Pyrimido[4,5-b]indole derivatives and use thereof in the expansion of hematopoietic stem cells

Abstract

Pyrimido[4,5-b]indole derivatives are provided. These compounds are useful to expand hematopoietic stem cell populations, particularly, human hematopoietic stem cell populations. The compounds are also useful in the medical treatment of diseases that involve hematopoietic stem cells.

1 . A compound of general formula I or II 
       
         
           
           
               
               
           
         
         or a salt or a prodrug thereof, 
         wherein: 
         Z is
 1) —P(O)(OR 1 )(OR 1 ), 
 2) —C(O)OR 1 , 
 3) —C(O)NHR 1 , 
 4) —C(O)N(R 1 )R 1 , 
 5) —C(O)R 1 , 
 6) —CN, 
 7) —SR 1 , 
 8) —S(O) 2 NH 2 , 
 9) —S(O) 2 NHR 1 , 
 10) —S(O) 2 N(R 1 )R 1 , 
 11) —S(O)R 1 , 
 12) —S(O) 2 R 1 , 
 13) -L, 
 14) -benzyl optionally substituted with 1, 2 or 3 R A  or R 1  substituents, 
 15) -L-heteroaryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and the heteroaryl groups, 
 16) -L-heterocyclyl optionally substituted with one or more R A  or R 1  substituents attached on either one or both the L and the heterocyclyl groups, 
 17) -L-aryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and the heteroaryl groups, 
 18) -heteroaryl optionally substituted with one or more R A  or R 1  substituents, or 
 19) -aryl optionally substituted with one or more R A  or R 1  substituents, 
 
         and wherein each substituent is optionally attached to the L group if it is not already present, 
         and wherein, when (R 1 ) and R 1  are attached to a nitrogen atom, optionally they join together with the nitrogen atom to form a 3 to 7-membered ring which optionally includes one or more other heteroatom selected from N, O and S, optionally the is substituted with one or more R 1  or R A ; 
         W is
 1) —H, 
 2) -halogen, 
 3) —OR 1 , 
 4) -L-OH, 
 5) -L-OR 1 , 
 6) —SR 1 , 
 7) —CN, 
 8) —P(O)(OR 1 )(OR 1 ), 
 9) —NHR 1 , 
 10) —N(R 1 )R 1 , 
 11) -L-NH 2 , 
 12) -L-NHR 1 , 
 13) -L-N(R 1 )R 1 , 
 14) -L-SR 1 , 
 15) -L-S(O)R 1 , 
 16) -L-S(O) 2 R 1 , 
 17) -L-P(O)(OR 1 )(OR 1 ), 
 18) —C(O)OR 1 , 
 19) —C(O)NH 2 , 
 20) —C(O)NHR 1 , 
 21) —C(O)N(R 1 )R 1 , 
 22) —NHC(O)R 1 , 
 23) —NR 1 C(O)R 1 , 
 24) —NHC(O)OR 1 , 
 25) —NR 1 C(O)OR 1 , 
 26) —OC(O)NH 2 , 
 27) —OC(O)NHR 1 , 
 28) —OC(O)N(R 1 )R 1 , 
 29) —OC(O)R 1 , 
 30) —C(O)R 1 , 
 31) —NHC(O)NH 2 , 
 32) —NHC(O)NHR 1 , 
 33) —NHC(O)N(R 1 )R 1 , 
 34) —NR 1 C(O)NH 2 , 
 35) —NR 1 C(O)NHR 1 , 
 36) —NR 1 C(O)N(R 1 )R 1 , 
 37) —NHS(O) 2 R 1 , 
 38) —NR 1 S(O) 2 R 1 , 
 39) —S(O) 2 NH 2 , 
 40) —S(O) 2 NHR 1 , 
 41) —S(O) 2 N(R 1 )R 1 , 
 42) —S(O)R 1 , 
 43) —S(O) 2 R 1 , 
 44) —OS(O) 2 R 1 , 
 45) —S(O) 2 OR 1 , 
 46) -benzyl optionally substituted with 1, 2 or 3 R A  or R 1  substituents, 
 47) -L-heteroaryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and the heteroaryl groups, 
 48) -L-heterocyclyl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and the heterocyclyl groups, 
 49) -L-aryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and aryl groups, 
 50) -L-NR 1 (R 1 ), 
 51) -L-) 2 NR 1 , 
 52) -L-(N(R 1 )-L) n -N(R 1 )R 1 , 
 53) -L-(N(R 1 )-L) n -heteroaryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and heteroaryl groups, 
 54) -L-(N(R 1 )-L) n -heterocyclyl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and heterocyclyl groups, 
 55) -L-(N(R 1 )-L) n -aryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and aryl groups, 
 56) —O-L-N(R 1 )R 1 , 
 57) —O-L-heteroaryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and heteroaryl groups, 
 58) —O-L-heterocyclyl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and heterocyclyl groups, 
 59) —O-L-aryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and aryl groups, 
 60) —O-L) 2 -NR 1 , 
 61) —O-L-(N(R 1 )-L) n -N(R 1 )R 1 , 
 62) —O-L-(N(R 1 )-L) n -heteroaryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and heteroaryl groups, 
 63) —O-L-(N(R 1 )-L) n -heterocyclyl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and heterocyclyl groups, 
 64) —O-L-(N(R 1 )-L) n -aryl optionally substituted with one or more R A  or R 1  substituents, 
 65) —S-L-heteroaryl optionally substituted with one or more R A  or R 1  substituents, 
 66) —S-L-heterocyclyl optionally substituted with one or more R A  or R 1  substituents, 
 67) —S-L-aryl optionally substituted with one or more R A  or R 1  substituents attached on either or both the L and aryl groups, 
 68) —S-L) 2 NR 1 , 
 69) —S-L-(N(R 1 )-L) n -N(R 1 )R 1 , 
 70) —S-L-(N(R 1 )-L) n -heteroaryl optionally substituted with one or more R A  substituents, 
 71) —S-L-(N(R 1 )-L) n -heterocyclyl optionally substituted with one or more R A  substituents, 
 72) —S-L-(N(R 1 )-L) n -aryl optionally substituted with one or more R A  substituents, 
 73) —NR 1 (R 1 ), 
 74) —(N(R 1 )-L) n -N(R 1 )R 1 , 
 75) —N(R 1 )L) 2 -NR 1 , 
 76) —(N(R 1 )-L) n -N(R 1 )R A , 
 77) —(N(R 1 )-L) n -heteroaryl optionally substituted with one or more R A  or R 1  substituents, 
 78) —(N(R 1 )-L) n -heterocyclyl optionally substituted with one or more R A  or R 1  substituents, 
 79) —(N(R 1 )-L) n -aryl optionally substituted with one or more R A  or R 1  substituents, 
 80) -heteroaryl optionally substituted with one or more R A  substituents, or 
 81) -aryl optionally substituted with one or more R A  substituents, 
 
         and wherein each substituent is optionally attached to the L group if it is not already present, 
         and wherein when two R 1  substituents are present on the same nitrogen atom, then each R 1  substituent is independently selected from the list of R 1  values described thereafter, 
         and wherein n is an integer equal to either 0, 1, 2, 3, 4, or 5, 
         and wherein, when (R 1 ) and R 1  are attached to a nitrogen atom, optionally they join together with the nitrogen atom to form a 3 to 7-membered ring which optionally includes one or more other heteroatom selected from N, O and S, optionally the ring is substituted with one or more R 1  or R A ; 
         L is
 1) —C 1-6  alkyl, 
 2) —C 2-6  alkenyl, 
 3) —C 2-6  alkynyl, 
 4) —C 3-7 cycloalkyl, 
 5) —C 3-7  cycloalkenyl, 
 6) heterocyclyl, 
 7) —C 1-6  alkyl-C 3-7  cycloalkyl, 
 8) —C 1-6  alkyl-heterocyclyl, 
 9) aryl, or 
 10) heteroaryl, 
 
         and wherein the alkyl, the alkenyl, the alkynyl, the cycloalkyl, the cycloalkenyl, the heterocyclyl, the aryl and the heteroaryl groups are each independently optionally substituted with one or two R A  substituent; 
         R 1  is
 1) —H, 
 2) —C 1-6  alkyl, 
 3) —C 2-6  alkenyl, 
 4) —C 2-6  alkynyl, 
 5) —C 3-7  cycloalkyl, 
 6) —C 3-7  cycloalkenyl, 
 7) —C 1-5  perfluorinated, 
 8) -heterocyclyl, 
 9) -aryl, 
 10) -heteroaryl, 
 11) -benzyl, or 
 12) 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoyl, 
 
         and wherein the alkyl, the alkenyl, the alkynyl, the cycloalkenyl, the perfluorinated alkyl, the heterocyclyl, the aryl, the heteroaryl and the benzyl groups are each independently optionally substituted with 1, 2 or 3 R A  or R 1  substituents; 
         R 2  is
 1) —H, 
 2) —C 1-6  alkyl, 
 3) —SR 1 , 
 4) —C(O)R 1 , 
 5) —S(O)R 1 , 
 6) —S(O) 2 R 1 , 
 7) -benzyl optionally substituted with 1, 2 or 3 R A  or R 1  substituents, 
 8) -L-heteroaryl optionally substituted with one or more R A  or R 1  substituents attached on either one or both the L and the heteroaryl groups, 
 9) -L-heterocyclyl optionally substituted with one or more R A  or R 1  substituents attached on either one or both the L and the heterocyclyl groups, 
 10) -L-aryl optionally substituted with one or more R A  or R 1  substituents attached on either one or both the L and the aryl groups, 
 11) -heteroaryl optionally substituted with one or more R A  or R 1  substituents, or 
 12) -aryl optionally substituted with one or more R A  or R 1  substituents, 
 
         and wherein each substituent is optionally attached to the L group if it is not already present; 
         R A  is
 1) -halogen, 
 2) —CF 3 , 
 3) —OH, 
 4) —OR 1 , 
 5) -L-OH, 
 6) -L-OR 1 , 
 7) —OCF 3 , 
 8) —SH, 
 9) —SR1, 
 10) —CN, 
 11) —NO 2 , 
 12) —NH 2 , 
 13) —NHR 1 , 
 14) —NR 1 R 1 , 
 15) -L-NH 2 , 
 16) -L-NHR 1 , 
 17) -L-NR 4 R 1 , 
 18) -L-SR 1 , 
 19) -L-S(O)R 1 , 
 20) -L-S(O) 2 R 1 , 
 21) —C(O)OH, 
 22) —C(O)OR 1 , 
 23) —C(O)NH 2 , 
 24) —C(O)NHR 1 , 
 25) —C(O)N(R 1 )R 1 , 
 26) —NHC(O)R 1 , 
 27) —NR 1 C(O)R 1 , 
 28) —NHC(O)OR 1 , 
 29) —NR 1 C(O)OR 1 , 
 30) —OC(O)NH 2 , 
 31) —OC(O)NHR 1 , 
 32) —OC(O)N(R 1 )R 1 , 
 33) —OC(O)R 1 , 
 34) —C(O)R 1 , 
 35) —NHC(O)NH 2 , 
 36) —NHC(O)NHR 1 , 
 37) —NHC(O)N(R 1 )R 1 , 
 38) —NR 1 C(O)NH 2 , 
 39) —NR 1 C(O)NHR 1 , 
 40) —NR 1 C(O)N(R 1 )R 1 , 
 41) —NHS(O) 2 R 1 , 
 42) —NR 1 S(O) 2 R 1 , 
 43) —S(O) 2 NH 2 , 
 44) —S(O) 2 NHR 1 , 
 45) —S(O) 2 N(R 1 )R 1 , 
 46) —S(O)R 1 , 
 47) —S(O) 2 R 1 , 
 48) —OS(O) 2 R 1 , 
 49) —S(O) 2 OR 1 , 
 50) -benzyl, 
 51) —N 3 , or 
 52) —C(—N═N—)(CF 3 ), 
 
         and wherein the benzyl group is optionally substituted with 1, 2 or 3 R A  or R 1  substituents.