Maytansinoid derivatives
Disclosed herein are maytansinoid drug linker derivatives which can be linked to a antigen binding unit (Abu), and maytansinoid drugs linked with an antigen binding unit (Drug-Linker-Antigen binding Unit: D-L-Abu), for targeted delivery to disease tissues. D-L-Abu, D-L-Abu derivatives, and methods relating to the use of such drug conjugates to treat antigen positive cells in cancers and immunological disorders are provided.
1. A compound of Formula I or I-1:
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O; and
in Formula I, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula I-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo.
2. The compound of claim 1 , which is:
or a salt thereof.
3. The compound of claim 1 , which is a compound of Formula III or III-1:
or a salt thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl; and
in Formula III, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula III-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo.
4. The compound of claim 1 , which is a compound of Formula IV-1:
or a salt thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl; and
m is an integer of 1 to 20.
5. The compound of claim 1 , selected from the group consisting of
or a salt thereof.
6. The compound of claim 1 , selected from the group consisting of
or a salt thereof.
7. The compound of claim 1 , which is a compound of Formula V-1:
or a salt thereof.
8. A compound of Formula II or II-1:
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O; and
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — group is independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —;
substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo.
9. The compound of claim 8 , which is:
or a salt thereof.
10. A compound of Formula Ia or Ia-1:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
in Formula Ia, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula Ia-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
Abu is an antigen binding unit.
11. The compound of claim 10 which is:
or a salt thereof.
12. The compound of claim 10 , which is of Formula IIIa or IIIa-1:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
in Formula IIIa, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula IIIa-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
Abu is an antigen binding unit.
13. The compound of claim 10 , which is of Formula IVa-1:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
m is selected from an integer of 1 to 20; and
Abu is an antigen binding unit.
14. The compound of claim 10 , selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 10 , selected from the group consisting of
or a pharmaceutically acceptable salt thereof.
16. A compound of Formula IIa or IIa-1:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O;
in Formula IIa, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula IIa-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
Abu is an antigen binding unit.
17. The compound of claim 16 , which is:
or a pharmaceutically acceptable salt or solvate thereof.
18. The compound of claim 10 , wherein Abu is an antigen binding unit with binding specificity to human EGFR.
19. The compound of claim 10 , wherein Abu is an antigen binding unit with binding specificity to human CD20.
20. The compound of claim 10 , wherein Abu is an antigen binding unit with binding specificity to human Her2.
21. The compound of claim 18 , wherein Abu is an antibody, antibody fragment, or cell specific ligands.
22. The compound of claim 10 , wherein Abu is an antibody comprising SEQ ID 1 and 2, or SEQ ID 3 and 4, or SEQ ID 5 and 6, or SEQ ID 7 and 8, or SEQ ID 9 and 10, SEQ ID 11 and 12, or SEQ ID 13 and 14.
23. The compound of claim 10 , wherein Abu is an antibody comprising Bat0202 (SEQ ID NO: 1) and/or Bat0204 (SEQ ID NO: 2).
24. The compound of claim 10 , wherein Abu is Bat0206.
25. The compound of claim 10 , wherein Abu is selected from C225, EGF-ABX, EGF-ABX, NIMO, Matu, rituxamab, Cetuximab, trastuzumab and Pertuzumab.
26. A drug-linker-antigen binding unit conjugate wherein the drug is a maytansinoid and the antigen binding unit is Bat0206.
27. A compound of Formula Id or IId:
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH; and
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
in Formula Id, L b is selected from C 1 -C 20 alkylene optionally substituted with C 1 -C 4 alkyl, —SO 3 H or —P(O)(OH) 2 , C 3 -C 8 cycloalkylene optionally substituted with C 1 -C 4 alkyl, and C 1 -C 20 alkylene which is optionally substituted with C 1 -C 4 alkyl, —SO 3 H or —P(O)(OH) 2 and wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —S—S—, —SO 2 NR 8 —, or —NR 6 SO 2 ;
in Formula IId, L b is selected from C 1 -C 20 alkylene optionally substituted with C 1 -C 4 alkyl, —SO 3 H or —P(O)(OH) 2 , C 3 -C 8 cycloalkylene optionally substituted with C 1 -C 4 alkyl, and C 1 -C 20 alkylene which is optionally substituted with C 1 -C 4 alkyl, —SO 3 H or —P(O)(OH) 2 and wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, 3-8 membered heterocycloalkylene optionally substituted with one or more C 1 -C 4 alkyl or oxo, —O—, —S—, —S—S—, —NR 8 —, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 ;
BAT0206 is an Anti-EGFR antibody.
28. The compound of claim 27 , wherein, in Formula Id, L b is C 1 -C 20 alkylene which is substituted with C 1 -C 4 alkyl, —SO 3 H or —P(O)(OH) 2 and wherein one or more of the —CH 2 — groups are independently replaced with —S—, —S—S—,
29. The compound of claim 27 , selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —;
substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
BAT0206 is an Anti-EGFR antibody.
30. The compound of claim 27 , selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10; and
BAT0206 is an Anti-EGFR antibody.
31. The compound of claim 27 , selected from the group consisting of
or a pharmaceutically acceptable salt or solvate thereof,
wherein
BAT0206 is an Anti-EGFR antibody.
32. A compound of Formula Ib or Ib-1:
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O;
in Formula Ib, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula Ib-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
AA is an amino acid or thiolated amino acid.
33. The compound of claim 30 , which is selected from the group consisting of
or a salt thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
in Formulae IIIb′ and IIIb, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formulae IIIb′-1 and IIIb-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
AA is an amino acid or thiolated amino acid.
34. The compound of claim 32 , which is of Formula IVb-1:
or a salt thereof,
wherein
X is H or Cl;
Y is H or methyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1 -C 6 alkyl;
m is selected from an integer of 1 to 20; and
AA is an amino acid or thiolated amino acid.
35. The compound of claim 32 , wherein AA is
wherein represents point of connection to the rest of the molecule.
36. The compound of claim 32 , selected from the group consisting of
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
m is selected from an integer of 1 to 20.
37. A compound selected from the group consisting of:
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O;
L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 ,wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
AA is an amino acid or thiolated amino acid.
38. A pharmaceutical composition comprising a compound of claim 10 .
39. A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of claim 10 .
40. A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of Formula Ib or Ib-1,
wherein the compound of Formula Ib or Ib-1 is generated as a result of a metabolic chemical reaction following administration of a compound of claim 9 to the patient.
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O;
in Formula Ib, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula Ib-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo; and
AA is an amino acid or thiolated amino acid.
41. The method of claim 40 , wherein the compound of Formula Ib or Ib-1 is
42. A method of treating a proliferative, inflammatory or immunologic disease or condition in a patient in need thereof comprising administering an effective amount of a compound of Formula IIb or IIb-1,
wherein the compound of Formula IIb or IIb-1 is generated as a result of a metabolic chemical reaction following administration of a compound of claim 14 to the patient.
43. The method of claim 40 , wherein the antigen binding unit is an antibody comprising SEQ ID 1 and 2, or SEQ ID 3 and 4, or SEQ ID 5 and 6, or SEQ ID 7 and 8, or SEQ ID 9 and 10, SEQ ID 11 and 12, or SEQ ID 13 and 14, or an equivalent thereof.
44. A method of preparing a compound of claim 10 or a pharmaceutically acceptable salt thereof, comprising contacting an antigen binding unit with a compound of Formula I or I-1:
or a salt thereof,
wherein
X is hydrogen or halo;
Y is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, and —C(═O)R 5 ;
R 1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R 5 and —OR 5 ;
R 2 is hydrogen or C 1 -C 6 alkyl;
R 3 is methyl, —CH 2 OH, or —CH 2 C(═O)R 6 ;
R 4 is —OH or —SH;
R 5 is C 1 -C 6 alkyl or benzyl;
R 6 is C 1 -C 6 alkyl, phenyl or benzyl;
R 7 is hydrogen, C 1 -C 6 alkyl or an amino acid side chain;
R 8 is hydrogen or C 1-6 alkyl;
each Z is independently hydrogen or C 1 -C 4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O; and
in Formula I, L is selected from substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —S—, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo;
in Formula I-1, L is selected from optionally substituted C 1 -C 20 alkylene, C 3 -C 8 cycloalkylene, optionally substituted C 1 -C 20 alkylene wherein one or more of the —CH 2 — groups are independently replaced with C 3 -C 8 cycloalkylene, —O—, —S—, —NR 8 —, —C(O)—, —C(═O)NR 8 —, —NR 8 C(═O)—, —SO 2 NR 8 —, or —NR 8 SO 2 —; substituted C 1 -C 20 alkylene is C 1 -C 20 alkylene substituted with 1 to 4 —SO 3 H, —P(O)(OH) 2 or R 23 , wherein each R 23 is independently C 1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C 1-4 alkyl, —CONR 11 R 11 , —CO 2 H, and —NR 11 R 11 , wherein each R 11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R 11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo.
45. A method of preparing a compound of Formula Va-1:
or a pharmaceutically acceptable salt thereof, comprising contacting an antigen binding unit with a compound of Formula V-1:
or a salt thereof.
46. The method of claim 44 , wherein the antigen binding unit is an antibody comprising SEQ ID 1 and 2, or SEQ ID 3 and 4, or SEQ ID 5 and 6, or SEQ ID 7 and 8, or SEQ ID 9 and 10, SEQ ID 11 and 12, or SEQ ID 13 and 14.