Tricyclic heterocycle derivatives having HIV replication inhibitory effect

Patent metadata

Field	Value
Publication number	US-9975906-B2
Application number	US-201515311757-A
Country	US
Kind code	B2
Filing date	May 15, 2015
Priority date	May 16, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The present invention provides the following compound having anti-HIV activity of formula:

wherein, A 1 is C, CR 1A or N;
A 2 is C, CR 2A , or N; A 3 is CR 3A , CR 3A R 3B , N, NR 3C , O, S, SO, or SO 2 ; A 4 is CR 4A , CR 4A R 4B , N, NR 4C , O, S, SO, or SO2; A 5 is C, CR 5A , or N; T 1 ring is substituted or unsubstituted monocyclic carbocycle or substituted or unsubstituted monocyclic heterocycle; R 1 is halogen, cyano, nitro or —X 1 —R 11 ; R 2 is substituted or unsubstituted alkyl and the like; n is 1 or 2; R 3 is hydrogen, substituted or unsubstituted aromatic carbocyclyl; R 4 is hydrogen or a carboxy protecting group; the other symbols are as specified in the description.

First claim

The invention claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt thereof,
wherein
A 1 is C, CR 1A , or N;
A 2 is C, CR 2A , or N;
A 3 is CR 3A , CR 3A R 3B , N, NR 3C , O, S, SO, or SO 2 ;
A 4 is CR 4A , CR 4A R 4B , N, NR 4C , O, S, SO, or SO 2 ;
A 5 is C, CR 5A , or N;
A 6 is C, CR 6A , or N;
R 1A , R 2A , R 3A , R 3B , R 4A , R 4B , R 5A , and R 6A are each independently hydrogen, halogen, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted alkyl carbonyl, substituted or unsubstituted alkenyl carbonyl, substituted or unsubstituted alkynyl carbonyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocycle oxy, substituted or unsubstituted non-aromatic carbocycle oxy, substituted or unsubstituted aromatic heterocycle oxy, substituted or unsubstituted non-aromatic heterocycle oxy, substituted or unsubstituted aromatic carbocycle thio, substituted or unsubstituted non-aromatic carbocycle thio, substituted or unsubstituted aromatic heterocycle thio, substituted or unsubstituted non-aromatic heterocycle thio, substituted or unsubstituted aromatic carbocycle amino, substituted or unsubstituted non-aromatic carbocycle amino, substituted or unsubstituted aromatic heterocycle amino, substituted or unsubstituted non-aromatic heterocycle amino, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted aromatic carbocyclylalkylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylalkylcarbonyl, substituted or unsubstituted aromatic heterocyclylalkyl carbonyl, substituted or unsubstituted non-aromatic heterocyclylalkylcarbonyl, substituted or unsubstituted amino, or substituted or unsubstituted carbamoyl;
R 3C and R 4C are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyl oxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, or substituted or unsubstituted non-aromatic heterocyclyl; or,
R 3A and R 3B may be taken together to form oxo, R 4A and R 4B may be taken together to form oxo;
R 3A and R 4A may be taken together with an adjacent atom to form substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle, the carbocycle or heterocycle may be further fused to;
R 3A and R 4C may be taken together with an adjacent atom to form substituted or unsubstituted monocyclic heterocycle, the heterocycle may be further fused to;
R 3C and R 4A may be taken together with an adjacent atom to form substituted or unsubstituted monocyclic heterocycle, the heterocycle may be further fused to;
R 3C and R 4C may be taken together with an adjacent atom to form substituted or unsubstituted monocyclic heterocycle, the heterocycle may be further fused to;
R 3A and R 3B may be taken together with an adjacent atom to form substituted or unsubstituted spiro ring, the spiro ring may be further fused to;
R 4A and R 4B may be taken together with an adjacent atom to form substituted or unsubstituted spiro ring, the spiro ring may be further fused to;
R 4B may be taken together with an atom on the circular arc of T 1 ring to form substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle, the carbocycle or heterocycle may be further fused to;
R 4C may be taken together with an atom on the circular arc of T1 ring to form substituted or unsubstituted monocyclic heterocycle, the heterocycle may be further fused to;
the broken line means the presence or absence of bond, the adjacent broken lines do not exist at the same time, the carbon atoms on 1st, 2nd, and 3rd position are sp 2 carbon;
T 1 ring is substituted or unsubstituted monocyclic carbocycle or substituted or unsubstituted monocyclic heterocycle, (1) the carbocycle or heterocycle may be fused with the other substituted or unsubstituted carbocycle or substituted or unsubstituted heterocycle, and/or (2) two atoms which are not adjacent to one another constituting the carbocycle or heterocycle may be bridged by substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene or substituted or unsubstituted alkynylene;
R 1 is halogen, cyano, nitro or —X 1 —R 11 ,
X 1 is a bond, —O—, —S—, —NR 12 —, —CO—, —SO—, —SO 2 —O—CO—, —CO—O—, —NR 12 —CO—, —CO—NR 12 —, —NR 12 —CO—O—, —NR 12 —CO—NR 13 , —NR 12 —SO 2 — or —SO 2 —NR 12 —,
R 11 is hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, or substituted or unsubstituted heterocyclyl,
R 12 and R 13 are each independently hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl or substituted or unsubstituted alkynyl,
when X 1 is —NR 12 —, —CO—NR 12 or —SO 2 —NR 12 —, R 11 and R 12 may be taken together with an adjacent nitrogen atom to form substituted or unsubstituted heterocyclyl,
X 1 is —NR 12 —CO—NR 13 —, R 11 and R 13 may be taken together with an adjacent nitrogen atom to form substituted or unsubstituted heterocyclyl,
R 1 may be taken together with a carbon atom or a nitrogen atom on the circular arc of T 1 ring to form substituted or unsubstituted monocyclic carbocycle, or substituted or unsubstituted monocyclic heterocycle, the carbocycle or heterocycle may be further fused to;
R 2 is each substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted cycloalkyloxy, or substituted or unsubstituted cycloalkenyloxy;
n is 1 or 2;
R 3 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocycle alkenyl, substituted or unsubstituted non-aromatic carbocycle alkenyl, substituted or unsubstituted aromatic heterocycle alkenyl, substituted or unsubstituted non-aromatic heterocycle alkenyl, substituted or unsubstituted aromatic carbocycle alkynyl, substituted or unsubstituted non-aromatic carbocycle alkynyl, substituted or unsubstituted aromatic heterocycle alkynyl, or substituted or unsubstituted non-aromatic heterocycle alkynyl; and
R 4 is hydrogen or a carboxy protecting group.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1 , wherein the formula (I) is one of formulas (I-A), (I-B) and (I-C):

Assignees

• Shionogi & Co

Inventors

• Kawasuji Takashi
• Taniyama Daisuke
• Sugiyama Shuichi
• Tamura Yoshinori

Classifications

• A61P31/18

  for HIV · CPC title

• A61P31/12

  Antivirals · CPC title

• C07D513/06 Primary

  Peri-condensed systems · CPC title

• A61K31/519

  ortho- or peri-condensed with heterocyclic rings · CPC title

• C07D487/06

  Peri-condensed systems · CPC title