Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR

Patent metadata

Field	Value
Publication number	US-9617293-B2
Application number	US-201615093178-A
Country	US
Kind code	B2
Filing date	Apr 7, 2016
Priority date	May 19, 2014
Publication date	Apr 11, 2017
Grant date	Apr 11, 2017

Abstract

Compounds of Formula (A) are described herein and the uses thereof for the treatment of diseases, conditions and/or disorders mediated by pharmaceutical compositions and the uses thereof as asialoglycoprotein receptor (ASGPR) targeting agents.

First claim

What is claimed is:

1. A compound of Formula (A)

wherein
R 1 is Z—X—Y wherein X is a linker of any of structures L1-L10

wherein each T is independently absent or is alkylene, alkenylene, or alkynylene, wherein one or more —CH 2 — groups of the alkylene, alkenylene, or alkynylene may each independently be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R 4 )— wherein the heteroatom groups are separated by at least 2 carbon atoms;
each Q is independently absent or is C(O), C(O)—NR 4 , NR 4 —C(O), O—C(O)—NR 4 , NR 4 —C(O)—O, —CH 2 —, a heteroaryl, or a heteroatom group selected from O, S, S—S, S(O), S(O) 2 , and NR 4 , wherein at least two carbon atoms separate the heteroatom groups O, S, S—S, S(O), S(O) 2 and NR 4 from any other heteroatom group;
each R 4 is independently —H, —(C 1 -C 20 )alkyl, or (C 3 -C 6 )cycloalkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 )2, —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halo atoms; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein if n is greater than 1, each T and each Q of each (T-Q-T-Q) is independently selected;
Y is an amino acid sequence, a nucleic acid sequence, or an oligomer, and
Z is absent or is —C≡C—, —CH═CH—, —CH 2 —, —CH 2 —O—, —C(O)—N(R 4 )—, —CH 2 —S—, —CH 2 —S(O)—, —CH 2 —S(O) 2 —, —CH 2 —S(O) 2 —N(R 4 )—, —C(O)—O—, —CH 2 —N(R 4 )—, —CH 2- N(R 4 )—C(O)—, —CH 2 —N(R 4 )—S(O) 2 —, —CH 2 —N(R 4 )—C(O)—O—, —CH 2 —N(R 4 )—C(O)—N(R 4 )—, —CH 2 —O—C(O)—, —CH 2 —O—C(O)—N(R 4 )—, —CH 2 —O—C(O)—O—, or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with R 5 ;
R 2 is —OH, —N 3 , —N(R 3 ) 2 , —N(R 3 )—C(O)—R 3 , —N(R 3 )—C(O)—N(R 3 ) 2 , —N(R 3 )—C(O)—OR 3 , tetrazole, or triazole, wherein the tetrazole and triazole are optionally substituted with R 3 ;
each R 3 is independently —H, —(C 1 -C 5 )alkyl, halo-substituted (C 1 -C 5 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein a —CH 2 — group of the alkyl or cycloalkyl may be replaced with a heteroatom group selected from —O—, —S—, and —N(R 4 )— and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms;
each R 4 is independently —H, —(C 1 -C 20 )alkyl, or (C 3 -C 6 )cycloalkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with one to six halo atoms; and
each R 5 is independently —H, (C 3 -C 20 )cycloalkyl or (C 1 -C 20 )alkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OW, and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with one to six halo atoms;
or a pharmaceutically acceptable salt thereof.

2. A compound of Formula (A)

wherein
R 1 is —Z—X—Y, —Z—Y, or —X—Y wherein X is a linker of any of structures L1-L10

wherein each T is independently absent or is alkylene, alkenylene, or alkynylene, wherein one or more —CH 2 — groups of the alkylene, alkenylene, or alkynylene may each independently be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R 4 )— wherein the heteroatom groups are separated by at least 2 carbon atoms;
each Q is independently absent or is C(O), C(O)—NR 4 , NR 4 —C(O), O—C(O)—NR 4 , NR 4 —C(O)—O, —CH 2 —, a heteroaryl, or a heteroatom group selected from O, S, S—S, S(O), S(O) 2 , and NR 4 , wherein at least two carbon atoms separate the heteroatom groups O, S, S—S, S(O), S(O) 2 and NR 4 from any other heteroatom group;
each R 4 is independently —H, —(C 1 -C 20 )alkyl, or (C 3 -C 6 )cycloalkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may be replaced with —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 )2, —OW, and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halo atoms; and
each n is independently 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, or 40, wherein if n is greater than 1, each T and each Q of each (T-Q-T-Q) is independently selected;
Y is an amino acid sequence, a nucleic acid sequence, or an oligomer, and
Z is —C≡C—, —CH═CH—, —CH 2 —, —CH 2 —O—, —C(O)—N(R 4 )—, —CH 2 —S—, —CH 2 —S(O)—, —CH 2 —S(O) 2 —, —CH 2 —S(O) 2 —N(R 4 )—, —C(O)—O—, —CH 2 —N(R 4 )—, —CH 2- N(R 4 )—C(O)—, —CH 2 —N(R 4 )—S(O) 2 —, —CH 2 —N(R 4 )—C(O)—O—, —CH 2 —N(R 4 )—C(O)—N(R 4 )—, —CH 2 —O—C(O)—, —CH 2 —O—C(O)—N(R 4 )—, —CH 2 —O—C(O)—O—, or aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with R 5 ;
R 2 is —OH, —N 3 , —N(R 3 ) 2 , —N(R 3 )—C(O)—R 3 , —N(R 3 )—C(O)—N(R 3 ) 2 , —N(R 3 )—C(O)—OR 3 , —N(R 3 )—S(O) 2 —R 3 , tetrazole, or triazole, wherein the tetrazole and triazole are optionally substituted with R 3 ;
each R 3 is independently —H, —(C 1 -C 5 )alkyl, halo-substituted (C 1 -C 5 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein one or more —CH 2 — groups of the alkyl or cycloalkyl may each be replaced with a heteroatom group independently selected from —O—, —S—, and —N(R 4 )— and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms;
each R 4 is independently —H, —(C 1 -C 20 )alkyl, or (C 3 -C 6 )cycloalkyl wherein one to six —CH 2 — groups of the alkyl or cycloalkyl separated by at least two carbon atoms may each be replaced with a heteroatom independently selected from —O—, —S—, or —N(R 4 )—, and —CH 3 of the alkyl may be replaced with a heteroatom group selected from —N(R 4 ) 2 , —OR 4 , and —S(R 4 ) wherein the heteroatom groups are separated by at least 2 carbon atoms; and wherein the alkyl and cycloalkyl may be substituted with halo atoms;
each R 5 is independently —H, (C 3 -C 20 )cycloalkyl or (C 1 -C 60 )alkyl wherein one to six —CH 2 — groups of the cycloalkyl or one to 20 —CH 2 — groups of the alkyl may each be replaced with heteroatoms independently selected from —O—, —S—, and —N(R 4 )—

Assignees

• Pfizer

Inventors

• Liras Spiros
• Mascitti Vincent
• Thuma Benjamin

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P7/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title