Inhibitors of complement factors and uses thereof
Disclosed are compounds of formula I and II and pharmaceutically acceptable salts thereof. Also disclosed are methods of treating a neurodegenerative disorder, an inflammatory disease, an autoimmune disease, an ophthalmic disease or a metabolic disorder using the compounds disclosed herein.
1 . A method of treating a disease or condition selected from myasthenia gravis, rheumatoid arthritis, dermatomyositis, chronic idiopathic demyelinating polyneuropathy, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia, and cold agglutinin disease in an individual in need thereof, comprising administering a compound represented by formula I or II:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is hydrogen, halogen, amino, hydroxyl, alkoxy, or alkylthio;
W is N;
V and X are selected such that either V is CR a and X is N, or V is N and X is CR b ;
R a is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, or alkyl;
R b is hydrogen, halogen, nitro, cyano, amino, hydroxyl, alkoxy, alkylthio, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each U independently is N or CR c ;
each R c independently is hydrogen, halogen, alkyl, or alkoxy;
ring Z 1 is a five- or six-membered aryl or heteroaryl;
ring Z 2 is a five- or six-membered heterocycle;
each R 2 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkoxy, alkylthio, acyl, amidino, azido, carbamoyl, carboxyl, carboxyester, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamido, sulfonyl urea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or two vicinal R 2 , together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered carbocycle, 5- or 6-membered heterocycle, 5- or 6-membered aryl, or 5- or 6-membered heteroaryl;
n is 0 or an integer selected from 1-4, as valency permits;
each R 6 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxyl, alkoxy, alkylthio, acyl, amidino, azido, carbamoyl, carboxyl, carboxyester, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamido, sulfonyl urea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or any two R 6 , together with the intervening carbon atom(s) to which they attach, combine to form a carbocycle or heterocycle;
q is 0 or an integer selected from 1-4, as valency permits;
R 3 is
or
M is N(R 8 ) 3 , N(R 8 ) 2 , OR 8 or SR 8 ;
each R 8 is independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
R 3a and R 3b independently are hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 3a and R 3b , together with the boron atom and the two intervening oxygen atoms that separate them, combine to form a monocyclic or polycyclic heterocyclyl; or R 3a , R 3b , and M, together with the boron atom and the intervening oxygen atoms, combine to form a polycyclic heterocycle.
2 . The method of claim 1 , wherein the compound is represented by formula I-a or II-a:
or a pharmaceutically acceptable salt thereof.
3 . The method of claim 1 , wherein R 1 is hydroxyl, C 1-3 alkoxy, or amino.
4 . The method of claim 1 , wherein each R 2 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkoxy, alkylthio, phosphonate, dialkylphosphine oxide, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
or two vicinal R 2 , together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered carbocycle, 5- or 6-membered heterocycle, 5- or 6-membered aryl, or 5- or 6-membered heteroaryl.
5 . The method of claim 1 , wherein R a is hydrogen, halogen, amino, hydroxyl, alkoxy or alkyl.
6 . The method of claim 1 , wherein R b is hydrogen, halogen, alkyl, alkenyl, alkynyl, carbocyclyl, or heterocyclyl.
7 . The method of claim 1 , wherein each R c independently is hydrogen, halogen, or alkyl.
8 . The method of claim 1 , wherein U is CR c .
9 . The method of claim 1 , wherein ring Z 1 is phenyl or a five- or six-membered heteroaryl.
10 . A method of treating a disease or condition selected from myasthenia gravis, rheumatoid arthritis, dermatomyositis, chronic idiopathic demyelinating polyneuropathy, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia, and cold agglutinin disease in an individual in need thereof, comprising administering a compound represented by formula I-c-1 or I-c-2:
or a pharmaceutically acceptable salt thereof, wherein
R 2a is alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
each R 2 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, alkoxy, alkylthio, acyl, amidino, azido, carbamoyl, carboxyl, carboxyester, guanidine, haloalkyl, haloalkoxy, heteroalkyl, imino, oxime, phosphonate, dialkylphosphine oxide, sulfonyl, sulfonamido, sulfonyl urea, sulfinyl, sulfinic acid, sulfonic acid, thiocyanate, thiocarbonyl, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl;
or two vicinal R 2 , together with the intervening carbon atoms to which they attach, combine to form a 5- or 6-membered carbocycle, 5- or 6-membered heterocycle, 5- or 6-membered aryl, or 5- or 6-membered heteroaryl;
n is 0 or an integer selected from 1-2;
R 3 is
M is N(R 8 ) 3 , N(R 8 ) 2 , OR 8 or SR 8 ;
each R 8 is independently hydrogen, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; and
R 3a and R 3b independently are hydrogen, alkyl, acyl, alkenyl, alkynyl, aralkyl, heteroaralkyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or R 3a and R 3b , together with the boron atom and the two intervening oxygen atoms that separate them, combine to form a monocyclic or polycyclic heterocyclyl; or R 3a , R 3b , and M, together with the boron atom and the intervening oxygen atoms, combine to form a polycyclic heterocycle.
11 . The method of claim 10 , wherein R 2a is methyl, difluoromethyl, —CF 2 CHF 2 , —CHFCF 3 , —CH 2 CF 3 , —(CH 2 CH 2 O) 2 CH 3 ,
wherein m is an integer from 2 to 6.
12 . The method of claim 1 , wherein R 3 is
wherein:
each R 5 independently is halogen, nitro, cyano, amino, acylamino, amido, hydroxyl, oxo, carboxy, alkoxy, alkylthio, alkyl, aralkyl, heteroaralkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; or any two R 5 , independently, together with the intervening carbon atom(s) to which they attach, combine to form a carbocycle or heterocycle; and
p is 0 or an integer selected from 1-6, as valency permits.
13 . The method of claim 12 , wherein R 3 is
14 . A method of treating a disease or condition selected from myasthenia gravis, rheumatoid arthritis, dermatomyositis, chronic idiopathic demyelinating polyneuropathy, autoimmune hemolytic anemia, warm autoimmune hemolytic anemia, and cold agglutinin disease in an individual in need thereof, comprising administering a compound selected from:
or a pharmaceutically acceptable salt thereof.
15 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
16 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
17 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
18 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
19 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
20 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
21 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
22 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
23 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
24 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
25 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
26 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
27 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
28 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
29 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
30 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
31 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
32 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
33 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
34 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
35 . The method according to claim 14 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
36 . The method according to claim 10 , wherein R 3 is