Therapeutic heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-11040033-B2
Application number	US-201815999548-A
Country	US
Kind code	B2
Filing date	Aug 20, 2018
Priority date	Aug 22, 2017
Publication date	Jun 22, 2021
Grant date	Jun 22, 2021

Abstract

Compounds having the following Formula I and/or Formula II and methods of their use and preparation are disclosed:

First claim

What is claimed is:

1. A compound of Formula I:

wherein
X 1 at each location in Formula I is independently N, CH, or CX R ;
X 2 is N or C, wherein R 2 is absent when X 2 is N;
X 4 at each location in Formula I is independently N, CH, or CR 1 ;
X 5 is CH, CX R , or CR 1 ;
X R is hydrogen, halogen, C 1-3 haloalkyl, or C 1-6 alkyl;
R 1 is hydrogen, deuterium, halogen, —CN, —OCF 3 , —OCHF 2 , or —CF 3 , wherein n is 0-5 and where if n is >1, R 1 can be independently the same or different from each other;
R 2 is hydrogen, halogen, C 1-6 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl;
R 3 is C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl; and
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

2. A compound of Formula I a :

wherein
X 1 at each location of Formula Ia is independently N, CH, or CX R ;
X 2 is N or C, wherein R 2 is absent when X 2 is N;
X 4 at each location of Formula Ia is independently N, CH, or CR 1 ;
X R is hydrogen, halogen, C 1-3 haloalkyl, or C 1-6 alkyl;
R 1 is hydrogen, deuterium, halogen, —CN, —OCF 3 , —OCHF 2 , or —CF 3 , wherein R 1 can be independently the same or different from each other;
R 2 is absent when X 2 is N; or R 2 is hydrogen, halogen, C 1-6 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl;
R 3 is C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl; and
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

3. A compound of Formula I b :

wherein
R 1 is halogen;
R 2 is hydrogen, C 1-3 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

4. A compound of Formula I c :

wherein
R 1 is halogen;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

5. A compound of Formula I e :

wherein
R 1 is halogen;
R 2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

6. A compound of Formula I f :

wherein
R 1 is halogen;
R 2 is hydrogen, C 1-3 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl;
R 3 is a C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is halogen, C 1-3 alkyl, C 1-3 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

7. A compound of Formula I h :

wherein
R 1 is halogen;
R 2 is hydrogen, C 1-3 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl;
R 3 is a 5-10 membered mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-3 haloalkyl, and C 1-3 alkyl; and
R 4 is C 1-3 alkyl or C 1-3 haloalkyl,

or a pharmaceutically acceptable salt thereof.

8. A compound of Formula I i :

wherein
X 1 at each location in Formula Ii is independently N, CH, or CX R ;
X 2 is N or C, wherein R 2 is absent when X 2 is N;
X 4 at each location in Formula Ii is independently N, CH, or CR 1 ;
X 5 is N, CH, or CR 1 ;
X R is hydrogen, halogen, C 1-3 haloalkyl, or C 1-6 alkyl;
R 1 is hydrogen, deuterium, halogen, —CN, —OCF 3 , —OCHF 2 , C 1-3 haloalkyl, or C 1-6 alkyl, wherein n is 0-5 and R 1 can be independently the same or different from each other;
R 2 is hydrogen, halogen, C 1-6 alkyl, or an unsubstituted or substituted aryl with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, and C 1-6 alkyl;
R 3 is C 3-6 cycloalkyl, C 3-6 heterocycle, or mono or bicyclic aryl or heteroaryl, wherein each mono or bicyclic aryl or heteroaryl is unsubstituted or substituted with one, two, or three substituents independently selected from halogen, —CN, C 1-6 haloalkyl, C 1-6 alkyl, and —C(O)N(R 5 )(R 6 );
R 4 is halogen, C 1-6 alkyl, C 1-6 haloalkyl, —OCF 3 , C 3-6 cycloalkyl, or a 4-12 membered heterocycle;
R 5 is hydrogen or C 1-6 alkyl; and
R 6 is hydrogen or C 1-6 alkyl,

or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is fluoro, chloro, or bromo.

10. The compound of claim 1 , or a pharm

Assignees

• Gilead Sciences Inc

Inventors

• Bartlett Mark J
• Corkey Britton Kenneth
• Cosman Jennifer Leigh
• Elbel Kristyna M
• Elzein Elfatih
• Kalla Rao V
• Koltun Dmitry
• Li Xiaofen
• Parkhill Eric Q
• Perry Thao

Classifications

• A61K35/17

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• C07K2317/24

  containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered · CPC title

• A61K31/5025

  ortho- or peri-condensed with heterocyclic ring systems · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K31/506

  not condensed and containing further heterocyclic rings · CPC title