COMPOUNDS FOR TARGETED DEGRADATION OF BRD9

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Patent No.: US None
App. No.: 18/945,284

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Abstract

BRD9 protein degradation compounds or pharmaceutically acceptable salts thereof are provided for the treatment of disorders mediated by BRD9, including but not limited to abnormal cellular proliferation.

Claims (59)

1 . A compound selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, and Formula VI:

or a pharmaceutically acceptable salt thereof;

wherein:

each a is independently 0, 1, or 2;

each y is independently 0, 1, or 2;

X 3 , X 4 , X 5 , and X 6 are selected from the group consisting of N, CH and CR 3 , wherein no more than 3 of X 3 , X 4 , X 5 , and X 6 are N;

X 7 is N or CH;

X 8 and X 9 are each independently at each occurrence selected from the group consisting of N and CH; wherein at least one of X 8 or X 9 is CH;

X 12 is a 5-membered heteroaryl group with 1, 2, or 3 atoms independently selected from the group consisting of N, O, and S, wherein X 12 is optionally substituted with 1, 2, or 3 groups independently selected from R 3 ;

X 17 is aryl, heteroaryl, bicycle, or cycloalkyl, each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 3 ;

Q 1 is independently at each occurrence selected from the group consisting of NH, N(alkyl), N(haloalkyl), CH 2 , O, and S; wherein if X 7 is N, then Q 1 is CH 2 ;

R is independently at each occurrence selected from the group consisting of hydrogen, C 1 -C 4 haloalkyl, C 1 -C 4 alkyl, fluorine, chlorine, bromine, iodine, CH 2 F, CHF 2 , CF 3 , CH 2 Cl, CHCl 2 , CCl 3 , CH 2 Br, CHBr 2 , and CBr 3 ;

R 1 is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, or cycloalkyl;

R 3 is independently at each occurrence selected from the group consisting of hydrogen, hydroxyl, alkoxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, cycloalkyl, fluorine, chlorine, bromine, and iodine;

B is selected from B 1 and B 2 ;

B 1 is selected from the group consisting of:

B 2 is selected from the group consisting of:

X 10 is C(R 7 ) 2 , C(O), or O;

X 11 is heterocycle, heteroaryl, aryl, cycloalkyl, or a bicycle, each of which X 11 groups is optionally substituted with 1, 2, 3, or 4 groups independently selected from R 3 ;

or X 10 and X 11 are taken together to form

X 13 , X 14 , X 15 , and X 16 are independently selected from the group consisting of N, CH, and CR 4 , wherein no more than 3 of X 13 , X 14 , X 15 , and X 16 are N;

each R 4 is independently selected from the group consisting of hydrogen, aryl, heteroaryl, C 1 -C 4 alkoxy, C 1 -C 4 haloalkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 alkyl, fluorine, chlorine, bromine, and iodine;

wherein two R 4 groups on adjacent carbon atoms may optionally combine to form a fused cycle, wherein the fused cycle is optionally substituted with 1, 2, or 3 R substituents;

R 5 is hydrogen, C 1 -C 4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl, or cycloalkyl;

each R 6 is independently selected from the group consisting of hydrogen, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, fluorine, chlorine, bromine, and iodine;

each R 7 is independently hydrogen or C 1 -C 4 alkyl;

R 8 is hydrogen, C 1 -C 4 alkyl, allyl, crotyl, alkenyl, alkynyl, haloalkyl, or cycloalkyl;

L is a bivalent Linker of formula:

wherein:

X 1 and X 2 are independently at each occurrence selected from the group consisting of bond, heterocycle, NR 2 , C(R 2 ) 2 , O, C(O), and S;

R 2 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, heterocycle, aryl, heteroaryl, —C(O)H, —C(O)OH, —C(O)alkyl, —C(O)Oalkyl, —C(O)(aryl or heteroaryl), —C(O)O(aryl or heteroaryl), alkene, and alkyne;

R 20 , R 21 , R 22 , R 23 , and R 24 are independently at each occurrence selected from the group consisting of a bond, alkyl, —C(O)—, —C(O)O—, —OC(O)—, —SO 2 —, —S(O)—, —C(S)—, —C(O)NR 2 —, —NR 2 C(O)—, —O—, —S—, —NR 2 —, —C(R 40 R 40 )—, —P(O)(OR 26 )O—, —P(O)(OR 26 )—, bicycle, alkene, alkyne, haloalkyl, alkoxy, aryl, heterocycle, heteroaryl, lactic acid, glycolic acid, and carbocycle; each of which is optionally substituted with 1, 2, 3, or 4 substituents independently selected from R 40 ;

R 26 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, arylalkyl, heteroarylalkyl, alkene, alkyne, aryl, heteroaryl, and heterocycle; and

R 40 is independently at each occurrence selected from the group consisting of hydrogen, alkyl, alkene, alkyne, fluoro, bromo, chloro, hydroxyl, alkoxy, azide, amino, cyano, —NH(alkyl), —N(alkyl) 2 , —NHSO 2 (alkyl), —N(alkyl)SO 2 alkyl, —NHSO 2 (aryl, heteroaryl or heterocycle), —N(alkyl)SO 2 (aryl, heteroaryl or heterocycle), —NHSO 2 alkenyl, —N(alkyl)SO 2 alkenyl, —NHSO 2 alkynyl, —N(alkyl)SO 2 alkynyl, haloalkyl, aryl, heteroaryl, heterocycle, and cycloalkyl.

2 . The compound of claim 1 , wherein Q 1 is NH and X 7 is CH.

3 . The compound of claim 1 , wherein Q 1 is O and X 7 is CH.

4 . The compound of claim 1 , wherein Q 1 is N(CH 3 ) and X 7 is CH.

5 . The compound of claim 1 of Formula I: