Cytotoxic peptides and antibody drug conjugates thereof

1. A compound of formula I:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly and C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

2. A compound of formula IIa:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-; —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)- or —C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

G is halogen, —OH, —SH or —S—C 1 -C 6 alkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl or halogen; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly and C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —O(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

R 7 is independently selected for each occurrence from the group consisting of F, Cl, I, Br, NO 2 , CN and CF 3 ;

R 10 is hydrogen, —C 1 -C 10 alkyl, —C 3 -C 8 -carbocyclyl, -aryl, —C 1 -C 10 heteroalkyl, —C 3 -C 8 heterocyclo, —C 1 -C 10 alkylene-aryl, -arylene—C 1 -C 10 alkyl, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo), —(C 3 -C 8 carbocyclo)-C 1 -C 10 alkyl, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo), and —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkyl, where aryl on R 10 comprising aryl is optionally substituted with [R 7 ] h ;

h is 1, 2, 3, 4 or 5; and

X is O or S;

provided that when R 3A is hydrogen X is S.

3. A compound of formula IIIa:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

R 11 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 1 alkylene-(C 3 -C 10 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 10 heterocyclo)-, or -(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

R 7 is independently selected for each occurrence from the group consisting of F, Cl, I, Br, NO 2 , CN and CF 3 ;

R 10 is hydrogen, —C 1 -C 10 alkyl, —C 3 -C 8 -carbocycle, aryl, —C 1 -C 10 heteroalkyl, —C 3 -C 8 heterocyclo, —C 1 -C 10 alkylene-aryl, -arylene-C 1 -C 10 alkyl, —C 1 -C 10 alkylene-(C 3 -C 10 -carbocyclo), —(C 3 -C 10 carbocyclo)-C 1 -C 10 alkyl, —C 1 -C 10 alkylene-(C 3 -C 10 heterocyclo), and -(C 3 -C 10 heterocyclo)-C 1 -C 10 alkyl, where aryl on R 10 comprising aryl is optionally substituted with [R 7 ] h ;

X is O or S

R 6 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl; and

h is 1, 2, 3, 4 or 5.

4. A compound of formula IIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

L is an antibody;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -O 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly and C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene—C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

5. A compound of formula IIIb:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

R 11 is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z is

L is an antibody;

X is O or S.

6. A compound of formula IIc:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

R 1′ is

Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z′ is

L is an antibody;

D is —C(R 4A′ )(R 4B′ )— or is absent;

R 2′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, or is absent if is present;

R 3A′ and R 3B′ are either of the following:

(i) R 3A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B′ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R 3B′ is C 2 -C 4 alkylene and forms 5-7 member ring as indicated by ; or

(ii) R 3A′ and R 3B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A′ and R 4B′ are either of the following:

(i) R 4A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A′ and R 4B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly and C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

7. A compound of formula IIIc:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

Y is is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-;

Z′ is

L is an antibody;

X is O or S.

8. A compound of formula IId:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

L is an antibody;

[linker] is a divalent linker;

D is —C(R 4A′ )(R 4B′ )— or is absent;

R 2′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, or is absent if , is present;

R 3A′ and R B′ are either of the following:

(i) R 3A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B′ is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R 3B′ is C 2 -C 4 alkylene and forms 5-7 member ring as indicated by ; or

(ii) R 3A′ and R 3B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A′ and R 4B′ are either of the following:

(i) R 4A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A′ and R 4B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

C 1 -C 10 heterocyclyl, C 3 -C 8 carbocycly and C 6 -C 14 aryl optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of —C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′—O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

or R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —C 1 -C 8 alkyl-N(R′) 2 , —C 1 -C 8 alkyl-C(O)R′, —C 1 -C 8 alkyl-C(O)OR′, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)N(R′) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′, —SR′ and arylene-R′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 1 -C 8 heterocyclyl, C 1 -C 10 alkylene-C 3 -C 8 heterocyclyl and aryl, or two R′ can, together with the nitrogen to which they are attached, form a C 1 -C 10 heterocyclyl;

R 6 is hydrogen, —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, —C 2 -C 8 alkynyl or —C 1 -C 8 haloalkyl;

R 12 is hydrogen, C 1 -C 4 alkyl, C 1 -C 10 heterocyclyl or C 6 -C 14 aryl;

R 13 is C 1 -C 10 heterocyclyl; and

X is O or S;

provided that when R 3A is hydrogen X is S.

9. A compound of formula IIId:

or a pharmaceutically acceptable salt or solvate thereof, wherein, independently for each occurrence,

W is

R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 2 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl;

R 3A and R 3B are either of the following:

(i) R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl; or

(ii) R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 4A and R 4B are either of the following:

(i) R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene;

R 5 is

optionally substituted with 1, 2, 3, 4 or 5 groups independently selected from the group consisting of C 1 -C 8 alkyl, —O—(C 1 -C 8 alkyl), —C(O)R′, —OC(O)R′, —C(O)OR′, —C(O)NH 2 , —C(O)NHR′, —C(O)N(R) 2 , —NHC(O)R′, —S(O) 2 R′, —S(O)R′, —OH, halogen, —N 3 , —NH 2 , —NH(R′), —N(R′) 2 , —CN, —NHC(═NH)NH 2 , —NHCONH 2 , —S(═O) 2 R′ and —SR′, wherein each R′ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl and unsubstituted aryl;

[linker] is a divalent linker;

L is an antibody;

X is O or S.

10. The compound, salt or solvate of claim 1 , wherein

W is

11. The compound, salt or solvate of claim 1 , wherein R 1 is hydrogen, C 1 -C 8 alkyl or C 1 -C 8 haloalkyl.

12. The compound, salt or solvate of claim 2 , wherein R 1 is

13. The compound, salt or solvate of claim 4 wherein R 1 is

14. The compound, salt or solvate of claim 1 , wherein R 3A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and R 3B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen.

15. The compound, salt or solvate of claim 1 , wherein R 3A and R 3B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene.

16. The compound, salt or solvate of claim 1 , wherein R 4A is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and R 4B is C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or R 4A and R 4B taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene.

17. The compound, salt or solvate of claim 6 , wherein R 3A′ and R 3B′ are defined as either of the following:

(i) R 3A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, aralkyl or halogen; and

R 3B′ C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl, halogen or aralkyl, or R 3B′ is C 2 -C 4 alkylene and forms 5-7 member ring as indicated by ; or

(ii) R 3A′ and R 3B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene.

18. The compound, salt or solvate of claim 6 , wherein R 4A′ and R 4B′ are defined as either of the following:

(i) R 4A′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; and

R 4B′ is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 8 carbocyclyl, C 1 -C 10 heterocyclyl, aryl, heteroaralkyl or aralkyl; or

(ii) R 4A′ and R 4B′ taken together are C 2 -C 8 alkylene or C 1 -C 8 heteroalkylene.

19. The compound, salt or solvate of claim 1 , wherein R 5 is

20. The compound, salt or solvate of claim 2 , wherein Y is —C 2 -C 20 alkylene-, —C 2 -C 20 heteroalkylene-, —C 3 -C 8 carbocyclo-, -arylene-, —C 3 -C 8 heterocyclo-, —C 1 -C 10 alkylene-arylene-, -arylene-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 -carbocyclo)-, —(C 3 -C 8 -carbocyclo)-C 1 -C 10 alkylene-, —C 1 -C 10 alkylene-(C 3 -C 8 heterocyclo)-, or —(C 3 -C 8 heterocyclo)-C 1 -C 10 alkylene-.

21. The compound, salt or solvate of claim 5 , wherein antibody is selected from trastuzumab, oregovomab, edrecolomab, cetuximab, a humanized monoclonal antibody to the vitronectin receptor (α v β 3 ); alemtuzumab; a humanized anti-HLA-DR antibody for the treatment of non-Hodgkin's lymphoma; 131I Lym-1; a murine anti-HLA-Dr10 antibody for the treatment of non-Hodgkin's lymphoma; a humanized anti-CD2 mAb for the treatment of Hodgkin's Disease or non-Hodgkin's lymphoma; labetuzumab; bevacizumab; ibritumomab tiuxetan; ofatumumab; panitumumab; rituximab; tositumomab; ipilimumab; gemtuzumab; an anti-IL13 antibody; and an anti-Notch antibody.

22. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

23. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

24. A payload-linker comprising a radical of a compound of claim 22 or 23 .

25. An antibody drug conjugate comprising a radical of a compound of any of claims 1 , 2 , or 3 .

26. A compound, or a pharmaceutically acceptable salt or solvate thereof, selected from:

27. An antibody-drug-conjugate comprising a radical of a compound of any one of claims 22 , 23 , 24 , 25 , or 26 .

28. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and pharmaceutically acceptable excipient.

29. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 4 .

30. The compound:

or a pharmaceutically acceptable salt or solvate thereof.

31. The compound:

or a pharmaceutically acceptable salt or solvate thereof.

32. The compound:

or a pharmaceutically acceptable salt or solvate thereof.

33. The compound:

or a pharmaceutically acceptable salt or solvate thereof.

34. The compound:

or a pharmaceutically acceptable salt or solvate thereof.

35. The compound:

or a pharmaceutically acceptable salt or solvate thereof.

36. The compound:

or a pharmaceutically acceptable salt or solvate thereof.