TDO2 and IDO1 inhibitors

Patent metadata

Field	Value
Publication number	US-11603373-B2
Application number	US-201816626219-A
Country	US
Kind code	B2
Filing date	Jun 20, 2018
Priority date	Jun 28, 2017
Publication date	Mar 14, 2023
Grant date	Mar 14, 2023

Abstract

Presently provided are inhibitors of cellularly expressed TD02 and IDO1, and pharmaceutical compositions thereof, useful for modulating an activity of tryptophan 2,3 dioxygenase and indoleamine 2,3-dioxygenase 1; 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
wherein each R a is independently 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, —N(R)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 , —P(O)R 2 , —OC(O)R, —OC(O)OR, —OC(O)N(R) 2 , —N(R)C(O)R, —N(R)C(O)OR or —N(R)C(O)N(R) 2 ;
n is 0, 1, 2, 3 or 4;
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, C 1-6 haloalkyl, C 1-6 alkyl-O—C 1-6 alkyl, —C 1-6 alkyl-NHC(O)H, optionally substituted C 3-6 cycloalkyl, optionally substituted 4-10 membered heterocycloalkyl, optionally substituted —C 1-6 alkyl-(4-10 membered heterocycloalkyl), optionally substituted heteroaryl, optionally substituted —C 1-6 alkyl-heteroaryl.

2. The compound of claim 1 , wherein n is 0, 1, 2 or 3.

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

4. The compound of claim 1 , wherein each R a is independently 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, —N(R)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 or —N(R)C(O)N(R) 2 .

5. The compound of claim 1 , wherein each R a is independently C 1-6 alkyl, —C(O)OR, —C(O)N(R) 2 , —C(O)R, —N(R)C(O)R, —S(O)N(R) 2 , —S(O) 2 R, —P(O)R 2 , —OC(O)R, —OC(O)OR or —OC(O)N(R) 2 .

6. The compound of claim 1 , wherein each R a is independently —C(O)OR, —C(O)R, —N(R)C(O)R, —S(O)N(R) 2 , —S(O) 2 R or —P(O)R 2 .

7. The compound of claim 1 of formula (Ia),

or a stereoisomeric mixture thereof.

8. The compound of claim 1 , wherein each R is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, fluoromethyl, difluoromethyl, —CH 2 CHF 2 , —(CH 2 ) 2 —O—CH 3 , —CH(CH 3 )NHC(O)H, —(CH 2 ) 2 —C(O)NMe 2 , —CH 2 CN, cyclopropyl, difluorocyclopropyl, cyclopropane-1-carbonitrile, cyclobutyl, 1-methylpyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 1,3,5-trimethylpyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methylpyridin-3-yl, —(CH 2 ) 2 -pyridin-3-yl, phenyl-N-methylacetamide, —CH 2 -piperidin-1-yl, 1-methylindolin-2-one, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, —CH 2 -piperidin-2-one, 1-methylpiperidin-2-one, —CH(CH 3 )-(1H-1,2,4-triazol-1-yl), 1-methyl-1H-pyrazol-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, —CH 2 -(tetrahydro-2H-pyran-4-yl), —CH 2 -(pyrrolidin-2-one), —CH 2 -(1-methylpyrrolidin-2-one), —CH 2 -(5-methylisoxazol-3-yl), —(CH 2 ) 2 -(1-methyl-1H-pyrazol-4-yl), 1H-imidazol-4-yl, —CH 2 -(1H-tetrazol-5-yl), —CH 2 -(3-methylisoxazol-5-yl), piperidine-1-carboxamide, 1,1-dioxidotetrahydrothiophen-3-yl or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl.

9. The compound of claim 7 , wherein each R is independently hydrogen, methyl, ethyl, isopropyl, tert-butyl, fluoromethyl, difluoromethyl, —CH 2 CHF 2 , —(CH 2 ) 2 —O—CH 3 , —CH(CH 3 )NHC(O)H, —(CH 2 ) 2 —C(O)NMe 2 or —CH 2 CN.

10. The compound of claim 1 , wherein each R is independently hydrogen, methyl, cyclopropyl, difluorocyclopropyl, cyclopropane-1-carbonitrile, cyclobutyl, 1-methylpyrazol-4-yl, 1-methyl-1H-pyrazol-3-yl, 1,3,5-trimethylpyrazol-4-yl, 1,3,5-trimethyl-1H-pyrazol-4-yl, 1,2-dimethyl-1H-imidazol-4-yl, 3,5-dimethylisoxazol-4-yl, 4-methylpyridin-3-yl, —(CH 2 ) 2 -pyridin-3-yl, phenyl-N-methylacetamide, —CH 2 -piperidin-1-yl, 1-methylindolin-2-one, 6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazinyl, —CH 2 -piperidin-2-one, 1-methylpiperidin-2-one, —CH(CH 3 )-(1H-1,2,4-triazol-1-yl), 1-methyl-1H-pyrazol-3-yl, tetrahydro-2H-pyran-4-yl, tetrahydrofuran-3-yl, —CH 2 -(tetrahydro-2H-pyran-4-yl), —CH 2 -(pyrrolidin-2-one), —CH 2 -(1-methylpyrrolidin-2-one), —CH 2 -(5-methylisoxazol-3-yl), —(CH 2 ) 2 -(1-methyl-1H-pyrazol-4-yl), 1H-imidazol-4-yl, —CH 2 -(1H-tetrazol-5-yl), —CH 2 -(3-methylisoxazol-5-yl), piperidine-1-carboxamide, 1,1-dioxidotetrahydrothiophen-3-yl or 5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyridin-6-yl.

11. A compound that is
tert-butyl 1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-7-azaspiro[3.5]nonane-7-carboxylate;
tert-butyl 1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-8-azaspiro[4.5]decane-8-carboxylate;
tert-butyl 5-hydroxy-6-(5H-imidazo[4,3-a]isoindol-5-yl)-2-azaspiro[3.4]octane-2-carboxylate;
6-(5H-imidazo[1,5-b]isoindol-5-yl)-2-methylsulfonyl-2-azaspiro[3.3]heptan-7-ol;
7-fluoromethanesulfonyl-2-(5H-imidazo[4,3-a]isoindol-5-yl)-7-azaspiro[3.5]nonan-1-ol;
methyl 1-hydroxy-2-(5H-imidazo[4,3-a]isoindol-5-yl)-8-azaspiro[4.5]decane-8-carboxylate;
1-(1-hydroxy-2-(5H-imidazo[4,3-a]isoindol-5-yl)-8-azaspiro[4.5]decan-8-yl)ethan-1-one;
tert-butyl 2′-hydroxy-3′-(5H-imidazo[5,1-a]isoindol-5-yl)-8-azaspiro[bicyclo[3.2.1]octane-3,1′-cyclobutane]-8-carboxylate;
1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-8-thiaspiro[4.5]decane 8,8-dioxide;
7-((difluoromethyl)sulfonyl)-2-(5H-imidazo[5,1-a]isoindol-5-yl)-7-azaspiro[3.5]nonan-1-ol;
(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-7-azaspiro[3.5]nonan-7-yl)dimethylphosphine oxide;
6-(5H-imidazo[5,1-a]isoindol-5-yl)-2-(methylsulfonyl)-2-azaspiro[3.4]octan-5-ol;
1-(5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)-2-azaspiro[3.4]octan-2-yl)ethan-1-one;
5-hydroxy-6-(5H-imidazo[5,1-a]isoindol-5-yl)-2-azaspiro[3.4]octane-2-sulfonamide;
2-methoxyethyl 1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-8-azaspiro[4.5]decane-8-carboxylate;
cyclopropyl(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-8-azaspiro[4.5]decan-8-yl)methanone;
2-[[3-hydroxy-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-7-yl]sulfonyl]acetonitrile;
tert-butyl 2′-hydroxy-3′-(5H-imidazo[5,1-a]isoindol-5-yl)-3-azaspiro[bicyclo[3.2.1]octane-8,1′-cyclobutane]-3-carboxylate;
2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-(oxetan-3-ylsulfonyl)-7-azaspiro[3.5]nonan-3-ol;
tert-butyl (1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)spiro[3.5]nonan-7-yl)carbamate;
(2,2-difluorocyclopropyl)(1-hydroxy-2-(5H-imidazo[5,1-a]isoindol-5-yl)-8-azaspiro[4.5]decan-8-yl)methanone;
2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-(1-methylpyrazol-4-yl)sulfonyl-7-azaspiro[3.5]nonan-3-ol;
2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-(1,3,5-trimethylpyrazol-4-yl)sulfonyl-7-azaspiro[3.5]nonan-3-ol;
7-(2,3-dimethylimidazol-4-yl)sulfonyl-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-3-ol;
2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-isopropylsulfonyl-7-azaspiro[3.5]nonan-3-ol;
7-(3,5-dimethylisoxazol-4-yl)sulfonyl-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-3-ol;
7-(1,2-dimethylimidazol-4-yl)sulfonyl-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-3-ol;
2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-[(4-methyl-3-pyridyl)sulfonyl]-7-azaspiro[3.5]nonan-3-ol;
1-[3-hydroxy-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-7-yl]-3-(3-pyridyl)propan-1-one;
N-[4-[[3-hydroxy-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-7-yl]sulfonyl]phenyl]-N-methyl-acetamide;
1-[4-[[3-hydroxy-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-7-yl]sulfonyl]-1-piperidyl]ethanone;
7-cyclobutylsulfonyl-2-(5H-imidazo[1,5-b]isoindol-5-yl)-7-azaspiro[3.5]nonan-3-ol;
5-[[3-hydr

Assignees

• Genentech Inc

Inventors

• Pei Zhonghua
• Pastor Richard
• Gazzard Lewis
• Parr Brendan
• Liu Wendy
• Mendonca Rohan
• Wu Guosheng
• Yuen Po-Wai

Classifications

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• C07D335/00

  Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C07D221/00

  Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 · CPC title