Conjugates of CC-1065 analogs and bifunctional linkers

1. A compound of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

RM is a reactive moiety,

L is independently absent or a linking group linking RM to one or more V 1 and/or Y;

each V 1 is independently absent or a conditionally-cleavable or conditionally-transformable moiety, which can be cleaved or transformed by a chemical, photochemical, physical, biological, or enzymatic process;

each Y is a self-eliminating spacer system which is comprised of 1 or more self-elimination ω-amino aminocarbonyl cyclization spacers selected from

and each Y is linked to V 1 , optionally L, and one or more Z;

p is a number representing a degree of branching and is a positive integer;

z is a positive integer equal to or smaller than the total number of attachment sites for Z;

each Z is independently a compound of formula (I), (II), (I′), or (II′):

or a pharmaceutically acceptable salt thereof, wherein

DB is a DNA-binding moiety which is selected from

R 1 is a leaving group;

R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , R 12 , and R 19 are independently selected from the group consisting of H, OH, SH, NH 2 , N 3 , NO 2 , NO, CF 3 , CN, C(O)NH 2 , C(O)H, C(O)OH, halogen, R a , SR a , S(O)R a , S(O) 2 R a , S(O)OR a , S(O) 2 OR a , OS(O)R a , OS(O) 2 R a , OS(O)OR a , OS(O) 2 OR a , OR a , NHR a , N(R a )R b , + N(R a )(R b )R c , P(O)(OR a )(OR b ), OP(O)(OR a )(OR b ), SiR a R b R c , C(O)R a , C(O)OR a , C(O)N(R a )R b , OC(O)R a , OC(O)OR a , OC(O)N(R a )R b , N(R a )C(O)R b , N(R a )C(O)OR, and N(R a )C(O)N(R b )R c , wherein

R a , R b , and R c are independently selected from H and optionally substituted C 1-3 alkyl or C 1-3 heteroalkyl,

or R 3 +R 3′ and/or R 4 +R 4′ are independently selected from ═O, ═S, ═NOR 18 , ═C(R 18 )R 18′ , and ═NR 18 , R 18 and R 18′ being independently selected from H and optionally substituted C 1-3 alkyl, two or more of R 2 , R 2′ , R 3 , R 3′ , R 4 , R 4′ , and R 12 optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;

X 2 is selected from the group consisting of O, C(R 14 )(R 14′ ), and NR 14′ , wherein R 14 and R 14′ have the same meaning as defined for R 7 and are independently selected, or R 14′ and R 7 are absent resulting in a double bond between the atoms designated to bear R 7 and R 14′ ;

R 5 , R 5′ , R 6 , R 6′ , R 7 , and R 7′ are independently selected from the group consisting of H, OH, SH, NH 2 , N 3 , NO 2 , NO, CF 3 , CN, C(O)NH 2 , C(O)H, C(O)OH, halogen, R e , SR e , S(O)R e , S(O) 2 R e , S(O)OR e , S(O) 2 OR e , OS(O)R e , OS(O) 2 R e , OS(O)OR e , OS(O) 2 OR e , OR e , NHR e , N(R e )R e , + N(R e )(R f )R g , P(O)(OR e )(OR f ), OP(O)(OR e )(OR f ), SiR e R f R g , C(O)R e , C(O)OR e , C(O)N(R e )R f , OC(O)R e , OC(O)OR e , OC(O)N(R e )R f , N(R e )C(O)R f , N(R e )C(O)OR f , N(R e )C(O)N(R f )R g , and a water-soluble group, wherein

R e , R f , and R g are independently selected from H and optionally substituted (CH 2 CH 2 O) ee CH 2 CH 2 X 13 R e1 , C 1-15 alkyl, C 1-15 heteroalkyl, C 3-15 cycloalkyl, C 1-15 heterocycloalkyl, C 5-15 aryl, or C 1-15 heteroaryl, wherein ee is selected from 1 to 1000, X 13 is selected from O, S, and NR f1 , and R f1 and R e1 are independently selected from H and C 1-3 alkyl, one or more of the optional substituents in R e , R f , and/or R g optionally being a water-soluble group, two or more of R e , R f , and R g optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles,

or R 5 +R 5′ and/or R 6 +R 6′ and/or R 7 +R 7′ are independently selected from ═O, ═S, ═NOR e3 , ═C(R e3 )R e4 , and ═NR e3 , R e3 and R e4 being independently selected from H and optionally substituted C 1-3 alkyl, or R 5′ +R 6′ and/or R 6′ +R 7′ and/or R 7′ +R 14′ are absent, resulting in a double bond between the atoms designated to bear R 5′ and R 6′ , and/or R 6′ and R 7′ , and/or R 7′ and R 14′ , respectively, two or more of R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , R 14 , and R 14′ optionally being joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;

X 1 is selected from the group consisting of O, S, and NR 13 , wherein R 13 is selected from H and optionally substituted C 1-8 alkyl or C 1-8 heteroalkyl and not joined with any other substituent;

one of R 4 and R 4′ may optionally be joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;

one of R 2 , R 2′ , R 3 , and R 3′ and one of R 5 and R 5′ may optionally be joined by one or more bonds to form one or more optionally substituted carbocycles and/or heterocycles;

a and b are independently selected from 0 and 1;

and

one or more of X 1 , R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , R 14 , and R 14′ may optionally in addition be substituted by or be a substituent of formula (V):

wherein each V 2′ is absent or a functional moiety,

each L 2′ is independently absent or a linking group linking V 2′ to L′,

q′ is a number representing a degree of branching and is a positive integer,

L′, V 1′ , Y′, Z′, p′, and z′ has the same meaning as defined for L, V 1 , Y, Z, p, and z, respectively, and is independently selected, the one or more substituents of formula (V) being independently connected via Y′ to one or more of X 1 , R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , R 14 , R 14′ , and/or to one or more atoms bearing these R substituents;

each Z is independently connected to Y through either Xi, an atom in R 5 , R 5′ , R 6 , R 6′ , R 7 , R 7′ , R 14 , R 14′ , or an atom bearing any of these R substituents,

V 1 , Y, and Z may contain protecting groups, and the one or more V 2′ -L 2′ moieties optionally present in Z as defined hereinabove may optionally and independently be RM′ instead, which is a reactive moiety, and wherein, if there is more than 1 reactive moiety in (IV), some or all reactive moieties are the same or different.

2. The compound according to claim 1 wherein the reactive moiety RM is

wherein

X 35 is selected from the group consisting of halide, hydroxy, OC(O)R dd , and OC(O)OR dd , or C(O)—X 35 is an active ester, X 36 is selected from the group consisting of halide, mesyloxy, triflyloxy, and tosyloxy, and R dd is selected from the group consisting of optionally substituted C 1-10 alkyl, C 1-10 heteroalkyl, C 3-10 cycloalkyl, C 1-10 heterocycloalkyl, C 5-10 aryl, and C 1-10 heteroaryl.

3. The compound according to claim 1 , which is

or an isomer, or a mixture of isomers, wherein R 5a is selected from H, methyl and methoxy, AZ is

V 1 is selected from the group consisting of valylcitrulline, valyllysine, phenylalanyllysine, alanylphenylalanyllysine, and D-alanylphenylalanyllysine, CL is

and L is selected from the group consisting of

4. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.

5. The compound according to claim 1 , wherein the compound has the formula

6. A pharmaceutical composition comprising a compound according to claim 2 and a pharmaceutically acceptable carrier.

7. A pharmaceutical composition comprising a compound according to claim 3 and a pharmaceutically acceptable carrier.

8. A pharmaceutical composition comprising a compound according to claim 5 and a pharmaceutically acceptable carrier.