Oral complement factor D inhibitors
Disclosed are compounds of formula (I), and pharmaceutically acceptable salts thereof, which are inhibitors of the complement system. Also provided are pharmaceutical compositions comprising such a compound, and methods of using the compounds and compositions in the treatment or prevention of a disease or condition characterized by aberrant complement system activity.
1 . A compound of formula (Ia), or a pharmaceutically acceptable salt thereof:
wherein:
ring
is arylene or heteroarylene;
represents
or
ring
is aryl or heteroaryl;
J represents —CH 2 —, —NH—, —CH 2 CH 2 —, —C(O)—, —O—, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, —CH(aryl)-, —C(alkyl) 2 -, —CH(cycloalkyl)-, or
K represents a bond, —O—, —NH—, —C(O)—, —CH 2 —, —S—, —S(O)—, —SO 2 —, —N(alkyl)-, —CH(alkyl)-, or —CH(cycloalkyl)-;
wherein at least one of J and K is a bond, —C(O)—, —CH 2 —, —CH 2 CH 2 —, —CH(alkyl)-, or —CH(aryl)-;
L C represents a bond, —CH 2 —, —CH(alkyl)-, —CH(cycloalkyl)-, —CH(hydroxyalkyl)-, —CH(haloalkyl)-, —CH 2 CH 2 —, —CF 2 —, —CH(F)—, —CF(alkyl)-, —C(O)—, —CD 2 -, or —CH(D)-;
L D represents —CH 2 —, —CH 2 CH 2 —, —CF 2 —, —CH(F)—, —CD 2 -, —CH(D)-, —CH(alkyl)-, —CH(cycloalkyl)-, —CHNH 2 —, —CH(NH(alkyl))-, —CH(NH(cycloalkyl))-, or a bond;
R A represents H, halo, hydroxyl, cyano, amino, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (cycloalkyl)alkoxy, (heterocycloalkyl)alkoxy, optionally substituted (heteroaryl)alkoxy, haloalkyl, haloalkoxy, (hydroxy)haloalkyl, alkoxyalkyl, optionally substituted aminoalkyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted cycloalkyl, optionally substituted (cycloalkyl)alkyl, optionally substituted (cycloalkyl)alkenyl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, —C(O)OH, —C(O)NH 2 —, —C(O)N(alkyl) 2 -, —CH 2 C(O)OH, —NO 2 , —CH 2 NH(optionally substituted alkyl), —CH 2 N(Boc)(optionally substituted alkyl), —CH 2 NH((cycloalkyl)alkyl), —CH 2 N(alkyl)(cycloalkyl), —CH 2 N(alkyl)((cycloalkyl)alkyl), —NH(optionally substituted alkyl), —NH(cycloalkyl), —NH((cycloalkyl)alkyl), —NH((heterocycloalkyl)alkyl), —N(alkyl) 2 , —N(alkyl)((cycloalkyl)alkyl, —N(alkyl)((heterocycloalkyl)alkyl, —NH(heteroarylalkyl), —CH 2 O(optionally substituted aryl), —C(O)O(alkyl), —C(O)NH(optionally substituted alkyl), —C(O)NH((cycloalkyl)alkyl), —NHC(O)O(alkyl), or —CH 2 N(alkyl) 2 ;
R B represents H, —C(O)O(alkyl), halogen, cyano, amino, —C(O)OH, —CH 2 C(O)OH, —C(O)NH 2 , —C(O)NH(cycloalkyl), —C(O)NH(alkyl), —C(O)NH(aryl), —C(O)NH(heteroaryl), —C(O)(alkyl), alkylaminoalkyl, alkylaminocycloalkyl, alkoxyalkyl, hydroxyalkyl, haloalkyl, (hydroxy)haloalkyl, or tosyl, or is optionally substituted alkyl, aryl, heteroaryl, cycloalkyl, (cycloalkyl)alkyl, or heterocycloalkyl;
R C represents H, halo, —OH, or amino, or is optionally substituted alkoxy, alkyl, cycloalkyl, heterocycloalkyl, or (heteroaryl)alkoxy;
R D represents H, halo, hydroxyl, cyano, —NH 2 , —NH(Ac), —NH(alkyl), —N(alkyl) 2 , —NH(CO)(alkyl), —CH 2 NH 2 , —CH 2 NHC(O)(alkyl), —C(O)NH 2 , —C(O)OH, or —NHC(O)O(alkyl), or is optionally substituted alkyl, alkoxyl, cycloalkyl, (cycloalkyl)alkyl, hydroxyalkyl, aminoalkyl, haloalkoxyl, or haloalkyl;
R 1 represents H or optionally substituted alkyl; and
m, n, p, and q are each independently 0, 1, or 2.
2 . The compound of claim 1 , wherein:
J represents —CH 2 —, —NH—, —CH 2 CH 2 —, or —C(O)—;
K represents a bond, —O—, —NH—, or —C(O)—;
wherein if J represents —NH—, then K is a bond or —C(O)—;
L C represents —CH 2 —, —CH(alkyl)-, or —CH(hydroxyalkyl)-;
R A represents H, halo, hydroxyl, alkyl, alkoxyl, hydroxyalkyl, optionally substituted aryloxy, (aryloxy)alkyl, (heterocycloalkyl)alkoxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted (heterocycloalkyl)alkyl, —C(O)OH, —NO 2 , —CH 2 NH(optionally substituted alkyl), —CH 2 NH((cycloalkyl)alkyl), —NH((cycloalkyl)alkyl), —CH 2 O(optionally substituted aryl), —C(O)O(alkyl), —C(O)NH(optionally substituted alkyl), —C(O)NH((cycloalkyl)alkyl), —NHC(O)O(alkyl), or —CH 2 N(alkyl) 2 ;
R B represents H, —C(O)O(alkyl), alkyl, —C(O)OH, hydroxyalkyl, tosyl, heterocycloalkyl, —C(O)NH 2 , or —C(O)NH(cycloalkyl);
R C represents H or halo;
R D represents H or halo, hydroxyl, alkyl, alkoxyl, —NH 2 , —C(O)NH 2 , —NHC(O)O(alkyl), or haloalkoxyl; and
R 1 represents H or alkyl.
3 . The compound of claim 1 , having the structure of formula (Ia-1):
4 . The compound of claim 1 , having the structure of formula (Ia-2):
5 . The compound of claim 1 , wherein
represents
6 . The compound of claim 1 , wherein
represents
7 . The compound of claim 1 , wherein L C represents —CH 2 —.
8 . The compound of claim 1 , wherein R C represents H.
9 . The compound of claim 1 , wherein R C represents halo.
10 . The compound of claim 1 , wherein -J-K— represents —CH 2 —, —NH—, —CH 2 —O—, —CH 2 CH 2 —O—, —C(O)—NH—, or —NHC(O)—.
11 . The compound of claim 1 , wherein -J-K— represents —CH 2 —O— or —C(O)—NH—.
12 . The compound of claim 1 , wherein ring
is aryl.
13 . The compound of claim 1 , wherein
represents
14 . The compound of claim 1 , wherein
represents
15 . The compound of claim 1 , wherein
represents
16 . The compound of claim 1 , wherein R 1 is H.
17 . The compound of claim 1 , wherein L D represents —CH 2 —, —CH 2 CH 2 —, or a bond.
18 . The compound of claim 1 , wherein L D represents —CH 2 —.
19 . The compound of claim 1 , wherein R D represents H, halo, hydroxyl, alkyl, or alkoxyl.
20 . The compound of claim 1 , wherein R D represents H.
21 . The compound of claim 1 , wherein R B represents H, alkyl, or —C(O)OH.
22 . The compound of claim 1 , wherein R B represents H.
23 . The compound of claim 1 , wherein R A represents H, alkyl, alkoxyl, or —CH 2 O(optionally substituted aryl).
24 . The compound of claim 1 , wherein R A represents H.
25 . The compound of claim 1 , wherein the compound is selected from the group consisting of:
26 . A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
27 . A method of treating or preventing a disease or condition characterized by aberrant complement system activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
28 . The compound of claim 1 , wherein R C represents F.