Maytansinoid derivatives

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-C6 alkyl;
• each Z is independently hydrogen or C1-C4 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 C1-C20 alkylene, C3-C8 cycloalkylene substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —S—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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 C1-C20 alkylene, C3-C8 cycloalkylene, optionally substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —O—, —S—, —NR8—, —C(O)—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo.

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(C═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-6 alkyl;
• each Z is independently hydrogen or C1-C4 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 C1-C20 alkylene, C3-C8 cycloalkylene, optionally substituted C1-C20 alkylene wherein one or more of the —CH2— group is independently replaced with C3-C8 cycloalkylene, —O—, —S—, —NR8—, —C(O)—, —C(C═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 together with the nitrogen form a heterocyclic, wherein the heterocyclic is optionally substituted with one or two oxo.

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(C═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-6 alkyl;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• in Formula Ia, L is selected from substituted C1-C20 alkylene, C3-C8 cycloalkylene, substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —S—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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 C1-C20 alkylene, C3-C8 cycloalkylene, optionally substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —C(C═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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.

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(C═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-6 alkyl;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• each Z is independently hydrogen or C1-C4 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 C1-C20 alkylene, C3-C8 cycloalkylene, substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —S—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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 C1-C20 alkylene, C3-C8 cycloalkylene, optionally substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —O—, —S—, —NR8—, —C(O)—, —C(C═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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.

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(C═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• and
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-6 alkyl;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
• and
• in Formula Id, Lb is selected from C1-C20 alkylene optionally substituted with C1-C4 alkyl, —SO3H or —P(O)(OH)2, C3-C8 cycloalkylene optionally substituted with C1-C4 alkyl, and C1-C20 alkylene which is optionally substituted with C1-C4 alkyl, —SO3H or —P(O)(OH)2 and wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —S—, —S—S—, —SO2NR8—, or —NR6SO2;
• in Formula IId, Lb is selected from C1-C20 alkylene optionally substituted with C1-C4 alkyl, —SO3H or —P(O)(OH)2, C3-C8 cycloalkylene optionally substituted with C1-C4 alkyl, and C1-C20 alkylene which is optionally substituted with C1-C4 alkyl, —SO3H or —P(O)(OH)2 and wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, 3-8 membered heterocycloalkylene optionally substituted with one or more C1-C4 alkyl or oxo, —O—, —S—, —S—S—, —NR8—, —C(C═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2;
• BAT0206 is an Anti-EGFR antibody.

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(C═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-6 alkyl;
• each Z is independently hydrogen or C1-C4 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 C1-C20 alkylene, C3-C8 cycloalkylene, substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —S—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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 C1-C20 alkylene, C3-C8 cycloalkylene, optionally substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —O—, —S—, —C(O)—, —C(C═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-20 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and —NR11R11, wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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.

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, C1-C6 alkyl, C3-C6 cycloalkyl, and —C(C═O)R5;
• R1 is selected from the group consisting of hydrogen, —OH, —OC(═O)R5 and —OR5;
• R2 is hydrogen or C1-C6 alkyl;
• R3 is methyl, —CH2OH, or —CH2C(═O)R6;
• R4 is —OH or —SH;
• R5 is C1-C6 alkyl or benzyl;
• R6 is C1-C6 alkyl, phenyl or benzyl;
• R7 is hydrogen, C1-C6 alkyl or an amino acid side chain;
• R8 is hydrogen or C1-6 alkyl;
• each Z is independently hydrogen or C1-C4 alkyl, or the two Z with the carbon atom to which they are attached form a C═O;
• L is selected from optionally substituted C1-C20 alkylene, C3-C5 cycloalkylene, optionally substituted C1-C20 alkylene wherein one or more of the —CH2— groups are independently replaced with C3-C8 cycloalkylene, —O—, —S—, —NR6—, —C(O)—, —C(═O)NR8—, —NR8C(═O)—, —SO2NR8—, or —NR8SO2—;
• substituted C1-C20 alkylene is C1-C20 alkylene substituted with 1 to 4 —SO3H, —P(O)(OH)2 or R23, wherein each R23 is independently C1-6 alkyl optionally substituted with 1 or 2 substituents independently selected from the group consisting of —SH, —S—C1-4 alkyl, —CONR11R11, —CO2H, and wherein each R11 is independently hydrogen, alkyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, and heterocyclic, or the two R11 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.

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 Vc,

• wherein the compound of Formula Vc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula VIa or VIIa,
• or a pharmaceutically acceptable salt thereof, to the patient,
• wherein
• Abu described in Formula VIa and VIIa is antigen binding unit;
• and
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 Vc,

• wherein the compound of Formula Vc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula XVa, XVIa, XVIIIa, or XIXa
• or a pharmaceutically acceptable salt thereof, to the patient,
• wherein
• Abu described in Formula XVa, XVIa, XVIIIa, or XIXa is antigen binding unit;
• and
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 VIIIc,

• wherein the compound of Formula VIIIc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula VIIIa,
• or a pharmaceutically acceptable salt thereof, to the patient,
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 IXc,

• wherein the compound of Formula IXc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula IXa,
• or a pharmaceutically acceptable salt thereof, to the patient
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 Xc,

• wherein the compound of Formula Xc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula Xa,
• or a pharmaceutically acceptable salt thereof, to the patient,
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 XIc,

• wherein the compound of Formula XIc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula XIa,
• or a pharmaceutically acceptable salt thereof, to the patient.
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 XIIc,

• wherein the compound of Formula XIIc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula XIIa,
• or a pharmaceutically acceptable salt thereof, to the patient,
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 XIVc,

• wherein the compound of Formula XIVc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula XIVa,
• or a pharmaceutically acceptable salt thereof, to the patient.
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

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 XVIIc,

• wherein the compound of Formula XVIIc is generated as a result of a metabolic chemical reaction following administration of a compound of Formula XVIIa,
• or a pharmaceutically acceptable salt thereof, to the patient.
• wherein
• Abu is antigen binding unit;
• p is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.