WDR5 inhibitors and modulators
Quinazolin-4(3H)-one, 2,3-dihydroquinazolin-4(1H)-one, 3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one, and 3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione compounds and derivatives inhibit WDR5 and associated protein-protein interactions, and the compounds and their pharmaceutical compositions are useful for treating disorders and conditions in a subject, such as cancer cell proliferation.
1 . A compound of formula (I)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is G 1 or —(CR a R b ) p -G 1 ;
p is 1, 2, or 3;
G 1 is a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, a 4- to 12-membered heterocyclyl, or a C 3-10 carbocycle optionally fused to a phenyl or to a 5- to 6-membered heteroaryl, wherein G 1 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, oxo, —OR 1a , —N(R 1a ) 2 , —SR 1a , cyano, —C(O)OR 1a , —C(O) N(R 1a ) 2 , —C(O)R 1a , —SOR 1b , —SO 2 R 1b , —SO 2 N(R 1a ) 2 , —NR 1a C(O)R 1a , —NR 1a C(O)OR 1b , —NR 1a C(O)N(R 1a ) 2 , —NR 1a S(O) 2 R 1b , —NR 1a S(O) 2 N(R 1a ) 2 , and -L 1 -G 1a ;
L is —(CR 2a R 2b ) n —, wherein is a single bond and X is O, NR 3 , or S; or L is —C(R 2c ): wherein is a double bond and X is N;
n is 1, 2, or 3;
R 1a , at each occurrence, is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, —C 2-4 alkylene-Y, G 1a , or —C 1-6 alkylene-G 1a , wherein two R 1a , together with a common nitrogen atom to which the R 1a attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OH, and —OC 1-4 alkyl;
Y, at each occurrence, is independently —OH, —OC 1-4 alkyl, —NH 2 , —NHC 1-4 alkyl, or —N(C 1-4 alkyl) 2 ,
R 1b , at each occurrence, is independently C 1-6 alkyl, C 1-6 haloalkyl, G 1a , or —C 1-6 alkylene-G 1a ;
L 1 is a bond or C 1-3 alkylene;
G 1a , at each occurrence, is independently C 3-8 cycloalkyl, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, or 4- to 10-membered heterocyclyl, wherein G 1a is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OR 1c , —N(R 1c ) 2 , —SR 1c , cyano, —C(O)OR 1c , —C(O)N(R 1c ) 2 , —C(O)R 1c , —SOR 1d , —SO 2 R 1d , —SO 2 N(R 1c ) 2 , —NR 1c C(O)R 1c , —NR 1c C(O)OR 1d , —NR 1c C(O)N(R 1c ) 2 , —NR 1c S(O) 2 R 1d , and —NR 1c S(O) 2 N(R 1d ) 2 ;
R a , at each occurrence, is independently hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, —C 1-6 alkylene-R aa , G 1b , or —C 1-6 alkylene-G 1b , wherein each C 1-6 alkylene is optionally substituted with 1-4 halogen;
R aa , at each occurrence, is independently —OR 1e , —N(R 1e ) 2 , —SR 1e , cyano, —C(O)OR 1e , —C(O)N(R 1e ) 2 , —C(O)R 1e , —SOR 1f , —SO 2 R 1f , —SO 2 N(R 1e ) 2 , —NR 1e C(O)R 1e , —NR 1e C(O)OR 1f , —NR 1e C(O)N(R 1e ) 2 , —NR 1e S(O) 2 R 1f , or —NR 1e S(O) 2 N(R 1e ) 2 ;
G 1b , at each occurrence, is independently a C 3-6 carbocycle or a 4- to 10-membered heterocyclyl, wherein the C 3-6 carbocycle and 4- to 10-membered heterocyclyl are optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OR 1e , —N(R 1e ) 2 , —SR 1e , cyano, —C(O)OR 1e , —C(O)N(R 1e ) 2 , —C(O)R 1e , —SOR 1f , —SO 2 R 1f , —SO 2 N(R 1e ) 2 , —NR 1e C(O)R 1e , —NR 1e C(O)OR 1f , —NR 1e C(O)N(R 1e ) 2 , —NR 1e S(O) 2 R 1f , and —NR 1e S(O) 2 N(R 1e ) 2 ;
R b is hydrogen or C 1-4 alkyl;
or alternatively one R a and one R b together with the carbon atom to which they are attached form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring;
or alternatively one R a and one R b are taken together to form an oxo group;
R 2a and R 2b , at each occurrence, are independently hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or —C 1-3 alkylene-C 3-6 cycloalkyl; or alternatively one R 2a and one R 2b are taken together with the atom or atoms to which they attach to form a 3-8 membered saturated or partially unsaturated carbocyclic or heterocyclic ring that is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, and —OC 1-4 alkyl; or alternatively one R 2a and one R 2b are taken together to form an oxo group;
R 2c is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-6 cycloalkyl, or —C 1-3 alkylene-C 3-6 cycloalkyl;
R 3 is hydrogen or C 1-6 alkyl;
R 4 is halogen, C 1-6 haloalkyl, C 1-6 haloalkenyl, —OR 4a , —SR 4a , —N(R 4a ) 2 , —S(O)R 4b , —S(O) 2 R 4b , —S(O) 2 N(R 4a ) 2 , —C(O)N(R 4a ) 2 , —C(O)R 4a , —NR 4a C(O) R 4a , —NR 4a C(O)OR 4b , —NR 4a C(O)N(R 4a ) 2 , —NR 4a S(O) 2 R 4b , —NR 4a S(O) 2 N(R 4a ) 2 , or G 2 ;
R 4a at each occurrence, is independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, G 2 , or —C 1-3 alkylene-G 2 ;
R 4b is C 1-6 alkyl, C 1-6 haloalkyl, G 2 , or —C 1-3 alkylene-G 2 ;
G 2 , at each occurrence, is independently a C 3-10 carbocycle, a 6- to 12-membered aryl, a 5- to 12-membered heteroaryl, or a 4- to 12-membered heterocycle, wherein G 2 is optionally substituted with 1-5 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, C 1-6 haloalkyl, oxo, —OR 4c , —N(R 4c ) 2 , —SR 4c , cyano, —C(O)OR 4c , —C(O)N(R 4c ) 2 , —C(O)R 4c , —SOR 4d , —SO 2 R 4d , —SO 2 N(R 4c ) 2 , —NR 4c C(O)R 4c , —NR 4c C(O)OR 4d , —NR 4c C(O)N(R 4c ) 2 , —NR 4c S(O) 2 R 4d , —NR 4c S(O) 2 N(R 4c ) 2 , C 3-8 cycloalkyl, and —C 1-3 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen;
R 1c , R 1e , and R 4c , at each occurrence, are independently hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or —C 1-6 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen, wherein alternatively two R 1c , two R 1e , and/or two R 4c , together with a common nitrogen atom to which the R 1c , R 1e , and/or R 4c attach form a 4- to 8-membered saturated or partially unsaturated heterocyclic ring, optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, oxo, —OH, and —OC 1-4 alkyl;
R 1d , R 1f , and R 4c , at each occurrence, are independently C 1-6 alkyl, C 1-6 haloalkyl, C 3-8 cycloalkyl, or —C 1-6 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of C 1-4 alkyl and halogen;
R 5 and R 6 are each independently hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, or —OC 1-4 alkyl;
R 7a and R 7b are independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl, and C 1-4 haloalkyl, or R 7a and R 7b are taken together to form an oxo group;
R 8 is
indolyl, pyrrolopyridinyl, or imidazolyl, wherein the indolyl, pyrrolopyridinyl, and imidazolyl are optionally substituted with 1-3 substituents independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, and —C 1-3 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, OH, and —OC 1-4 alkyl;
wherein X 1 is NR 13 , O, or S;
R 10a and R 10b are independently hydrogen, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, or —C 1-3 alkylene-C 3-8 cycloalkyl;
R 12 , at each occurrence, is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, or —C 1-3 alkylene-C 3-8 cycloalkyl;
R 13 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, or —C 1-3 alkylene-C 3-8 cycloalkyl;
wherein each cycloalkyl in R 10a , R 10b , R 12 , and R 13 is further optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, OH, and —OC 1-4 alkyl; and
t is 0, 1, 2, 3, or 4;
wherein R 30 , at each occurrence, is independently halogen, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-6 cycloalkyl; and
X 2 is CH 2 , O, or NH.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 8 is the imidazolyl, indolyl, or pyrrolopyridinyl, which are selected from the group consisting of
and
R 20 , at each occurrence, is independently C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, or —C 1-3 alkylene-C 3-8 cycloalkyl, wherein each C 3-8 cycloalkyl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-4 alkyl, C 1-4 haloalkyl, OH, and —OC 1-4 alkyl.
3 . The compound of claim 2 , or a pharmaceutically acceptable salt thereof, wherein
R 8 is
and
R 20a is hydrogen, C 1-4 alkyl, or C 3-4 cycloalkyl.
4 . The compound of claim 3 , or a pharmaceutically acceptable salt thereof, wherein R 8 is
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is G 1 ; and
G 1 is a 6- to 12-membered aryl, an 8- to 10-membered heteroaryl, an 8- to 11-membered heterocycle, or a C 5-7 carbocycle fused to a phenyl or to a 5- to 6-membered heteroaryl, wherein the 8- to 11-membered heterocycle is a 5- to 7-membered monocyclic heterocycle fused to a phenyl or to a 5- to 6-membered heteroaryl, and wherein G 1 is optionally substituted as defined in claim 1 .
6 . The compound of claim 5 , or a pharmaceutically acceptable salt thereof, wherein R 1 is
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein
R 1 is —(CR a R b ) p -G 1 ;
p is 1; and
G 1 is a phenyl or a 5- to 6-membered heteroaryl, wherein G 1 is optionally substituted as defined in claim 1 .
8 . The compound of claim 7 , or a pharmaceutically acceptable salt thereof, wherein
G 1 is
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is G 2 ; and G 2 is a phenyl or a 5- to 6-membered heteroaryl, and optionally substituted as defined in claim 1 .
10 . The compound of claim 9 , or a pharmaceutically acceptable salt thereof, wherein G 2 is phenyl, pyridinyl, pyrazolyl, or thiazolyl, and G 2 is optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C 1-6 alkyl, and C 1-6 haloalkyl.
11 . The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein G 2 is
12 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-A)
13 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula (II-B1)
14 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b are independently hydrogen or C 1-4 alkyl.
15 . The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R 2a and R 2b form an oxo.
16 . A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17 . A method of treating cancer comprising administering to a subject in need thereof, a therapeutically effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.
18 . A method of inhibiting cancer cell proliferation, comprising administering to a subject in need thereof, the compound of claim 1 , or a pharmaceutically acceptable salt thereof, in an amount effective to inhibit the cancer cell proliferation.