Use of tetrahydroindazolylbenzamide and tetrahydroindolylbenzamide derivatives for the treatment of human immunodeficiency virus (hiv) and acquired immune deficiency syndrome (aids)

Patent metadata

Field	Value
Publication number	US-2016143884-A1
Application number	US-201514952421-A
Country	US
Kind code	A1
Filing date	Nov 25, 2015
Priority date	Nov 26, 2014
Publication date	May 26, 2016
Grant date	—

Abstract

Provided are methods of treating or inhibiting Human Immunodeficiency Virus (HIV) infection, or treating or inhibiting Acquired Human Immunodeficiency Syndrome (AIDS) in a subject in need thereof, comprising administering an Hsp90 inhibitor in a therapeutically effective amount.

First claim

What is claimed is:

1 . A method for treating or inhibiting Human Immunodeficiency Virus (HIV) infection, or treating or inhibiting Acquired Human Immunodeficiency Syndrome (AIDS), in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of an Hsp90 inhibitor of formula (I):

or a pharmaceutically acceptable salt thereof, wherein
R 3 and R 4 are independently
(a) H,
(b) halo, or
(c) a C 1 -C 15 alkyl group where up to six of the carbon atoms in said alkyl group are optionally replaced independently by R 22 , carbonyl, ethenyl, ethynyl or a moiety selected from N, O, S, SO 2 , or SO, with the proviso that two 0 atoms, two S atoms, or an O and S atom are not immediately adjacent each other,
wherein
R 22 is
(i) heteroaryl,
(ii) aryl,
(iii) saturated or unsaturated C 3 -C 10 cycloalkyl, or
(iv) saturated or unsaturated C 2 -C 10 heterocycloalkyl, wherein each aryl, heteroaryl, saturated or unsaturated cycloalkyl, or saturated or unsaturated heterocycloalkyl, independently, is optionally substituted with at least one group, which independently is hydroxy, halo, amino, cyano, carboxy, carboxamido, nitro, oxo, —S—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 -aryl, —SO—(C 1 -C 6 )alkyl, —SO-aryl, —SO 2 NH 2 , —SO 2 NH—(C 1 -C 6 )alkyl, —SO 2 NH-aryl, (C 1 -C 6 )alkoxy, or mono- or di-(C 1 -C 10 )alkylamino; and

each R 22 is optionally fused to a C 6 -C 10 aryl group, C 5 -C 8 saturated cyclic group, or a C 5 -C 10 heterocycloalkyl group;

wherein each (c) moiety is optionally substituted at any available position with C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, hydroxy, carboxy, carboxamido, oxo, halo, amino, cyano, nitro, —SH, —S—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 NH 2 , —SO 2 NH—(C 1 -C 6 )alkyl, —SO 2 NH—aryl, —SO 2 -aryl, —SO—(C 1 -C 6 )alkyl, —SO 2 -aryl, C 1 -C 6 alkoxy, C 2 -C 10 alkenyloxy, C 2 -C 10 alkynyloxy, mono- or di-(C 1 -C 10 )alkylamino, —OC 1 -C 10 alkyl-Z, —O—C(O)C 1 -C 10 alkyl-Z, or R 23 , wherein
Z is OR 0 or —N(R 30 ) 2 , wherein
each R 30 is independently —H or C 1 -C 6 alkyl, or N(R 30 ) 2 represents pyrrolidinyl, piperidinyl, piperazinyl, azepanyl, 1,3- or 1,4-diazepanyl, or morpholinyl, each of which is optionally substituted with hydroxy, amino, aminoalkyl, C 1 -C 6 alkyl, mono- or di(C 1 -C 6 )alkylamino, C 1 -C 6 alkoxy, or halogen;
R 0 is —H, —C 1 -C 10 alkyl, —C 2 -C 10 alkenyl, —C 2 -C 10 alkynyl, aryl, heteroaryl, or —C 1 -C 6 acyl;

R 23 is
(1) heteroaryl,
(2) aryl,
(3) saturated or unsaturated C 5 -C 10 cycloalkyl, or
(4) saturated or unsaturated C 5 -C 10 heterocycloalkyl, and the R 23 groups are optionally substituted with at least one group which independently is hydroxy, oxo, halo, amino, cyano, nitro, —SH, —S—(C 1 -C 6 )alkyl, —SO 2 —(C 1 -C 6 )alkyl, —SO 2 -aryl, —SO—(C 1 -C 6 )alkyl, —SO-aryl, —SO 2 NH 2 , —SO 2 NH—(C 1 -C 6 )alkyl, —SO 2 NH-aryl, (C 1 -C 6 )alkoxy, or mono- or di-(C 1 -C 10 )alkylamino; and

wherein one or both of R 3 and R 4 is optionally substituted with a group R 50 where R 50 is:

wherein
d and k are integers independently selected from 1 and 2;
R 201 is (C 1 -C 6 )alkyl where the alkyl is optionally substituted with (C 3 -C 7 )cycloalkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, hydroxy, halogen, nitro, or cyano; and
T is O or NR 202 where R 202 is hydrogen or (C 1 -C 6 )alkyl; and
R 301 and R 302 are independently hydrogen or (C 1 -C 6 )alkyl, and R 303 is absent, hydrogen, or (C 1 -C 6 )alkyl;

R 7 is O, S, NH, N—OH, N—NH 2 , N—NHR 22 , N—NH—(C 1 -C 6 alkyl), N—O—(C 0 -C 6 )alkyl-R 22 , N—(C 1 -C 6 alkenoxy); or N—(C 1 -C 6 alkoxy optionally substituted with carboxy);
Y is N or CR C , wherein
each R C independently is hydrogen, halogen, cyano, nitro, —O(O)R C′ , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, C 1 -C 10 haloalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkyl(C 1 -C 10 )alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein
each alkyl, aryl, cycloalkyl, heterocycloalkyl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, cyano, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, carboxamide, heterocycloalkyl, aryl, or heteroaryl, wherein
the aryl and heteroaryl groups are optionally substituted with from 1-4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, halo(C 1 -C 6 )alkyl, or carboxamide;

R C′ is —C 1 -C 6 alkyl, —OR C″ , or —N(R CN ) 2 , wherein
R C″ is —H, C 1 -C 10 alkyl, C 1 -C 10 haloalkyl, C 3 -C 7 cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;

each R CN is independently —H, —C 1 -C 10 alkyl, —C 1 -C 10 -aloalkyl, —C 3 -C 7 cycloalkyl, -heterocycloalkyl, —C 1 -C 6 acyl, -aryl, or -heteroaryl, wherein
each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, or carboxamide;

X 1 is N or CR C ;
Q 1 , Q 2 , and Q 3 are independently N or CR Q , wherein one and only one of Q 1 ,
Q 2 , and Q 3 is C—R 21 , and wherein
each R Q is independently hydrogen, halogen, —N(R CN ) 2 , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 7 cycloalkyl, aryl, or heteroaryl, or R 21 , wherein each alkyl, cycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, or carboxamide;
R 21 is cyano, —C(O)OH, —C(O)—O(C 1 -C 6 alkyl), or a group of the formula

wherein
R 1 and R 2 are independently H, hydroxy, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, heteroaryl, aryl, C 3 -C 8 cycloalkyl, heterocycloalkyl, wherein
each alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is optionally substituted with from 1-4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, or carboxamide;

or R 1 and R 2 together with the nitrogen to which they are both attached, form a heterocycloalkyl which optionally contains one or more additional heteroatoms which are, independently, O, N, S, or N(R CN ); and
X 4 is O, S, NH, NOH, N—NH 2 , N—NHaryl, N—NH—(C 1 -C 6 alkyl), or N—(C 1 -C 6 alkoxy);

X 2 and X 3 are independently C, O, N, or S(O) p wherein
p is 0, 1, or 2; and

n is 0, 1, 2, 3, or 4;
provided that when
(i) X 2 is C, then
R 5 and R 6 are independently H, C 1 -C 6 alkyl, or aryl, wherein the aryl is optionally substituted with from 1-4 groups that are independently C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, hydroxy, amino, mono- or di-(C 1 -C 6 )alkylamino, nitro, halo(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkoxy, or carboxamide, wherein any two adjacent substituted aryl positions, together with the carbon atoms to which they are attached, form an unsaturated cycloalkyl or heterocycloalkyl; or
R 5 and R 6 together with the carbon to which

Assignees

• Esanex Inc
• Ohio State Innovation Foundation
• Univ Duke

Inventors

• Orlemans Everardus O M
• Haynes Barton F
• Ferrari Guido
• Haystead Timothy
• Kwiek Jesse John

Classifications

• A61P31/18

  for HIV · CPC title

• A61K31/416 Primary

  condensed with carbocyclic ring systems, e.g. indazole · CPC title

• A61K31/4178

  not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin · CPC title

• A61K31/42

  Oxazoles · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title