Phosphonate compounds for treatment of complement mediated disorders

Patent metadata

Field	Value
Publication number	US-9663543-B2
Application number	US-201514631785-A
Country	US
Kind code	B2
Filing date	Feb 25, 2015
Priority date	Feb 25, 2014
Publication date	May 30, 2017
Grant date	May 30, 2017

Abstract

Compounds, methods of use, and processes for making inhibitors of complement factor D comprising Formula I, or a pharmaceutically acceptable salt or composition thereof wherein R 12 or R 13 on the A group is a phosphonate (R 32 ) are provided. The inhibitors described herein target factor D and inhibit or regulate the complement cascade at an early and essential point in the alternative complement pathway, and reduce factor D's ability to modulate the classical and lectin complement pathways. The inhibitors of factor D described herein are capable of reducing the excessive activation of complement, which has been linked to certain autoimmune, inflammatory, and neurodegenerative diseases, as well as ischemia-reperfusion injury and cancer.

First claim

What is claimed is:

1. A compound of Formula I

and the pharmaceutically acceptable salts thereof, wherein:
Q 1 is C(R 1 R 1′ );
Q 2 is C(R 2 R 2′ );
Q 3 is C(R 3 R 3′ );
X 1 is N and X 2 is CH;
R 1 , R 1′ , R 2 , R 2′ , R 3 , and R 3′ are independently chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 thioalkyl, hydroxyC 1 -C 6 alkyl, aminoC 1 -C 6 alkyl, —C 0 -C 4 alkylNR 9 R 10 , —C(O)OR 9 , —OC(O)R 9 , —NR 9 C(O)R 10 , —C(O)NR 9 R 10 , —OC(O)NR 9 R 10 , —NR 9 C(O)OR 10 , C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, where R 9 and R 10 are independently chosen at each occurrence from hydrogen, C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), and —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl);
or R 1 and R 2 form a 3- to 6-membered carbocyclic or aryl ring;
or R 2 and R 3 form a 3- to 6-membered carbocyclic ring;
or R 1 and R 1′ , or R 2 and R 2′ , or R 3 and R 3′ form a 3- to 6-membered carbocyclic spiro ring;
or R 2 and R 2′ or R 3 and R 3′ form a 3- to 6-membered heterocyclic spiro ring;
each of which ring is unsubstituted or substituted with 1 or more substituents independently chosen from halogen, hydroxyl, cyano, —COOH, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 1 -C 4 alkoxy, C 2 -C 4 alkanoyl, hydroxyC 1 -C 4 alkyl, (mono- and di-C 1 -C 4 alkylamino)C 0 -C 4 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
or R 1 and R 1′ or R 2 and R 2′ form a carbonyl group;

A is a group selected from:

R 5 and R 6 are independently selected from —CHO, —C(O)NH 2 , —C(O)NH(CH 3 ), C 2 -C 6 alkanoyl, hydrogen, hydroxyl, halogen, cyano, nitro, —COOH, —SO 2 NH 2 , vinyl, C 1 -C 6 alkyl (including methyl), C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C(O)C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —P(O)(OR 9 ) 2 , —OC(O)R 9 , —C(O)OR 9 , —C(O)N(CH 2 CH 2 R 9 )(R 10 ), —NR 9 C(O)R 10 , phenyl, or 5- to 6-membered heteroaryl; and wherein each R 5 and R 6 other than hydrogen, hydroxyl, cyano, and —COOH is unsubstituted or optionally substituted;
R 8 and R 8′ are independently chosen from hydrogen, halogen, hydroxyl, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 1 -C 6 alkoxy, and (C 1 -C 4 alkylamino)C 0 -C 2 alkyl; or R 8 and R 8′ form an oxo group; or R 8 and R 8′ taken together with the carbon that they are bonded to form a 3-membered carbocyclic ring;

X 11 is N or CR 11 ;
X 12 is CR 12 ;
X 13 is CR 13 ;
X 14 is N or CR 14;
one of R 12 and R 13 is chosen from R 31 and the other of R 12 and R 13 is chosen from R 32 :
R 31 is chosen from hydrogen, halogen, hydroxyl, nitro, cyano, amino, —COOH, C 1 -C 2 haloalkyl, C 1 -C 2 haloalkoxy, C 1 -C 6 alkyl, —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), C 2 -C 6 alkenyl, C 2 -C 0 alkanoyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, —C(O)OR 9 , C 1 -C 6 thioalkyl, —C 0 -C 4 alkylNR 9 R 10 , —C(O)NR 9 R 10 , —SO 2 R 9 , —SO 2 NR 9 R 10 , —OC(O)R 9 , and —C(NR 9 )NR 9 R 10 , each of which R 31 other than hydrogen, halogen, hydroxyl, nitro, cyano, C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy is unsubstituted or substituted with one or more substituents independently selected from halogen, hydroxyl, nitro, cyano, amino, —COOH, —CONH 2 C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy, and each of which R 31 is also optionally substituted with one substituent chosen from phenyl and 4- to 7-membered heterocycle containing 1, 2, or 3 heteroatoms independently chosen from N, O, and S; which phenyl or 4- to 7-membered heterocycle is unsubstituted or substituted with one or more substituents independently chosen from halogen, hydroxyl, nitro, cyano, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, (mono- and di-C 1 -C 6 alkylamino)C 0 -C 4 alkyl, C 1 -C 6 alkylester, —C 0 -C 4 alkyl)(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 32 is —P(O)R 20 R 20 ;
R 20 is independently chosen at each occurrence from hydroxyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, C 1 -C 6 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl-, (aryl)C 0 -C 4 alkyl-, —O—C 0 -C 4 alkyl(aryl), —O—C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl-O— having 1, 2, or 3 heteroatoms independently chosen from N, O, and S; (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl-O— having 1, 2, or 3 heteroatoms independently chosen from N, O, and S; —O(CH 2 ) 2-4 O(CH 2 ) 8-18 , —OC(R 20a ) 2 OC(O)OR 20b , —OC(R 20a ) 2 OC(O)R 20b , —NR 9 R 10 , an N-linked amino acid or an N-linked amino acid ester and each R 20 can be optionally substituted;
R 20a is independently chosen at each occurrence from hydrogen, C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (aryl)C 0 -C 4 alkyl-, (aryl)C 2 -C 8 alkenyl- or (aryl)C 2 -C 8 alkynyl-; or
two R 20a groups can be taken together with the carbon that they are bonded to form a 3-6 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, or a 3-6 membered carbocyclic ring;
R 20b is independently chosen at each occurrence from C 1 -C 8 alkyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, (aryl)C 0 -C 4 alkyl, (aryl)C 2 -C 8 alkenyl or (aryl)C 2 -C 8 alkynyl;
R 11 and R 14 , are independently chosen at each occurrence from hydrogen, halogen, hydroxyl, nitro, cyano, —O(PO)(OR 9 ) 2 , —(PO)(OR 9 ) 2 , C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 2 -C 6 alkanoyl, C 1 -C 6 alkoxy, C 1 -C 6 thioalkyl, —C 0 -C 4 alkyl(mono- and di-C 1 -C 6 alkylamino), —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl), —C 0 -C 4 alkoxy(C 3 -C 7 cycloalkyl), C 1 -C 2 haloalkyl, and C 1 -C 2 haloalkoxy;
R 21 and R 22 are independently chosen at each occurrence from hydrogen, hydroxyl, cyano, amino, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, —C 1 -C 4 alkylOC(O)OC 1 -C 6 alkyl, —C 1 -C 4 alkylOC(O)C 1 -C 6 alkyl, —C 1 -C 4 alkylC(O)OC 1 -C 6 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each R 21 and R 22 can be optionally substituted;
R 23 is independently chosen at each occurrence from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, (aryl)C 0 -C 4 alkyl, (C 3 -C 7 cycloalkyl)C 0 -C 4 alkyl, (phenyl)C 0 -C 4 alkyl, (4- to 7-membered heterocycloalkyl)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and (5- or 6-membered unsaturated or aromatic heterocycle)C 0 -C 4 alkyl having 1, 2, or 3 heteroatoms independently chosen from N, O, and S, and each R 23 can be optionally substituted;
R 24 and R 25 are taken together with the nitrogen to which they are attached to form a 4- to 7-membered monocyclic heterocycloalkyl group, or a 6- to 10-membered bicyclic heterocyclic group having fused, spiro, or bridged rings, and each R 24 and R 25 can be optionally substituted;
L is a bond or is chosen from the formulas

where R 17 is hydrogen, C 1 -C 6 alkyl, or —C 0 -C 4 alkyl(C 3 -C 7 cycloalkyl) and R 18 and R 18′ are independently chosen from hydrogen, halogen, hydroxymethyl, and methyl; and m is 0, 1, 2, or 3;
—(C 0 -C 4 alkyl)(aryl); —(C 0 -C 4 alkyl)(

Assignees

• Achillion Pharmaceuticals Inc

Inventors

• Wiles Jason Allan
• Hashimoto Akihiro
• Gadhachanda Venkat Rao
• Pais Godwin
• Wang Qiuping
• Chen Dawei
• Wang Xiangzhu
• Agarwal Atul
• Deshpande Milind
• Phadke Avinash S

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · 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

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/06

  Antianaemics · CPC title