CDK inhibitors
The disclosure relates to multicyclic heteroatom-containing compounds which have CDK inhibitory activity, methods of making the same, and uses thereof. The compounds have the general structural formula (I): The compounds can be used for treating a type of cancer, for example by inhibiting a cyclin-dependent kinase (CDK), such as CDK2, CDK4, and/or CDK6. The disclosure further provides exemplary synthetic routes for such compounds.
1 . A compound represented by structural formula (I):
or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
ring A is
ring B is a 3-10 membered heterocyclyl or 5-10 membered heteroaryl selected from:
each of which is optionally substituted with one or two R 2 groups;
ring C is
each of which is optionally substituted with one or two R 12 ;
Linker L is a bond, —(CH 2 ) q —, —(CH 2 ) q O—, —NR a (CH 2 ) q —, —C(O)N(R a )—, —C(O)N(R a )—, or —S(O) 2 —;
each instance of R a is H or CH 3 ;
R 1 is H, deuterium, halogen, or C 1-4 alkyl;
each instance of R 2 is H, deuterium, halogen, —OH, CN, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, —(CH 2 ) n OR 6 , —(CH 2 ) n SR 6 , —(CH 2 ) n C(O)R 6 , —(CH 2 ) n C(O)OR 6 , —(CH 2 ) n S(O) m R 6 , —(CH 2 ) n NR 7 R 8 , —(CH 2 ) n C(O)NR 7 R 8 , —(CH 2 ) n NR 7 C(O)R 6 , —(CH 2 ) n NR 7 S(O) m R 6 , C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl represented by R 2 is each optionally substituted with one or more groups selected from deuterium, halogen, CN, —OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, and NR 7 R 8 ; or
when ring B is 3-10 membered heterocyclyl, two R 2 attached to the same ring atom of ring B may form C 3-6 cycloalkyl or 3-6 membered heterocyclyl optionally substituted with one or more groups selected from deuterium, halogen, CN, —OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, and NR 7 R 8 ;
each instance of R 3 is independently selected from H, deuterium, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl; wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl represented by R 3 is optionally substituted with one or more groups selected from deuterium, halogen, CN, —OH, C 1-8 alkyl, and C 1-8 haloalkyl;
each instance of R 4 is independently selected from H, deuterium, halogen, CN, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C(O)C 1-8 alkyl, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl; wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C-s alkoxy, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl represented by R 4 or in the group represented by R 4 is each optionally substituted with one or more groups selected from deuterium, halogen, —OH, C 1-8 alkyl and C 1-8 haloalkyl; or
two R 4 groups attached to the same ring atom of ring A form C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is optionally substituted with one or more groups selected from deuterium, halogen, CN, —OH, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 alkoxy, C 18 haloalkoxy, and NR 7 R 8 ;
each instance of R S is H, deuterium, halogen, —OH, CN, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, C(O)C 1-4 alkyl, or 3-6 membered heterocyclyl;
each instance of R 6 is independently H, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl, wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-8 cycloalkyl, 3-10 membered heterocyclyl, 6-14 membered aryl, or 5-14 membered heteroaryl represented by R 6 is each optionally substituted with one or more groups selected from halogen, CN, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, and NR 7 R 8 ;
each instance of R 7 and R 8 is independently H, C 1-4 alkyl or cyclopropyl;
each instance of R 12 is H, deuterium, halogen, —OH, CN, NH 2 , C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl; wherein the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 1-8 alkoxy, C 3-8 cycloalkyl, or 3-10 membered heterocyclyl represented by R 12 is optionally substituted with one or more groups selected from halogen, CN, —OH, C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 alkoxy;
q is 0, 1, or 2;
n is 0, 1, 2, 3, 4, or 5; and
m is 0, 1, or 2.
2 . The compound of claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring C is
3 . The compound of claim 2 , or a pharmaceutically acceptable salt, or a stereoisomer thereof,
wherein
each instance of R 3 is H, deuterium, C 1-4 alkyl optionally substituted with —OH, or C 3-6 cycloalkyl optionally substituted with —OH;
each instance of R 4 is H, deuterium, halogen, C 1-4 alkyl optionally substituted with fluoro, C 2-4 alkenyl, C 3-6 cycloalkyl optionally substituted with methyl, or 3-6 membered heterocyclyl; or two R 4 groups attached to the same ring atom of ring A form C 3-6 cycloalkyl or 3-6 membered heterocyclyl, each of which is optionally substituted with one or more groups selected from halogen, CN, —OH, C 1-2 alkyl, C 1-2 alkoxy, and NR 7 R 8 ; and
R 5 is H, deuterium, halogen, CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, or C 1-4 haloalkoxy.
4 . The compound of claim 3 , wherein the compound is represented by structural formulae (II-A)-(II-J):
or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 12 is H, F, Cl, CH 3 , or CF 3 ; and k is 0, 1, or 2.
5 . The compound of claim 4 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein L is a bond, —(CH 2 )—, —O(CH 2 )—, —C(═O)—, or —S(O) 2 —.
6 . The compound of claim 5 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
each instance of R 2 is H, halogen, CN, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, —(CH 2 ) n OR 6 , —(CH 2 ) n C(O)R 6 , —(CH 2 ) n C(O)OR 6 , —(CH 2 ) n S(O) 2 R 6 , —(CH 2 ) n NR 7 R 8 , —(CH 2 ) n C(O)NR 7 R 8 , —(CH 2 ) n C(O)NHR 7 , —(CH 2 ) n NR 7 C(O)R 6 , —(CH 2 ) n NR 7 S(O) 2 R 6 , C 3-8 cycloalkyl, 3-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or
two R 2 attached to the same ring atom of ring B form 3-6 heterocyclyl (when ring B is 3-10 membered heterocyclyl) optionally substituted with one or more groups selected from halogen, —OH, C 1-2 alkyl, C 1-2 haloalkyl, C 1-2 alkoxy, C 1-2 haloalkoxy, and NR 7 R 8 ;
each instance of R 6 is independently H, C 1-4 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, 3-7 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl represented by R 6 is each optionally substituted with halogen, CN, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or NR 7 R 8 ; and
n is 0, 1, or 2.
7 . The compound of claim 6 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 is H, F, Cl, or CH 3 .
8 . The compound of claim 7 or a pharmaceutically acceptable salt, or a stereoisomer thereof wherein ring B is
each of which is optionally substituted with one or two R 2 groups.
9 . The compound of claim 8 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
each instance of R 2 is H, halogen, CN, —OH, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxyalkyl, —(CH 2 ) n S(O) 2 C 1-4 alkyl, —(CH 2 ) n NR 2 R 8 , C 3-4 cycloalkyl, or 3-6 membered heterocyclyl; and n is 0, 1, or 2; or
two R 2 attached to the same ring atom of ring B form 3-6 heterocyclyl when ring B is 4-7 membered heterocyclyl.
10 . The compound of claim 9 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is
wherein R 1 is H, methyl, or halogen.
11 . The compound of claim 10 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein R 1 is H or F.
12 . The compound of claim 11 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
each instance of R 3 is H, C 1-3 alkyl optionally substituted with —OH, or C 3-6 cycloalkyl optionally substituted with —OH;
each instance of R 4 is H, halogen, C 1-3 alkyl, C 2-4 alkenyl, cyclopentyl, tetrahydro-2H-pyranyl, or 3,6-dihydro-2H-pyranyl; and
each instance of R 5 is H, F, CN, methoxy, or OCHF 2 .
13 . The compound of claim 12 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein L is a bond.
14 . The compound of claim 13 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B is
each of which is optionally substituted with one or two R 2 groups.
15 . The compound of claim 14 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
each instance of R 2 is H, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, NH 2 , N(CH 3 ) 2 , NHcyclopropyl, —(CH 2 ) n S(O) 2 C 1-3 alkyl, cyclopropyl, azetidinyl optionally substituted with F, oxetanyl, morpholinyl, piperidinyl, tetrahydro-2H-pyranyl, or
two R 2 attached to the same ring atom of ring B form 2,5-pyrrolidinedionyl or 2-pyrrolidonyl when ring B is piperidinyl; and
n is 0, 1, or 2.
16 . The compound of claim 15 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring A is
17 . The compound of claim 16 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein
each instance of R 3 is H or C 1-3 alkyl;
each instance of R 4 is H or C 1-3 alkyl; and
each instance of R 5 is H, F, or OMe.
18 . The compound of claim 17 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring C is unsubstituted.
19 . The compound of claim 18 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein ring B is
each of which is optionally substituted with one or two R 2 groups.
20 . The compound of claim 19 or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein each instance of R 2 is H, halogen, CN, C 1-3 alkyl, C 1-3 haloalkyl, C 1-3 hydroxyalkyl, NH 2 , N(CH 3 ) 2 , or NHcyclopropyl.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt, or a stereoisomer thereof, wherein the compound is selected from:
22 . A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt, or a stereoisomer thereof, and a pharmaceutically acceptable carrier.