 4;
- or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
188 more elements
A compound which is selected from the group consisting of:
- (20R)-19,20,21,22-Tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (20S)-19,20,21,22-Tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (20R)-14-Chloro-19,20,21,22-tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatri-azacycloeicosine-9-carbonitrile;
- (20S)-14-Chloro-19,20,21,22-tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatri-azacycloeicosine-9-carbonitrile;
- (21R)-20,21,22,23-Tetrahydro-17-oxo-5H,17H,19H-18,21-methano-6,10:12,16-dimethenoimidazo[3,4-h][1,8,11,15]oxatriazacycloheneicosine-9-carbonitrile;
- (21S)-20,21,22,23-Tetrahydro-17-oxo-5H,17H,19H-18,21-methano-6,10:12,16-dimethenoimidazo[3,4-h][1,8,11,15]oxatriazacycloheneicosine-9-carbonitrile;
- (21R)-20,21,22,23-Tetrahydro-5H,19H-18,21-methano-6,10:12,16-dimetheno-16H-imidazo[4,3-n][1,8,12,15,7]oxatriazathia-cycloheneicosine-9-carbonitrile 17,17-dioxide;
- (21S)-20,21,22,23-Tetrahydro-5H,19H-18,21-methano-6,10:12,16-dimetheno-16H-imidazo[4,3-n][1,8,12,15,7]oxatriazathia-cycloheneicosine-9-carbonitrile 17,17-dioxide;
- (20S)-19,20,21,22-Tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20R)-19,20,21,22-Tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (5R,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (5S,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (5R,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (5S,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (5R,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (5S,20R)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (5R,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (5S,20S)-19,20,21,22-Tetrahydro-5-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (17R,20S)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17S,20S)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17R,20R)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17S,20R)-17-(3-Chlorophenyl)-19,20,21,22-tetrahydro-19-oxo-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17R,20S)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (17S,20S)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (17R,20R)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (17S,20R)-19,20,21,22-Tetrahydro-19-oxo-17-phenyl-5H,18H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriaza-cycloeicosine-9-carbonitrile;
- (20S)-19,20,21,22-Tetrahydro-21-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20R)-19,20,21,22-Tetrahydro-21-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20R)-19,20,22,23-Tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriaza-cyclononadecosine-9-carbonitrile;
- (20S)-19,20,22,23-Tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriaza-cyclononadecosine-9-carbonitrile;
- (20R)-15-Bromo-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20S)-15-Bromo-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20R)-15-Cylopropylethynyl-19,20,21,22tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20S)-15-Cyclopropylethynyl-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20S)-15-(2-Cyclopropylethyl)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20R)-15-(2-Cyclopropylethyl)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20R)-19,20,21,22-Tetrahydro-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20S)-19,20,21,22-Tetrahydro-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20S)-19,20,22,23-Tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (20R)-19,20,22,23-Tetrahydro-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatrizacyclononadecosine-9-carbonitrile;
- (5R,20R)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
- (5S,20R)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
- (5S,20S)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
- (5R,20S)-19,20,22,23-Tetrahydro-5-hydroxy-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
- (20S)-19,20,21,22,23,24-hexahydro-19,22-dioxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
- (20R)-19,20,21,22,23,24-hexahydro-19,22-dioxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
- (20S)-19,20,21,22,23,24-hexahydro-19-oxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
- (20R)-19,20,21,22,23,24-hexahydro-19-oxo-5H,18H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,6,9,14]oxatriazacycloeiscosine-9-carbonitrile;
- 15-Bromo-19,20,21,22-tetrahydro-19-oxo-17H-18,20-ethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17R,20R)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatraacycloeicosine-9-carbonitrile;
- (17S,20R)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- 17S,20S)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17R,20S)-19,20,21,22-tetrahydro-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (20S)-19,20,22,23-Tetrahydro-21-methyl-9-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (20R)-19,20,22,23-Tetrahydro-21-methyl-19-oxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (17R,20R)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17S,20R)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17S,20S)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (17R,20S)-19,20,21,22-tetrahydro-21-methyl-19-oxo-17H-15,17:18,20-diethano-6,10:12,16-dimetheno-16H-imidazo[3,4-h][1,8,11,14]oxatriazacycloeicosine-9-carbonitrile;
- (20R)-16-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (20S)-16-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (23S)-22,23,24,25-tetrahydro-22-oxo-16H,21H-21,23-ethano-6,10:12,16-dimethenobenz[g]imidazo[4,3-n][1,9,12,15]oxatriazacycloheneicosine-9-carbonitrile;
- (23R)-22,23,24,25-tetrahydro-22-oxo-16H,21H-21,23-ethano-6,10:12,16-dimethenobenz[g]imidazo[4,3-n][1,9,12,15]oxatriazacycloheneicosine-9-carbonitrile;
- (20S)-25-aza-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20R)-25-aza-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20S)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,3,6,9,12]oxatetraaza-cyclooctadecosine-9-carbonitrile;
- (20R)-19,20,21,22-tetrahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,3,6,9,12]oxatetraaza-cyclooctadecosine-9-carbonitrile;
- (21S)-19,20,22,23-tetrahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecosine-9-carbonitrile;
- (21R)-19,20,22,23-tetrahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,7,10,13]oxatriazacyclononadecosine-9-carbonitrile;
- (20S)-19,20,21,22-tetrahydro-3-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20R)-19,20,21,22-tetrahydro-3-methyl-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20S)-19,20,22,23-tetrahydro-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (20R)-19,20,22,23-tetrahydro-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (21S)-19,20,22,23,24-pentahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,7,10,14]oxatriazacycloeicosine-9-carbonitrile;
- (21R)-19,20,22,23,24-pentahydro-18-oxo-5H,21H-19,21-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-m][1,7,10,14]oxatriazacycloeicosine-9-carbonitrile;
- (20S)-17-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (20R)-17-bromo-19,20,22,23-tetrahydro-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[4,3-l][1,6,9,13]oxatriazacyclononadecosine-9-carbonitrile;
- (5S,20S)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
- (5R,20S)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatriazacyclononadecosine-9-carbonitrile;
- (5S,20R)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatrizacyclononadecosine-9-carbonitrile;
- (5R,20R)-5-amino-19,20,22,23-tetrahydro-5-methyl-19,22-dioxo-5H,21H-18,20-ethano-12,14-etheno-6,10-methenobenz[d]imidazo[3,4-l][1,6,9,12]oxatrizacyclononadecosine-9-carbonitrile:
- (20S)-15,16,17,17a,19,20,21,22-octahydro-15-oxa-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20R)-15,16,17,17a,19,20,21,22-octahydro-15-oxa-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriazacyclooctadecosine-9-carbonitrile;
- (20S)-15,16,17,17a,19,20,21,22-octahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- (20R)-15,16,17,17a,19,20,21,22-octahydro-19-oxo-5H-18,20-ethano-12,14-etheno-6,10-metheno-18H-benz[d]imidazo[4,3-k][1,6,9,12]oxatriaza-cyclooctadecosine-9-carbonitrile;
- or a pharmaceutically acceptable salt, an optical isomer or stereoisomer thereof.
83 more elements
Dependencies are inferred from the claim text.