Inhibitors of indoleamine 2,3-dioxygenase
A compound of Formula I: or pharmaceutically acceptable enantiomers, or salts thereof. The present invention also relates to the use of compounds of Formula (I) as selective inhibitors of indoleamine 2,3-dioxygenase. The invention also relates to the use of the compounds of Formula (I) for the treatment or prevention of diseases cancer, infections, central nervous system disease or disorder, and immune-related disorders, either as a single agent or in combination with other therapies.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof wherein,
R 1 is selected from the group consisting of:
R 11 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 12 is halogen, (1-2C)alkyl (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, (3-8C)cycloalkyl, or cyano, all alkyl, alkoxy and cycloalkyl groups optionally being substituted with one or more halogen;
R 13 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 15 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 2 is selected from the group consisting of:
a) hydrogen,
b) (1-6C)alkyl,
wherein (1-6C)alkyl optionally can be substituted,
R 3 is selected from the group consisting of:
a) (6-10C)aryl,
b) (1-9C)heteroaryl,
c) (3-8C)cycloalkyl,
d) (2-7C)heterocycloalkyl,
e) (1-6C)alkyl,
f) (1-6)alkylamino,
g) (3-6C)cycloalkylamino
h) (6-10C)arylamino,
i) (1-9C)heteroarylamino,
j) (2-7C)heterocycloalkylamino,
wherein all groups optionally can be substituted,
R 4 is selected from the group consisting of:
a) hydrogen,
b) (1-6C)alkyl,
wherein (1-6C)alkyl optionally can be substituted,
R 5 is selected from the group consisting of:
a) hydrogen,
b) (1-6C)alkyl,
wherein (1-6C)alkyl optionally can be substituted,
A is selected from CH(R a ), C(O), S(O) or SO 2 ,
R a is selected from the group consisting of:
a) hydrogen,
b) (1-6C)alkyl,
wherein (1-6C)alkyl optionally can be substituted with fluorine or hydroxyl.
2. The compound according to claim 1 wherein R 2 is hydrogen, and A is C(O) or CH(R a ).
3. The compound according to claim 1 wherein R 4 and R 5 are selected from the group of hydrogen, methyl, and ethyl, whereby if one of R 4 and R 5 is not hydrogen, the other one must be hydrogen.
4. The compound according to claim 1 wherein R 1 is
R 11 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 12 is halogen, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, (3-8C)cycloalkyl, or cyano, all alkyl, alkoxy and cycloalkyl groups optionally being substituted with one or more halogen;
R 13 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 14 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 15 is H, halogen, (1-2C)alkyl or (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen.
5. The compound according to claim 1 wherein R 1 is
R 11 , R 15 , R 14 is H or fluorine,
R 12 is halogen, (1-2C)alkyl, (2-3C)alkenyl or (2-3C)alkynyl, all alkyl groups optionally being substituted with one or more halogen,
R 13 is H or halogen.
6. The compound according to claim 1 wherein R 3 is selected from the group consisting of (6-10C)aryl, (1-9C)heteroaryl, (3-8C)cycloalkyl, (2-7C)heterocycloalkyl, and (1-6C)alkyl, preferably (6-10C)aryl, (1-9C)heteroaryl and (3-8C)cycloalkyl, wherein all groups optionally can be substituted.
7. The compound according to claim 1 wherein R 3 is
R 31 and R 35 are independently selected from the group consisting of:
hydrogen, halogen, cyano, (1-2C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl and (1-2C)alkoxy, all alkyl and alkoxy groups optionally being substituted with one or more halogen; R 32 and R 34 are independently selected from the group consisting of:
hydrogen, halogen, cyano, (1-6C)alkyl, (2-3C)alkenyl, (2-3C)alkynyl, (1-2C)alkoxy, (1-3C)alkoxy(1-6C)alkylaminocarbonyl, amino, nitro, (1-6C)alkylcarbonylamino or (1-6C)alkylsulfonylamino, all alkyl and alkoxy groups optionally being substituted with one or more halogen;
R 33 is selected from the group consisting of:
hydrogen, halogen, cyano, (1-6C)alkyl, (2-3C)alkenyl, (2-6C)alkynyl, (1-3C)alkoxy, (6-10C)aryl, (1-5C)heteroaryl, (2-7C)heterocycloalkyl, (3-8C)cycloalkyl, (6-10C)aryloxy, (1-6C)alkylsulfonylamino(1-6C)alkyl, aminosulfonylamino(1-6C)alkyl, (3-8C)cycloalkyl(1-6C)alkyl, (1-6C)alkylcarbonylamino(2-6C)alkynyl, amino(2-6C)alkynyl, aminosulfonylamino(2-6C)alkynyl, (3-8C)cycloalkyl(2-3C)alkynyl, (1-6C)alkylsulfonylamino(2-6C)alkynyl, (1-3C)alkoxy(1-6C)alkylaminocarbonyl, (6-10C)aryl(1-6C)alkyl, (1-3C)alkylsulfonyl(6-10C)aryl, di[(1-6C)alkyl]amino, all alkyl and alkoxy groups optionally being substituted with one or more halogen or hydroxy, all (1-5C)heteroaryl groups optionally being substituted with one or more halogen or one or more (1-6C)alkyl.
8. The compound according to claim 1 wherein R 3 is
R 31 and R 35 are independently selected from the group consisting of: hydrogen, fluoro and chloro; R 32 and R 34 are hydrogen; R 33 hydrogen, halogen, (1-6C)alkyl, (2-3C)alkenyl, (2-6C)alkynyl, (1-3C)alkoxy, (6-10C)aryl, (1-5C)heteroaryl, (3-8C)cycloalkyl, (1-6C)alkylsulfonylamino(1-6C)alkyl, aminosulfonylamino(1-6C)alkyl, (3-8C)cycloalkyl(1-6C)alkyl, amino(2-6C)alkynyl, aminosulfonylamino(2-6C)alkynyl, (3-8C)cycloalkyl(2-3C)alkynyl, (1-6C)alkylsulfonylamino(2-6C)alkynyl, (1-3C)alkoxy(1-6C)alkylaminocarbonyl, di[(1-6C)alkyl]amino, all alkyl and alkoxy groups optionally being substituted with one or more halogen or hydroxy, all (1-5C)heteroaryl groups optionally being substituted with one or more halogen or one or more (1-6C)alkyl.
9. A method for inhibiting an indoleamine 2,3-dioxygenase (IDO1), comprising contacting the IDO1 with the compound or the pharmaceutically acceptable salt thereof according to claim 1 .
10. A pharmaceutical composition comprising the compound or the pharmaceutically acceptable salt thereof according to claim 1 , and one or more pharmaceutically acceptable excipients.
11. The pharmaceutical composition according to claim 10 , which further comprises at least one additional therapeutically active agent.
12. A method of treating an increase in indoleamine 2,3-dioxygenase (IDO1) activity associated with diseases, disorders or conditions, comprising administering the compound or the pharmaceutically acceptable salt thereof according to claim 1 to a patient in need of the treating.
13. The method according to claim 12 , wherein the diseases, disorders or conditions are selected from cancer, viral or parasitic infections, central nervous system diseases, neuropsychiatric and neurodegenerative diseases, cerebrovascular disease, and immune-related disorders.
14. The compound or the pharmaceutically acceptable salt thereof according to claim 1 , wherein the compound or the pharmaceutically acceptable salt thereof has an inhibitory potency on indoleamine 2,3-dioxygenase (IDO1) with an IC 50 of 25 μM or less.
15. The method according to claim 12 , wherein the diseases, disorders or conditions is selected from the group of infection with influenza virus or Leishmania major , depression, Huntington's disease, Parkinson's disease, AIDS dementia complex, infections of the central nervous system, malaria, ischemia, hypoxia at birth, traumatic brain injury, epilepsy, anxiety, schizophrenia, inflammatory bowel disease (IBD), colitis Crohn's disease, obesity, and diabetes.