Compositions for use for the inhibition of dihydroorotate dehydrogenase
Disclosed herein are compounds, 6-substituted-2-(phenylheteroaryl)quinoline-4-carboxylic acid analogs, that are inhibitors of dihydroorotate dehydrogenase (DHODH). The disclosed compounds can be used in the treatment of a variety of disorders and diseases in which inhibition of DHODH can be clinically useful, including cancer, such as a hematological cancer, including acute myeloid leukemia (AML); graft-versus-host-diseases; autoimmune disorders; and disorders associated with T-cell proliferation. 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 disclosure.
1 . A compound having a formula represented by a structure:
wherein each of Z 1 , Z 2 , Z 3 , and Z 4 is independently selected from CH and N; wherein at least one Z 1 , Z 2 , Z 3 , or Z 4 is N;
wherein R 1 is selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ;
wherein one of R 5a , R 5b , R 5c , R 5d , and R 5e is selected from a group having formula represented by a structure:
—R 20 , —R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 40 ,
wherein A 1 is selected from —O— and —NR 50 —;
wherein R 50 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl;
wherein A 2 is selected from —O— and —NR 60 —;
wherein R 60 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl;
wherein A 3 is selected from —O— and —NR 70 —;
wherein R 70 is selected from hydrogen, —C1-C10 alkyl, —C1-C10 aminoalkyl, and —C1-C10 hydroxyalkyl;
wherein R 20 is selected from halogen, —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 hydroxyalkyl, —C1-C10 alkylamino, and —C1-C10 alkoxy;
wherein each of R 30 and R 31 is independently selected from —C1-C10 alkanediyl, —C1-C10 haloalkanediyl, —C1-C10 aminoalkanediyl, and —C1-C10 hydroxyalkanediyl; and
wherein R 40 is selected from —C1-C10 alkyl, —C1-C10 haloalkyl, —C1-C10 aminoalkyl, —C1-C10 hydroxyalkyl, and —(CH 2 ) n Ar 1 ;
wherein n is an integer selected from 1, 2, and 3; and
wherein Ar 1 is a phenyl group substituted with 0, 1, 2, 3, 4, or 5 groups independently selected from halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —C 1 -C 4 alkyl, —C 1 -C 4 alkoxy, —C 1 -C 4 haloalkyl, —C 1 -C 4 aminoalkyl, —C 1 -C 4 alkylamino, —C 1 -C 4 haloalkylamino, —C1-C4 hydroxyalkyl, —C 1 -C 4 halohydroxyalkyl, cycloalkyl, and heterocycloalkyl;
and wherein four of R 5a , R 5b , R 5c , R 5d , and R 5e are independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 ;
or a pharmaceutically acceptable salt thereof.
2 . The compound of claim 1 , wherein R 1 is selected from halogen, —SF 5 , —CF 3 , and —CF 2 CF 3 .
3 . The compound of claim 2 , wherein R 1 is halogen.
4 . The compound of claim 3 , wherein R 1 is F.
5 . The compound of claim 1 , wherein R 5c is halogen, C1-C7 haloalkyl, or —O(C1-C7 haloalkyl).
6 . The compound of claim 5 , wherein R 5c is halogen.
7 . The compound of claim 6 , wherein R 5c is F.
8 . The compound of claim 5 , wherein R 5c is —OCF 3 , —OCH 2 CF 3 , or —OCF 2 CF 3 .
9 . The compound of claim 1 , wherein R 50 is —OH, —O(C1-C7 alkyl), —C1-C7 hydroxyalkyl, —O—(C1-C7 hydroxyalkyl), —CH 2 O(C1-C7 alkyl), or —(CH 2 ) 2 O(C1-C7 alkyl).
10 . The compound of claim 1 , wherein R 5a is selected from a group having formula represented by a structure:
—R 20 , —R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 ; and wherein each of R 5b , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .
11 . The compound claim 10 , wherein R 20 is selected from —C2-C7 alkylamino and —C2-C7 alkoxy.
12 . The compound of claim 1 , wherein R 5b is selected from a group having formula represented by a structure:
—R 20 , —R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 -R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 ;
and wherein each of R 5a , R 5c , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .
13 . The compound of claim 12 , wherein R 20 is selected from —C2-C7 alkylamino and —C2-C7 alkoxy.
14 . The compound of claim 1 , wherein R 5c is selected from a group having formula represented by a structure:
—R 20 , —R 30 -A 1 -R 40 , -A 1 -R 40 , -A 1 -R 30 -A 2 R 40 , or -A 1 -R 30 -A 2 -R 31 -A 3 -R 41 ;
and wherein each of R 5a , R 5b , R 5d , and R 5e is independently selected from hydrogen, halogen, —SF 5 , —CN, —N 3 , —OH, —NH 2 , —CF 3 , and —CF 2 CF 3 .
15 . The compound of claim 14 , wherein R 20 is selected from —C2-C7 alkylamino and —C2-C7 alkoxy.
16 . The compound of claim 1 , having a structure represented by a formula:
17 . The compound of claim 1 , present as:
18 . 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.
19 . A method for the treatment of a disease or disorder in a mammal comprising the step of administering to the mammal a therapeutically effective amount of at least one compound of claim 1 , or a pharmaceutically acceptable salt thereof.
20 . The method of claim 19 , wherein the disorder is a cancer.