Maytansinoid Derivatives

Abstract

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.

What is claimed: 
     
         1 . 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; 
 AA is an amino acid. 
 
       
     
     
         2 . The compound of  claim 1 , which is 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein 
         AA is an amino acid. 
       
     
     
         3 . The compound of  claim 1  or  2 , wherein AA is 
       
         
           
           
               
               
           
         
       
       wherein   represents point of connection to the rest of the molecule. 
     
     
         4 . The compound of  claim 1  or  2  is: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound of Formula Ib: 
       
         
           
           
               
               
           
         
         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, optionally substituted C 1 -C 20  alkylene wherein one or more of the —CH 2 — groups are independently replaced with —O—, —NR 8 —, —C(O)—, or —C(═O)NR 8 —; 
         substituted C 1 -C 20  alkylene is C 1 -C 20  alkylene substituted with 1 to 4 R 23 , wherein each R 23  is independently unsubstituted C 1-6  alkyl; and 
         AA is an amino acid or thiolated amino acid. 
       
     
     
         6 . The compound of  claim 5 , wherein AA is 
       
         
           
           
               
               
           
         
       
       wherein   represents point of connection to the rest of the molecule. 
     
     
         7 . 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; 
 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 —, —NR 8 SO 2 —; or —(CH 2 ) m —, wherein m is selected from an integer of 1 to 20; 
 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. 
 
       
     
     
         8 . The compound of  claim 7 , which is selected from: 
       
         
           
           
               
               
           
         
         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; 
 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 —, —NR 8 SO 2 —; or —(CH 2 ) m —, wherein m is selected from an integer of 1 to 20; 
 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. 
 
       
     
     
         9 . The compound of  claim 7 , which is of Formula IVb or 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. 
 
       
     
     
         10 . The compound of  claim 7 , which is of Formula Vb: 
       
         
           
           
               
               
           
         
         or a salt thereof, 
         wherein
 AA is an amino acid or thiolated amino acid. 
 
       
     
     
         11 . The compound of  claim 7 , wherein AA is 
       
         
           
           
               
               
           
         
       
       wherein   represents point of connection to the rest of the molecule. 
     
     
         12 . The compound of  claim 7 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         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 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 —, —NR 8 SO 2 —; or —(CH 2 ) m —, wherein m is selected from an integer of 1 to 20; 
 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 
 m is selected from an integer of 1 to 20. 
 
       
     
     
         13 . A compound of Formula 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 —SU; 
 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  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 —, —NR 8 SO 2 —; or —(CH 2 ) m —, wherein m is selected from an integer of 1 to 20; 
 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. 
 
       
     
     
         14 . A pharmaceutical composition comprising a compound of  claim 1 . 
     
     
         15 . 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 1 .