Dash inhibitors, and uses related thereto

Abstract

Disclosed are potent immuno-DASH inhibitors, and their use in the treatment of cell proliferative diseases.

1 . A method for enhancing an immune response against a cancer, comprising:
 administering to a patient in need thereof a therapeutically effective amount of an immuno-DASH inhibitor, thereby enhancing a cell-mediated immune response against the cancer,   wherein:   (a) at the therapeutically effective amount, the immuno-DASH inhibitor is characterized by a pharmacokinetic profile of being an inhibitor of DPP8, DPP9 and DPP4; and   (b) the immuno-DASH inhibitor has: i) an in vivo IC 50  for DPP4 inhibition of less than 50 nM, and ii) an intracellular IC 50  for DPP8 and DPP9 inhibition less than 50 nM.   
     
     
         2 . The method of  claim 1 , wherein the immuno-DASH inhibitor is represented by a compound of compound represented by formula I, or II, or III, or IV, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         ring A represents a 3-10 membered ring structure or ring A, along with each occurrence of R 1a  represents a 7-12 membered polycyclic ring structure; 
         ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon; 
         R 1  represents, for each occurrence, a hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —CF 3 , —(CH 2 ) m —R 3 , —(CH 2 ) m OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         R 1a  represents a lower alkyl, —(CH 2 ) m —, —(CH 2 ) m —O—(CH 2 ) m —; —(CH 2 ) m —N—(CH 2 ) m —; or —(CH 2 ) m  S—(CH 2 ) m —; 
         R 2  represents, for each occurrence, hydrogen, alkyl, alkynyl, —(CH 2 ) m —R 3 , —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)(CH 2 ) m —R 3 ; 
         R 3  represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; 
         R 4  represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —(CH 2 ) m —R 3 , —(CH 2 ) n —OH, —(CH 2 ) n —O-alkyl, —(CH 2 ) n —O-alkenyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) n —SH, —(CH 2 ) n —S-alkyl, —(CH 2 ) n —S-alkenyl, —(CH 2 ) n —S-alkynyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 , —C(O)C(O)NH 2 , or —C(O)C(O)OR 8 ; 
         R 5  represents O or S; 
         R 6  represents N 3 , SH, NH 2 , NO 2  or OR 8 ; 
         R 7  represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5  and R 6  taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; 
         R 8  represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; 
         R 9  and R 10 , each independently, are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(O)OH, —O-lower alkyl-C(O)OH, -guanidinyl; —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         X is O or S; 
         X 1  represents a halogen; 
         X 2  represents a halogen; 
         Y is C or N; 
         Y 1  and Y 2  are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid; 
         W represents —CN, —CH═NR 4 , a functional group which reacts with an active site residue of the target, or 
       
       
         
           
           
               
               
           
         
         n is 0, 1, 2, or 3; 
         m is 0, 1, 2, or 3; and 
         p is 1, 2, or 3. 
       
     
     
         3 . A method for treating a myeloproliferative disease, comprising:
 administering to a patient in need thereof a therapeutically effective amount of an immuno-DASH inhibitor, thereby enhancing an immune response against the myeloproliferative disease,   wherein:   (a) at the therapeutically effective amount, the immuno-DASH inhibitor is characterized by a pharmacokinetic profile of being an inhibitor of DPP8, DPP9 and DPP4; and   (b) the immuno-DASH inhibitor has: i) an in vivo IC 50  for DPP4 inhibition of less than 50 nM, and ii) an intracellular IC 50  for DPP8 and DPP9 inhibition less than 50 nM.   
     
     
         4 . The method of  claim 1 , wherein the immuno-DASH inhibitor is represented by a compound represented by formula I, or II, or III, or IV, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         ring A represents a 3-10 membered ring structure or ring A, along with each occurrence of R 1 , represents a 7-12 membered polycyclic ring structure; 
         ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon; 
         R 1  represents, for each occurrence, a hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —CF 3 , —(CH 2 ) m —R 3 , —(CH 2 ) m OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         R 1a  represents a lower alkyl, —(CH 2 ) m —, —(CH 2 ) m —O—(CH 2 ) m —; —(CH 2 ) m —N—(CH 2 ) m —; 
         or —(CH 2 ) m  S—(CH 2 ) m —; 
         R 2  represents, for each occurrence, hydrogen, alkyl, alkynyl, —(CH 2 ) m —R 3 , —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)—(CH 2 ) m —R 3 ; 
         R 3  represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; 
         R 4  represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —(CH 2 ) m —R 3 , —(CH 2 ) n —OH, —(CH 2 ) n —O-alkyl, —(CH 2 ) n —O-alkenyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) n —SH, —(CH 2 ) n —S-alkyl, —(CH 2 ) n —S-alkenyl, —(CH 2 ) n —S-alkynyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 , —C(O)C(O)NH 2 , or —C(O)C(O)OR 8 ; 
         R 5  represents O or S; 
         R 6  represents N 3 , SH, NH 2 , NO 2  or OR 8 ; 
         R 7  represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5  and R 6  taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; 
         R 8  represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; 
         R 9  and R 10 , each independently, are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(O)OH, —O-lower alkyl-C(O)OH, -guanidinyl; —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         X is O or S; 
         X 1  represents a halogen; 
         X 2  represents a halogen; 
         Y is C or N; 
         Y 1  and Y 2  are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid; 
         W represents —CN, —CH═NR 4 , a functional group which reacts with an active site residue of the target, or 
       
       
         
           
           
               
               
           
         
         n is 0, 1, 2, or 3; 
         m is 0, 1, 2, or 3; and 
         p is 1, 2, or 3. 
       
     
     
         5 . A method for treating a relapse of a cancer, comprising:
 administering to a patient in remission of a cancer a therapeutically effective amount of an immuno-DASH inhibitor, thereby increasing G-CSF and CXCL1 cytokines in serum and enhance T-cell immunity against a cancer,   wherein:   (a) at the therapeutically effective amount, the immuno-DASH inhibitor is characterized by a pharmacokinetic profile of being an inhibitor DPP8, DPP9 and DPP4; and   (b) the immuno-DASH inhibitor has: i) an in vivo IC50 for DPP4 inhibition of less than 50 nM, and ii) an intracellular IC50 for DPP8 and DPP9 inhibition less than 50 nM.   
     
     
         6 . The method of  claim 5 , wherein the immuno-DASH inhibitor is represented by a compound represented by formula I, or II, or III, or IV, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         ring A represents a 3-10 membered ring structure or ring A, along with each occurrence of R 1a  represents a 7-12 membered polycyclic ring structure; 
         ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon; 
         R 1  represents, for each occurrence, a hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —CF 3 , —(CH 2 ) m —R 3 , —(CH 2 ) m OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         R 1a  represents a lower alkyl, —(CH 2 ) m —, —(CH 2 ) m —O—(CH 2 ) m —; —(CH 2 ) m —N—(CH 2 ) m —; or —(CH 2 ) m  S—(CH 2 ) m —; 
         R 2  represents, for each occurrence, hydrogen, alkyl, alkynyl, —(CH 2 ) m —R 3 , —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)(CH 2 ) m —R 3 ; 
         R 3  represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; 
         R 4  represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —(CH 2 ) m —R 3 , —(CH 2 ) n —OH, —(CH 2 ) n —O-alkyl, —(CH 2 ) n —O-alkenyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) n —SH, —(CH 2 ) n —S-alkyl, —(CH 2 ) n —S-alkenyl, —(CH 2 ) n —S-alkynyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 , —C(O)C(O)NH 2 , or —C(O)C(O)OR 8 ; 
         R 5  represents O or S; 
         R 6  represents N 3 , SH, NH 2 , NO 2  or OR 8 ; 
         R 7  represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5  and R 6  taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; 
         R 8  represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; 
         R 9  and R 10 , each independently, are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(O)OH, —O-lower alkyl-C(O)OH, -guanidinyl; —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         X is O or S; 
         X 1  represents a halogen; 
         X 2  represents a halogen; 
         Y is C or N; 
         Y 1  and Y 2  are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid; 
         W represents —CN, —CH═NR 4 , a functional group which reacts with an active site residue of the target, or 
       
       
         
           
           
               
               
           
         
         n is 0, 1, 2, or 3; 
         m is 0, 1, 2, or 3; and 
         p is 1, 2, or 3. 
       
     
     
         7 .- 46 . (canceled) 
     
     
         47 . A compound represented by formula I, or II, or III, or IV, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein 
         ring A represents a 3-10 membered ring structure or ring A, along with each occurrence of R 1 , represents a 7-12 membered polycyclic ring structure; 
         ring Z represents a 4-10 membered heterocycle including the N and the Ca carbon; 
         R 1  represents, for each occurrence, a hydrogen, a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl, a thiocarbonyl, an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, —CF 3 , —(CH 2 ) m —R 3 , —(CH 2 ) m OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ) n —O—(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, or —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         R 1a  represents a lower alkyl, —(CH 2 ) m —, —(CH 2 ) m —O—(CH 2 ) m —; —(CH 2 ) m —N—(CH 2 ) m —; or —(CH 2 ) m  S—(CH 2 ) m —; 
         R 2  represents, for each occurrence, hydrogen, alkyl, alkynyl, —(CH 2 ) m —R 3 , —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)(CH 2 ) m —R 3 ; 
         R 3  represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; 
         R 4  represents a hydrogen, an alkyl, an alkenyl, an alkynyl, —(CH 2 ) m —R 3 , —(CH 2 ) n —OH, —(CH 2 ) n —O-alkyl, —(CH 2 ) n —O-alkenyl, —(CH 2 ) n —O-alkynyl, —(CH 2 ) n —O—(CH 2 ) m —R 7 , —(CH 2 ) n —SH, —(CH 2 ) n —S-alkyl, —(CH 2 ) n —S-alkenyl, —(CH 2 ) n —S-alkynyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 , —C(O)C(O)NH 2 , or —C(O)C(O)OR 8 ; 
         R 5  represents O or S; 
         R 6  represents N 3 , SH, NH 2 , NO 2  or OR 8 ; 
         R 7  represents hydrogen, a lower alkyl, an amine, OR 8 , or a pharmaceutically acceptable salt, or R 5  and R 6  taken together with the phosphorous atom to which they are attached complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; 
         R 8  represents, hydrogen, a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl or heterocyclyl; 
         R 9  and R 10 , each independently, are absent or represents one, two, or three substitutions to the ring A or to the ring Z to which they are appended, each of which can independently be a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, an isocyano, a thiocyanato, an isothiocyanato, a cyanato, a nitro, an azido, a sulfate, a sulfonate, a sulfonamido, lower alkyl-C(O)OH, —O-lower alkyl-C(O)OH, -guanidinyl; —(CH 2 ) m —R 7 , —(CH 2 ) m —OH, —(CH 2 ) m —O-lower alkyl, —(CH 2 ) m —O-lower alkenyl, —(CH 2 ), —O(CH 2 ) m —R 3 , —(CH 2 ) m —SH, —(CH 2 ) m —S-lower alkyl, —(CH 2 ) m —S-lower alkenyl, —(CH 2 ) n —S—(CH 2 ) m —R 3 ; 
         X is O or S; 
         X 1  represents a halogen; 
         X 2  represents a halogen; 
         Y is C or N; 
         Y 1  and Y 2  are independently OH, or together with the boron atom to which they are attached represent a group that is hydrolysable to a boronic acid, or together with the boron atom to which they are attached form a 5-8 membered ring that is hydrolysable to a boronic acid; 
         W represents —CN, —CH═NR 4 , a functional group which reacts with an active site residue of the target, or 
       
       
         
           
           
               
               
           
         
         n is 0, 1, 2, or 3; 
         m is 0, 1, 2, or 3; and 
         p is 1, 2, or 3. 
       
     
     
         48 .- 88 . (canceled) 
     
     
         89 . The compound of  claim 47 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         90 .- 97 . (canceled) 
     
     
         98 . The compound of  claim 89 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         99 . The compound of  claim 89 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         100 . The compound of  claim 47 , wherein the compound is represented by: 
       
         
           
           
               
               
           
         
       
     
     
         101 . A pharmaceutical composition, comprising a compound of  claim 47 ; and a pharmaceutically acceptable excipient. 
     
     
         102 .- 112 . (canceled)