IP Library › Granted Patent US 9,624,188

Granted Patent B2

US 9,624,188 · App. 14/775,976 · Granted Apr 18, 2017

IDO inhibitors

Inventors: James Aaron Balog (Lambertville, NJ); Audris Huang (New Hope, PA); Bin Chen (Lambertville, NJ); Libing Chen (Newtown, PA); Weifang Shan (Princeton, NJ)

Assignee: Bristol-Myers Squibb Company

C07D305/06 A61K31/196 A61K31/337 A61K31/41 A61K31/42 A61K31/498 A61K31/505 A61K45/06 C07C275/42 C07D239/42 C07D241/42 C07D255/02 C07D261/14 C07C2101/14

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Quick Facts

Patent No.: US 9,624,188
App. No.: 14/775,976
Granted: Apr 18, 2017
Kind: B2

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Abstract

There are disclosed compounds that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase (IDO), pharmaceutical compositions containing said compounds and methods of treating proliferative disorders, such as cancer, viral infections and/or autoimmune diseases utilizing the compounds of the invention. Formula (I).

Claims (154)

1. A compound of formula I

wherein

X is

W is N or CR 10 ;

Y is N or CR 11 ;

V is N or CR 12 ;

R 1 is optionally substituted aryl-C 1 -C 10 -alkyl, or optionally substituted aryl;

R 2 is —CO 2 H, optionally substituted heterocyclyl, optionally substituted —CONHSO 2 R 14 , optionally substituted —CONHCOR 13 , optionally substituted —SO 2 NHCOR 13 or optionally substituted —NHSO 2 R 14 ;

R 13 is optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;

R 14 is CF 3 or optionally substituted C 1 -C 10 alkyl;

R 3 is H, halo, CN, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;

R 4 is H or optionally substituted C 1 -C 10 alkyl;

R 5 and R 6 are independently H, optionally substituted C 1 -C 10 alkyl or OH, or

R 5 and R 6 are taken together with the carbon to which they are attached to form

R 7 and R 8 are independently H, optionally substituted C 1 -C 10 alkyl, optionally substituted C 1 -C 10 -alkoxy-C 1 -C 10 -alkyl, optionally substituted C 1 -C 10 alkoxy, optionally substituted aryl, optionally substituted aryl-C 1 -C 10 -alkyl, optionally substituted 5- to 8-membered heteroaryl, or optionally substituted C 3 -C 8 cycloalkyl;

R 9 is optionally substituted aryl, optionally substituted C 1 -C 10 alkylaryl, optionally substituted C 1 -C 10 alkoxyaryl, optionally substituted heteroaryl, optionally substituted C 1 -C 10 -alkyl heteroaryl, optionally substituted aryl-C 1 -C 10 -alkylaryl, optionally substituted aryloxyaryl, optionally substituted C 1 -C 10 alkyl, optionally substituted C 2 -C 10 alkenyl, optionally substituted C 2 -C 10 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, or optionally substituted C 4 -C 8 cycloalkenyl;

R 10 , R 11 and R 12 are H;

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 of formula II

wherein

X is

R 1 is optionally substituted aryl-C 1 -C 10 -alkyl, or optionally substituted aryl;

R 13 is optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;

R 14 is CF 3 or optionally substituted C 1 -C 10 alkyl;

R 3 is H, halo, CN, optionally substituted C 1 -C 10 alkyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 2 -C 10 alkenyl or optionally substituted C 2 -C 10 alkynyl;

R 4 is H or optionally substituted C 1 -C 10 alkyl;

R 5 and R 6 are independently H, optionally substituted C 1 -C 10 alkyl or OH, or

R 5 and R 6 are taken together with the carbon to which they are attached to form

R 10 , R 11 and R 12 are H;

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

3. The compound according to claim 2 wherein X is NR 7 R 8 and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 2 wherein X is OR 1 and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

5. The compound according to claim 3 wherein

X is NR 7 R 8 ;

R 2 is CO 2 H or

R 3 is H or C 1 -C 6 alkyl;

R 4 is H or C 1 -C 6 alkyl;

R 5 and R 6 are independently H, C 1 -C 6 alkyl, CF 3 or OH,

or R 5 and R 6 are taken together with the carbon to which they are attached to form

R 7 and R 8 are independently selected from C 1 -C 6 alkyl, C 1 -C 6 -alkoxy-C 1 -C 10 alkyl, C 1 -C 6 alkoxy, or optionally substituted aryl-C 1 -C 6 -alkyl;

R 9 is aryl, C 1 -C 6 alkylaryl, C 1 -C 6 alkoxyaryl, or optionally substituted heteroaryl;

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 4

wherein

X is OR 1 ;

R 1 is aryl-C 1 -C 6 -alkyl or aryl(C 3 -C 8 cycloalkyl)C 1 -C 6 alkyl;

R 2 is CO 2 H;

R 3 is H;

R 4 is H;

R 5 and R 6 are independently selected from H or C 1 -C 6 alkyl;

R 9 is C 1 -C 6 alkylaryl or haloaryl;

and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

7. The compound according to claim 1 which is 3-(4-(diisobutylamino)-3-(3-(3-methylisoxazol-5-yl)ureido)phenyl)butanoic acid, and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising one or more compounds according to claim 1 and a pharmaceutically acceptable carrier or diluent.

9. A method of inhibiting the activity of indoleamine 2,3-dioxygenase comprising contacting said indoleamine 2,3-dioxygenase with a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.

10. The compound of claim 1 that is

3-(4-(diisobutylamino)-3-(3-(p-toly)ureido)phenyl)-2-methylpropanoic acid;

2-(3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)oxetan-3-yl)acetic acid;

3-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid;

3-(4-(diisobutylamino)-3-(3-(2-fluorophenyl)ureido)phenyl)butanoic acid;

3-(3-(3-(4-chloro-2-fluorophenyl)ureido)-4-(diisobutylamino)phenyl)butanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)butanoic acid;

3-(4-(diisobutylamino)-3-(3-(6-methylpyridin-3-yl)ureido)phenyl)butanoic acid;

3-(4-((4-chlorobenzyl)(2-methoxyethyl)amino)-3-(3-(p-toly)ureido)phenyl)butanoic acid;

3-(3-(3-(2-fluorophenyl)ureido)-4-(1-phenylpropoxy)phenyl)butanoic acid;

3-(4-(1-phenylpropoxy)-3-(3-(p-toly)ureido)phenyl)butanoic acid;

3-(4-(cyclopropyl(phenyl)methoxy)-3-(3-(p-toly)ureido)phenyl)butanoic acid;

3-(4-(3-5 phenylpropoxy)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid; 3-(4-(diisobutylamino)-3-(3-(3-methylisoxazol-5-yl)ureido)phenyl)butanoic acid;

3-(4-(diisobutylamino)-3-(3-(p-toly)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(2-fluorophenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-phenoxyphenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(3-(3-(4-chlorophenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-fluorophenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(3-(3-(2,4-dichlorophenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-phenylureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-isopropylphenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-ethylphenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-(trifluoromethyl)phenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-methoxyphenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(o-toly)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(3-(3-(2-chloro-4-methylphenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoic acid;

3-(3-(3-(4-benzylphenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoic acid;

3-(3-(3-(4-(difluoromethoxy)phenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(4-ethoxyphenyl)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)-4,4,4-trifluorobutanoic acid;

3-(4-(diisobutylamino)-3-(3-(m-toly)ureido)phenyl)-4,4,4-trifluorobutanoic acid;

1-(5-(2-(1H-tetrazol-5-yl)ethyl)-2-(diisobutylamino)phenyl)-3-(p-tolyl)urea;

1-(5-(2-(1H-tetrazol-5-yl)ethyl)-2-(diisobutylamino)phenyl)-3-(4-fluorophenyl)urea;

2-(1-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropyl)acetic acid;

(R)-3-(4-(diisobutylamino)-3-(3-(quinoxalin-6-yl)ureido)phenyl)butanoic acid;

(S)-3-(4-(diisobutylamino)-3-(3-(quinoxalin-6-yl)ureido)phenyl)butanoic acid;

(R)-3-(4-(diisobutylamino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)butanoic acid;

(S)-3-(4-(diisobutylamino)-3-(3-(pyrimidin-5-yl)ureido)phenyl)butanoic acid;

(S)-3-(4-(diisobutylamino)-3-(3-(2-5 methylpyrimidin-5-yl)ureido)phenyl)butanoic acid;

(R)-3-(4-(diisobutylamino)-3-(3-(2-methylpyrimidin-5-yl)ureido)phenyl)butanoic acid;

(R)-3-(4-(diisobutylamino)-3-(3-(p-toly)ureido)phenyl)butanoic acid;

(R)-3-(4-(diisobutylamino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)butanoic acid; (S)-3-(4-(diisobutylamino)-3-(3-(p-toly)ureido)phenyl)butanoic acid;

(S)-3-(4-(diisobutylamino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)butanoic acid;

(R)-3-(3-(2-(4-cyanophenyl)acetamido)-4-(diisobutylamino)phenyl)butanoic acid;

3-(4-(diisobutylamino)-3-(3-(3-(trifluoromethyl)isoxazol-5-yl)ureido)phenyl)butanoic acid;

3-(3-(3-(3-cyclopropylisoxazol-5-yl)ureido)-4-(diisobutylamino)phenyl)butanoic acid;

3-(4-(diisobutylamino)-3-(3-(5-methylisoxazol-3-yl)ureido)phenyl)butanoic acid;

or 3-(4-(cyclohexyl(isobutyl)amino)-3-(3-(p-tolyl)ureido)phenyl)butanoic acid; and/or a stereoisomer, a tautomer or a pharmaceutically acceptable salt thereof.

11. The method of claim 9 comprising contacting said indoleamine 2,3-dioxygenase with a compound according to claim 1 that is