发明名称 Pyrimido[4,5-B]indole derivatives and use thereof in the expansion of hematopoietic stem cells
摘要 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.
申请公布号 US9409906(B2) 申请公布日期 2016.08.09
申请号 US201314374953 申请日期 2013.01.25
申请人 UNIVERSITE DE MONTREAL 发明人 Sauvageau Guy;Gareau Yves;Ruel Réjean;Gingras Stéphane;Fares Iman
分类号 C07D471/04;C07D487/04;A61K35/28 主分类号 C07D471/04
代理机构 Buchanan Ingersoll & Rooney P.C. 代理人 Buchanan Ingersoll & Rooney P.C.
主权项 1. A compound of general formula I or II or a salt thereof, wherein: Z is 1) —P(O)(OR1)(OR1), 2) —C(O)OR1, 3) —C(O)NHR1, 4) —C(O)N(R1)R1, 5) —C(O)R1, 6) —CN, 7) —SR1, 8) —S(O)2NH2, 9) —S(O)2NHR1, 10) —S(O)2N(R1)R1, 11) —S(O)R1, 12) —S(O)2R1, 13) -L, 14) -benzyl optionally substituted with 1, 2 or 3 RA or R1 substituents, 15) -L-heteroaryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and the heteroaryl groups, 16) -L-heterocyclyl optionally substituted with one or more RA or R1 substituents attached on either one or both the L and the heterocyclyl groups, 17) -L-aryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and the heteroaryl groups, 18) -heteroaryl optionally substituted with one or more RA or R1 substituents, or 19) -aryl optionally substituted with one or more RA or R1 substituents, and wherein each substituent is optionally attached to the L group if it is not already present, and wherein, when (R1) and R1 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 R1 or RA; W is 1) —OR1, wherein R1 is —C1-6 alkyl, —C2-6 alkenyl, —C2-6 alkynyl, C3-7 cycloalkyl, —C3-7 cycloalkenyl, —C1-5 perfluorinated, -heterocyclyl, -aryl, -heteroaryl, -benzyl, or 5-[(3aS,4S,6aR)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl]pentanoyl, 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 RA or R1 substituents;2) -L-OH,3) -L-OR1,4) —SR1,5) —CN,6) —P(O)(OR1)(OR1),7) —NHR1,8) —N(R1)R1,9) -L-NH2,10) -L-NHR1,11) -L-N(R1)R1,12) -L-SR1,13) -L-S(O)R1,14) -L-S(O)2R1,15) -L-P(O)(OR1)(OR1),16) —C(O)OR1,17) —C(O)NH2,18) —C(O)NHR1,19) —C(O)N(R1)R1,20) —NHC(O)R1,21) —NR1C(O)R1,22) —NHC(O)OR1,23) —NR1C(O)OR1,24) —OC(O)NH2,25) —OC(O)NHR1,26) —OC(O)N(R1)R1,27) —OC(O)R1,28) —C(O)R1,29) —NHC(O)NH2,30) —NHC(O)NHR1,31) —NHC(O)N(R1)R1,32) —NR1C(O)NH2,33) —NR1C(O)NHR1,34) —NR1C(O)N(R1)R1,35) —NHS(O)2R1,36) —NR1S(O)2R1,37) —S(O)2NH2,38) —S(O)2NHR1,39) —S(O)2N(R1)R1,40) —S(O)R1,41) —S(O)2R1,42) —OS(O)2R1,43) —S(O)2OR1,44) -benzyl optionally substituted with 1, 2 or 3 RA or R1 substituents,45) -L-heteroaryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and the heteroaryl groups,46) -L-heterocyclyl optionally substituted with one or more RA or R1 substituents attached on either or both the L and the heterocyclyl groups,47) -L-aryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and aryl groups,48) -L-NR1(R1),49) -(L-)2NR1,50) -L-(N(R1)-L)n-N(R1)R1,51) -L-(N(R1)-L)n- heteroaryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and heteroaryl groups,52) -L-(N(R1)-L)n- heterocyclyl optionally substituted with one or more RA or R1 substituents attached on either or both the L and heterocyclyl groups,53) -L-(N(R1)-L)n- aryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and aryl groups,54) —O-L-N(R1)R1,55) —O-L- heteroaryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and heteroaryl groups,56) —O-L- heterocyclyl optionally substituted with one or more RA or R1 substituents attached on either or both the L and heterocyclyl groups,57) —O-L- aryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and aryl groups,58) —(O-L)2-NR1,59) —O-L-(N(R1)-L)n-N(R1)R1,60) —O-L-(N(R1)-L)n- heteroaryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and heteroaryl groups,61) —O-L-(N(R1)-L)n- heterocyclyl optionally substituted with one or more RA or R1 substituents attached on either or both the L and heterocyclyl groups,62) —O-L-(N(R1)-L)n- aryl optionally substituted with one or more RA or R1 substituents,63) —S-L- heteroaryl optionally substituted with one or more RA or R1 substituents,64) —S-L- heterocyclyl optionally substituted with one or more RA or R1 substituents,65) —S-L- aryl optionally substituted with one or more RA or R1 substituents attached on either or both the L and aryl groups,66) —(S-L)2NR1,67) —S-L-(N(R1)-L)n-N(R1)R1,68) —S-L-(N(R1)-L)n- heteroaryl optionally substituted with one or more RA substituents,69) —S-L-(N(R1)-L)n- heterocyclyl optionally substituted with one or more RA substituents,70) —S-L-(N(R1)-L)n- aryl optionally substituted with one or more RA substituents,71) —NR1(R1),72) —(N(R1)-L)n-N(R1)R1,73) —N(R1)L)2-NR1,74) —(N(R1)-L)n-N(R1)RA,75) —(N(R1)-L)n- heteroaryl optionally substituted with one or more RA or R1 substituents,76) —(N(R1)-L)n- heterocyclyl optionally substituted with one or more RA or R1 substituents,77) —(N(R1)-L)n- aryl optionally substituted with one or more RA or R1 substituents,78) -heteroaryl optionally substituted with one or more RA substituents, or79) -aryl optionally substituted with one or more RA substituents, and wherein each substituent is optionally attached to the L group if it is not already present, and wherein when two R1 substituents are present on the same nitrogen atom, then each R1 substituent is independently selected from the list of R1 values described thereafter, and wherein n is an integer equal to either 0, 1, 2, 3, 4, or 5, and wherein, when (R1) and R1 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 R1 or RA; L is 1) —C1-6 alkyl,2) —C2-6 alkenyl,3) —C2-6 alkynyl,4) —C3-7 cycloalkyl,5) —C3-7 cycloalkenyl,6) heterocyclyl,7) —C1-6 alkyl-C3-7 cycloalkyl,8) —C1-6 alkyl-heterocyclyl,9) aryl, or10) 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 RA substituent; R1 is 1) —H,2) —C1-6 alkyl,3) —C2-6 alkenyl,4) —C2-6 alkynyl,5) —C3-7 cycloalkyl,6) —C3-7 cycloalkenyl,7) —C1-5 perfluorinated,8) -heterocyclyl,9) -aryl,10) -heteroaryl,11) -benzyl, or12) 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 RA or R1 substituents; R2 is 1) —H,2) —C1-6 alkyl,3) —SR1,4) —C(O)R1,5) —S(O)R1,6) —S(O)2R1,7) -benzyl optionally substituted with 1, 2 or 3 RA or R1 substituents,8) -L-heteroaryl optionally substituted with one or more RA or R1 substituents attached on either one or both the L and the heteroaryl groups,9) -L-heterocyclyl optionally substituted with one or more RA or R1 substituents attached on either one or both the L and the heterocyclyl groups,10) -L-aryl optionally substituted with one or more RA or R1 substituents attached on either one or both the L and the aryl groups,11) -heteroaryl optionally substituted with one or more RA or R1 substituents, or12) -aryl optionally substituted with one or more RA or R1 substituents, and wherein each substituent is optionally attached to the L group if it is not already present; RA is 1) -halogen,2) —CF3,3) —OH,4) —OR1,5) -L-OH,6) -L-OR1,7) —OCF3,8) —SH,9) —SR1,10) —CN,11) —NO2,12) —NH2,13) —NHR1,14) —NR1R1,15) -L-NH2,16) -L-NHR1,17) -L-SR1,18) -L-S(O)R1,19) -L-S(O)2R1,20) —C(O)OH,21) —C(O)OR1,22) —C(O)NH2,23) —C(O)NHR1,24) —C(O)N(R1)R1,25) —NHC(O)R1,26) —NR1C(O)R1,27) —NHC(O)OR1,28) —NR1C(O)OR1,29) —OC(O)NH2,30) —OC(O)NHR1,31) —OC(O)N(R1)R1,32) —OC(O)R1,33) —C(O)R1,34) —NHC(O)NH2,35) —NHC(O)NHR1,36) —NHC(O)N(R1)R1,37) —NR1C(O)NH2,38) —NR1C(O)NHR1,39) —NR1C(O)N(R1)R1,40) —NHS(O)2R1,41) —NR1S(O)2R1,42) —S(O)2NH2,43) —S(O)2NHR1,44) —S(O)2N(R1)R1,45) —S(O)R1,46) —S(O)2R1,47) —OS(O)2R1,48) —S(O)2OR1,49) -benzyl,50) —N3, or51) —C(—N═N—)(CF3), and wherein the benzyl group is optionally substituted with 1, 2 or 3 RA or R1 substituents provided that the compound of Formula (I) is other than
地址 Montreal, Quebec CA