Inhibitors of the kynurenine pathway
Inventors
Banerjee, Monali • Middya, Sandip • Shrivastava, Ritesh • Raina, Sushil • Surya, Arjun • Yadav, Dharmendra B. • Yadav, Veejendra K. • Kapoor, Kamal Kishore • Venkatesan, Aranapakam • Smith, Roger A. • Thompson, Scott K.
Assignees
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Publication Number
US-10294212-B2
Publication Date
2019-05-21
Expiration Date
Abstract
The present application provides novel inhibitors of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxygenase, metabolites thereof, and pharmaceutically acceptable salts or prodrugs thereof. Also provided are methods for preparing these compounds. A therapeutically effective amount of one or more of the compounds of formula (I) is useful in treating diseases resulting from dysregulation of the kynurenine pathway. Compounds of formula (I) act by inhibiting the enzymatic activity or expression of indoleamine 2,3-dioxygenase-1 and/or indoleamine 2,3-dioxygenase-2 and/or tryptophan 2,3-dioxy-genase.
Core Innovation
The invention relates to compounds of formula (I) with a defined furo[2,3-c]pyridine-2,3-diamine scaffold and related fused heteroaromatic diamine frameworks, including pharmaceutically acceptable salts. The compounds are characterized by substituent-defined variables X1, X2, X3, X4, Y, Z, R1, R2, R4, R5, R6, R7, RA, RB, and n, with broad substituent options and multiple functional group selections.
The disclosure presents specific N3-aryl substituted furo[2,3-c]pyridine-2,3-diamine derivatives and related fused heteroaryl derivatives within the broader formula (I) scaffold. Representative examples include halogenated phenyl, pyridinyl, phenoxy, benzonitrile-containing aryl substituents, and other fluorinated, difluoropyridyl, indole-based, pyrimidine-based, imidazopyridine-based, imidazole carboxamide, pyrrolyl, and benzofused substituents, together with structural depictions and analytical data.
The document further describes compound families framed as kynurenine pathway inhibitors, including inhibitors targeting indoleamine 2,3-dioxygenase IDO1/IDO2 and/or tryptophan 2,3-dioxygenase TDO, as well as (bis)carbamate prodrugs used to modulate pharmacokinetic properties. It also references metabolite and prodrug classes, including specific prodrug formulae and pharmaceutical compositions comprising the compounds with a pharmaceutically acceptable carrier.
Claims Coverage
The provided claim coverage centers on one independent claim defining a broad formula (I) compound class with extensive substituent definitions and coverage of pharmaceutically acceptable salts. Dependent claims narrow the scope through specific R5 ring-system selections, restricted R1 and R2 options, explicit selections from listed furo[2,3-c]pyridine-2,3-diamine derivatives, and a pharmaceutical composition claim. In total, the consolidated claim coverage reflects one broad scaffold with multiple dependent refinements.
Compound of formula (I) with defined substituent framework
A compound of formula (I) wherein X1, X2, X3, X4, Y, Z, R1, R2, R4, R5, R6, R7, n, RA, and RB are defined by broad substituent and ring-member options, and the claim covers pharmaceutically acceptable salts thereof.
R5 restricted to benzo[d]dioxolane or tetrahydronaphthalene
The compound of formula (I) is defined such that R5 is either benzo[d]dioxolane or tetrahydronaphthalene.
Selected furo[2,3-c]pyridine-2,3-diamine derivatives
The compound is selected from a listed group of specific furo[2,3-c]pyridine-2,3-diamine derivatives, including named N3-aryl substituted variants, or a pharmaceutically acceptable salt thereof.
R1 substituent restriction
In the compound of formula (I), R1 is selected from H, halogen, CN, C1-C6 hydroxyalkyl, C1-C6 alkoxy, or C1-C6 alkyl.
R2 substituent restriction
In the compound of formula (I), R2 is selected from H and further functional groups and optionally substituted aryl/alkoxy/alkyl/aryloxy groups with defined carbon-count ranges, including mono or bicyclic C6-C14 aryl.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Overall, the claims define a broad substituted heteroaromatic compound class of formula (I), then narrow it through specific substituent restrictions, an explicit list of named derivatives, and a pharmaceutical composition embodiment. The claim coverage repeatedly preserves the same core scaffold while refining R5, R1, and R2 selections.
Stated Advantages
Modulate pharmacokinetic properties.
Documented Applications
Inhibiting indoleamine 2,3-dioxygenase IDO1/IDO2 and/or tryptophan 2,3-dioxygenase TDO for diseases associated with dysregulated kynurenine pathway and immune suppression.
Cancer, including tumor growth contexts.
Infections, including HIV, malaria, and Leishmaniasis.
Autoimmune/inflammatory diseases.
CNS/neurodegenerative and neuropsychiatric disorders.
Cardiovascular disease.
Kidney-related conditions.
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