Linkers for antibody drug conjugates

1. A compound of the formula:

wherein:

A 1 , A 2 , and A 3 are each independently alkanediyl C1-12 , arenediyl C1-12 , heteroarenediyl C1-12 , cycloalkanediyl C1-12 , heterocycloalkanediyl C1-12 , or a substituted version thereof, or a canonical amino acid residue;

X, Y, and Z are each independently —[O(CH 2 ) q ]—, —[O(CHW′) q ]—, or —[O(CW′W″) q ]—;

wherein:

W′ and W″ are each independently amino, hydroxy, halo, mercapto, alkyl C1-12 , cycloalkyl C1-12 , alkenyl C1-12 , alkynyl C1-12 , aryl C1-12 , aralkyl C1-12 , heteroaryl C1-12 , heteroaralkyl C1-12 , heterocycloalkyl C1-12 , acyl C1-12 , acyloxy C1-12 , alkylamino C1-12 , or a substituted version of thereof;

q is 1-3;

m, n, o, and p are each independently 0-12;

r is 1, 2, or 3;

R 1 , R 2 , and R 3 are each independently —NH 2 , —NHR 4 , —NR 4 R 5 , —N 3 , or a conjugating group;

wherein:

R 4 and R 5 are each independently alkyl C1-12 , cycloalkyl C1-12 , alkenyl C1-12 , alkynyl C1-12 , aryl C1-12 , aralkyl C1-12 , heteroaryl C1-12 , heteroaralkyl C1-12 , heterocycloalkyl C1-12 , acyl C1-12 , acyloxy C1-12 , alkylamino C1-12 , or a substituted version thereof, or a monovalent amino protecting group; or

R 4 and R 5 are taken together and is a divalent amino protecting group;

provided that at least one of R 1 , R 2 , and R 3 is —NH 2 and at least one of R 1 , R 2 , and R 3 is —N 3 ;

or a compound of the formula:

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein X is —[O(CH 2 ) q ]— or —[O(CHW′) q ]—.

3. The compound of claim 1 , wherein Y is —[O(CH 2 ) q ]— or —[O(CHW′) q ]—.

4. The compound of claim 1 , wherein Z is —[O(CH 2 ) q ]— or —[O(CHW′) q ]—.

5. The compound of claim 1 , wherein W′ is amino, hydroxy, halo, or mercapto.

6. The compound of claim 1 , wherein W′ is alkyl C1-12 , cycloalkyl C1-12 , acyl C1-12 , acyloxy C1-12 , alkylamino C1-12 , or a substituted version of any of these groups.

7. The compound of claim 1 , wherein two of R 1 , R 2 , and R 3 are —N 3 .

8. The compound of claim 1 , wherein one of R 1 , R 2 , and R 3 is —NH 2 , —NHR 4 , or —NR 4 R 5 .

9. The compound of claim 1 , wherein q is 1.

10. The compound of claim 1 , wherein q is 2.

11. The compound of claim 1 , wherein q is 3.

12. The compound of claim 1 , wherein the compound is further defined as:

13. A conjugate of the formula:

(X 1 —Z 1 ) r -L-A 4   (IV)

wherein:

X 1 is a drug;

L is a linker of claim 1 ;

Z 1 is a spacer group;

r is 1-12; and

A 4 is a cell targeting moiety.

14. A compound of the formula:

wherein:

X 1 is a covalent bond, alkanediyl (C≤12) , or substituted alkanediyl (C≤12) ;

R 1 is hydrogen, —(OCH 2 CH 2 ) n1 ZR 6 , or substituted —(OCH 2 CH 2 ) n1 ZR 6 , wherein:

n1 is 0-50; and

R 6 is hydrogen, hydroxy, amine, mercapto, hydroxylamine, hydrazine, or azide; or

alkyl (C≤12) , alkenyl (C≤12) , alkynyl (C≤12) , alkylhydrazine (C≤12) , or a substituted version of any of these groups;

a polyglycine comprising from 1 to 6 glycine units; or

a substructure of the formula:

wherein:

A 1 and A 2 are each independently absent or arenediyl (C≤12) , substituted arenediyl (C≤12) , heteroarenediyl (C≤12) , or substituted heteroarenediyl (C≤12) , and form a fused arene (C≤12) , substituted arene (C≤12) , heteroarene (C≤12) , or substituted heteroarene (C≤12) ;

A 4 or A 5 are each independently selected from a covalent bond, alkanediyl (C≤8) , or substituted alkanediyl (C≤8) ;

R d , R e , R e ′, and R h are each independently selected from hydrogen, halo, sulfate, tosylate, mesylate, aryl (C≤8) , or substituted aryl (C≤8) ;

R f is halo;

R g is amine, hydrazine, alkylamino (C≤8) , substituted alkylamino (C≤8) , dialkylamino (C≤8) , substituted dialkylamino (C≤8) , alkylhydrazine (C≤8) , or substituted alkylhydrazine (C≤8) ;

X 4 is O, N, CH 2 , or X 4 is alkanediyl (C≤8) or substituted alkanediyl (C≤8) that forms a fused cycloalkane group consisting of 3 to 8 ring atoms;

R 16 is hydroxy, amino, or oxo;

R 17 is carboxy; or

 alkyl (C≤12) , amido (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , —C(O)NR 20 R 20 ′, or a substituted version of any of these groups wherein:

 R 20 and R 20 ′ are each independently hydrogen; or

 alkyl (C≤12) , aryl (C≤12) , or a substituted version of either of these groups;

R 18 and R 19 are each independently hydroxy, amino, halo; or

 alkyl (C≤12) , aryl (C≤12) , or a substituted version of either of these groups;

Z is a covalent bond, alkanediyl (C≤12) , —C(O)-alkanediyl (C≤12) , —C(O)-alkanediyl (C≤12) —C(O)NH—, or a substituted version of any of these groups;

R 2 is hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , or a monovalent amino protecting group;

W is a covalent bond or a polyvalent polymer having 21 connection points;

n3 is 1 to 20 provided that when W is a covalent bond then n3 is 1 and when W is a polyvalent polymer then n3 is less than or equal to one less than the number of connection points;

Each X is independently a covalent bond, alkanediyl (C≤12) , or substituted alkanediyl (C≤12) ;

Each X 2 is independently alkanediyl (C≤12) or substituted alkanediyl (C≤12) ;

Each R 3 is independently hydroxy, or amino; or

alkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , amido (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; or

—X 9 —C(O)R 7 , wherein:

X 9 is O, —NR b —, or a covalent bond;

R b is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a monovalent amino protecting group;

R 7 is hydroxy or amino; or

alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , or a substituted version of any of these groups; or

-A 3 SO 2 NR 21 R 21 ′, -A 3 P(O)(OH)OR 22 , or -A 3 SO 2 OR 22 ′, wherein:

A 3 is O, —NR c —, or a covalent bond;

 R c is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a monovalent amino protecting group;

R 21 , R 21 ′, R 22 , and R 22 ′ are each independently hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , or a substituted version of any of these groups;

Each R 23 is independently the side chain moiety of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, a hydroxyl-protected version of tyrosine, or an amino-protected version of tryptophan; and

Each R 24 is independently the side chain moiety of alanine, ornithine, lysine, arginine, citrulline, or an amino-protected version thereof;

Each Q is independently a group of the formula:

wherein:

Each R 5 is independently hydrogen or —C(O)—R 8 , wherein:

R 8 is a chemotherapeutic agent;

Each X 5 is independently a covalent bond, O, S, —NH—, alkanediyl (C≤12) , substituted alkanediyl (C≤12) , —(OCH 2 CH 2 ) n2 —, or substituted —(OCH 2 CH 2 ) n2 —, wherein:

n2 is 0-50; or

a group of the formula:

wherein:

 R a and R a ′ are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

 X 6 is O or —NR 26 R 26 ′—, wherein:

 R 26 and R 26 ′ are each independently alkyl (C≤12) or substituted alkyl (C≤12) ;

X 7 is a covalent bond, O, S, —NH—, —(OCH 2 CH 2 ) n3 —, or substituted —(OCH 2 CH 2 ) n3 —, wherein:

 n3 is 0-50; or

 a group of the formula:

 wherein:

 Y 1 is O or S;

 Y 2 is O, S, —NH—, or —NR 27 —, wherein:

 R 27 is alkyl (C≤12) or substituted alkyl (C≤12) ; and

 X 8 is a covalent bond, O, S, —NH—, —(OCH 2 CH 2 ) n3 —, or substituted —(OCH 2 CH 2 ) n3 —;

or a pharmaceutically acceptable salt thereof.

15. A conjugate of the formula:

T-L  (VI)

wherein:

T is a cell targeting moiety; and

L is a linker of claim 14 .

16. A compound of the formula:

wherein:

X 1 is alkyl (C≤12) or substituted alkyl (C≤12) ;

R 2 is hydrogen, alkyl (C≤12) , substituted alkyl (C≤12) , acyl (C≤12) , substituted acyl (C≤12) , or a monovalent amino protecting group;

W is a covalent bond or a polyvalent polymer having 21 connection points;

n3 is 1 to 20 provided that when W is a covalent bond n3 is 1 and when W is a polyvalent polymer n3 is less than or equal to one less than the number of connection points;

Each X is independently a covalent bond, alkanediyl (C≤12) , or substituted alkanediyl (C≤12) ;

Each X 2 is independently alkanediyl (C≤12) or substituted alkanediyl (C≤12) ;

Each R 3 is independently hydroxy, or amino; or

alkoxy (C≤12) , acyloxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , amido (C≤12) , heteroaryl (C≤12) , or a substituted version of any of these groups; or

—X 9 —C(O)R 7 , wherein:

X 9 is O, —NR b —, or a covalent bond;

R b is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a monovalent amino protecting group;

R 7 is hydroxy or amino; or

alkoxy (C≤12) , alkylamino (C≤12) , dialkylamino (C≤12) , or a substituted version of any of these groups; or

-A 3 SO 2 NR 21 R 21 ′, -A 3 P(O)(OH)OR 22 , or -A 3 SO 2 OR 22 ′, wherein:

A 3 is O, —NR c —, or a covalent bond;

R c is hydrogen, alkyl (C≤6) , substituted alkyl (C≤6) , or a monovalent amino protecting group;

R 21 , R 21 ′, R 22 , and R 22 ′ are each independently hydrogen, alkyl (C≤12) , cycloalkyl (C≤12) , aryl (C≤12) , heteroaryl (C≤12) , aralkyl (C≤12) , heteroaralkyl (C≤12) , or a substituted version of any of these groups;

Each R 23 is independently the side chain moiety of alanine, valine, leucine, isoleucine, phenylalanine, tyrosine, tryptophan, a hydroxyl-protected version of tyrosine, or an amino-protected version of tryptophan; and

Each R 24 is independently the side chain moiety of alanine, ornithine, lysine, arginine, citrulline, or an amino-protected version thereof;

Each Q is independently a group of the formula:

wherein:

Each R 5 is independently hydrogen or —C(O)—R 8 , wherein:

R 8 is a chemotherapeutic agent;

Each X 5 is independently a covalent bond, O, S, —NH—, alkanediyl (C≤12) , substituted alkanediyl (C≤12) , —(OCH 2 CH 2 ) n2 —, or substituted —(OCH 2 CH 2 ) n2 —, wherein:

n2 is 0-50; or

a group of the formula:

wherein:

R a and R a ′ are each independently hydrogen, alkyl (C≤12) , or substituted alkyl (C≤12) ;

X 6 is O or —NR 26 R 26 ′—, wherein:

 R 26 and R 26 ′ are each independently alkyl (C≤12) or substituted alkyl (C≤12) ;

X 7 is a covalent bond, O, S, —NH—, —(OCH 2 CH 2 ) n3 —, or substituted —(OCH 2 CH 2 ) n3 —, wherein:

 n3 is 0-50; or

 a group of the formula:

 wherein:

 Y 1 is O or S;

 Y 2 is O, S, —NH—, or —NR 27 —, wherein:

 R 27 is alkyl (C≤12) or substituted alkyl (C≤12) ; and

 X 8 is a covalent bond, O, S, —NH—, —(OCH 2 CH 2 ) n3 —, or substituted —(OCH 2 CH 2 ) n3 —;

or a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound or conjugate of claim 1 and an excipient.

18. A method of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of claim 1 or a conjugate thereof.