TDO2 Inhibitors
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
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-10800780-B2
Publication Date
2020-10-13
Expiration Date
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.
Core Innovation
The disclosure relates to compounds of structural formula (I), including stereoisomers, enantiomers, diastereoisomers, racemic mixtures, and pharmaceutically acceptable salts. A hydroxy moiety is bonded to ring A, with ring A defined as C3-8 cycloalkyl or 3-7 membered heterocyclyl, and in alternative scope as C3-10 cycloalkyl or 3-7 membered heterocyclyl, while ring B is defined as C3-7 cycloalkyl, 3-7 membered heterocyclyl, aryl or heteroaryl. The formula allows variable substituents through R1, Ra, R2, R3, R4, m, and n, with R4 as —OH and enumerated substituent sets including oxo, halogen, cyano, nitro, alkyl, haloalkyl, alkoxy, amino, thio, carbonyl, and sulfonyl-containing groups.
The document also provides a large enumerated genus of imidazo[5,1-a]isoindol-5-yl substituted alcohol scaffolds and related fused heterocycle alcohols. These compounds include cyclobutan-1-ol, cyclopentan-1-ol, cyclohexan-1-ol, tetrahydroisoquinolin-8-ol, tetrahydro-2H-pyran-3-ol, tetrahydro-2H-pyran-4-ol, tetrahydrofuran-3-ol, piperidine-derived alcohols, spirocyclic and fused ring systems, and related imidazo[4,3-a]isoindole or other fused imidazo variants. Functional-group variations such as fluoro, difluoro, methylsulfonyl, ethylsulfonyl, cyclopropylsulfonyl, nitrile, carboxamide, sulfonamide, and related hydroxyl-bearing heterocycle alcohols are also included.
The record further includes explicitly defined stereochemical embodiments and analytical characterization. Enantiomers, diastereoisomers, racemic mixtures, and pharmaceutically acceptable salts are repeatedly stated, and some examples refer to chiral separation and absolute configuration assignment by X-ray crystallography. The examples are characterized by 1H NMR and LCMS, and the disclosed compounds are repeatedly described as fused imidazo/isoindole-like bicyclic heteroaromatic scaffolds linked to hydroxyl-bearing saturated ring systems.
Claims Coverage
The consolidated claim coverage spans a broad formula (I) compound genus, a narrower formula (I) subset with additional substituent constraints, and independent claims that enumerate specific imidazo[5,1-a]isoindole-containing ring-alcohol compounds, including stereochemically defined members. In total, the independent claims cover five inventive feature groups centered on ring A hydroxy attachment, ring definitions, substituent sets, and explicit compound enumerations.
Compound of formula (I) with hydroxy moiety bonded to ring A
A compound of formula (I), or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the hydroxy moiety is bonded to ring A, ring A is C3-8 cycloalkyl or 3-7 membered heterocyclyl, and each Ra is independently a substituent of the A ring or the B ring.
Variable ring A, ring B, and substituent set for formula (I)
Ring A is C3-10 cycloalkyl or 3-7 membered heterocyclyl, ring B is C3-7 cycloalkyl, 3-7 membered heterocyclyl, aryl or heteroaryl, m is 0, 1, 2, 3 or 4, R4 is —OH, n is 0 or 1, and each Ra and R2 is selected from the enumerated substituent sets including oxo, halogen, cyano, nitro, C1-6 alkyl, C1-6 haloalkyl, OR, NR2, SR, C(O)OR, C(O)N(R)2, C(O)R, and selected S(O)- and OC(O)-containing groups.
Restricted formula (I) with specified R3 and R2
A compound of formula (I) wherein R3 is methyl, ethyl, propyl, butyl, —O-methyl, —O-ethyl, —O-propyl, or —O-butyl; R4 is —OH; n is 0 or 1; and each R2 is independently hydrogen, C1-6 alkyl or C1-6 haloalkyl.
Enumerated imidazo[5,1-a]isoindol-5-yl substituted saturated ring alcohol compounds
A compound selected from the explicitly listed imidazo[5,1-a]isoindol-5-yl substituted cyclobutan-1-ol, cyclopentan-1-ol, cyclohexan-1-ol, tetrahydroisoquinolin-8-ol, tetrahydro-2H-pyran-3-ol, tetrahydro-2H-pyran-4-ol, piperidinyl, spiro and related fused saturated ring alcohol structures, including pharmaceutically acceptable salts, enantiomers, diastereoisomers, and racemic mixtures.
Stereochemically defined imidazo[5,1-a]isoindol substituted alcohol compounds
A compound selected from explicitly listed stereochemical forms such as (1R,2R), (1S,2S), (1S,2R), and (1R,2S) variants of imidazo[5,1-a]isoindol-5-yl substituted cyclobutan-1-ol, cyclopentan-1-ol, cyclohexan-1-ol, tetrahydroisoquinolin-8-ol, tetrahydro-2H-pyran-3-ol, tetrahydro-2H-pyran-4-ol, and related saturated ring alcohol scaffolds, including pharmaceutically acceptable salt forms.
Overall, the claims cover a broad formula (I) genus with a hydroxy moiety bonded to ring A and defined ring-size and substituent parameters, a narrower formula (I) subset with specified R3, R4, n, and R2 limits, and large enumerations of specific imidazo[5,1-a]isoindole-containing ring-alcohol compounds, including explicit stereochemical and salt forms.
Stated Advantages
Modulating IDO1/TDO2 in cells.
Treating IDO1/TDO2-mediated immunosuppression.
Treating conditions benefiting from tryptophan degradation inhibition.
Enhancing anti-cancer therapy.
Treating cancer-associated immunosuppression.
Documented Applications
Modulating IDO1/TDO2 in cells.
Treating IDO1/TDO2-mediated immunosuppression associated with a disease by administering a compound that inhibits TDO2 and optionally IDO1.
Treating conditions benefiting from tryptophan degradation inhibition.
Enhancing anti-cancer therapy.
Treating cancer-associated immunosuppression.
Treatment of TDO2-mediated immunosuppression associated with a disease by administering an effective TDO2-inhibiting amount of a compound of claim 1 to a subject in need.
TDO2-mediated immunosuppression therapeutic use.
Evaluation context of TDO2 tryptophan catabolism to N-formylkynurenine detected by RapidFire RF-MS and NFK GreenScreen™ fluorescence in SW48 and A172+IFNg cells, with reported TDO2 cell fluor EC50 values and selectivity versus IDO.
Interested in licensing this patent?