Therapeutic compounds

Patent metadata

Field	Value
Publication number	US-9873680-B2
Application number	US-201514836774-A
Country	US
Kind code	B2
Filing date	Aug 26, 2015
Priority date	Aug 29, 2014
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

Compounds of formula I:

or salts thereof are disclosed. Also disclosed are pharmaceutical compositions comprising a compound of formula I, processes for preparing compounds of formula I, intermediates useful for preparing compounds of formula I and therapeutic methods for treating a Retroviridae viral infection including an infection caused by the HIV virus.

First claim

What is claimed is:

1. A compound of formula I:

wherein
A 1 is C—Z 3 or nitrogen;
A 2 is C—Z 3 or nitrogen;
R 1 is 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 membered heterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 membered heterocycle of R 1 is optionally substituted with 1, 2, 3, 4 or 5 Z 4 groups, wherein the Z 4 groups are the same or different;
each R 3a and R 3b is independently H or (C 1 -C 3 )alkyl;
Z 1 is 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 membered heterocycle, wherein any 6-12 membered aryl, 5-14 membered heteroaryl, or 3-14 membered heterocycle of Z 1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1a or Z 1b , wherein the Z 1a and Z 1b groups are the same or different;
each Z 1a is independently oxo, (C 3 -C 7 )carbocycle, 5-12 membered heteroaryl, 3-12 membered heterocycle, halogen, —CN, —OR n1 , —OC(O)R p1 , —OC(O)NR q1 R r1 , —SR n1 , —S(O)R p1 , —S(O) 2 OH, —S(O) 2 R p1 , —S(O) 2 NR q1 R r1 , —NR q1 R r1 , —NR n1 COR p1 , —NR n1 CO 2 R p1 , —NR n1 CONR q1 R r1 , —NR n1 S(O) 2 R p1 , —NR n1 S(O) 2 OR p1 , —NR n1 S(O) 2 NR q1 R r1 , —C(O)R n1 , —C(O)OR n1 , —C(O)NR q1 R r1 and —S(O) 2 NR n1 COR p1 , wherein any (C 3 -C 7 )carbocycle, 5-12 membered heteroaryl and 3-12 membered heterocycle of Z 1a is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d groups, wherein the Z 1c and Z 1d groups are the same or different;
each Z 1b is independently (C 1 -C 8 )alkyl optionally substituted with 1, 2, 3, 4 or 5 halogen, which are the same or different;
each Z 1c is independently halogen, —CN, —OH, —NH 2 , —C(O)NR q2 R r2 , or (C 1 -C 8 )heteroalkyl;
each Z 1d is independently (C 1 -C 8 )alkyl or (C 1 -C 8 )haloalkyl;
each R n1 is independently H, (C 1 -C 8 )alkyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl of R n1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d groups, wherein the Z 1c and Z 1d groups are the same or different, and wherein any (C 1 -C 8 )alkyl of R n1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c groups, wherein the Z 1c groups are the same or different;
each R p1 is independently (C 1 -C 8 )alkyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl of R p1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d groups, wherein the Z 1c and Z 1d groups are the same or different, and wherein any (C 1 -C 8 )alkyl of R p1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c groups, wherein the Z 1c groups are the same or different;
each R q1 and R r1 is independently H, (C 1 -C 8 )alkyl, (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl, wherein any (C 3 -C 7 )carbocycle, 3-7 membered heterocycle, or 5-6 membered monocyclic-heteroaryl of R q1 or R r1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d groups, wherein the Z 1c and Z 1d groups are the same or different, and wherein any (C 1 -C 8 )alkyl of R q1 or R r1 is optionally substituted with 1, 2, 3, 4 or 5 Z 1c groups, wherein the Z 1c groups are the same or different, or R q1 and R r1 together with the nitrogen to which they are attached form a 5, 6 or 7-membered heterocycle, wherein the 5, 6 or 7-membered heterocycle is optionally substituted with 1, 2, 3, 4 or 5 Z 1c or Z 1d groups, wherein the Z 1c and Z 1d groups are the same or different;
each R q2 and R r2 is independently H, (C 1 -C 8 )alkyl, (C 3 -C 7 )carbocycle, or R q2 and R r2 together with the nitrogen to which they are attached form a 5, 6, or 7-membered heterocycle;
Z 2 is (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, 6-12 membered aryl, 5-12 membered heteroaryl, 3-12 membered heterocycle, wherein any (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, 6-12 membered aryl, 5-12 membered heteroaryl, or 3-12 membered heterocycle of Z 2 is substituted with 1 or 2 Z 2b groups and optionally 1, 2, or 3 Z 2c groups, wherein the Z 2b and Z 2c groups are the same or different;
each R n3 is independently H or (C 1 -C 4 )alkyl;
each R q3 and R r3 is independently H or (C 1 -C 4 )alkyl;
each Z 2b is independently 6-12 membered aryl, 5-12 membered heteroaryl, 3-9 membered carbocycle, 3-12 membered heterocycle, or amino substituted with 3-12 membered heterocycle, 5-12 membered heteroaryl, 3-9 membered carbocycle, or 3-12 membered heterocycle, wherein any 6-12 membered aryl, 5-12 membered heteroaryl, 3-9 membered carbocycle, or 3-12 membered heterocycle of Z 2b is optionally substituted with 1, 2, 3, 4, or 5 Z 2d groups;
each Z 2c is independently oxo, halogen, —CN, —OR n4 , —OC(O)R p4 , —OC(O)NR q4 R r4 , —SR n4 , —S(O)R p4 , —S(O) 2 OH, —S(O) 2 R p4 , —S(O) 2 NR q4 R r4 , —NR q4 R r4 , —NR n4 COR p4 , —NR n4 CO 2 R p4 , —NR n4 CONR q4 R r4 , —NR n4 S(O) 2 R p4 , —NR n4 S(O) 2 OR p4 , —NR n4 S(O) 2 NR q4 R r4 , —NO 2 , —C(O)R n4 , —C(O)OR n4 , —C(O)NR q4 R r4 , or (C 1 -C 4 ) alkyl optionally substituted with 1, 2, or 3 halogen or —OR n4 ;
each Z 2d is independently oxo, halogen, —CN, —OR n4 , —OC(O)R p4 , —OC(O)NR q4 R r4 , —SR n4 , —S(O)R p4 , —S(O) 2 OH, —S(O) 2 R p4 , —S(O) 2 NR q4 R r4 , —NR q4 R r4 , —NR n4 COR p4 , —NR n4 CO 2 R p4 , —NR n4 CONR q4 R r4 , —NR n4 S(O) 2 R p4 , —NR n4 S(O) 2 OR p4 , —NR n4 S(O) 2 NR q4 R r4 , —NO 2 , —C(O)R n4 , —C(O)OR n4 , —C(O)NR q4 R r4 , or (C 1 -C 4 ) alkyl optionally substituted with 1, 2, or 3 halogen or —OR n4 ;
each R n4 is independently H, (C 1 -C 4 )alkyl optionally substituted with 1, 2, or 3 —OH groups, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )heteroalkyl;
each R p4 is independently (C 1 -C 8 )alkyl, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )heteroalkyl;
each R q4 and R r4 is independently H, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, or (C 1 -C 4 )heteroalkyl;
each Z 3 is independently H or —NR q4 R r4 ;
each Z 4 is independently oxo, (C 1 -C 8 )alkyl, (C 3 -C 7 )carbocycle, halogen, —CN, —OR n5 , —NR q5 R r5 , —NR n5 COR p5 , —NR n5 CO 2 R p5 , —C(O)R n5 , —C(O)OR n5 , or —C(O)NR q5 R r5 , wherein any (C 3 -C 7 )carbocycle or (C 1 -C 8 )alkyl of Z 4 is optionally substituted with 1, 2, 3, 4 or 5 Z 4a groups, wherein the Z 4a groups are the same or different;
each Z 4a is independently halogen, —CN, or —OR n6 ;
each R n5 , R p5 , R q5 , R r5 , and R n6 is independently H or (C 1 -C 4 )alkyl;
each Z 5 is independently halogen, which may be same or different; and
n is 0, 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the moiety

wherein Z 5a is H or halogen.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3a and R 3b are each H.

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, which is a compound of formula II

wherein Z 3 is H or —NH 2 and Z 5a is H or halogen.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Z 2 is (C 2 -C 8 )alkynyl or 5-6 membered C-linked-monocyclic-heteroaryl, wherein any (C 2

Assignees

• Gilead Sciences Inc

Inventors

• Brizgys Gediminas
• Canales Eda
• Halcomb Randall L
• Hu Yunfeng Eric
• Kato Darryl
• Link John O
• Liu Qi
• Saito Roland D
• Tse Winston C
• Zhang Jennifer R

Classifications

• C07D405/14

  containing three or more hetero rings · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/444

  containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone · CPC title

• A61K31/4709

  Non-condensed quinolines and containing further heterocyclic rings · CPC title

• C07D493/04

  Ortho-condensed systems · CPC title