Methods using hdac11 inhibitors

Abstract

The present invention provides methods and uses of inhibitors of histone deacetylase 11 (HDAC11) in the treatment of diseases and/or disorders, such as, for example, cell proliferative diseases.

1 .- 49 . (canceled) 
     
     
         50 . A method of treating cancer in a patient in need thereof, comprising administering to a patient an effective amount of a HDAC11 inhibitor. 
     
     
         51 . The method of  claim 50 , wherein one or more cancer cells in the patient exhibit stem cell-like properties. 
     
     
         52 . The method of  claim 50 , wherein the cancer is a hematological cancer. 
     
     
         53 . A method of treating a patient having a myeloproliferative disorder, comprising administering to the patient a HDAC11 inhibitor and a second therapeutic agent. 
     
     
         54 . The method of  claim 53 , wherein the second therapeutic agent is a JAK2 inhibitor. 
     
     
         55 . The method of  claim 53 , wherein the myeloproliferative disorder is resistant to a JAK2 inhibitor. 
     
     
         56 . The method of  claim 53 , wherein the second therapeutic agent is a hedgehog pathway inhibitor. 
     
     
         57 . The method of  claim 50 , wherein the patient has received a first line therapy, and any cancer cells surviving from the first line therapy are reduced or eliminated after treatment with the HDAC11 inhibitor. 
     
     
         58 . A compound of Formula I′ or a pharmaceutically acceptable salt thereof, 
       
         
           
           
               
               
           
         
         wherein: 
         Q is —H, —OC(O)NR 6 (C 1 -C 6 )alkylaryl, or —OC(O)O(C 1 -C 6 )alkylaryl; 
         Z is —CH 2 —, O, S or NR 6 ; 
         X 1 , X 2 , X 3 , and X 4  are each independently, at each occurrence, N or CR 1 ; 
         Y 1 , Y 2 , Y 3 , and Y 4  are each independently N or CR 1 ; 
         L is NR 6 , O, or —(CR 1 R 2 ) p —; 
         R 1  and R 2  are independently, at each occurrence, —H, —R 3 , —R 4 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —OH, —OR 3 , halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 R 5 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 3 , —R 5 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 N(R 3 ) 2 —, —S(O) 2 R 5 , —C(O)R 5 , —C(O)OR 5 , —NR 3 S(O) 2 R 5 , —S(O)R 5 , —S(O)NR 3 R 4 , —NR 3 S(O)R 5 , heterocycle, aryl, or heteroaryl; 
         or R 1  and R 2  can combine with the carbon atom to which they are both attached to form a spirocycle, spiroheterocycle, or spirocycloalkenyl, each optionally substituted with one or more independent occurrences of R 3  and R 4 ; 
         or two occurrences of R 1 , when on adjacent atoms, can combine to form a cycloalkyl, a heterocycle, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or a cycloalkenyl, each optionally substituted with one or more independent occurrences of R 3  and R 4 ; 
         R 3  and R 4  are independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, oxo, or —(CHR 5 ) p N(C 1 -C 6 alkyl) 2 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkly) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocycle, aryl, or heteroaryl; 
         R 5  is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH, halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl) or —(CH 2 ) p N(C 1 -C 6 alkyl) 2 ; 
         R 6  is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4  wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocycle, aryl, or heteroaryl; 
         and 
         p is 0, 1, 2, 3, 4, 5, or 6. 
       
     
     
         59 . A compound of Formula II or a pharmaceutically acceptable salt thereof. 
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts thereof, wherein: 
       
       X 1 , X 2 , X 3 , X 4 , X 5 , and X 6  are each independently, at each occurrence, —CR 1 R 2 —, —NR 3 —, —O—, —C(O)—, —S(O) 2 —, —S(O)—, or —S—; 
       Y 1 , Y 2 , and Y 3  are each independently N or CR 1 ; 
       L is a bond, —(CR 1 R 2 ) p —, —C(O)NR 3 —, —S(O) 2 —, —S(O) 2 NR 3 —, —S(O)—, —S(O)NR 3 —, —C(O)(CR 1 R 2 ) p O—, or —C(O)(CR 1 R 2 ) p —; 
       R is independently —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, —C 5 -C 12 spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P, or O, wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, spirocycle, heterocyclyl, spiroheterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, oxo, —NO 2 , —CN, —R 1 , —R 2 , —SR 3 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 NR 3 R 4 , —S(O) 2 R 1 , —C(O)R 1 , —C(O)OR 1 , —NR 3 S(O) 2 R 1 , —S(O)R 1 , —S(O)NR 3 R 4 , —NR 3 S(O)R 1 , heterocycle, aryl, or heteroaryl; 
       R 1  and R 2  are independently, at each occurrence, —H, —R 3 , —R 4 , —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, —OH, halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O) 2 R 5 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, or —(CHR 5 ) p NR 3 R 4 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —OR 3 , —NHR 3 , —NR 3 R 4 , —S(O) 2 N(R 3 ) 2 —, —S(O) 2 R 5 , —C(O)R 5 , —C(O)OR 5 , —NR 3 S(O) 2 R 5 , —S(O)R 5 , —S(O)NR 3 R 4 , —NR 3 S(O)R 5 , heterocycle, aryl, or heteroaryl; 
       or R 1  and R 2  can combine with the carbon atom to which they are both attached to form a spirocycle, spiroheterocycle, or spirocycloalkenyl; 
       or R 1  and R 2 , when on adjacent atoms, can combine to form a cycloalkyl, a heterocycle, aryl, heteroaryl containing 1-5 heteroatoms selected from the group consisting of N, S, P and O, or a cycloalkenyl; 
       or R 1  and R 2 , when on non-adjacent atoms, can combine to form an optionally bridging cycloalkyl, an optionally bridging heterocycle, or an optionally bridging cycloalkenyl; 
       R 3  and R 4  are independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P, and O, —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 (C 1 -C 6 alkyl), —(C 1 -C 6 alkyl)S(O) 2 R 5 , —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, or —(CHR 5 ) p N(C 1 -C 6 alkyl) 2 , wherein each alkyl, alkenyl, cycloalkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more substituents selected from —OH, halogen, —NO 2 , oxo, —CN, —R 5 , —O(C 1 -C 6 )alkyl, —NH(C 1 -C 6 )alkyl, —N(C 1 -C 6 alkly) 2 , —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 NHC 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)S(O) 2 C 1 -C 6 alkyl, —S(O)R 5 , —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)R 5 , heterocycle, aryl, or heteroaryl; 
       R 5  is independently, at each occurrence, —H, —C 1 -C 6 alkyl, —C 2 -C 6 alkenyl, —C 4 -C 8 cycloalkenyl, —C 2 -C 6 alkynyl, —C 3 -C 8 cycloalkyl, heterocyclyl, aryl, heteroaryl containing 1-5 heteroatoms selected from N, S, P and O, —OH, halogen, —NO 2 , —CN, —NHC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl) 2 , —S(O) 2 NH(C 1 -C 6 alkyl), —S(O) 2 N(C 1 -C 6 alkyl) 2 , —S(O) 2 C 1 -C 6 alkyl, —C(O)C 1 -C 6 alkyl, —C(O)OC 1 -C 6 alkyl, —N(C 1 -C 6 alkyl)SO 2 C 1 -C 6 alkyl, —S(O)(C 1 -C 6 alkyl), —S(O)N(C 1 -C 6 alkyl) 2 , —N(C 1 -C 6 alkyl)S(O)(C 1 -C 6 alkyl) or —(CH 2 ) p N(C 1 -C 6 alkyl) 2 ; 
       p is 0, 1, 2, 3, 4, 5, or 6; 
       n is 0, 1, 2, 3, or 4; 
       m is 0, 1, or 2; 
       q is 1 or 2; 
       r is 1 or 2; 
       wherein the sum q+r≤3 and 
       wherein the sum m+n≤4.