Therapeutic heterocyclic compounds

Patent metadata

Field	Value
Publication number	US-11229638-B2
Application number	US-201816641166-A
Country	US
Kind code	B2
Filing date	Aug 20, 2018
Priority date	Aug 22, 2017
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

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 II:

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 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 0-4 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. The compound of claim 1 having the structure of Formula IIa:

wherein
X 1 at each location of Formula IIa 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 IIa 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 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. The compound of claim 1 having the structure of Formula IIb:

wherein
R 1 is halogen or hydrogen;
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 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 a 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 having the structure of Formula IIc:

wherein
R 1 is halogen or hydrogen;
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 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 a 4-12 membered heterocycle,

or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

7. A method of inhibiting the activity of an IDO1 protein by contacting the protein with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.

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

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K31/519

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

• C07K2317/24

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