Methods and composition of 4-substituted benzoylpiperazine-1-substituted carbonyls as beta-catenin/B-cell lymphoma 9 inhibitors
In one aspect, the invention relates to 4-substituted benzoylpiperazine-1-substituted carbonyls having a structure represented by a formula: derivatives thereof, and related compounds; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g., various tumors and cancers, associated with β-catenin/BCL9 protein-protein interaction dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
1. A compound having a structure represented by a formula:
wherein A is —N— or —CR 8 —;
wherein R 8 is hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein L 1 is optionally present, and when present, is O, S, or NH;
wherein L 2 is optionally present, and when present, is O, S, NR 9 , or —(CR 10a R 10b ) n —,
wherein n is an integer having the value of 1, 2, or 3;
wherein R 9 is hydrogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein each occurrence of R 10a and R 10b is independently hydrogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein each of R 1a and R 1b is independently hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, or C1-C3 polyhaloalkyl;
wherein each of R 2a , R 2b , and R 2c is independently hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 polyhaloalkyl;
wherein R 3 is Cy 3 or Ar 1 ;
wherein Cy 3 is a C3-C8 cycloalkyl or a C2-C7 heterocycloalkyl; and wherein Cy 3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H;
wherein Ar 1 is selected from aryl and heteroaryl, and wherein Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H;
wherein R 4 is hydrogen, halogen, unsubstituted C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 polyhaloalkyl;
wherein each occurrence of R 5 is independently selected from hydrogen, unsubstituted C1-C8 alkyl, C1-C8 monohaloalkyl, or C1-C8 polyhaloalkyl;
wherein R 6 is C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy 1 ; and wherein Cy 1 is a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom, and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, unsubstituted C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
wherein R 7 is H 2 N—(C1-C6 alkyl)-(C═O)—; HO—(C1-C6 alkyl)-(C═O)—; C1-C6 aminoalkyl, C1-C6 hydroxyalkyl, or Cy 2 ; and wherein Cy 2 is a C2-C7 heterocycloalkyl comprising at least one oxygen or nitrogen atom; and wherein Cy 2 is substituted 0, 1, 2, or 3 groups independently selected from halogen, unsubstituted C1-C4 alkyl, C1-C4 monohaloalkyl, and C1-C4 polyhaloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein L 2 is not present.
3. The compound of claim 1 , wherein Cy 2 has a structure represented by a formula:
and wherein R 10 is hydrogen, methyl, ethyl, propyl, or isopropyl.
4. The compound of claim 1 , wherein each of R 1a , R 1b , R 2a , R 2b , and R 2c is hydrogen.
5. The compound of claim 1 , wherein R 3 is phenyl substituted 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H.
6. The compound of claim 1 , wherein R 3 is cyclohexyl substituted 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H.
7. The compound of claim 1 , having a structure represented by a formula:
wherein R 3 is cyclohexyl or phenyl substituted 0, 1, 2, or 3 groups independently selected from halogen, —CN, unsubstituted C1-C3 alkyl, C1-C3 monohaloalkyl, C1-C3 polyhaloalkyl, unsubstituted cyclopropyl, and —CO 2 H; wherein R 4 is —F, —Br, methyl, ethyl, —CFH 2 , —CF 2 H, or —CF 3 ; wherein R 10 is hydrogen, methyl, ethyl, propyl, or isopropyl; and wherein R 11 is hydrogen, methyl, ethyl, propyl, or isopropyl.
8. A compound selected from:
or a pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.