Pyrrolidine derivatives and their use as complement pathway modulators

Patent metadata

Field	Value
Publication number	US-9468661-B2
Application number	US-201314409893-A
Country	US
Kind code	B2
Filing date	Jun 27, 2013
Priority date	Jun 28, 2012
Publication date	Oct 18, 2016
Grant date	Oct 18, 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 complement pathway modulators for the treatment of ocular diseases. 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 formula (II):

Wherein
m is an integer of between 0 and 2p+4;
p is 0, 1, 2, or 3;
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 amino, C 1 -C 4 alkyl, hydroxymethyl, CH 2 OMe, or mono-, di- and tri-fluoromethyl, NHMe;
R 6 and R 7 are independently selected from hydrogen and halogen;
R 8 is hydrogen, fluoro, C 1 -C 4 alkyl or hydroxymethyl;
R 9 is hydrogen, halogen, hydroxy or methoxy; or
R 6 and R 7 , taken in combination, form a cyclopropane ring; or
R 8 and R 9 , taken in combination, form a cyclopropane ring;
R 10 is hydrogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, hydroxyC 1 -C 4 alkyl or C 1 -C 4 alkoxyC 1 -C 4 alkyl;
R 11 is hydrogen or C 1 -C 4 alkyl; or
CR 10 R 11 , taken in combination, form a geminal cyclopropyl ring;
R 12 is independently selected at each occurrence from the group consisting of hydrogen, halogen, and C 1 -C 4 alkyl;
R 13 is independently selected at each occurrence from the group consisting of hydrogen, C 1 -C 4 alkyl, halogen, haloC 1 -C 4 alkyl, or two geminal R 13 , together form a spiroC 3 -C 6 cycloalkyl, or two vicinal R 13 form a double bond;
R A and R B , are each 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, 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.

2. A compound of claim 1 , or a salt thereof, according to formula (IIa):

3. The compound of claim 1 , or a salt thereof, wherein at least two of Z 1 , Z 2 and Z 3 are not N.

4. The compound of claim 1 , or a salt thereof, wherein Z 3 is CR 3 ;
R 1 is hydrogen, halogen or C 1 -C 4 alkyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, CO 2 H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, wherein the alkyl and the alkoxy is unsubstituted or substituted with optionally substituted heteroaryl having 5 or 6 ring atoms and 1, 2 or 3 ring heteroatoms selected from N, O or S, and wherein optional heteroaryl substituents are selected from halogen, C 1 -C 4 alkyl;
R 4 is hydrogen; and
R 5 is amino or C 1 -C 4 alkyl.

5. The compound of claim 1 , or a salt thereof, wherein Z 1 is N;
Z 2 is CR 2 ;
Z 3 is CR 3 ;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, CO 2 H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
R 4 is hydrogen; and
R 5 is amino or C 1 -C 4 alkyl.

6. The compound of claim 1 , or a salt thereof, wherein Z 2 is N;
Z 1 is CR 1 ;
R 1 is selected from from the group consisting of hydrogen and C 1 -C 4 alkyl;
Z 3 is CR 3 ;
R 3 is selected from the group consisting of hydrogen, halogen, CO 2 H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
R 4 is hydrogen; and
R 5 is amino or C 1 -C 4 alkyl.

7. The compound of claim 1 , or a salt thereof, wherein Z 3 is N;
Z 1 is CH;
Z 2 is CR 2 ;
R 2 is selected from the group consisting of hydrogen, halogen, CO 2 H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy;
R 4 is hydrogen; and
R 5 is amino or C 1 -C 4 alkyl.

8. The compound of claim 1 , or a salt thereof, wherein Z 1 is CH;
Z 2 is CR 2 ;
Z 3 is CR 3 ;
R 2 and R 3 are independently selected from the group consisting of hydrogen, halogen, CO 2 H, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, wherein the alkyl or alkoxy is unsubstituted or substituted with optionally substituted heteroaryl having 5 or 6 ring atoms and 1, 2 or 3 ring heteroatoms selected from N, O or S, and wherein the heteroaryl is optionally substituted with 1 or 2 halogen or C 1 -C 4 alkyl groups;
R 4 is hydrogen; and
R 5 is amino or C 1 -C 4 alkyl.

9. The compound of claim 1 , or a salt thereof, wherein
R 6 and R 7 taken in combination form a cyclopropane ring;
R 8 is hydrogen, methyl or hydroxymethyl; and
R 9 is hydrogen.

10. The compound of claim 1 , or a salt thereof, wherein
R 6 and R 7 are hydrogen; and
R 8 and R 9 taken in combination form a cyclopropane ring.

11. The compound of claim 1 , or a salt thereof, wherein
R 6 is hydrogen;
R 8 is hydrogen or methyl;
R 7 is fluoro; and
R 9 is hydrogen or methoxy.

12. The compound of claim 1 , or a salt thereof, wherein R 11 and R 12 are hydrogen.

13. The compound of claim 1 , or a salt thereof, wherein m is 1, 2, or 3 or 4; and R 13 is independently selected at each occurrence from fluoro, chloro and C 1 -C 4 alkyl.

14. The compound of claim 1 , or a salt thereof, wherein p is 0; m is 2 or 3 or 4; R 10 is hydrogen or methyl; and
Two R 13 are fluoro or chloro and one or two optional R 13 groups are independently selected C 1 -C 4 alkyl.

15. The compound of claim 1 , or a salt thereof, wherein p is 1, 2, or 3; m is 0 or 1; R 10 is hydrogen or methyl; and R 13 is methyl.

16. The compound of claim 1 , or a salt thereof, according to formula IIb:

Wherein m is 0 or 1 or 2; and R 13 is methyl.

17. The compound of claim 1 , or a salt thereof, selected from the group consisting of
(1R,3S,5R)-2-[2-(3-Acetyl-pyrazolo[3,4-b]pyridin-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid cyclopropylmethyl-amide;
(1R,3S,5R)-2-[2-(3-Acetyl-pyrazolo[3,4-b]pyridin-1-yl)-acetyl]-2-aza-bicyclo[3.1.0]hexane-3-carboxylic acid (2,2,3,3-tetramethyl-cyclopropylmethyl)-amide;
(1R,3S,5R)-2-[2-(3-Acetyl-pyrazolo[3,4-c]pyridin-1-yl)-acetyl]-2-aza-bicyclo

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

Classifications

• A61P37/02

  Immunomodulators · CPC title

• A61P33/00

  Antiparasitic agents · CPC title

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P7/06

  Antianaemics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title