CYCLIC DINUCLEOTIDES AS ANTICANCER AGENTSThe present invention is directed to compounds of formulae (I) and (II) 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.A compound of the formulawhereinX is independently O or S;X1, X2, X3 and X4 are each independently O or NH;Rf and R2 are independentlywith the proviso that one of R1 and R2 must each 7} is independently N or CRa;Z2 is NRb;Ra is H, halogen, C i-6 alkyl substituted with 0-6 Rs, Cs-6 cycloalkyl substituted with 0-6 R5, CN, N02, OH, OR'1, SRai, -C(0)NRa!Ral, -COORal, -0C(0)Ral, - 0C(0)NRa]Ral, -NRalRa!, -NRa! C(0)Ral, - NRalCOORal, -NRa3C(0)NRalRal, - NRalS(0)2Ral, -NRalS(0)2NRalRal, -S(0)Rai, - S(0)NRa3Ral, -S(0)2Ral or S(0)2NRaiRai;Rb is H, Ci-6 alkyl substituted with 0-6 R5, C3-6 cycloalkyl substituted with 0-6 R -C(0)Rai, -C(0)NRa!Ral, -S(0)2.Ral or S(0)2NRa3Ral;Ral is H, Ci-3 alkyl or C3-6 cycloalkyl;R3 and R4 are independently H, CH3, halogen, -NRalRai or ORal;R3a and R4a are independently H, CH3, halogen, -NRalRal or ORal; orR and R3a or R4 and R4a may independently be taken together to form a 3-4 niembered carbocycle; orR3 and R3a or R4 and R4a may independently be taken together to form a C=CH2 substituent;R’ is H, halogen, C1-3 alkyl substituted with 0-6 Ra, C3-6 cycloaikyl substituted with 0-6 Ra, aryl substituted with 0-6 Ra or heteroaryl substituted with 0-6 Ra, CN, NO2, OH, ORal, SRal, -C(0)NRalRal, -COORai, -OC(0)Ral, -OC(0)NRaiRal, -NRalRai, -NRal C(0)Ral, - NRalCOORa!, -NRalC(0)NRalRal, -NRa!S(0)2Ra!, -NRalS(0)2NRa3Ral, - S(0)Rai, - S(0)NRalRal, -S(0)2Ra! or S(0)2NRalRai;R5ais H or Ci- alkyl substituted with 0-6 R5;R6 is H, halogen, C i-3 alkyl substituted with 0-6 R5, CN, N02, OH, ORa!, SRai, - C(0)NRaiRai, -COORal, - NRalCOORal, -NRa3C(0)NRa3Ral, -NRalS(0)2Ral, -NRalS(0)2NRalRal, -S(0)Ra3, - S(0)NRalRal, -S(0)2Ral or S(0)2NRalRal;R8 is H, halogen, C1-3 alkyl substituted with 0-6 Ra, CN, N02, OH, ORal, SRal, - C(0)NRa3Ral, -COORai, - NRalCOORal, -NRa 1 C (0)NRa 3Ral, -NRalS(0)2Ral, -NRalS(0)2NRalRal, -S(0)Ral, - S(0)NRalRal, -S(0)2Ral or S(Q)2NRalRai;each Y is independently CRa or N;m is 0, 1 , 2 or 3;or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof. 2, The compound according to claim 1 of the formula whereinX is S;X1, X2, X3 and X4 are each independently O or NH;Rf and R2 are independe tlywith the proviso that one of R1 and R2 must be each Z1 is independently N or CRa;Z2 is NRb;Ra is H, halogen, Ci-6 alkyl substituted with 0-6 R3, C3-6 cycloalkyl substituted with 0-6 R5, CN, NO2, OH, OR'1, SRai, -C(0)NRa!Ral, -COORal, -0C(0)Ral, - 0C(0)NRalRa], -NRalRal, -NRal C(0)Ral, - NRalCOORal, -NRalC(0)NRalRa], - NRalS(0)2Ral, -NRalS(0)2NRalRal, -S(0)Ral, - S(0)NRalRal, -S(0)2Ral or S(0)2NRalRal;Rb is H, Ci-6 alkyl substituted with 0-6 Rs, C3-6 cycloalkyl substituted with 0-6 Rs,-C(0)Ral, -C(0)NRalRa], -S(0)2Ra! or S(0)2NRalRal;Ra! is H, Ci-3 alkyl or C3-6 cycloalkyl; R3 and R4 are independently H, CHi, halogen, -NRalRa! or ORa!;R3a and R4a are independently H, CH3, halogen, -NR3lRal or ORal; orR3 and R3a or R4 and R4a may independently be taken together to form a 3-4 membered carbocycle; orR3 and R3a or R4 and R4a may independently be taken together to form a C ( I k substituent;R3 is H, halogen, C r -3 alkyl substituted with 0-6 Ra, C3-6 cycloalkyl substituted with 0-6 Ra, aryl substituted with 0-6 Ra or heteroaryl substituted with 0-6 Ra, CN, NO2, OH, ORa! , SRai, -C(0)NRalRal, -COORai, -OC(0)Ral, -OC(0)NRalRal, -NRalRal, -NRa! C(0)Ral, - NRalCOORai, -NRalC(0)NRalRal, -NRalS(0)2Ral, -NRalS(0)2NRalRal, - S(0)Rai, - S(0)NRa!Ral, -S(0)2Ral or S(0)?.NRalRa!;R3a is H or C3-3 alkyl substituted with 0-6 R5;R6 is H, halogen, C1-3 alkyl substituted with 0-6 R5, CN, NO2, OH, ORal, SRal, - C(0)NRalRal, -COORai, - NRalCOORal, -NRalC(0)NRalRa!, -NRa!S(0)2Ra!, -NRalS(0)2NRa!Ral, -S(0)Ral, - S(0)NRa]Ral, -S(0)2Ral or S(0)2NRaiRai;R8 is H, halogen, Ci-3 alkyl substituted with 0-6 R3, CN, NQ2, OH, ORal, SRal, - C(0)NRalRa], -COORa!, - NRaiCOORal, -NRa]C(0)NRalRal, -NRaiS(0)2Rai, -NRa!S(0)2NRaiRa -S(0)Ra - S(0)NRalRal, -S(0)2Ral or S(0)2NRalRal;each Y is independently CRa or N:m is 0, l, 2 or 3;or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof.
항암제로서의 시클릭 디뉴클레오티드본 발명은 하기 나타낸 바와 같이 화학식 I 및 II의 화합물, 뿐만 아니라 본 발명의 화합물을 포함하는 제약상 허용되는 조성물, 및 다양한 장애의 치료에서 상기 조성물을 사용하는 방법에 관한 것이다. 여기서 모든 치환기는 본원에 정의되어 있다.하기 화학식의 화합물 또는 그의 제약상 허용되는 염, 호변이성질체 또는 입체이성질체. 여기서X는 독립적으로 O 또는 S이고; X1, X2, X3 및 X4는 각각 독립적으로 O 또는 NH이고; R1 및 R2는 독립적으로이고; 단 R1 및 R2 중 1개는 이어야만 하고; 각각의 Z1은 독립적으로 N 또는 CRa이고; Z2는 NRb이고;Ra는 H, 할로겐, 0-6개의 R5로 치환된 C1-6 알킬, 0-6개의 R5로 치환된 C3-6 시클로알킬, 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 또는 S(O)2NRa1Ra1이고; Rb는 H, 0-6개의 R5로 치환된 C1-6 알킬, 0-6개의 R5로 치환된 C3-6 시클로알킬, -C(O)Ra1, -C(O)NRa1Ra1, -S(O)2Ra1 또는 S(O)2NRa1Ra1이고;Ra1은 H, C1-3 알킬 또는 C3-6 시클로알킬이고; R3 및 R4는 독립적으로 H, CH3, 할로겐, -NRa1Ra1 또는 ORa1이고; R3a 및 R4a는 독립적으로 H, CH3, 할로겐, -NRa1Ra1 또는 ORa1이거나; 또는 R3 및 R3a 또는 R4 및 R4a는 독립적으로 함께 3-4원 카르보사이클을 형성할 수 있거나; 또는 R3 및 R3a 또는 R4 및 R4a는 독립적으로 함께 C=CH2의 치환기를 형성할 수 있고; R5는 H, 할로겐, 0-6개의 Ra로 치환된 C1-3 알킬, 0-6개의 Ra로 치환된 C3-6 시클로알킬, 0-6개의 Ra로 치환된 아릴 또는 0-6개의 Ra로 치환된 헤테로아릴, 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 또는 S(O)2NRa1Ra1이고;R5a는 H 또는 0-6개의 R5로 치환된 C1-3 알킬이고; R6은 H, 할로겐, 0-6개의 R5로 치환된 C1-3 알킬, 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 또는 S(O)2NRa1Ra1이고;R8은 H, 할로겐, 0-6개의 R5로 치환된 C1-3 알킬, 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 또는 S(O)2NRa1Ra1이고; 각각의 Y는 독립적으로 CRa 또는 N이고; m은 0, 1, 2 또는 3이다.