TDO2 Inhibitors

Patent metadata

Field	Value
Publication number	US-10800780-B2
Application number	US-201616065397-A
Country	US
Kind code	B2
Filing date	Dec 23, 2016
Priority date	Dec 24, 2015
Publication date	Oct 13, 2020
Grant date	Oct 13, 2020

Abstract

Presently provided are inhibitors of cellularly expressed TDO2 and pharmaceutical compositions thereof, useful for modulating an activity of tryptophan 2, 3 dioxygenase; treating immunosuppression; treating a medical conditions that benefit from the inhibition of tryptophan degradation; enhancing the effectiveness of an anti-cancer treatment comprising administering an anti-cancer agent; and treating tumor-specific immunosuppression associated with cancer.

First claim

The invention claimed is:

1. A compound of formula (I):

or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof,
wherein
R 1 is

wherein the hydroxy moiety is bonded to the A ring, and each R a is independently a substituent of the A ring or the B ring;

ring A is C 3-8 cycloalkyl or 3-7 membered heterocyclyl, and
the hydroxy moiety is bonded to the A ring and each R a is independently a substituent of the A ring or the B ring;

or
wherein, unless stated otherwise above,
ring A is C 3-10 cycloalkyl or 3-7 membered heterocyclyl, and
ring B is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, aryl or heteroaryl,
m is 0, 1, 2, 3 or 4,
R 4 is —OH,
each R a is independently selected from oxo, halogen, cyano, nitro, C 1-6 alkyl, —C 1-6 haloalkyl, C 1-6 alkyl-cyano, —OR, —NR 2 , —SR, —C(O)OR, —C(O)N(R) 2 , —C(O)R, —S(O)R, —S(O)OR, —S(O)N(R) 2 , —S(O) 2 R, —S(O) 2 OR, —S(O) 2 N(R) 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR, and —N(R)C(O)N(R) 2 ;
n is 0 or 1;
each R 2 is independently halogen, cyano, C 1-6 alkyl, C 3 cycloalkyl, —C 1-6 haloalkyl, —OR, —NR 2 or —SR; and
each R is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

2. A compound of formula (I),

wherein R 1 is

wherein R 3 is methyl, ethyl, propyl, butyl, —O-methyl, —O-ethyl, —O-propyl, or —O-butyl;

wherein R 3 is a methyl, ethyl, propyl, or butyl;

or

R 4 is —OH;
n is 0 or 1;
each R 2 is independently hydrogen, C 1-6 alkyl or C 1-6 haloalkyl.

3. The compound of claim 1 , wherein each R a is independently selected from halogen, C 1-6 alkyl, —OR, —S(O) 2 R and —S(O) 2 N(R) 2 .

4. The compound of claim 1 , wherein n is 1.

5. The compound of claim 1 , wherein each R 2 is independently halogen.

6. The compound of claim 2 , wherein R 2 is halogen.

7. The compound of any of claim 1 , wherein n is 0.

8. The compound of claim 1 of formula (Ie):

9. A compound that is
2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol,
7-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-8-ol,
3-(5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol,
4-(5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol,
7-(5H-imidazo[4,3-a]isoindol-5-yl)-5H,6H,7H,8H-imidazo[1,5-a]pyridin-8-ol,
6-(5H-imidazo[4,3-a]isoindol-5-yl)-5,6,7,8-tetrahydroisoquinolin-5-ol,
1-(3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one,
tert-butyl 3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate,
tert-butyl 4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-carboxylate,
1-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)ethan-1-one,
2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol,
2-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile,
1-(ethylsulfonyl)-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-4-ol,
1-(ethylsulfonyl)-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-3-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.3]heptan-1-ol,
4,4-difluoro-2-((S)-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)-2,3-dihydro-1H-inden-1-ol,
2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol,
4-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclobutan-1-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)-3,3-dimethylcyclobutan-1-ol,
5-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclopentan-1-ol,
6-(5H-imidazo[5,1-a]isoindol-5-yl)-2,2-dimethylcyclohexan-1-ol,
2-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol,
4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol,
2-(3-hydroxy-4-(-5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile,
3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)pyrrolidine-1-sulfonamide,
9-hydroxy-8-(5H-imidazo[5,1-a]isoindol-5-yl)-6,7,8,9-tetrahydro-4H-quinolizin-4-one,
4-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-ol,
6-(5H-imidazo[5,1-a]isoindol-5-yl)-5,6,7,8-tetrahydroquinolin-5-ol,
4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrofuran-3-amine,
4-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-3-ol,
3-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-tetrahydro-2H-pyran-4-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)-1-methylcyclobutan-1-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)-6-(methylsulfonyl)-1,2,3,4-tetrahydronaphthalen-1-ol,
3-(5H-imidazo[5,1-a]isoindol-5-yl)bicyclo[2.2.2]octan-2-ol,
3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydrothiophene 1,1-dioxide,
3-hydroxy-4-(5H-imidazo[5,1-a]isoindol-5-yl)piperidine-1-sulfonamide,
1-(ethylsulfonyl)-4-(5H-imidazo[5,1-a]isoindol-5-yl)pyrrolidin-3-ol,
tert-butyl 7-hydroxy-6-(5H-imidazo[1,5-b]isoindol-5-yl)-2-azaspiro[3.3]heptane-2-carboxylate,
4-(5H-imidazo[5,1-a]isoindol-5-yl)tetrahydro-2H-pyran-4-ol,
3-(5H-imidazo[5,1-a]isoindol-5-yl)thietan-3-ol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol,
3-(5H-imidazo[5,1-a]isoindol-5-yl)oxetan-3-ol,
3,3-difluoro-1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol,
4,4-difluoro-1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclohexan-1-ol,
3,3-bis(fluoromethyl)-1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclobutan-1-ol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)cyclopentan-1-ol,
5-(5H-imidazo[5,1-a]isoindol-5-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-4-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)-7-oxaspiro[3.5]nonan-1-ol,
2-(4-hydroxy-3-(5H-imidazo[5,1-a]isoindol-5-yl)piperidin-1-yl)acetonitrile,
6-(5H-imidazo[5,1-a]isoindol-5-yl

Assignees

• Genentech Inc
• Newlink Genetics Corp

Inventors

• Lin Xingyu
• Yuen Po-Wai
• Mendonca Rohan
• Parr Brendan
• Pastor Richard
• Pei Zhonghua
• Gazzard Lewis
• Jaipuri Firoz
• Kumar Sanjeev
• Li Xiaokai
• Pavana Roheeth
• POTTURI Hima
• Velvadapu Venkata
• Waldo Jesse
• Zhang Zuhui
• Wu Guosheng
• Sellers Benjamin Douglas

Classifications

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61K38/16

  Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)} · CPC title

• A61K2300/00

  Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00 · CPC title