UBE2K MODULATORS AND METHODS FOR THEIR USE
Provided are compounds of Formula (I): and pharmaceutically acceptable salts and compositions thereof, which are useful for treating conditions associated with modulation of UBE2K.
1 . A compound having the Formula I:
or a pharmaceutically acceptable salt thereof, wherein
Z 1 and Z 2 are each independently N or CH;
X is N or CH;
ring A is phenyl or a 5- to 9-membered heteroaryl, each of which are optionally substituted with 1 to 3 groups selected from R 5 ;
Y is CH 2 , —CHR a , —CR a R b , or SO;
R a and R b are each independently halo, (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl; or R a and R b together with the carbon atom they are bound for a 3- to 6-membered cycloalkyl or a 3- to 6-membered heterocyclyl, each of which are optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, (C 1 -C 6 )alkylOH, (C 1 -C 6 )alkylO(C 1 -C 6 )alkyl, and OH;
R 1 is halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, or —NR c R d , wherein two available hydrogen atoms on said halo(C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkoxy may be taken together to which the carbon atoms they are attached to form a 3- to 6-membered cycloalkyl optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R c and R d are each independently hydrogen (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkylO(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkylO(C 1 -C 6 )alkyl, (C 1 -C 6 )alkyl-O-halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl-O-halo(C 1 -C 6 )alkyl, or (C 1 -C 6 )alkylOH; or R c and R d together with the nitrogen atom they are bound form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, and oxo;
R 2 is CN, halo, OH, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, or halo(C 1 -C 6 )alkoxy; or R 1 and R 2 , when on adjacent carbon atoms, are taken together with the carbon atoms to which they are attached to form a 5- or 6-membered oxygen containing heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 6 )alkyl, and halo(C 1 -C 6 )alkyl;
R 3 is hydrogen, (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl;
R 4 is CN, halo, OH, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —NH(C 1 -C 6 )alkyl, —N[(C 1 -C 6 )alkyl] 2 , or a 5- to 6-membered heterocyclyl; and
p is 0 or 1.
2 . The compound of claim 1 , wherein the compound is of the Formula:
or a pharmaceutically acceptable salt thereof.
3 . (canceled)
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3 is hydrogen.
5 . (canceled)
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y is CH 2 .
7 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 is N and Z 2 is CH; Z 1 is CH and Z 2 is N; or Z 1 and Z 2 are each CH.
8 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 1 and Z 2 are each CH.
9 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or a 5- to 6-membered heteroaryl, each of which are optionally substituted with 1 to 3 groups selected from R 5 .
10 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl, pyridyl, furanyl, or pyrazolyl, each of which are optionally substituted with 1 to 3 groups selected from R 5 .
11 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl or furanyl, each of which are optionally substituted with 1 to 3 groups selected from R 5 .
12 . (canceled)
13 . (canceled)
14 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are on adjacent carbon atoms and are taken together with the carbon atoms they are attached to form a dioxolanyl optionally substituted with 1 or 2 halo.
15 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is halo(C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkoxy, or —NR c R d ; and R c is hydrogen and R d is halo(C 1 -C 4 )alkyl; or R c and R d are taken together to form a 4- to 7-membered heterocyclyl optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 4 )alkyl, and oxo.
16 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —OCF 3 , —OCHF 2 , —OCH 2 CF 3 , —CF 3 , —CH 2 CF 3 , —CHF 2 , piperidinyl, pyrrolidinyl, azapanyl, morpholinyl, thiomorpholinyl, piperazinyl, or azetidinyl and wherein each of said heterocyclic ring is optionally substituted with 1 to 3 groups selected from halo, (C 1 -C 4 )alkyl, and oxo.
17 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2 is CN, halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, or (C 1 -C 4 )alkoxy.
18 . (canceled)
19 . (canceled)
20 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein p is 0.
21 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is halo, (C 1 -C 4 )alkyl, halo(C 1 -C 4 )alkyl, (C 1 -C 4 )alkoxy, —N[(C 1 -C 4 )alkyl] 2 , or a 6-membered heterocyclyl.
22 . (canceled)
23 . The compound of claim 1 , wherein the compound is selected from
or a pharmaceutically acceptable salt of any of the foregoing.
24 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
25 . A method of treating cancer in a subject comprising administering a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to the subject.
26 . The method of claim 25 , wherein the cancer is selected from solid and liquid tumors.