ACETAMIDO-PHENYLBENZAMIDE DERIVATIVES AND METHODS OF USING THE SAME
The present disclosure relates to compounds of Formula (I): and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for the treatment of disorders in which expression of P-glycoprotein and/or cytochrome P450 (e.g., CYP3A4) is modulated (e.g., cancers which have developed multi-drug resistance).
1 . A compound of Formula (I):
or a pharmaceutically acceptable prodrug, solvate, enantiomer, stereoisomer, tautomer, or salt thereof, wherein:
A is C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl or heterocyclyl is optionally substituted with oxo;
each R x and R y is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogen, —CN, —OH, or —NH 2 ;
each R 1 and R 4 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
each R 2 and R 3 is independently H, C 2-6 alkenyl, C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 2-6 alkenyl, —O—C 2-6 alkynyl, —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 ) 2 , —C(O)NR 11 —S(O) 2 R 11 , —C(O)NR 11 —S(O) 2 —OR 11 , or —C(O)NR 11 —S(O) 2 —N(R 11 ) 2 , wherein either R 2 or R 3 is not H;
each R 5 and R 6 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 13-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 13-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, or —C(O)R 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 7 , or
R 5 and R 6 together with the atoms to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more R 7 ;
each R 7 is independently oxo, halogen, —OH, —NH 2 , —CN, —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —O—(CH 2 ) t —R 8 , —NH—(CH 2 ) t —R 8 , C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 ;
R 8 is —OH, C 1-6 alkoxy, C 1-6 alkoxy-OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —SH, —S(C 1-6 alkyl), C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 9 ;
each R 9 is independently —(CH 2 ) u -(5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S) or —(CH 2 ) u —(C 6-10 aryl), wherein the heteroaryl or aryl is optionally substituted with one or more halogen, —CN, —OH, or —NH 2 ;
each R 10 is independently halogen, —OH, —NH 2 , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S;
each R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5-to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, halogen, —CN, —OH, or —NH 2 , or
two R 11 together with the atom to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, —CN, —OH, or —NH 2 ;
each n, m, and p is independently 0 or 1;
t is 1, 2, or 3; and
u is 0, 1, 2, or 3,
wherein R 5 and R 6 together with the atoms to which they are attached form a heterocyclyl or heteroaryl, A is not phenyl,
2 . A compound of Formula (I):
or a pharmaceutically acceptable prodrug, solvate, enantiomer, stereoisomer, tautomer, or salt thereof, wherein:
A is
each R x and R y is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogen, —CN, —OH, or —NH 2 ;
each R 1 and R 4 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
each R 2 and R 3 is independently H, C 2-6 alkenyl, C 2-6 alkynyl, —O—C 1-6 alkyl, —O—C 2-6 alkenyl, —O—C 2-6 alkynyl, —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 ) 2 , —C(O)NR 11 —S(O) 2 R 11 , —C(O)NR 11 —S(O) 2 —OR 11 , or —C(O)NR 11 —S(O) 2 —N(R 11 ) 2 , wherein either R 2 or R 3 is not H;
each R 5 and R 6 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 13-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 13-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, or —C(O)R 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 7 , or
R 5 and R 6 together with the atoms to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more R 7 ;
each R 7 is independently oxo, halogen, —OH, —NH 2 , —CN, —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —O—(CH 2 ) t —R 8 , —NH—(CH 2 ) t —R 8 , C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 ;
R 8 is —OH, C 1-6 alkoxy, C 1-6 alkoxy-OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —SH, —S(C 1-6 alkyl), C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 9 ;
each R 9 is independently —(CH 2 ) u -(5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S) or —(CH 2 ) u —(C 6-10 aryl), wherein the heteroaryl or aryl is optionally substituted with one or more halogen, —CN, —OH, or —NH 2 ;
each R 10 is independently halogen, —OH, —NH 2 , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S;
each R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5-to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, halogen, —CN, —OH, or —NH 2 , or
two R 11 together with the atom to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, —CN, —OH, or —NH 2 ;
each n, m, and p is independently 0 or 1;
t is 1, 2, or 3; and
u is 0, 1, 2, or 3,
wherein R 5 and R 6 together with the atoms to which they are attached form a heterocyclyl, A is
3 . A compound of Formula (II):
or a pharmaceutically acceptable prodrug, solvate, enantiomer, stereoisomer, tautomer, or salt thereof, wherein:
each R x and R y is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, halogen, —CN, —OH, or —NH 2 ;
each R 1 and R 4 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl;
each R 2 and R 3 is independently H, C 2-6 alkenyl, C 2-6 alkynyl, —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 ) 2 , —C(O)NR 11 —S(O) 2 R 11 , —C(O)NR 11 —S(O) 2 —OR 11 , or —C(O)NR 11 —S(O) 2 —N(R 11 ) 2 , wherein either R 2 or R 3 is not H;
each R 5 and R 6 is independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, 3- to 13-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 13-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, or —C(O)R 7 , wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 7 , or
R 5 and R 6 together with the atoms to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more R 7 ;
each R 7 is independently oxo, halogen, —OH, —NH 2 , —CN, —C(O)R 10 , —C(O)OR 10 , —C(O)N(R 10 ) 2 , C 1-3 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —O—(CH 2 ) t —R 8 , —NH—(CH 2 ) t —R 8 , C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 10 ;
R 8 is —OH, C 1-6 alkoxy, C 1-6 alkoxy-OH, —NH 2 , —NH(C 1-6 alkyl), —N(C 1-6 alkyl) 2 , —SH, —S(C 1-6 alkyl), C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkoxy, alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl is optionally substituted by one or more R 9 ;
each R 9 is independently —(CH 2 ) u -(5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S) or —(CH 2 ) u —(C 6-10 aryl), wherein the heteroaryl or aryl is optionally substituted with one or more halogen, —CN, —OH, or —NH 2 ;
each R 10 is independently halogen, —OH, —NH 2 , —CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S;
each R 11 is independently H, C 1-6 alkyl, C 2-6 alkenyl, or C 2-6 alkynyl, wherein the alkyl, alkenyl, or alkynyl is optionally substituted with one or more C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5-to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more C 3-10 cycloalkyl, 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, oxo, halogen, —CN, —OH, or —NH 2 , or
two R 11 together with the atom to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is optionally substituted with one or more C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, —CN, —OH, or —NH 2 ;
each n, m, and p is independently 0 or 1;
t is 1, 2, or 3; and
u is 0, 1, 2, or 3.
4 . The compound of claim 1 , wherein each R x and R y is independently H, C 1-6 alkyl, or —OH.
5 . The compound of claim 1 , wherein each R 1 and R 4 is independently H or C 1-6 alkyl.
6 . The compound of claim 1 , wherein each R 2 and R 3 is independently —O—C 1-6 alkyl, —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 11 ) 2 , or —C(O)NR 11 —S(O) 2 R 11 .
7 . The compound of claim 1 , wherein each R 5 and R 6 is independently H, C 1-6 alkyl, C 3-10 cycloalkyl, 3- to 13-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, 5- to 13-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, or —C(O)R 7 , wherein the alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more R 7 .
8 .- 9 . (canceled)
10 . The compound of claim 1 , wherein R 5 and R 6 together with the atoms to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl or heteroaryl is substituted with one or more R 7 .
11 . The compound of claim 1 , wherein each R 7 is independently oxo, halogen, —OH, —NH 2 , —CN, —C(O)R 10 , C 1-3 alkyl, C 2-6 alkynyl, —O—(CH 2 ) t —R 8 , C 6-10 aryl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkyl, alkynyl, aryl, or heteroaryl is optionally substituted with one or more R 10 .
12 . (canceled)
13 . The compound of claim 1 , wherein R 8 is —OH, C 1-6 alkoxy, C 1-6 alkoxy-OH, —NH 2 , —N(C 1-6 alkyl) 2 , —S(C 1-6 alkyl), 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the alkoxy, alkyl, heterocyclyl, or heteroaryl is optionally substituted by one or more R 9 .
14 . (canceled)
15 . The compound of claim 1 , wherein each R 9 is independently —(CH 2 ) u -(5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S) or —(CH 2 ) u —(C 6-10 aryl), wherein the heteroaryl or aryl is optionally substituted with one or more halogen or —OH.
16 . (canceled)
17 . The compound of claim 1 , wherein each R 10 is independently C 1-6 alkyl, C 1-6 haloalkyl, or 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S.
18 . The compound of claim 1 , wherein each R 11 is independently H, C 1-6 alkyl optionally substituted with one or more 3- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, C 6-10 aryl, or 5-to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, wherein the heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more 5- to 10-membered heteroaryl comprising 1-4 heteroatoms selected from N, O, and S, C 1-6 alkyl, or oxo.
19 .- 20 . (canceled)
21 . The compound of claim 1 , wherein two R 11 together with the atom to which they are attached form a 4- to 10-membered heterocyclyl comprising 1-4 heteroatoms selected from N, O, and S, optionally substituted with one or more C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, —CN, —OH, or —NH 2 .
22 .- 28 . (canceled)
29 . The compound of claim 1 , wherein either R 2 or R 3 is not H.
30 . The compound of claim 1 , wherein when R 5 and R 6 together with the atoms to which they are attached form a heterocyclyl or heteroaryl, A is not
31 . The compound of claim 1 , wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-a′), (I-b′), (II-a), or (II-a′):
or a pharmaceutically acceptable prodrug, solvate, enantiomer, stereoisomer, tautomer, or salt thereof.
32 .- 35 . (canceled)
36 . The compound of claim 1 , wherein the compound is selected from Table 1.
37 . A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable prodrug, solvate, enantiomer, stereoisomer, tautomer, or salt thereof, and a pharmaceutically acceptable diluent or carrier.
38 . A method of modulating P-glycoprotein activity and/or cytochrome P450 activity, comprising contacting a cell with an effective amount of a compound of claim 1 .
39 . A method of treating or preventing a disease or disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
40 .- 46 . (canceled)