Compounds and methods for treating, detecting, and identifying compounds to treat apicomplexan parasitic diseases

Patent metadata

Field	Value
Publication number	US-11964944-B2
Application number	US-202217831049-A
Country	US
Kind code	B2
Filing date	Jun 2, 2022
Priority date	Dec 21, 2015
Publication date	Apr 23, 2024
Grant date	Apr 23, 2024

Abstract

Disclosed herein are novel compounds for treating apicomplexan parasite related disorders, methods for their use; cell line and non-human animal models of the dormant parasite phenotype and methods for their use in identifying new drugs to treat apicomplexan parasite related disorders, and biomarkers to identify disease due to the parasite and its response to treatment.

First claim

We claim:

1. A compound of the structure of
(a) Formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
ring A combines with Y 1 and Y 2 to form a C 3-7 cycloalkenyl or heteroaryl ring,
wherein the C 3-7 cycloalkenyl or heteroaryl is optionally substituted by halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR, cyano or phenyl;

Y 1 is N;
Y 2 is C or N;
X 1 is C(R x1 ) or N,
wherein R x1 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 2 is C(R x2 ) or N,
wherein R x2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 3 is O, N(R), S or C 1-3 alkyl;
X 4 is C or N;
X 5 is C or N;
R 1 is hydrogen or C 1-3 alkyl;
R 2 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, —CH 2 OH, —CH 2 OR or —C(O)OR;
n is 0, 1, 2, 3 or 4;
each R 3 is independently halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR or SF 5 ;
or two R 3 groups, together with the carbons to which they are attached, form a 1,3-dioxolane; and
each R is independently hydrogen or C 1-3 alkyl; or
(b) Formula (I-p):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
ring A combines with Y 1 and Y 2 to form a C 3-7 cycloalkenyl or heteroaryl ring, wherein the C 3-7 cycloalkenyl or heteroaryl is optionally substituted by halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR, cyano or phenyl;
Y 1 is N;
Y 2 is C or N;
X 1 is C(R x1 ) or N,
wherein R x1 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 2 is C(R x2 ) or N,
wherein R x2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 3 is O, N(R), S or C 1-3 alkyl;
X 5 is C or N;
P is —C(O)OR′, —C(O)R′, —C(O)NR′ 2 , wherein R′ is hydrogen, C 1-3 alkyl or —CH 2 OR;
R 2 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, —CH 2 OH, —CH 2 OR, —C(O)OR or —CH 2 OP;
P is —C(O)OR′, —C(O)R′, —C(O)NR′ 2 or —OP(O)(OR′)OR′, wherein each R′ is independently hydrogen or C 1-3 alkyl;
n is 0, 1, 2, 3 or 4;
each R 3 is independently halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR or SF 5 ;
or two R 3 groups, together with the carbons to which they are attached, form a 1,3-dioxolane; and
each R is independently hydrogen or C 1-3 alkyl.

2. The compound of claim 1 , having the structure of (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
ring A combines with Y 1 and Y 2 to form a C 3-7 cycloalkenyl or heteroaryl ring,
wherein the C 3-7 cycloalkenyl or heteroaryl is optionally substituted by halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR, cyano or phenyl;

Y 1 is N;
Y 2 is C or N;
X 1 is C(R x1 ) or N,
wherein R x1 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 2 is C(R x2 ) or N,
wherein R x2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 3 is O, N(R), S or C 1-3 alkyl;
X 4 is C or N;
X 5 is C or N;
R 1 is hydrogen or C 1-3 alkyl;
R 2 is hydrogen, C 1-3 alkyl, C 1-3 haloalkyl, —CH 2 OH, —CH 2 OR or —C(O)OR;
n is 0, 1, 2, 3 or 4;
each R 3 is independently halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR or SF 5 ;
or two R 3 groups, together with the carbons to which they are attached, form a 1,3-dioxolane; and
each R is independently hydrogen or C 1-3 alkyl.

3. The compound of claim 1 , having the structure of (Ia):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
ring A combines with Y 1 and Y 2 to form a C 3-7 cycloalkenyl or heteroaryl ring,
wherein the C 3-7 cycloalkenyl or heteroaryl is optionally substituted by halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR, cyano or phenyl;

Y 1 is N;
Y 2 is C or N;
X 1 is C(R x1 ) or N,
wherein R x1 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 2 is C(R x2 ) or N,
wherein R x2 is hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy or C 1-3 haloalkyl;

X 3 is O, N(R), S or C 1-3 alkyl;
R 1 is hydrogen or C 1-3 alkyl;
R 2 is hydrogen, C 1-3 alkyl or —C(O)OR;
n is 0, 1, 2, 3 or 4;
each R 3 is independently halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O—C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR or SF 5 ; and
each R is independently hydrogen or C 1-3 alkyl.

4. The compound of claim 3 , having
(a) the structure of Formula (Ib):

(b) the structure of Formula (Ic):

5. The compound of claim 3 , having the structure of Formula (III):

wherein
ring A combines with the nitrogen atom and carbon atom with which it is attached to form a heteroaryl ring.

6. The compound of claim 5 , having the structure of Formula (IIIa):

wherein
Y 3 is C(R 5 ) or N; and
R 4 and R 5 are independently hydrogen, halogen, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 haloalkyl, —O —C 1-3 haloalkyl, —S—C 1-3 haloalkyl, —C(O)OR, cyano or phenyl.

7. The compound of claim 6 , having the structure of Formula (IIIb):

8. The compound of claim 7 , wherein R 4 is hydrogen or C 1-3 alkyl.

9. The compound of claim 7 , having the structure of Formula (IIIb-1):

10. The compound of claim 6 , having the structure of Formula (IIIc):

11. The compound of claim 10 , wherein
R 4 is hydrogen or C 1-3 alkylor phenyl; and
R 5 is hydrogen or cyano.

12. The compound of claim 10 , having the structure of Formula (IIIc-1):

13. The compound of claim 1 , having the structure of Formula (IV):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
ring A combines with Y 1 and Y 2 to form a C 3-7 cyc

Assignees

• Univ Chicago
• Univ Leeds Innovations Ltd
• The J Craig Venter Inst
• Inst Systems Biology
• U S Government As Represented By The Secretary Of The Army Medical Command Medcom
• The Univ Of Strathclyde
• J Craig Venter Inst Inc
• Univ Sheffield
• The Univ Of Leeds
• The Government Of The United States

Inventors

• Mcleod Rima
• Mcphillie Martin
• Fishwick Colin W G
• Lorenzi Hernan Alejandro
• Wang Kai
• Kim Taek-Kyun
• Zhou Yong
• Hood Leroy E
• Zhou Ying
• El Bissati Kamal
• Hickman Mark
• Li Qigui
• Roberts Craig

Classifications

• C07D215/233 Primary

  only one oxygen atom which is attached in position 4 · CPC title

• A61P33/06

  Antimalarials · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D471/04

  Ortho-condensed systems · CPC title