US2020383984A1PendingUtilityA1
Heteroaryl compounds, pharmaceutical compositions thereof, and their therapeutic use
Assignee: YISSUM RES DEV CO OF HEBREW UNIV JERUSALEM LTDPriority: Feb 8, 2018Filed: Feb 7, 2019Published: Dec 10, 2020
Est. expiryFeb 8, 2038(~11.6 yrs left)· nominal 20-yr term from priority
C07D 495/04C07D 471/04C07D 413/04C07D 405/14C07D 403/04A61P 31/18A61P 17/16A61P 17/00A61K 31/506A61K 31/437A61P 35/00
56
PatentIndex Score
0
Cited by
0
References
0
Claims
Abstract
Provided herein are heteroaryl compounds, for example, a compound of Formula I or IA, and pharmaceutical compositions thereof. Also provided herein are methods of their use for treating, ameliorating, or preventing one or more symptoms of a disorder, disease, or condition mediated by a casein kinase 1 (CK1), an interleukin-1 receptor associated kinase (IRAK1), or a cyclin-dependent kinase 9 (CDK9). Formula: (I),(IA)
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound of Formula I or IA:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:
U and V are each independently —O— and ═C(R 4 )—; or U and V are each independently ═N— and —N(R 5 )—;
W, X, Y, and Z are each independently ═C(R 6 )— or ═N—, with the proviso that at least one of W, X, Y, and Z is ═N—; or W, X, and Z are each independently ═C(R 6 )—, —N(R 7 )—, ═N—, —O—, or —S—; and Y is a bond;
R 1 and R 2 are each independently (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or R 1 and R 2 together with the N atom to which they are attached form heteroaryl or heterocyclyl;
each R 3 , R 4 , and R 6 is independently (a) hydrogen, deuterium, cyano, halo, or nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —SR 1a , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c or —S(O) 2 NR 1b R 1c ;
R 5 and R 7 are each independently (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and
R 2a , R 2b , R 2c , and R 2d are (i) or (ii):
(i) R 2a and R 2b are each independently (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or R 2a and R 2b together with the N atom to which they are attached form heteroaryl or heterocyclyl; and
R 2c and R 2d are each independently (a) hydrogen, deuterium, or cyano; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 2c and R 2d are linked together to form —O—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 alkynylene; or
(ii) R 2a and R 2c together with the C and N atoms to which they are attached form heterocyclyl;
R 2b is (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1a , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ;
R 2d is (a) hydrogen, deuterium, or cyano; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; and
each R 1a , R 1b , R 1c , and R 1d is independently hydrogen, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or R 1a and R 1c together with the C and N atoms to which they are attached form heterocyclyl; or R 1b and R 1c together with the N atom to which they are attached form heterocyclyl;
wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, alkynyl, alkynylene, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q, where each Q is independently selected from (a) deuterium, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; and (c) —C(O)R a , —C(O)OR a , —C(O)NR b R c , —C(O)SR a , —C(NR a )NR b R c , —C(S)R a , —C(S)OR a , —C(S)NR b R c , —OR a , —OC(O)R a , —OC(O)OR a , —OC(O)NR b R c , —OC(O)SR a , —OC(═NR a )NR b R c , —OC(S)R a , —OC(S)OR a , —OC(S)NR b R c , —OS(O)R a , —OS(O) 2 R a , —OS(O)NR b R c , —OS(O) 2 NR b R c , —NR b R c , —NR a C(O)R d , —NR a C(O)OR d , —NR a C(O)NR b R c , —NR a C(O)SR d , —NR a C(═NR d )NR b R c , —NR a C(S)R d , —NR a C(S)OR d , —NR a C(S)NR b R c , —NR a S(O)R d , —NR a S(O) 2 R d , —NR a S(O)NR 1b R 1c , —NR a S(O) 2 NR b R c , —SR a , —S(O)R a , —S(O) 2 R a , —S(O)NR b R c , and —S(O) 2 NR b R c , wherein each R a , R b , R c , and R d is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ; or (iii) R b and R c together with the N atom to which they are attached form heterocyclyl, optionally substituted with one or more, in one embodiment, one, two, three, or four, substituents Q a ;
wherein each Q a is independently selected from the group consisting of (a) deuterium, cyano, halo, and nitro; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R e , —C(O)OR e , —C(O)NR f R g , —C(O)SR e , —C(NR e )NR f R g , —C(S)R e , —C(S)OR e , —C(S)NR f R g , —OR e , —OC(O)R e , —OC(O)OR e , —OC(O)NR f R g , —OC(O)SR e , —OC(═NR e )NR f R g , —OC(S)R e , —OC(S)OR e , —OC(S)NR f R g , —OS(O)R e , —OS(O) 2 R e , —OS(O)NR f R g , —OS(O) 2 NR f R g , —NR f R g , —NR e C(O)R h , —NR e C(O)OR f , —NR e C(O)NR f R g , —NR e C(O)SR f , —NR e C(═NR h )NR f R g , —NR e C(S)R h , —NR e C(S)OR f , —NR e C(S)NR f R g , —NR e S(O)R h , —NR e S(O) 2 R h , —NR e S(O)NR f R g , —NR e S(O) 2 NR f R g , —SR e , —S(O)R e , —S(O) 2 R e , —S(O)NR f R g , and —S(O) 2 NR f R g ; wherein each R e , R f , R g , and R h is independently (i) hydrogen or deuterium; (ii) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl; or (iii) R f and R g together with the N atom to which they are attached form heterocyclyl.
2 . The compound of claim 1 , having the structure of Formula I:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
3 . The compound of claim 2 , wherein R 2 is C 3-12 cycloalkyl, optionally substituted with one or more substituents Q.
4 . The compound of claim 2 , wherein R 2 is cyclohexyl, bicyclo[2.2.1]heptyl, or bicyclo[2.2.2]octyl, each optionally substituted with one or more substituents Q.
5 . The compound of any one of claims 2 to 4 , having the structure of Formula II:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein:
R 2a , R 2b , R 2c , and R 2d are (i) or (ii):
(i) R 2a and R 2b are each independently (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1a , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or R 2a and R 2b together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and
R 2c and R 2d are each independently (a) hydrogen, deuterium, or cyano; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or R 2c and R 2d are linked together to form —O—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 alkynylene, wherein the alkylene, heteroalkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents Q; or
(ii) R 2a and R 2c together with the C and N atoms to which they are attached form heterocyclyl, which is optionally substituted with one or more substituents Q;
R 2b is (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1a , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; and
R 2d is (a) hydrogen, deuterium, or cyano; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q.
6 . The compound of claim 5 , having the structure of Formula IIa:
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
7 . The compound of claim 5 , having the structure of Formula III:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6a , R 6b and R 6c are each independently R 6 .
8 . The compound of claim 5 , having the structure of Formula VI:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6b , R 6c , and R 6d are each independently R 6 .
9 . The compound of claim 5 , having the structure of Formula VIII:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6b and R 6d are each independently R 6 .
10 . The compound of claim 5 , having the structure of Formula IX:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6b and R 6c are each independently R 6 .
11 . The compound of claim 10 , having the structure of Formula IXa:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
12 . The compound of claim 10 or 11 , wherein R 6b is hydrogen, —OR 1a , or —NR 1b R 1c .
13 . The compound of claim 12 , wherein R 6b is hydrogen, hydroxyl, or amino.
14 . The compound of any one of claims 10 to 13 , wherein R 6c is hydrogen, halo, or C 1-6 alkyl, where the alkyl is optionally substituted with one or more substituents Q.
15 . The compound of claim 14 , wherein R 6c is hydrogen, fluoro, chloro, methyl, or trifluoromethyl.
16 . The compound of any one of claims 5 to 15 , wherein:
R 2a and R 2b are each independently (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or R 2a and R 2b together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and
R 2c and R 2d are each independently (a) hydrogen, deuterium, or cyano; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or R 2c and R 2d are linked together to form —O—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 alkynylene, wherein the alkylene, heteroalkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents Q.
17 . The compound of claim 16 , wherein R 2a is hydrogen, methyl, trifluoroethyl, methoxyethyl, pentynyl, phenyl, benzyl, (pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl.
18 . The compound of claim 16 , wherein R 2a is hydrogen, methyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl, but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl.
19 . The compound of any one of claims 16 to 18 , wherein R 2b is hydrogen, methyl, trifluoroethyl, methoxyethyl, phenyl, benzyl, (pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl, methoxyacetyl, or (pyrazolyl)carbonyl.
20 . The compound of claim 19 , wherein R 2b is hydrogen, methyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, phenyl, benzyl, (pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl, or (pyrazol-4-yl)carbonyl.
21 . The compound of any one of claims 5 to 20 , wherein R 2c is hydrogen.
22 . The compound of any one of claims 5 to 21 , wherein R 2d is hydrogen.
23 . The compound of any one of claims 5 to 22 , wherein R 2c and R 2d are in a trans configuration in the cyclohexyl ring.
24 . The compound of any one of claims 5 to 20 , wherein R 2c and R 2d are linked together to form C 2-6 alkylene, optionally substituted with one or more substituents Q.
25 . The compound of claim 24 , wherein R 2c and R 2d are linked together to form methylene or eth-1,2-ylene.
26 . The compound of any one of claims 2 to 25 , wherein R 1 is hydrogen.
27 . The compound of any one of claims 2 to 26 , wherein R 3 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
28 . The compound of claim 27 , wherein R 3 is butylmethyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl; each of which is independently and optionally substituted with one or more substituents Q.
29 . The compound of claim 27 , wherein R 3 is t-butylmethyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl), cyclobutylmethyl, or cyclopentylmethyl.
30 . The compound of any one of claims 2 to 29 , wherein U is —O—.
31 . The compound of any one of claims 2 to 30 , wherein V is ═C(R 4 )—.
32 . The compound of any one of claims 2 to 29 , wherein U is ═C(R 4 )—.
33 . The compound of any one of claims 2 to 29 and 32 , wherein V is —O—.
34 . The compound of claim 31 or 32 , wherein R 4 is methyl, isopropyl, cyclopentyl, oxetanyl, tetrahydrofuryl, or tetrahydropyranyl.
35 . The compound of claim 34 , wherein R 4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl, tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
36 . The compound of any one of claims 2 to 29 , wherein U is ═N—.
37 . The compound of any one of claims 2 to 29 and 36 , wherein V is ═N(R 5 )—.
38 . The compound of claim 37 , wherein R 5 is methyl, isopropyl, cyclopentyl, oxetanyl, tetrahydrofuryl, or tetrahydropyranyl.
39 . The compound of claim 37 , wherein R 5 is methyl, isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl, tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
40 . The compound of any one of claims 2 to 29 and 36 , wherein V is ═C(R 4 )—.
41 . A compound of:
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
42 . The compound of claim 1 , having the structure of Formula IA:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
43 . The compound of claim 42 , having the structure of Formula IIA:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6a , R 6b and R 6c are each independently R 6 .
44 . The compound of claim 42 , having the structure of Formula VA:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R 6b , R 6c , and R 6d are each independently R 6 .
45 . The compound of claim 42 , having the structure of Formula VIIA:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6b and R 6d are each independently R 6 .
46 . The compound of claim 42 , having the structure of Formula VIIIA:
or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, wherein R 6b and R 6c are each independently R 6 .
47 . The compound of claim 46 , having the structure of Formula VIIIAa:
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
48 . The compound of claim 46 , having the structure of Formula VIIIAb:
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
49 . The compound of claim 47 or 48 , wherein R 6b is hydrogen, —OR 1a , or —NR 1b R 1c .
50 . The compound of claim 49 , wherein R 6b is hydrogen, hydroxyl, or amino.
51 . The compound of any one of claims 47 to 50 , wherein R 6c is hydrogen, halo, or C 1-6 alkyl, where the alkyl is optionally substituted with one or more substituents Q.
52 . The compound of claim 51 , wherein R 6c is hydrogen, fluoro, chloro, methyl, or trifluoromethyl.
53 . The compound of any one of claims 42 to 52 , wherein:
R 2a and R 2b are each independently (a) hydrogen or deuterium; (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or (c) —C(O)R 1a , —C(O)OR 1a , —C(O)NR 1b R 1c , —C(O)SR 1a , —C(NR 1a )NR 1b R 1c , —C(S)R 1a , —C(S)OR 1a , —C(S)NR 1b R 1c , —OR 1a , —OC(O)R 1a , —OC(O)OR 1a , —OC(O)NR 1b R 1c , —OC(O)SR 1a , —OC(═NR 1a )NR 1b R 1c , —OC(S)R 1a , —OC(S)OR 1a , —OC(S)NR 1b R 1c , —OS(O)R 1a , —OS(O) 2 R 1a , —OS(O)NR 1b R 1c , —OS(O) 2 NR 1b R 1c , —NR 1b R 1c , —NR 1a C(O)R 1d , —NR 1a C(O)OR 1d , —NR 1a C(O)NR 1b R 1c , —NR 1a C(O)SR 1d , —NR 1a C(═NR 1d )NR 1b R 1c , —NR 1a C(S)R 1d , —NR 1a C(S)OR 1d , —NR 1a C(S)NR 1b R 1c , —NR 1a S(O)R 1d , —NR 1a S(O) 2 R 1d , —NR 1a S(O)NR 1b R 1c , —NR 1a S(O) 2 NR 1b R 1c , —S(O)R 1a , —S(O) 2 R 1a , —S(O)NR 1b R 1c , or —S(O) 2 NR 1b R 1c ; or R 2a and R 2b together with the N atom to which they are attached form heteroaryl or heterocyclyl, each of which is optionally substituted with one or more substituents Q; and
R 2c and R 2d are each independently (a) hydrogen, deuterium, or cyano; or (b) C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-12 cycloalkyl, C 6-14 aryl, C 7-15 aralkyl, heteroaryl, or heterocyclyl, each of which is optionally substituted with one or more substituents Q; or R 2c and R 2d are linked together to form —O—, C 1-6 alkylene, C 1-6 heteroalkylene, C 2-6 alkenylene, or C 2-6 alkynylene, wherein the alkylene, heteroalkylene, alkenylene, and alkynylene are each optionally substituted with one or more substituents Q.
54 . The compound of any one of claims 42 to 53 , wherein R 2a and R 2b are each independently hydrogen, C 1-6 alkyl, C 2-6 alkynyl, C 7-14 aryl, C 7-14 aralkyl, or —C(O)R 1a ; or R 2a and R 2b together with the N atom to which they are attached form heteroaryl or heterocyclyl; where the alkyl, alkynyl, aryl, aralkyl, heteroaryl, and heterocyclyl is each optionally substituted with one or more substituents Q.
55 . The compound of claim 54 , wherein R 2a is hydrogen, methyl, trifluoroethyl, methoxyethyl, pentynyl, phenyl, benzyl, (pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl, methoxyacetyl, butynylcarbonyl, or (pyrazolyl)carbonyl.
56 . The compound of claim 54 , wherein R 2a is hydrogen, methyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, pent-4-ynyl, phenyl, benzyl, (pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl, but-3-ynylcarbonyl, or (pyrazol-4-yl)carbonyl.
57 . The compound of any one of claims 42 to 56 , wherein R 2b is hydrogen, C 1-6 alkyl, C 7-14 aryl, C 7-14 aralkyl, or —C(O)R 1a ; where the alkyl, aryl, and aralkyl are each optionally substituted with one or more substituents Q.
58 . The compound of claim 57 , wherein R 2b is hydrogen, methyl, trifluoroethyl, methoxyethyl, phenyl, benzyl, (pyrazolyl)methyl, (methylpyrazolyl)methyl, (pyrazolyl)ethyl, (pyridinyl)methyl, methoxyacetyl, or (pyrazolyl)carbonyl.
59 . The compound of claim 57 , wherein R 2b is hydrogen, methyl, 2,2,2-trifluoroethyl, 2-methoxyethyl, phenyl, benzyl, (pyrazol-3-yl)methyl, (pyrazol-4-yl)methyl, (1-methylpyrazol-4-yl)methyl, (3-methylpyrazol-4-yl)methyl, 1-(pyrazol-4-yl)ethyl, (pyridin-3-yl)methyl, 2-methoxyacetyl, or (pyrazol-4-yl)carbonyl.
60 . The compound of any one of claims 42 to 59 , wherein R 2c is hydrogen.
61 . The compound of any one of claims 42 to 60 , wherein R 2d is hydrogen.
62 . The compound of any one of claims 42 to 53 , wherein R 2c and R 2d are linked together to form C 2-6 alkylene, optionally substituted with one or more substituents Q.
63 . The compound of claim 62 , wherein R 2c and R 2d are linked together to form methylene or eth-1,2-ylene.
64 . The compound of any one of claims 42 to 63 , wherein R 1 is hydrogen.
65 . The compound of any one of claims 42 to 64 , wherein R 3 is C 1-6 alkyl, optionally substituted with one or more substituents Q.
66 . The compound of claim 65 , wherein R 3 is butylmethyl, cyclopropylmethyl, cyclobutylmethyl, or cyclopentylmethyl; each of which is independently and optionally substituted with one or more substituents Q.
67 . The compound of claim 65 , wherein R 3 is t-butylmethyl, cyclopropylmethyl, 1-methylcyclopropylmethyl, 1-hydroxy(cyclopropylmethyl), cyclobutylmethyl, or cyclopentylmethyl.
68 . The compound of any one of claims 42 to 67 , wherein R 4 is C 1-6 alkyl, C 3-12 cycloalkyl, or heterocyclyl, each of which is independently and optionally substituted with one or more substituents Q.
69 . The compound of claim 68 , wherein R 4 is C 1-6 alkyl, C 3-12 cycloalkyl, or 4- to 7-membered heterocyclyl, each of which is independently and optionally substituted with one or more substituents Q.
70 . The compound of claim 69 , wherein R 4 is methyl, isopropyl, cyclopentyl, oxetanyl, tetrahydrofuryl, or tetrahydropyranyl.
71 . The compound of claim 69 , wherein R 4 is methyl, isopropyl, cyclopentyl, oxetan-3-yl, tetrahydrofur-3-yl, tetrahydropyran-4-yl, or tetrahydropyran-3-yl.
72 . The compound of any one of claims 42 to 71 , wherein R 5 is hydrogen.
73 . A compound of:
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
74 . A compound of:
or a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.
75 . A pharmaceutical composition comprising a compound of any one of claims 1 to 74 , or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, a tautomer, a mixture of two or more tautomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a pharmaceutically acceptable excipient.
76 . The pharmaceutical composition of claim 75 , wherein the composition is in single dosage form.
77 . The pharmaceutical composition of claim 75 or 76 , wherein the composition is in an oral, parenteral, or intravenous dosage form.
78 . The pharmaceutical composition of claim 77 , wherein the oral dosage form is a tablet, capsule, or solution.
79 . The pharmaceutical composition of any one of claims 75 to 78 , further comprising a second therapeutic agent.
80 . A method of treating, preventing, or ameliorating one or more symptoms of a proliferative disease in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
81 . The method of claim 80 , wherein the proliferative disease is cancer.
82 . The method of claim 81 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, colon cancer, colorectal cancer, esophageal cancer, glioma, glioblastoma multiforme, head and neck cancer, leukemia, acute myelogenous leukemia, chronic myeloid leukemia, liver cancer, lung cancer, small cell lung cancer, non-small cell lung cancer, lymphoma, melanoma, myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, salivary gland cancer, sarcoma, osteosarcoma, skin cancer, squamous cell carcinoma, stomach cancer, testicular cancer, thyroid cancer, or uterine cancer.
83 . A method of treating, preventing, or ameliorating one or more symptoms of acquired immune deficiency syndrome (AIDS) in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
84 . A method of treating or preventing a virus infection in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
85 . The method of claim 84 , wherein the virus infection is a human immunodeficiency virus (HIV) infection.
86 . A method of treating, ameliorating, or preventing a skin disorder, disease, or condition in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
87 . A method of protecting a subject from ultraviolet radiation, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
88 . A method of increasing skin pigmentation in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
89 . A method of increasing eumelanin level in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
90 . A method of treating one or more symptoms of a disorder, disease, or condition mediated by a casein kinase 1 (CK1) in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
91 . A method of treating one or more symptoms of a disorder, disease, or condition mediated by an interleukin-1 receptor associated kinase (IRAK1) in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
92 . A method of treating one or more symptoms of a disorder, disease, or condition mediated by a cyclin-dependent kinase 9 (CDK9) in a subject, comprising administering to the subject a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
93 . A method of inhibiting the activity of a CK1 in a cell, comprising contacting the cell with a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
94 . A method of inhibiting the activity of an IRAK1 in a cell, comprising contacting the cell with a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
95 . A method of inhibiting the activity of a CDK9 in a cell, comprising contacting the cell with a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
96 . A method of inhibiting the growth of a cell, comprising contacting the cell with a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
97 . A method of inhibiting replication of a virus in a host, comprising contacting the host with a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .
98 . A method of increasing eumelanin level in a skin cell, comprising contacting the cell with a compound of any one of claims 1 to 74 or a pharmaceutical composition of any one of claims 75 to 79 .Cited by (0)
No later patents cite this yet.
References (0)
No backward citations on record.