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US 10,744,150 B2Granted
Cyclic dinucleotides as anticancer agents
AssigneeBristol-Myers Squibb Company
InventorsBrian E. Fink, Dharmpal S. Dodd, Lan-ying Qin, Zheming Ruan, Yufen Zhao, Lalgudi S. Harikrishnan, Muthoni G. Kamau, Steven J. Walker
Life of this patent
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Abstract
The present invention is directed to compounds of the formulae I, II and III as shown below wherein all substituents are defined herein, as well as pharmaceutically acceptable compositions comprising compounds of the invention and methods of using said compositions in the treatment of various disorders.
Claims54
A compound of formula I
- wherein
- X is O or S;
- X1, X2, X3 and X4 are each independently 0 or NH;
- R1 and R2 are independently
- Z1 is N or CRa;
- Z2 is NRb;
- Ra is H, halogen, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1 C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- Rb is H, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, —C(O)Ra1, —C(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- Ra1 is H or C1-3 alkyl;
- R3 is H, CH3, halogen, NH2 or OH;
- R3a is H, CH3, halogen, NH2 or OH;
- or
- R3 and R3a may be taken together to form a 3-4 membered carbocycle;
- or
- R3 and R3a may be taken together to form a C═CH2 substituent;
- R5 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R5a is H or C1-3 alkyl;
- R6 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R8 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R9 is H, halogen or methyl;
- Y is CR5 or N;
- m is 0, 1, 2 or 3;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
21 more elements
A compound of formula II
- wherein
- X is O or S;
- X1, X2, X3 and X4 are each independently O or NH;
- R1 and R2 are each independently
- Z1 is N or CRa;
- Z2 is NRb;
- Ra is H, halogen, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1 C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- Rb is H, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, —C(O)Ra1, —C(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- Ra1 is H or C1-3 alkyl;
- R4 is H, CH3, halogen, NH2 or OH;
- R4a is H, CH3, halogen, NH2 or OH;
- or
- R4 and R4a may be taken together to form a 3-4 membered carbocycle;
- or
- R4 and R4a may be taken together to form a C═CH2 substituent;
- R5 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R5a is H or C1-3 alkyl;
- R6 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R8 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R9 is H, halogen or methyl;
- Y is CR5 or N;
- m is 0, 1, 2 or 3;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
21 more elements
A compound which is
- (1R,6S,8R,9R,15R,17R,18R)-8,17-bis(6-amino-9H-purin-9-yl)-18-fluoro-3,12-disulfanyl-2,4, 11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione;
- (1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-8-{4-hydroxy-1H-imidazo[2,1-b]purin-1-yl}-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dithione;
- (1R,6S,8R,9R,15R,17R,18R)-8,17-bis(6-amino-9H-purin-9-yl)-3,12,18-trihydroxy-2,4,11,13, 16-pentaoxa-3λ2,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dithione;
- 9-[(1R,6 S, 8R, 9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-3,12-disulfanylidene-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]-6,9-dihydro-1H-purin-6-one;
- (1S,6S,8R,9R,15R,17R)-8-(6-amino-9H-purin-9-yl)-17-{4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-3-hydroxy-12-sulfanyl-3-sulfanylidene-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[1 3.3.0.06,9]octadecan-12-one;
- (1R,6S,8R,9R,15R,17R,18S)-8-(6-amino-9H-purin-9-yl)-17-{4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-18-fluoro-3,12-dihydroxy-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dithione;
- (1R,6S,8R,9R,15R,17R,18S)-17-{4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-8-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dithione
- 1-[(1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-3,12-disulfanylidene-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-17-yl]-1H,4H,5H-imidazo[2,1-b]purin-4-one;
- (1R,6S,8R,9R,15R,17R,18R)-8,17-bis(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dione;
- 1-[(1S,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-3,12-disulfanylidene-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-17-yl]-1H-1,2,3-benzotriazole-4-carboxamide;
- 1-[(1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-3,12-disulfanylidene-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-17-yl]-1H-1,2,3-benzotriazole-4-carboxamide;
- 1-[(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-3,12-disulfanylidene-2,4, 11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]-1H-1,2,3-benzotriazole-4-carboxamide;
- (1R,6S,8R,9R,15R,17R,18R)-18-hydroxy-8-(6-hydroxy-9H-purin-9-yl)-17-{4-oxo-1H,4H,5H-imidazo[2,1-b]purin-1-yl}-3,12-disulfanyl-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dione;
- (1R,6S,8R,9R,15R,17R,18R)-8-(6-amino-9H-purin-9-yl)-3,12,18-trihydroxy-17-{4-hydroxy-1H-imidazo[2,1-b]purin-1-yl}-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.2.1.06,9]octadecane-3,12-dithione;
- (1S,6S,8R,9R, 15R, 17R, 18R)-8-(6-amino-9H-purin-9-yl)-3,12,18-trihydroxy-17-(6-hydroxy-9H-purin-9-yl)-2,4, 11,13,16-pentaoxa-3λ5, 12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dithione;
- (1R,6S,8R,9R,15R,17R,18S)-8,17-bis(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydroxy-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecane-3,12-dithione;
- and
- 2-amino-9-[(1R,6S,8R,9R,15R,17R,18R)-17-(6-amino-9H-purin-9-yl)-18-fluoro-3,12-dihydr oxy-3,12-disulfanylidene-2,4,11,13,16-pentaoxa-3λ5,12λ5-diphosphatricyclo[13.3.0.06,9]octadecan-8-yl]-6,9-dihydro-1H-purin-6-one
- or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
16 more elements
A compound of formula III
- wherein
- X is O or S;
- X1, X2, X3 and X4 are each independently 0 or NH;
- R1 and R2 are each independently
- Z1 is N or CRa;
- Z2 is NRb;
- Ra is H, halogen, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1 C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- Rb is H, C1-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R5, —C(O)Ra1, —C(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- Ra1 is H or C1-3 alkyl;
- R5 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R5a is H or C1-3 alkyl;
- R6 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R8 is H, halogen, C1-3 alkyl, CN, NO2, OH, ORa1, SRa1, —C(O)NRa1Ra1, —COORa1, —OC(O)Ra1, —OC(O)NRa1Ra1, —NRa1Ra1, —NRa1C(O)Ra1, —NRa1COORa1, —NRa1C(O)NRa1Ra1, —NRa1S(O)2Ra1, —NRa1S(O)2NRa1Ra1, —S(O)Ra1, —S(O)NRa1Ra1, —S(O)2Ra1 or S(O)2NRa1Ra1;
- R9 is H, halogen or methyl;
- Y is CR5 or N;
- m is 0, 1, 2 or 3;
- n is 0 or 1;
- or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
15 more elements
Dependencies are inferred from the claim text.