Complement pathway modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9452990-B2
Application number	US-201314408216-A
Country	US
Kind code	B2
Filing date	Jun 19, 2013
Priority date	Jun 20, 2012
Publication date	Sep 27, 2016
Grant date	Sep 27, 2016

Abstract

The present invention provides a compound of formula I a method for manufacturing the compounds of the invention, and its therapeutic uses as inhibitor of the complement alternative pathway and particularly as inhibitor of Factor B for the treatment of e.g. age-related macular degeneration and diabetic retinopathy. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

1. A compound according to Formula I

or salt or stereoisomer thereof, wherein
R 1 is hydrogen or halogen
R 2 is C 1 -C 4 alkyl;
R 3 is hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, or haloC 1 -C 4 alkyl;
R 4 is halogen, cyano or hydrogen, wherein at least one of R 1 and R 4 is not hydrogen;
R 5 is independently selected at each occurrence from hydrogen, C 1 -C 6 alkyl, C 1 -C 4 alkoxyC 1 -C 4 alkyl, phenyl, and C 3 -C 6 cycloalkyl;
k is 0-3;
R 6 is CH 2 CHR 7 R 8 , or
R 6 is CH═CHR 9 , wherein R 9 is C 3 -C 6 cycloalkyl or phenyl optionally substituted with 0, 1, or 2 groups independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo C 1 -C 4 alkyl or cyano; or
R 6 is bicyclic heteroaryl having 1 or 2 ring heteroatoms independently selected from N, O or S, partially unsaturated carbocycle or partially unsaturated heterocycle having 1 or 2 ring heteroatoms independently selected from N, O or S, each of which is optionally substituted with 0 to 3 substituents independently selected from amino, halogen, cyano, hydroxy, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; or
R 6 is CH 2 heterocycle having 4 to 7 ring atoms and 1 or 2 ring heteroatoms selected from N, O or S, which is optionally substituted with 0, 1, or 2 groups independently selected from phenyl, halogen and C 1 -C 6 alkyl, or two substituents, taken in combination form a benzo ring optionally substituted with halogen;
R 7 is (CH 2 ) p NR 10 R 11 or C(O)NR A 2 , wherein R A is independently selected at each occurrence from hydrogen and C 1 -C 4 alkyl, or NR A 2 taken in combination form a 4-6 member azacycle;
p is 0 or 1;
R 8 is C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl; or
R 8 is phenyl optionally substituted with 0-2 R 12 ; or
R 8 is a 5 or 6 member heteroaryl having 1 or 2 ring heteroatoms selected from N, O and S and optionally substituted with 0-2 R 13 groups;
R 10 is hydrogen or C 1 -C 4 alkyl;
R 11 is hydrogen, optionally substituted C 1 -C 6 alkyl or C 1 -C 6 haloalkyl, wherein the optional substituents are selected from C 1 -C 4 alkoxy, C 3 -C 6 cycloalkyl and 4-6 member heterocycle having 1-2 ring heteroatoms selected from N, O and S; or
NR 10 R 11 , taken in combination form a 4 to 7 member saturated azacycle optionally substituted with 0, 1, or 2 C 1 -C 4 alkyl groups;
R 12 is independently selected at each occurrence from hydrogen, cyano, hydroxy, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 haloalkyl or C 1 -C 4 alkoxy;
R 13 is independently selected at each occurrence from hydrogen, C 1 -C 4 alkyl, or halogen.

2. The compound of claim 1 , wherein the compound is represented by formula (II):

or a salt thereof.

3. A compound of claim 1 , wherein the compound is represented by formula III

or salt thereof,
wherein R 5a is hydrogen, phenyl, C 1 -C 4 alkyl, methoxyC 1 -C 4 alkyl;
R 5b is hydrogen or C 1 -C 4 alkyl; and
R 5c is hydrogen or C 1 -C 4 alkyl.

4. The compound of claim 1 , which compound is a compound of formula (IV):

or salt thereof, wherein
R 5a is hydrogen, methyl, ethyl, propyl or phenyl;
R 5b is hydrogen or methyl;
x is 0, 1, or 2;
R 14 is independently selected at each occurrence from fluoro, chloro, hydroxy, methoxy and cyano;
R 15 is hydrogen or C 1 -C 4 alkyl; and
R 16 is hydrogen or amino.

5. The compound of claim 1 , which compound is a compound of formula (V):

or salt thereof, wherein
R 5a is hydrogen, methyl, ethyl, propyl or phenyl; and
R 5b is hydrogen or methyl.

6. The compound of 5 , wherein the compound is a compound of formula (V),
R 7 is NR 10 R 11 ;
R 9 is furyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkyl, pyridyl optionally substituted by fluoro, thienyl optionally substituted by chloro or C 1 -C 4 alkyl, or phenyl optionally substituted by cyano, halogen, mono- di- and trifluoromethyl, C 1 -C 4 alkyl, vinyl or ethynyl;
R 10 is hydrogen or methyl; and
R 11 s hydrogen, C 1 -C 6 haloalkyl or C 1 -C 6 alkyl optionally substituted with cyclopropyl, C 1 -C 4 alkoxy or 4-6 member heterocycle having 1 ring heteroatom selected from N, O and S; or
NR 10 R 11 , taken in combination, form a 4-6 member saturated azacycle.

7. The compound of claim 1 , which compound is a compound of formula (VI)

or salt thereof, wherein
R 9 is selected from C 3 -C 6 cycloalkyl or phenyl, wherein the phenyl is unsubstituted or substituted with cyano.

8. The compound of claim 1 , which compound is a compound of formula (VII):

wherein R 17 is C 1 -C 4 alkyl; and
n is 0 or 1;
m is 0, 1, or 2, wherein n+m is 1, 2, or 3; or a salt thereof.

9. The compound of claim 1 , in which R 4 is fluoro.

10. The compound of claim 1 , in which R 3 is methyl optionally substituted with 0, 1, 2 or 3 fluoro substitutents; or R 3 is methoxyC 1 -C 4 alkyl.

11. The compound of claim 3 , in which R 5a is hydrogen, methyl, ethyl, propyl or phenyl; and
R 5b and R 5b are each independently hydrogen or methyl.

12. The compound of claim 1 , in which the compound is selected from the group consisting of
1-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-3-cyclopropyl-propenone;
4-{3-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-3-oxo-propenyl}-benzonitrile;
(1-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-methoxymethyl-piperazin-1-yl]-3-cyclopropyl-propenone;
1-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-(2-methoxy-ethyl)-piperazin-1-yl]-3-cyclopropyl-propenone;
4-Amino-2-[4-(3-cyclopropyl-acryloyl)-piperazin-1-yl]-6,7-dimethoxy-quinazoline-8-carbonitrile;
1-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-methyl-piperazin-1-yl]-3-cyclobutyl-propenone;
4-{3-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-methyl-piperazin-1-yl]-3-oxo-propenyl}-benzonitrile;
4-{3-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-ethyl-piperazin-1-yl]-3-oxo-propenyl}-benzonitrile;
4-{3-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-propyl-piperazin-1-yl]-3-oxo-propenyl}-benzonitrile;
4-{3-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-3-phenyl-piperazin-1-yl]-3-oxo-propenyl}-benzonitrile;
4-(3-{4-[4-Amino-8-fluoro-6-methoxy-7-(2-methoxy-ethoxy)-quinazolin-2-yl]-piperazin-1-yl}-3-oxo-propenyl)-benzonitrile;
1-[4-(4-Amino-5-fluoro-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-3-cyclopropyl-propenone;
[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(1H-indol-2-yl)-methanone;
2-[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-piperazine-1-carbonyl]-1H-indole-5-carbonitrile;
[4-(4-Amino-8-fluoro-6,7-dimethoxy-quinazolin-2-yl)-piperazin-

Assignees

• Dechantsreiter Michael
• Grob Jonathan E
• Macsweeney Aengus
• Miltz Wolfgang
• Randl Stefan Andreas
• Sedrani Richard
• Sellner Holger
• Sirockin Finton
• Valeur Eric
• Novartis Ag

Inventors

• Dechantsreiter Michael
• Grob Jonathan E
• Macsweeney Aengus
• Miltz Wolfgang
• Randl Stefan Andreas
• Sedrani Richard
• Sellner Holger
• Sirockin Finton
• Valeur Eric

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title