Heterocyclic-substituted bis-1,8 naphthalimide compounds, antibody drug conjugates, and methods of use

1. A compound having Formula XV

or a pharmaceutically acceptable salt thereof, wherein

Y is independently selected from N(R b ), C(R a ) 2 , O, and S;

R a is independently selected from H, F, Cl, Br, I, OH, —N(R b ) 2 , —N(R b ) 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO 2 R b , —S(═O)R b , —SR b , —SO 2 N(R b ) 2 , —C(═O)R b , —CO 2 R b , —C(═O)N(R b ) 2 , —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, polyethyleneoxy, phosphonate, phosphate, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 1 -C 20 heterocycle, and C 1 -C 20 substituted heterocycle; or when taken together, two R a groups on the same carbon atom form a carbonyl (═O), or on different carbon atoms form a carbocyclic, heterocyclic, or aryl ring of 3 to 7 carbon atoms;

R b is independently selected from H, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 1 -C 20 heterocycle, and C 1 -C 20 substituted heterocycle;

where C 1 -C 8 substituted alkyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 substituted aryl, and C 2 -C 20 substituted heterocycle are independently substituted with one or more substituents selected from F, Cl, Br, I, OH, —N(R b ) 2 , —N(R b ) 3 + , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, C 1 -C 8 alkylsulfonate, C 1 -C 8 alkylamino, 4-dialkylaminopyridinium, C 1 -C 8 alkylhydroxyl, C 1 -C 8 alkylthiol, —SO 2 R b , —S(═O)R b , —SR b , —SO 2 N(R b ) 2 , —C(═O)R b , —CO 2 R b , —C(═O)N(R b ) 2 , —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, C 1 -C 8 alkyl, C 3 -C 12 carbocyclyl, C 6 -C 20 aryl, C 1 -C 20 heterocyclyl, polyethyleneoxy, phosphonate, and phosphate;

m is 3;

n is independently selected from 1, 2, and 3;

X 1 , X 2 , X 3 , and X 4 are independently selected from F, Cl, Br, I, OH, —N(R b ) 2 , —N(R b ) 3 + , —N(R b )C(═O)R b , —N(R b )C(═O)N(R b ) 2 , —N(R b )SO 2 N(R b ) 2 , —N(R b )SO 2 R b , OR, OC(═O)R b , OC(═O)N(R b ) 2 , C 1 -C 8 alkylhalide, carboxylate, sulfate, sulfamate, sulfonate, —SO 2 R b , —SO 2 Ar, —SOAr, —SAr, —SO 2 N(R b ) 2 , —SOR b , —CO 2 R b , —C(═O)N(R b ) 2 , —CN, —N 3 , —NO 2 , C 1 -C 8 alkoxy, C 1 -C 8 trifluoroalkyl, polyethyleneoxy, phosphonate, phosphate, C 1 -C 8 alkyl, C 1 -C 8 substituted alkyl, C 2 -C 8 alkenyl, C 2 -C 8 substituted alkenyl, C 2 -C 8 alkynyl, C 2 -C 8 substituted alkynyl, C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 1 -C 20 heterocyclyl, and C 1 -C 20 substituted heterocyclyl; or X 1 and X 2 together, and X 3 and X 4 together, independently form —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —; and

at least one of X 1 , X 2 , X 3 , and X 4 is nitrogen-linked imidazolyl.

2. The compound of claim 1 where n is 2.

3. The compound of claim 1 where each R a is H.

4. The compound of claim 1 wherein Y is N(R b ); n is 2; and R a and R b are H.

5. The compound of claim 4 having the structure:

6. The compound of claim 4 selected from the structures:

7. The compound of claim 1 wherein X 1 and X 2 together, or X 3 and X 4 together, independently form —CH 2 CH 2 — or —CH 2 CH 2 CH 2 —.

8. The compound of claim 1 wherein two X 1 , X 2 , X 3 , or X 4 on adjacent carbon atoms form a fused C 6 -C 20 aryl, C 6 -C 20 substituted aryl, C 1 -C 20 heterocycle, or C 1 -C 20 substituted heterocycle.

9. The compound of claim 8 selected from the structures:

10. The compound of claim 1 selected from the structures:

11. The compound of claim 1 selected from the structures:

12. The compound of claim 1 selected from

N,N′-(bis-aminoethyl-1,3-propanediamine)-bis-(4-N-imidazolyl)-1,8 naphthalimide;

N,N′-(bis-aminoethyl-1,3-propanediamine)-4-(N-imidazolyl)-4-hydroxyl-1,8 naphtalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-bromo, 4-N-imidazolyl 1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-N-imidazoly, 4-piperazinyl 1,8 naphthalimide;

N 1 —H, N 2 -methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-bis-(4-N-imidazolyl)-1,8 naphthalimide;

N 1 —H, N 2 -(methoxyethoxyethoxyacetamide)-(N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide);

N-(tert-butylglutaramide), bis-aminoethyl-1,3-propanediamine)-bis-4-N-imidazolyl-1,8 naphthalimide;

N,N′-(N-cyclopropylmethyl, bis-aminoethyl-1,3-propanediamine)-bis-4-N-imidazolyl-1,8 naphthalimide;

N 1 -methyl, N 2 —(N-methylglycyl)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-N-imidazolyl, 4-(4-mercaptopropylpiperazinyl)-1,8 naphthalimide;

N 1 -methyl, N 2 -(tert-butylglutaramide)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 -methyl, N 2 -(2-(2-(2-aminoethoxy)ethoxy)acetamido)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 -methyl, N 2 —(N-methylvaline)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 -methyl, N 2 —(N-methyl, N-tertbuytyloxy valine)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 —H, N 2 -tertbuytyloxycarbonyl)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 -methyl, N 2 -glutaramide)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N,N′-(bis-aminoethyl-1,3-propanediamine)-4-dimethylamino, 4-N-imidazolyl-1,8 naphthalimide;

N 1 -Boc, N 2 -(2-(2-(2-(N-Fmoc)aminoethoxy)ethoxy)acetamido)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 -Boc, N 2 -(2-(2-(2-aminoethoxy)ethoxy)acetamido)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-N-imidazolyl, 4-(3-aminopropyl)amino)-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-N-imidazolyl, 4-(6-aminohexyl)amino)-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-N-imidazolyl, 4-N-(2-(N-Fmoc)aminoethoxy-tetraethoxy)-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-N-imidazolyl, 4-N-(3-tertbutylpropionate-tetraethoxy)-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-thiol, 4-N-imidazolyl-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-dithio-(2-pyridyl), 4-N-imidazolyl-1,8 naphthalimide;

N 1 ,N 2 bis methyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-4-dithio-(3-propionic acid), 4-N-imidazolyl-1,8 naphthalimide;

N 1 -Boc, N 2 -(2-(2-(2-aminoethoxy)triethoxy)propionamido)-N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 —H, N 2 -glycyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 —H, N 2 —(N-methyl)glycyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 —H, N 2 —(N-methyl)alanyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 , N 2 bis glycyl, N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide;

N 1 , N 2 bis(N-methyl glycyl), N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide; and

N 1 , N 2 bis(N-methyl alanyl), N,N′-(bis-aminoethyl-1,3-propanediamine)-bis 4-N-imidazolyl-1,8 naphthalimide.

13. A pharmaceutical composition comprising an effective amount of the compound of claim 1 , and a pharmaceutically acceptable diluent, carrier or excipient.

14. An article of manufacture comprising

a compound of claim 1 ;

a container; and

a package insert or a label affixed to the container indicating that the compound can be used to treat cancer.

15. The article of manufacture of claim 14 wherein said package insert of label indicates that the compound can be used to treat cancer characterized by the overexpression of an ErbB2 receptor.

16. The article of manufacture of claim 14 wherein the cancer is breast cancer.