Therapeutic heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-11186579-B2
Application number	US-201916502721-A
Country	US
Kind code	B2
Filing date	Jul 3, 2019
Priority date	Jul 6, 2018
Publication date	Nov 30, 2021
Grant date	Nov 30, 2021

Abstract

Compounds having the following Formula (I), or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, and methods of their use and preparation are disclosed:

First claim

The invention claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
Y 1 is O or N;
----- is a single bond that is present or absent,
wherein ------ is absent when Y 1 is O and is present when Y 1 is N;

X 1 , X 2 , X 3 , and X 4 are each independently N or CH;
each

indicates that the ring in which it is contained is aromatic;
one of X 5 and X 6 is C and one of X 5 and X 6 is N;
one of X 7 and X 8 is CR 4 and one of X 7 and X 8 is N, provided that if X 5 is N, X 8 is CR 4 ;
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy of R 4 is unsubstituted or substituted with one, two, or three R 5 ; and
each R is independently hydroxyl, amino, C 1-4 alkyl or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy of R 5 is unsubstituted or substituted with C 1-3 alkyl or C 1-3 alkoxy.

2. The compound of claim 1 , wherein the compound is of Formula (Ia):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
X 1 , X 2 , X 3 , and X 4 are each independently N or CH;
each

indicates that the ring in which it is contained is aromatic;
one of X 5 and X 6 is C and one of X 5 and X 6 is N;
one of X 7 and X 8 is CR 4 and one of X 7 and X 8 is N, provided that if X 5 is N, X 8 is CR 4 ;
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl, or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy of R 4 is unsubstituted or substituted with one, two, or three R 5 ; and
each R 5 is independently hydroxyl, amino, C 1-4 alkyl or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy of R 5 is unsubstituted or substituted with C 1-3 alkyl or C 1-3 alkoxy.

3. The compound of claim 1 , wherein the compound is of Formula (Ib):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy of R 4 is unsubstituted or substituted with one, two, or three R 5 ; and
each R 5 is independently hydroxyl, amino, C 1-4 alkyl or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy of R 5 is unsubstituted or substituted with C 1-3 alkyl or C 1-3 alkoxy.

4. The compound of claim 1 , wherein the compound is of Formula (Ic):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy of R 4 is unsubstituted or substituted with one, two, or three R 5 ; and
each R 5 is independently hydroxyl, amino, C 1-4 alkyl or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy of R 5 is unsubstituted or substituted with C 1-3 alkyl or C 1-3 alkoxy.

5. The compound of claim 1 , wherein the compound is of Formula (Id):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy of R 4 is unsubstituted or substituted with one, two, or three R 5 ; and
each R 5 is independently hydroxyl, amino, C 1-4 alkyl or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy of R 5 is unsubstituted or substituted with C 1-3 alkyl or C 1-3 alkoxy.

6. The compound of claim 1 , wherein the compound is of Formula (Ie):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
X 1 is N or CH;
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selected from halo, CN, C 1-6 alkyl, and C 1-6 haloalkyl;
R 4 is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy, wherein the C 1-6 alkyl or C 1-6 alkoxy of R 4 is unsubstituted or substituted with one, two, or three R 5 ; and
each R 5 is independently hydroxyl, amino, C 1-4 alkyl or C 1-4 alkoxy, wherein the C 1-4 alkyl or C 1-4 alkoxy of R 5 is unsubstituted or substituted with C 1-3 alkyl or C 1-3 alkoxy.

7. The compound of claim 1 , wherein the compound is of Formula (If):

or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, wherein:
X 1 is N or CH;
n is 0, 1, 2, 3, or 4;
each R 1 is independently C 1-6 alkyl or halo;
R 2 is halo, C 1-6 alkyl or C 1-6 haloalkyl;
R 3 is 6-12 membered aryl or 5-12 membered heteroaryl, wherein the 6-12 membered aryl or 5-12 membered heteroaryl of R 3 is unsubstituted or substituted with one, two, or three substituents independently selec

Assignees

• Gilead Sciences Inc

Inventors

• Bartlett Mark J
• Corkey Britton Kenneth
• Elbel Kristyna M
• Kalla Rao V
• Li Xiaofen
• Perry Thao

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title

• A61K31/519

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• A61K2039/505

  comprising antibodies · CPC title