US2023039846A1PendingUtilityA1
Compounds and methods of use
Est. expiryFeb 28, 2038(~11.6 yrs left)· nominal 20-yr term from priority
C07D 217/14C07D 471/04C07D 217/04A61K 47/40A61P 35/00C07D 217/06A61K 45/06A61K 31/4545C07D 217/26A61K 31/5377C07D 495/04A61K 31/437C07D 217/16
60
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Claims
Abstract
This present disclosure relates to compounds with ferroptosis inducing activity, a method of treating a subject with cancer with the compounds, and combination treatments with a second therapeutic agent.
Claims
exact text as granted — not AI-modified1 - 49 . (canceled)
50 . A method of treating cancer in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (I):
or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, wherein:
ring A is C 4 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
X is NR 5 , O, or S;
p is 0, 1, 2, or 3;
q is 0, 1, 2, or 3;
R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —CN, —OH, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —S(O) 2 R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —S(O)R 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —NO 2 , —OR 8 , —C 1 -C 6 alkyl-OH, —C 1 -C 6 alkyl-OR 8 , or —Si(R 15 ) 3 ;
R 2 is —C(O)R 9 ;
each R 3 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 12 ) 3 , —SF 5 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)R 8 , —C(O)R 6 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl of R 3 is independently unsubstituted or substituted with one to three R 10 ;
each R 4 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 15 ) 3 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —OC(O)R 8 , —C(O)R 6 , —NR 12 C(O)OR 8 , —OC(O)N(R 7 ) 2 , —OC(O)CHR 8 N(R 12 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl of R 4 is independently unsubstituted or substituted with one to three R 10 ;
R 5 is hydrogen or C 1 -C 6 alkyl;
each R 6 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each R 6 is independently unsubstituted or substituted with one to three R 11 ;
each R 7 is independently hydrogen, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 6 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 6 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, or two R 7 , together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein each R 7 or ring formed thereby is independently unsubstituted or substituted with one to three R 11 ;
each R 8 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, heteroaryl, —C 1 -C 6 alkylC 3 -C 10 cycloalkyl, —C 2 -C 6 alkenylC 3 -C 10 cycloalkyl, —C 1 -C 6 alkylheterocyclyl, —C 2 -C 6 alkenylheterocyclyl, —C 1 -C 6 alkylaryl, —C 2 -C 6 alkenylaryl, —C 1 -C 6 alkylheteroaryl, or —C 2 -C 6 alkenylheteroaryl, wherein each R 8 is independently unsubstituted or substituted with one to three Ru;
R 9 is C 2 alkynyl that is unsubstituted or is substituted with one —CH 3 ;
each R 10 is independently halo, —CN, —OR 12 , —NO 2 , —N(R 12 ) 2 , —S(O)R 13 , —S(O) 2 R 13 , —S(O)N(R 12 ) 2 , —S(O) 2 N(R 12 ) 2 , —Si(R 12 ) 3 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —OC(O)R 12 , —OC(O)OR 12 , —OC(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —OC(O)CHR 12 N(R 12 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl of R 10 is independently unsubstituted or substituted with one to three Ru;
each R 11 is independently halo, —CN, —OR 12 , —NO 2 , —N(R 12 ) 2 , —S(O)R 13 , —S(O) 2 R 13 , —S(O)N(R 12 ) 2 , —S(O) 2 N(R 12 ) 2 , —Si(R 12 ) 3 , —C(O)R 12 , —C(O)OR 12 , —C(O)N(R 12 ) 2 , —NR 12 C(O)R 12 , —OC(O)R 12 , —OC(O)OR 12 , —OC(O)N(R 12 ) 2 , —NR 12 C(O)OR 12 , —OC(O)CHR 12 N(R 12 ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 10 cycloalkyl, heterocyclyl, aryl, or heteroaryl;
each R 12 is independently hydrogen, C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl;
each R 13 is independently C 1 -C 6 alkyl, or C 3 -C 10 cycloalkyl; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-.
51 . The method of claim 50 , wherein the compound is of formula (II):
or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof.
52 . The method of claim 50 , wherein ring A is C 4 -C 10 cycloalkyl.
53 . The method of claim 50 , wherein ring A is heterocyclyl.
54 . The method of claim 50 , wherein R 1 is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 3 -C 10 cycloalkyl, —NH 2 , —NHR 8 , —N(R 8 ) 2 , —OH, —OR 8 , —C 1 -C 6 alkyl-OH, or —C 1 -C 6 alkyl-OR 8 .
55 . The method of claim 50 , wherein the compound is of formula (IV):
or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof.
56 . The method of claim 50 , wherein each R 4 is independently halo, —CN, —OH, —OR 8 , —NH 2 , —NHR 8 , —N(R 8 ) 2 , —S(O) 2 R 8 , —S(O)R 8 , —S(O) 2 N(R 7 ) 2 , —S(O)N(R 7 ) 2 , —NO 2 , —Si(R 15 ) 3 , —C(O)OR 6 , —C(O)N(R 7 ) 2 , —NR 12 C(O)R 8 , —OC(O)R 8 , —C(O)R 6 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl, wherein each C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, or C 3 -C 10 cycloalkyl of R 4 is independently unsubstituted or substituted with one to three R 10 .
57 . The method of claim 50 , wherein p is 0.
58 . The method of claim 50 , wherein q is 0.
59 . The method of claim 50 , comprising administering a pharmaceutical composition comprising the compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
60 . A method of treating cancer in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound of formula (V):
or an enantiomer or pharmaceutically acceptable salt thereof, wherein:
X is N, O, or S;
A is a 4- to 7-membered cycloalkyl, 4- to 7-membered heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur;
R 1 is H, C 1 -C 6 alkyl, —C 1 -C 6 alkylhalo, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —SO 2 R 8 , —SOR 8 , NO 2 , —OR 8 , —C 1 -C 6 alkyl-OR 12 , or —Si(R 15 ) 3 ;
R 2 is —C(O)R 9 ;
R 3 is H, halo, —C(O)OR 10 , —C(O)N(R 11 ) 2 , —OC(O)R 10 , —C 0 -C 6 alkylC 3 -C 8 cycloalkyl, —C 0 -C 6 alkylheterocyclyl, —N(R 11 ) 2 , —SO 2 R 8 , —SOR 8 , —NO 2 , or —Si(R 15 ) 3 ;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
each R 6 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 NC 2 -C 6 alkenyl-;
each R 7 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O—C 1 -C 6 alkyl-, or R 12 O(O)C—C 1 -C 6 alkyl-, or two R 7 , together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 8 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 N—;
R 9 is C 2 alkynyl;
R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, or (R 15 ) 3 SiC 0 -C 6 alkyl-;
each R 11 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, R 12 O—C 1 -C 6 alkyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O(O)C—C 1 -C 6 alkyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, (R 15 ) 3 SiC 0 -C 6 alkyl-, or an N-protecting group, or two R 11 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with OH, halo, —NH 2 , or C 1 -C 6 alkyl, or when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 12 is independently H or C 1 -C 6 alkyl;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, or an N protecting group;
R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-;
wherein each C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
61 . The method of claim 60 , wherein the compound is of formula (Va):
or an enantiomer or pharmaceutically acceptable salt thereof,
wherein:
X is N, O, or S;
R 1 is C 1 -C 6 alkyl, —C 1 -C 6 alkylhalo, —C(O)OR 6 , —C(O)N(R 7 ) 2 , —OC(O)R 6 , —SO 2 R 8 , —SOR 8 , NO 2 , —OR 8 , —C 1 -C 6 alkyl-OR 12 , or —Si(R 15 ) 3 ;
R 2 is —C(O)R 9 ;
R 3 is —C(O)OR 10 , —C(O)N(R 11 ) 2 , —OC(O)R 10 , —C 0 -C 6 alkylC 3 -C 8 cycloalkyl, —C 0 -C 6 alkylheterocyclyl, —N(R 11 ) 2 , —SO 2 R 8 , —SOR 8 , —NO 2 , or —Si(R 15 ) 3 ;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
each R 6 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 NC 2 -C 6 alkenyl-;
each R 7 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O—C 1 -C 6 alkyl-, or R 12 O(O)C—C 1 -C 6 alkyl-, or two R 7 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 8 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 N—;
R 9 is C 2 alkynyl;
R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, or (R 15 ) 3 SiC 0 -C 6 alkyl-;
each R 11 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, R 12 O—C 1 -C 6 alkyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O(O)C—C 1 -C 6 alkyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, (R 15 ) 3 SiC 0 -C 6 alkyl-, or an N-protecting group, or two R 11 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with OH, halo, —NH 2 , or C 1 -C 6 alkyl, or when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 12 is independently H or C 1 -C 6 alkyl;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, or an N protecting group;
R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-;
wherein each C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
62 . The method of claim 60 , wherein the compound is of formula (Vg):
or an enantiomer or pharmaceutically acceptable salt thereof, wherein:
X is N, O, or S;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
each R 7 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O—C 1 -C 6 alkyl-, or R 12 O(O)C—C 1 -C 6 alkyl-, or two R 7 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
R 9 is C 2 alkynyl;
each R 11 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, R 12 O—C 1 -C 6 alkyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O(O)C—C 1 -C 6 alkyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, (R 15 ) 3 SiC 0 -C 6 alkyl-, or an N-protecting group, or two R 11 , together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with OH, halo, —NH 2 , or C 1 -C 6 alkyl, or when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 12 is independently H or C 1 -C 6 alkyl;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, or an N protecting group;
R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-;
wherein each C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
63 . The method of claim 60 , wherein the compound is of formula (Vi):
or an enantiomer or pharmaceutically acceptable salt thereof, wherein:
X is N, O, or S;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
R 6 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 NC 2 -C 6 alkenyl-;
R 8 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 N—;
R 9 is C 2 alkynyl;
each R 11 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, R 12 O—C 1 -C 6 alkyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O(O)C—C 1 -C 6 alkyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, (R 15 ) 3 SiC 0 -C 6 alkyl-, or an N-protecting group, or two R 11 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with OH, halo, —NH 2 , or C 1 -C 6 alkyl, or when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 12 is independently H or C 1 -C 6 alkyl;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, or an N protecting group;
R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-;
wherein each C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
64 . The method of claim 60 , wherein the compound is of formula (Vj):
or an enantiomer or pharmaceutically acceptable salt thereof, wherein:
X is N, O, or S;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
each R 7 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O—C 1 -C 6 alkyl-, or R 12 O(O)C—C 1 -C 6 alkyl-, or two R 7 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 7 groups is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, a 4- to 6-membered heterocyclyl, or (R 11 ) 2 N—, wherein the 4- to 6-membered heterocyclyl when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
R 8 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, or (R 11 ) 2 N—;
R 9 is C 2 alkynyl;
each R 11 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, R 12 O—C 1 -C 6 alkyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O(O)C—C 1 -C 6 alkyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, (R 15 ) 3 SiC 0 -C 6 alkyl-, or an N-protecting group, or two R 11 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with OH, halo, —NH 2 , or C 1 -C 6 alkyl, or when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 12 is independently H or C 1 -C 6 alkyl;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, or an N protecting group;
R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-;
wherein each C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
65 . The method of claim 60 , wherein the compound is of formula (Vn):
or an enantiomer or pharmaceutically acceptable salt thereof, wherein:
X is N, O, or S;
R 1 is C 1 -C 6 alkyl, —C 1 -C 6 alkylhalo, or —C 1 -C 6 alkyl-OR 12 ;
R 2 is —C(O)R 9 ;
R 3 is —C(O)OR 10 , —C(O)N(R 11 ) 2 , —OC(O)R 10 , —C 0 -C 6 alkylC 3 -C 8 cycloalkyl, —C 0 -C 6 alkylheterocyclyl, —N(R 11 ) 2 , —SO 2 R 8 , —SOR 8 , —NO 2 , or —Si(R 15 ) 3 ;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
R 8 is independently C 1 -C 6 alkyl, C 3 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 N—, or R 14 C 0 -C 6 alkyl-;
R 9 is C 2 alkynyl;
R 10 is C 1 -C 6 alkyl, C 2 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, or (R 15 ) 3 SiC 0 -C 6 alkyl-;
each R 11 is independently H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, R 12 O—C 1 -C 6 alkyl-, (R 11 ) 2 NC 1 -C 6 alkyl-, (R 11 ) 2 NC 2 -C 6 alkenyl-, R 12 O(O)C—C 1 -C 6 alkyl-, R 13 (NH 2 )CH—, R 14 C 0 -C 6 alkyl-, (R 15 ) 3 SiC 0 -C 6 alkyl-, or an N-protecting group, or two R 11 , together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl, wherein the heterocyclyl formed by the two R 11 groups has 0, 1, or 2 additional heteroatoms selected from nitrogen, oxygen, and sulfur, and the heterocyclyl is unsubstituted or substituted with OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkyl-O(O)C—, (R 11 ) 2 N—, or a 4- to 6-membered heterocyclyl, wherein the 4- to 6-membered heterocyclyl is unsubstituted or substituted with OH, halo, —NH 2 , or C 1 -C 6 alkyl, or when containing 2 or more N atoms is unsubstituted or substituted with an N-protecting group;
each R 12 is independently H or C 1 -C 6 alkyl;
each R 13 is independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3 -C 6 cycloalkylC 1 -C 6 alkyl-, C 3 -C 6 cycloalkylC 2 -C 6 alkenyl-, heterocyclylC 1 -C 6 alkyl-, heterocyclylC 2 -C 6 alkenyl-, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, heteroarylC 2 -C 6 alkenyl-, adamantyl, adamantylC 1 -C 6 aliphatic-, or an N protecting group;
R 14 is a bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and
each R 15 is independently C 1 -C 6 alkyl, C 2 -C 6 alkenyl, aryl, heteroaryl, arylC 1 -C 6 alkyl-, arylC 2 -C 6 alkenyl-, heteroarylC 1 -C 6 alkyl-, or heteroarylC 2 -C 6 alkenyl-;
wherein each C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, heterocyclyl, aryl, heteroaryl, or bridged bicyclic ring, by itself or attached to another moiety, are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
66 . The method of claim 60 , wherein the compound is of formula (Vp):
or an enantiomer or pharmaceutically acceptable salt thereof, wherein:
X is N, O, or S;
R 1 is C 1 -C 6 alkyl, —C 1 -C 6 alkylhalo, or —C 1 -C 6 alkyl-OR 12 ;
R 3 is —C 0 -C 6 alkylC 3 -C 8 cycloalkyl, or —C 0 -C 6 alkylheterocyclyl;
R 4 is independently halo, CN, —NH 2 , —SO 2 , C 1 -C 8 alkyl, —OR 12 , —C 1 -C 6 alkyl-OR 12 , —C 1 -C 6 alkyl-NR 12 , or —OC(O)R 12 ;
R 5 is H, C 1 -C 6 alkyl, or is absent when X is S or O;
p is 0, 1, 2, or 3;
R 9 is C 2 alkynyl;
R 12 is independently H or C 1 -C 6 alkyl;
wherein each C 0 -C 6 alkyl or —C 3 -C 8 cycloalkyl are independently unsubstituted or substituted with 1-3 substituents selected from the group consisting of OH, halo, —NH 2 , C 1 -C 6 alkyl, C 1 -C 6 alkyl-O—, R 12 O—C 1 -C 6 alkyl(O)C—, and R 12 O(O)C—.
67 . A method of treating cancer in a subject, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound, or a tautomer, stereoisomer, mixture of stereoisomers, isotopically enriched analog, or pharmaceutically acceptable salt thereof, selected from:
68 . The method of claim 50 , wherein the cancer is adrenocortical cancer, anal cancer, biliary cancer, bladder cancer, bone cancer, brain cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, head and neck cancer, hematologic cancer, intestinal cancer, liver cancer, lung cancer, oral cancer, ovarian cancer, pancreatic cancer, renal cancer, prostate cancer, salivary gland cancer, skin cancer, stomach cancer, testicular cancer, throat cancer, thyroid cancer, uterine cancer, vaginal cancer, sarcoma, or a soft tissue carcinoma.
69 . The method of claim 68 , wherein the cancer is osteosarcoma, glioma, astrocytoma, neuroblastoma, cancer of the small intestine, bronchial cancer, small cell lung cancer, non-small cell lung cancer, basal cell carcinoma, or melanoma.
70 . The method of claim 68 , wherein the cancer is a hematologic cancer selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), lymphoma, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), Hairy Cell chronic myelogenous leukemia (CML), multiple myeloma, Hodgkin's lymphoma, Non-Hodgkin's lymphoma, and Burkitt's lymphoma.
71 . The method of claim 50 , further comprising administering a therapeutically effective amount of a second therapeutic agent.
72 . The method of claim 71 , wherein the second therapeutic agent is an platinating agent, alkylating agent, anti-cancer antibiotic, antimetabolite, topoisomerase I inhibitor, topoisomerase II inhibitor, or antimicrotubule agent.Join the waitlist — get patent alerts
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