US 12,583,858 B2 · TDO2 inhibitors

TDO2 inhibitors

AssigneesGenentech, Inc., NewLink Genetics Corporation

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

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Abstract

Presently provided are inhibitors of cellularly expressed TD02 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.

Claims14

Dependent claims

A compound of the formula

or a pharmaceutically acceptable salt thereof wherein
Ring A is C3-8cycloalkyl, 3-7 membered heterocyclyl or heteroaryl;
m is 0, 1, 2 or 3;
R4 is OH;
and
each Ra is independently selected from halogen, C1-6alkyl, —S(O)2R, —C(O)N(R)2 and C1-6alkyl-cyano;
R2 is independently hydrogen, halogen, C1-C6 alkyl, C3cycloalkyl, C1-C6 haloalkyl, halogen, cyano, —OR, —NR2 or —SR;
and
each R is independently hydrogen, C1-6alkyl or C1-6haloalkyl.

6 more elements

A compound that is

1-(5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol,
2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
cyclopropyl(5H-imidazo[5,1-a]isoindol-5-yl)methanol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol,
1-(8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol,
(5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol,
1-(5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol,
cyclohexyl(5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(5H-imidazo[5,1-a]isoindol-5-yl) (pyridin-4-yl)methanol,
(1-fluorocyclopropyl) (5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol,
(R)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol,
(S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol,
(S)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethan-1-ol,
(R)-2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol,
(S)-2-(5H-imidazo[5,1-a]isoindol-5-yl)propan-2-ol,
(R)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol,
(R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol,
(S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol,
(S)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)ethane-1,2-diol,
(S)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(R)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(S)-cyclopropyl((S)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)-cyclopropyl((R)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(R)-cyclopropyl((S)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(R)-cyclopropyl((R)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol,
(R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-(tetrahydro-2H-pyran-4-yl)ethan-1-ol,
(S)-1-((R)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(R)-1-((R)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(R)-1-((S)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(S)-1-((S)-8-fluoro-5H-imidazo[5,1-a]isoindol-5-yl)-2-methylpropan-1-ol,
(R)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol,
(S)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol,
(R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol,
(S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)propan-1-ol,
(R)—((S)-5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol,
(S)—((R)-5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol,
(R)—((R)-5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol,
(S)—((S)-5H-imidazo[5,1-a]isoindol-5-yl)(tetrahydro-2H-pyran-4-yl)methanol,
(R)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol,
(R)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol,
(S)-1-((R)-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol,
(S)-1-((S)-5H-imidazo[5,1-a]isoindol-5-yl)-1-(1H-imidazol-2-yl)ethan-1-ol,
(R)-cyclohexyl((S)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)-cyclohexyl((R)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(R)-cyclohexyl((R)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)-cyclohexyl((S)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)—((R)-5H-imidazo[5,1-a]isoindol-5-yl) (pyridin-4-yl)methanol,
(R)—((S)-5H-imidazo[5,1-a]isoindol-5-yl) (pyridin-4-yl)methanol,
(S)—((S)-5H-imidazo[5,1-a]isoindol-5-yl) (pyridin-4-yl)methanol,
(R)—((R)-5H-imidazo[5,1-a]isoindol-5-yl) (pyridin-4-yl)methanol,
(R)-(1-fluorocyclopropyl) ((R)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)-(1-fluorocyclopropyl) ((S)-5H-imidazo[5,1-a]isoindol-5-yl)methanol,
(S)-(1-fluorocyclopropyl) ((R)-5H-imidazo[5,1-a]isoindol-5-yl)methanol, or
(R)-(1-fluorocyclopropyl) ((S)-5H-imidazo[5,1-a]isoindol-5-yl)methanol.

58 more elements

A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein
R1 is
C4-C6 cycloalkyl or 5-6-membered heterocyclyl, each of which is substituted with hydroxy on the carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl;
or
C4-C6 cycloalkyl substituted with =(spiro-(4-6-membered heterocyclyl)), each of which ring systems is further substituted with hydroxy on the carbon atom adjacent to the carbon atom bonded to the 5H-imidazo[5,1-a]isoindolyl;
and
wherein each R1 is optionally further substituted by one, two, three, or four Ra groups independently selected from, halogen, cyano, nitro, —OR, —NR2, —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)2R, —S(O)2OR, —S(O)2N(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;
wherein
R2 is independently C1-C6 alkyl, C3cycloalkyl, C1-C6 haloalkyl, halogen, cyano, —OR, —NR2 or —SR;
and
each R is independently hydrogen, C1-6alkyl or C1-6haloalkyl.

8 more elements

Dependencies are inferred from the claim text.

Facts

Application

17/068,574Filed 12 Oct 2020 · continuation

Priority

WO PCT/CN2015/09868524 Dec 2015

Published

US 2022/0306635 A129 Sep 2022

Granted

24 Mar 2026

Term ends

Not estimatedThe source records don’t support an estimate.

Classification9 codes

C07D 487/04
In which the condensed system contains two hetero rings: ortho-condensed systems
A61K 38/16
Medicinal preparations containing peptides: peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 35/00
Antineoplastic agents

Family

PCT/CN2016/111730Parent of this continuation · filed 23 Dec 2016

US 2022/0306635 A1Pre-grant publication · published 29 Sep 2022

Application16/065,397Parent of this continuation

US 10,800,780 B2Parent of this continuation

US 2019/0016726 A1Published application

US 12,583,858 B2This patent

From the US filing history. Foreign family members aren’t listed.