Complement pathway modulators and uses thereof

Patent metadata

Field	Value
Publication number	US-9487483-B2
Application number	US-201314409911-A
Country	US
Kind code	B2
Filing date	Jun 27, 2013
Priority date	Jun 28, 2012
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention provides a compound of formula (I): a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

First claim

What is claimed is:

1. A compound, or a salt thereof, according to the formula (I)

Wherein
A is a group selected from:

Wherein
Z 1 is C(R 1 ) or N;
Z 2 is C(R 2 ) or N;
Z 3 is C(R 3 ) or N, wherein at least one of Z 1 , Z 2 or Z 3 is not N;
R 1 is selected from the group consisting of hydrogen, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, haloC-C 6 alkyl, haloC-C 6 alkoxy C 1 -C 6 alkoxycarbonyl, CO 2 H and C(O)NR A R B ;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, hydroxy, NR C R D , cyano, CO 2 H, CONR A R B SO 2 C 1 -C 6 alkyl, and SO 2 NH 2 , SO 2 NR A R B , C 1 -C 6 alkoxycarbonyl, —C(NR A )NR C R D , C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, wherein each alkyl, alkenyl, alkoxy and alkenyloxy is unsubstituted or substituted with up to 4 substitutents independently selected from halogen, hydroxy, cyano, tetrazole, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, CO 2 H, C 1 -C 6 alkoxycarbonyl, C(O)NR A R B , NR C R D , optionally substituted phenyl, heterocycle having 4 to 7 ring atoms and 1, 2, or 3 ring heteroatoms selected from N, O or S, heteroaryl having 5 or 6 ring atoms and 1, 2 or 3 ring heteroatoms selected from N, O or S, and wherein optional phenyl and heteroaryl substituents are selected from halogen, hydroxy, C 1 -C 4 alkyl, C 1 -C 4 alkoxy and CO 2 H;
R 4 is selected from the group consisting of hydrogen, halogen, and C 1 -C 6 alkyl;
R 5 is C 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl, haloC 1 -C 4 alkyl C 1 -C 4 alkoxyC 1 -C 4 alkyl, amino, methylamino;
X 1 is CR 9 R 22 or sulfur;
X 2 is CR 7 R 8 , oxygen, sulfur, N(H) or N(C 1 -C 6 alkyl), wherein at least one of X 1 and X 2 is carbon; or
X 1 and X 2 , in combination, forms an olefin of the formula —C(R 7 )═C(H)— or —C(R 7 )═C(C 1 -C 4 alkyl)-, wherein the C(R 7 ) is attached to X 3 ;
X 3 is (CR 6 R 21 ) q or N(H) wherein q is 0, 1 or 2, wherein X 3 is CR 6 R 21 or (CR 6 R 21 ) 2 when either X 1 or X 2 is sulfur or X 2 is oxygen; or
X 2 and X 3 , taken in combination, are —N═C(H)— or —N═C(C 1 -C 4 alkyl)- in which the C(H) or C(C 1 -C 4 alkyl) is attached to X 1 ;
R 6 is selected from the group consisting of hydrogen and C 1 -C 6 alkyl;
R 7 is hydrogen, halogen, hydroxy, cyano, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, haloC 1 -C 6 alkyl, or C 1 -C 6 haloalkoxy;
R 8 is hydrogen, halogen, hydroxy, azide, cyano, COOH, C 1 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, C 1 -C 6 haloalkoxy, NR A R B , N(H)C(O)C 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with NR A R B , N(H)C(O)H or N(H)C(O)(C 1 -C 4 alkyl);
R 9 is selected from the group consisting of hydrogen, hydroxy, halogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, haloC 1 -C 6 alkoxy, NR A R B , N(H)C(O)C 1 -C 6 alkyl, N(H)C(O)OC 1 -C 6 alkyl and OC(O)NR C R D each of alkyl, alkoxy, alkenyl, and alkynyl substituents may be substituted with 0, 1, or 2 groups independently selected at each occurrence from the group consisting of halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and NR A R B ;
R 20 is hydrogen or C 1 -C 6 alkyl;
R 21 is selected from the group consisting of hydrogen, phenyl and C 1 -C 6 alkyl, which alkyl group is unsubstituted or substituted with hydroxy, amino, azide, and NHC(O)C 1 -C 6 alkyl;
R 22 is selected from the group consisting of hydrogen, halogen, hydroxy, amino and C 1 -C 6 alkyl;
CR 7 R 8 , taken in combination forms a spirocyclic 3 to 6 membered carbocycle which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen and methyl; or
R 7 and R 8 , taken in combination, form an exocyclic methylidene (═CH 2 );
R 7 and R 22 or R 8 and R 9 , taken in combination form an epoxide ring or a 3 to 6 membered carbocyclic ring system which carbocyclic ring is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyC 1 -C 4 alkyl, C 1 -C 6 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, CO 2 H, and C 1 -C 4 alkyl substituted with NR A R B ;
R 6 and R 7 or R 8 and R 21 , taken in combination, form a fused 3 membered carbocyclic ring system which is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen, methyl, ethyl, hydroxyC 1 -C 4 alkyl, C 1 -C 6 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, CO 2 H, and C 1 -C 4 alkyl substituted with NR A R B ;
R 20 and R 22 taken in combination form a fused 3 carbocyclic ring system;
R 9 and R 21 taken in combination form a form 1 to 3 carbon alkylene linker;
R 7 and R 20 taken in combination form 1 to 3 carbon alkylene linker;
Z is N or CR 16 ;
W 1 is a bond or CR 17 R 18 ;
W 2 is a bond or CH 2 ;
W 3 is CR 12 R 13 ; or W 3 is oxygen when (a) neither W 1 or W 2 is a bond and m is 1 or (b) W 1 is a bond, W 2 is CH 2 and m is 2;
R 10 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, hydroxyC 1 -C 4 alkyl, haloC 1 -C 4 alkyl, haloC 1 -C 4 alkoxy, CO 2 C 1 -C 4 alkyl, and C(O)NH 2 ;
R 11 is selected from the group consisting of hydrogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy and halogen;
or CR 10 R 11 , taken in combination form a spirocyclic carbocycle having 3 to 6 ring carbon atoms or a spirocyclic heterocycle having 3 to 6 ring atoms and one ring heteroatom selected from N O or S;
R 12 and R 13 are independently selected from the group consisting of hydrogen, C 1 -C 4 alkyl and halogen;
R 14 and R 15 are independently selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halogen, haloC 1 -C 4 alkyl and hydroxy;
R 16 is hydrogen, C 1 -C 4 alkyl optionally substituted by fluoro, hydroxy or methoxy;
R 17 is hydrogen or fluoro;
R 18 is hydrogen or fluoro; or
CR 17 R 18 —CR 10 R 11 , taken in combination, form a vinyl group of the formula —C(R 18 )═C(R 11 )—;
R A and R B , are each independently selected from the group consisting of hydrogen, C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, or hydroxyC 1 -C 6 alkyl; and
R C and R D are independently selected from the group consisting of hydrogen, and C 1 -C 6 alkyl, haloC 1 -C 6 alkyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, hydroxyC 1 -C 6 alkyl, or NR C R D , taken in combination, form a heterocycle having 4 to 7 ring atoms and 0 or 1 additional ring N, O or S atoms, which heterocycle is substituted with 0, 1, or 2 substituents independently selected from the group consisting of C 1 -C 4 alkyl, halogen, hydroxy, C 1 -C 4 alkoxy; and
m is 0, 1, or 2.

2. A compound, or a salt thereof, according to formula (II):

Wherein
A is a group selected from:

Z 1 is C(R 1 ) or N;
Z 2 is C(R 2 ) or N;
Z 3 is C(R 3 ) or N, wherein at least one of Z 1 , Z 2 or Z 3 is not N;
R 1 is selected from the group consisting of hydrogen, halogen, C

Assignees

• Novartis Ag

Inventors

• Altmann Eva
• Hommel Ulrich
• Lorthiois Edwige Liliane Jeanne
• Maibaum Jeurgen Klaus
• Ostermann Nils
• Quancard Jean
• Randl Stefan Andreas
• Rogel Olivier
• Vulpetti Anna
• Flohr Stefanie

Classifications

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P7/08

  Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock (artificial tears A61P27/04) · CPC title

• A61P37/08

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

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title