Oral complement factor D inhibitors

Patent metadata

Field	Value
Publication number	US-12558341-B2
Application number	US-202017767796-A
Country	US
Kind code	B2
Filing date	Oct 9, 2020
Priority date	Oct 9, 2019
Publication date	Feb 24, 2026
Grant date	Feb 24, 2026

Abstract

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.

First claim

What is claimed is:

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 represe

Assignees

• Biocryst Pharm Inc

Inventors

• Kotian Pravin L
• Babu Yarlagadda S
• Zhang Weihe
• Lu peng-cheng
• Spaulding Andrew E
• Lv Wei
• Dang zhao
• Raman Krishnan

Classifications

• C07D493/04

  Ortho-condensed systems · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D407/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/04

  directly linked by a ring-member-to-ring-member bond · CPC title