Granted Patent B2

US 11,414,385 · App. 16/063,877 · Granted Aug 16, 2022

Inventors: Rima McLeod (Chicago, IL); Martin McPhillie (Leeds, GB); Colin W. G. Fishwick (Leeds, GB); Hernan Alejandro Lorenzi (Rockville, MD); Kai Wang (Seattle, WA); Taek-Kyun Kim (Seattle, WA); Yong Zhou (Seattle, WA); Leroy E. Hood (Seattle, WA); Ying Zhou (Chicago, IL); Kamal El Bissati (Chicago, IL); Mark Hickman (Silver Spring, MD); QiGui Li (Silver Spring, MD); Craig Roberts (Glasgow, GB)

C07D215/233A61P33/06C07D401/12C07D405/12C07D471/04C07D487/04

Abstract

Claims (153)

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 C;

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) compound of the structure of 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 C;

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 C;

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 C;

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):

(c) the structure of Formula (II):

wherein ring A combines with the carbon atoms with which it is attached to form a C 3-7 cycloalkenyl;

(d) the structure of Formula (IIa):

or

(e) the structure of Formula (IIa-1):

wherein R 3 is hydrogen, halogen, C 1-3 alkyl or C 1-3 haloalkyl.

5. 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 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 C;

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 3 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 ; and

each R is independently hydrogen or C 1-3 alkyl.

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

wherein

ring A combines with the carbon atoms with which it is attached to form a C 3-7 cycloalkenyl.

7. The compound of claim 5 , having the structure of Formula (IVb):

8. A compound that is:

Structure

Name

2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)- one

2-methyl-3-(4-phenoxyphenyl)quinolin-4(1H)-one

1-ethyl-2-methyl-3-(4-phenoxyphenyl)quinolin- 4(1H)-one

3-(4-(4-chlorophenoxy)-3-hydroxyphenyl)-2- methylquinolin-4(1H)-one

2-methyl-3-(4-phenoxyphenyl)-5,6,7,8- tetrahydroquinolin-4(1H)-one

2-methyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)-5,6,7,8- tetrahydroquinolin-4(1H)-one

4-((5-(2-methyl-4-oxo-1,4,5,6,7,8- hexahydroquinolin-3-yl)pyridin-2-yl)oxy)benzoic acid

4-(4-(2-methyl-4-oxo-1,4,5,6,7,8- hexahydroquinolin-3-yl)phenoxy)benzoic acid

3-(4-(2-methyl-4-oxo-1,4,5,6,7,8- hexahydroquinolin-3-yl)phenoxy)benzoic acid

3-(4-(4-chlorophenoxy)phenyl)-2-methyl-5,6,7,8- tetrahydroquinolin-4(1H)-one

3-(4-(4-fluorophenoxy)phenyl)-2-methyl-5,6,7,8- tetrahydroquinolin-4(1H)-one

2-methyl-3-(4-(4- (trifluoromethyl)phenoxy)phenyl)-5,6,7,8- tetrahydroquinolin-4(1H)-one

3-(4-(3-chlorophenoxy)phenyl)-2-methyl-5,6,7,8- tetrahydroquinolin-4(1H)-one

3-(4-(3-fluorophenoxy)phenyl)-2-methyl-5,6,7,8- tetrahydroquinolin-4(1H)-one

1,2-dimethyl-3-(4-(4- (trifluoromethoxy)phenoxy)phenyl)-5,6,7,8- tetrahydroquinolin-4(1H)-one

3-(4-(4-chlorophenoxy)phenyl)-1,2-dimethyl- 5,6,7,8-tetrahydroquinolin-4(1H)-one

2-methyl-3-(4-(3- (trifluoromethoxy)phenoxy)phenyl)-5,6,7,8- tetrahydroquinolin-4(1H)-one

2-methyl-3-(4-(3- (trifluoromethyl)phenoxy)phenyl)-5,6,7,8- tetrahydroquinolin-4(1H)-one

3-(4-(3,5-dichlorophenoxy)phenyl)-2-methyl- 5,6,7,8-tetrahydroquinolin-4(1H)-one

3-(4-(3-chloro-4-fluorophenoxy)phenyl)-2-methyl- 5,6,7,8-tetrahydroquinolin-4(1H)-one

methyl 3-((5-(4-ethoxy-2-methyl-5,6,7,8-tetrahydroquinolin-3-yl)pyridin-2-yl)oxy) benzoate

1,2-dimethyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-5,6,7,8-tetrahydroquinolin-4-one

3-(4-(3,4-Dichlorophenoxy)phenyl)-2-methyl-5,6,7,8-tetrahydroquinolin-4(1H)-one

3-[4-(3-chloro-4-fluorophenoxy)phenyl]-2-methyl-5,6,7,8-tetrahydro-1H-quinolin-4-one

3-{4-[(2,6-dichloropyridin-4-yl)oxy]phenyl}-2-methyl-5,6,7,8-tetrahydro-1H-quinolin-4-one

3-[4-(3,5-dichlorophenoxy)phenyl]-2-methyl-5,6,7,8-tetrahydro-1H-quinolin-4(1H)-one

3 (4-(4-Trifluoromethoxyphenoxy)phenyl)-2-(carboxylate)-5,6,7,8-tetrahydroquinolin-4(1H)-one

3-(6-(4-Trifluoromethoxyphenoxy)pyrdin-3-yl)-2-methyl-5,6,7,8-tetrahydroquinolin-(4)-one

3-(4-Phenonxyphenyl)-1,2,3,4,5,6,7,8-octahydroquinazoline-2,4,dione

3-(4-(4-Trifluoromethoxyphenoxy)phenyl)-2-(methylhydroxy)-5,6,7,8-tetrahydroquinolin-4(1H)-one

3-[4-(2H-1,3-benzodioxol-5-yloxy)phenyl]-2-methyl-5,6,7,8-tetrahydro-1H-quinolin-4-one

6-Ethyl-3-(4-(4-trifluoromethoxyphenoxy)phenyl)-2-methyl-5,6,7,8-tetrahydroquinolin-4(1H)-one

3-(4-(4-Trifluoromethoxyphenoxy)phenyl)-2,6-dimethyl-5,6,7,8-tetrahydroquinolin-4(1H)-one

3-(4-(4-Trifluoromethoxyphenoxy)phenyl)-2,7-dimethyl-5,6,7,8-tetrahydroquinolin-4(1H)-one

7-Ethyl-2-methyl-3(4-(4-trifluoromethoxyphenoxy)phenyl)-5,6,7,8-tetrahydroquinolin-4(1H)-one

3-(4-(4-trifluoromethoxyphenoxy)phenyl)-2-methyl-1,7-naphthyrid-4(1H)-one

7-Trifluromethyl-2-methyl-3(4-(4-trifluoromethoxyphenoxy)phenyl)-5,6,7,8-tetrahydroquinolin-4(1H)-one

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

9. The compound of claim 1 that is 2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)-5,6,7,8-tetrahydroquinolin-4(1H)-one, or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent, excipient, or carrier.

11. A method for treating an apicomplexan parasitic infection, comprising administering to a subject in need thereof an amount effective to treat the infection of the compound or pharmaceutical composition of claim 1 .

Assignments (9)

Continuity (3)