US2018280422A1PendingUtilityA1
Substituted purine and 7-deazapurine compounds
Est. expiryDec 3, 2030(~4.4 yrs left)· nominal 20-yr term from priority
Inventors:Edward J. OlhavaRichard ChesworthKevin Wayne KuntzVictoria M. RichonRoy M. PollockScott R. Daigle
A61P 9/00A61P 43/00A61P 35/00A61P 35/02A61P 25/28A61P 29/00A61P 3/00A61K 31/52A61K 31/7076C07H 19/14A61K 31/7064C07D 487/04C07H 19/04A61K 31/519C07D 473/34C07H 19/167C07H 19/16A61P 25/00
61
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
The present invention relates to substituted purine and 7-deazapurine compounds. The present invention also relates to pharmaceutical compositions containing these compounds and methods of treating disorders in which DOT1-mediated protein methylation plays a part, such as cancer and neurological disorders, by administering these compounds and pharmaceutical compositions to subjects in need thereof.
Claims
exact text as granted — not AI-modified1 . (canceled)
2 . A method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a DOT1L inhibitor.
3 . A method of treating hematological cancer comprising administering to a subject in need thereof a therapeutically effective amount of a DOT1L inhibitor.
4 . A method of treating leukemia comprising administering to a subject in need thereof a therapeutically effective amount of a DOT1L inhibitor.
5 . The method of claim 4 , wherein the leukemia is acute myeloid leukemia, acute lymphocytic leukemia or mixed lineage leukemia.
6 . The method of claim 4 , wherein the leukemia is a MLL-rearranged leukemia.
7 . The method of claim 4 , wherein the leukemia is a leukemia characterized by a partial tandem duplication of the MLL gene (MLL-PTD).
8 . The method of claim 2 , wherein the DOT1L inhibitor is a compound having the structure of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
A is O or CH 2 ;
Q is H, NH 2 , NHR b , NR b R c , R b , or OR b , in which each of R b and R c independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M 1 -T 1 in which M 1 is a bond or C 1 -C 6 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxyl and T 1 is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R b and R c , together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, OC(O)—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R b , R c , and T 1 is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
X is N or CR x , in which R x is H, halo, hydroxyl, carboxyl, cyano, or R S1 , R S1 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R S1 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
L 1 is N(Y), S, SO, or SO 2 ;
L 2 is CO or absent when L 1 is N(Y) or L 2 is absent when L 1 is S, SO, or SO 2 , in which Y is H, R d , SO 2 R d , or COR d when L 2 is absent, or Y is H or R d when L 2 is CO, R d being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R d being optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 alkylsulfonyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, OC(O)—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, halo, hydroxyl, carboxyl, cyano, R S2 , R S2 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and each R S2 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 8 is H, halo or R S3 , R S3 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R S3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C 1 -C 6 alkoxyl, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 8 cycloalkyl;
R 9 is
in which each of R e , R f , R g , and R h , independently is -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or N(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R i is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR j , or CR j R k , each of R j and R k independently being H or C 1 -C 6 alkyl, or R j and R k taken together, with the carbon atom to which they are attached, form a C 3 -C 10 cycloalkyl ring, and E is -M 3 -T 3 , M 3 being a bond or C 1 -C 6 alkyl linker optionally substituted with halo or cyano, T 3 being C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, halo, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C 1 -C 6 alkoxyl;
q is 0, 1, 2, 3, or 4; m is 0, 1, or 2; and n is 0, 1, or 2.
9 . The method of claim 3 , wherein the DOT1L inhibitor is a compound having the structure of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
A is O or CH 2 ;
Q is H, NH 2 , NHR b , NR b R c , R b , or OR b , in which each of R b and R c independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M 1 -T 1 in which M 1 is a bond or C 1 -C 6 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxyl and T 1 is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R b and R c , together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, OC(O)—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R b , R c , and T 1 is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
X is N or CR x , in which R x is H, halo, hydroxyl, carboxyl, cyano, or R S1 , R S1 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R S1 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
L 1 is N(Y), S, SO, or SO 2 ;
L 2 is CO or absent when L 1 is N(Y) or L 2 is absent when L 1 is S, SO, or SO 2 , in which Y is H, R d , SO 2 R d , or COR d when L 2 is absent, or Y is H or R d when L 2 is CO, R d being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R d being optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 alkylsulfonyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, OC(O)—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, halo, hydroxyl, carboxyl, cyano, R S2 , R S2 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and each R S2 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 8 is H, halo or R S3 , R S3 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R S3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C 1 -C 6 alkoxyl, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 8 cycloalkyl;
R 9 is
in which each of R e , R f , R g , and R h , independently is -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or N(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R i is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR j , or CR j R k , each of R j and R k independently being H or C 1 -C 6 alkyl, or R j and R k taken together, with the carbon atom to which they are attached, form a C 3 -C 10 cycloalkyl ring, and E is -M 3 -T 3 , M 3 being a bond or C 1 -C 6 alkyl linker optionally substituted with halo or cyano, T 3 being C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, halo, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C 1 -C 6 alkoxyl;
q is 0, 1, 2, 3, or 4; m is 0, 1, or 2; and
n is 0, 1, or 2.
10 . The method of claim 4 , wherein the DOT1L inhibitor is a compound having the structure of Formula (II):
or a pharmaceutically acceptable salt thereof, wherein
A is O or CH 2 ;
Q is H, NH 2 , NHR b , NR b R c , R b , or OR b , in which each of R b and R c independently is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 7-membered heterocycloalkyl, 5 to 10-membered heteroaryl, or -M 1 -T 1 in which M 1 is a bond or C 1 -C 6 alkyl linker optionally substituted with halo, cyano, hydroxyl or C 1 -C 6 alkoxyl and T 1 is C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, or R b and R c , together with the N atom to which they attach, form 4 to 7-membered heterocycloalkyl having 0 or 1 additional heteroatoms to the N atom optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, OC(O)—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and each of R b , R c , and T 1 is optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
X is N or CR x , in which R x is H, halo, hydroxyl, carboxyl, cyano, or R S1 , R S1 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R S1 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
L 1 is N(Y), S, SO, or SO 2 ;
L 2 is CO or absent when L 1 is N(Y) or L 2 is absent when L 1 is S, SO, or SO 2 , in which Y is H, R d , SO 2 R d , or COR d when L 2 is absent, or Y is H or R d when L 2 is CO, R d being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl, and R d being optionally substituted with one or more substituents selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, C 1 -C 6 alkylsulfonyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl and with C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl further optionally substituted with C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, halo, hydroxyl, carboxyl, C(O)OH, C(O)O—C 1 -C 6 alkyl, OC(O)—C 1 -C 6 alkyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl;
each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , independently, is H, halo, hydroxyl, carboxyl, cyano, R S2 , R S2 being amino, C 1 -C 6 alkoxyl, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and each R S2 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl;
R 8 is H, halo or R S3 , R S3 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl, and R S3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano amino, C 1 -C 6 alkoxyl, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, and C 3 -C 8 cycloalkyl;
R 9 is
in which each of R e , R f , R g , and R h , independently is -M 2 -T 2 , in which M 2 is a bond, SO 2 , SO, S, CO, CO 2 , O, O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, NH, or N(R t ), R t being C 1 -C 6 alkyl, and T 2 is H, halo, or R S4 , R S4 being C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 8-membered heterocycloalkyl, or 5 to 10-membered heteroaryl, and each of O—C 1 -C 4 alkyl linker, C 1 -C 4 alkyl linker, R t , and R S4 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C6-C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, R i is H or C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, carboxyl, cyano, C 1 -C 6 alkoxyl, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, and 5 to 6-membered heteroaryl, D is O, NR j , or CR j R k , each of R j and R k independently being H or C 1 -C 6 alkyl, or R j and R k taken together, with the carbon atom to which they are attached, form a C 3 -C 10 cycloalkyl ring, and E is -M 3 -T 3 , M 3 being a bond or C 1 -C 6 alkyl linker optionally substituted with halo or cyano, T 3 being C 3 -C 10 cycloalkyl, C 6 -C 10 aryl, 5 to 10-membered heteroaryl, or 4 to 10-membered heterocycloalkyl, and T 3 being optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, thiol, carboxyl, cyano, nitro, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxyl, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxyl, C 1 -C 6 alkylthio, C 1 -C 6 alkylsulfonyl, C 1 -C 6 haloalkylsulfonyl, C 1 -C 6 alkylcarbonyl, C 1 -C 6 alkoxycarbonyl, oxo, amino, mono-C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino, C 3 -C 8 cycloalkyl, C 4 -C 12 alkylcycloalkyl, C 6 -C 10 aryl, C 6 -C 10 aryloxyl, C 7 -C 14 alkylaryl, C 6 -C 10 aminoaryloxyl, C 6 -C 10 arylthio, 4 to 6-membered heterocycloalkyl optionally substituted with halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, 5 to 6-membered heteroaryl optionally substituted with halo, C 1 -C 4 alkyl, and C 1 -C 6 alkyl that is substituted with hydroxy, halo, C 1 -C 6 alkoxycarbonyl, C 3 -C 8 cycloalkyl, C 6 -C 10 aryl, 4 to 6-membered heterocycloalkyl, or 5 to 6-membered heteroaryl optionally further substituted with halo, hydroxyl, or C 1 -C 6 alkoxyl;
q is 0, 1, 2, 3, or 4; m is 0, 1, or 2; and
n is 0, 1, or 2.
11 . The method of claim 8 , wherein A is O.
12 . The method of claim 9 , wherein A is O.
13 . The method of claim 10 , wherein A is O.
14 . The method of claim 8 , wherein Q is NH 2 or NHR b , in which R b is -M 1 -T 1 , M 1 being a bond or C 1 -C 6 alkyl linker and T 1 being C 3 -C 8 cycloalkyl.
15 . The method of claim 9 , wherein Q is NH 2 or NHR b , in which R b is -M 1 -T 1 , M 1 being a bond or C 1 -C 6 alkyl linker and T 1 being C 3 -C 8 cycloalkyl.
16 . The method of claim 10 , wherein Q is NH 2 or NHR b , in which R b is -M 1 -T 1 , M 1 being a bond or C 1 -C 6 alkyl linker and T 1 being C 3 -C 8 cycloalkyl.
17 . The method of claim 2 , wherein the DOT1L inhibitor is a compound selected from:
and pharmaceutically acceptable salts thereof.
18 . The method of claim 3 , wherein the DOT1L inhibitor is a compound selected from:
and pharmaceutically acceptable salts thereof.
19 . The method of claim 4 , wherein the DOT1L inhibitor is a compound selected from:
and pharmaceutically acceptable salts thereof.
20 . The method of claim 2 , wherein the DOT1L inhibitor is Compound 2:
or a pharmaceutically acceptable salt thereof.
21 . The method of claim 3 , wherein the DOT1L inhibitor is Compound 2:
or a pharmaceutically acceptable salt thereof.
22 . The method of claim 4 , wherein the DOT1L inhibitor is Compound 2:
or a pharmaceutically acceptable salt thereof.Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.