Compounds, compositions, and methods for the treatment of disease
Inventors
Iyer, Radhakrishnan P. • Sheri, Anjaneyulu • Meher, Geeta • Challa, Sreerupa • Zhou, Shenghua
Assignees
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Publication Number
US-11638716-B2
Publication Date
2023-05-02
Expiration Date
Abstract
Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
Core Innovation
The invention relates to a compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof. The compounds are defined by a linkage atom Z that is either S or O, with B1 and B2 as purinyl and pyrimidinyl nucleobases in either order. The scaffold further includes X1 and X2, each independently O or S, and Y1 and Y2, each independently O, S, or NR5.
Formula (I) further defines L1 and L2 as independently absent, C1-C6 alkyl, or C1-C6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with R6. The substituent framework includes R1 and R2 independently hydrogen, halo, —CN, C1-C20 alkyl, or OR7; R3 and R4 independently hydrogen, C1-C20 alkyl, C1-C20 heteroalkyl, OC(O)C1-C20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, with optional substitution by one or more R8; and R5, R6, R7, R8, and R9 defined by the listed substituent classes.
The disclosure describes a broad family of nucleobase-containing compounds with a shared Formula (I) scaffold and multiple illustrative chemical structures. The examples and family description show variation in substituent patterns while retaining the phosphorus-containing linker and the purinyl/pyrimidinyl nucleobase pairing.
Claims Coverage
The independent claim is directed to a Formula (I) compound family with one core scaffold and multiple inventive features. The coverage includes purinyl/pyrimidinyl nucleobase pairing, a sulfur/oxygen linkage atom, heteroatom choices at X1/X2 and Y1/Y2, optional L1/L2 spacers, and extensive substituent definitions for R1-R9.
Formula (I) compound with purinyl/pyrimidinyl nucleobase pairing
A compound of Formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, wherein B1 is a purinyl nucleobase and B2 is a pyrimidinyl nucleobase, or B2 is a purinyl nucleobase and B1 is a pyrimidinyl nucleobase.
Sulfur/oxygen linkage atom Z
The compound includes a linkage atom Z that is either S or O.
Independent X1/X2 selection as O or S
Each of X1 and X2 is independently O or S.
Independent Y1/Y2 selection as O, S, or NR5
Each of Y1 and Y2 is independently O, S, or NR5.
L1/L2 definition as absent, C1-C6 alkyl, or C1-C6 heteroalkyl
Each of L1 and L2 is independently absent, C1-C6 alkyl, or C1-C6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with R6.
Broad substituent variability defined by R1-R9
R1 and R2 are independently hydrogen, halo, —CN, C1-C20 alkyl, or OR7; R3 and R4 are independently hydrogen, C1-C20 alkyl, C1-C20 heteroalkyl, OC(O)C1-C20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, with optional substitution by one or more R8; R5 is hydrogen or C1-C20 alkyl; R6 is halo, —CN, C1-C20 alkyl, OR7, oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, with optional substitution by one or more R9; R7 is hydrogen, C1-C20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, with optional substitution by one or more R9; each R8 is independently selected from the listed alkyl, heteroalkyl, carbonyl, alkoxy, amine-linked, O-aryl, O-heteroaryl, C(O)-aryl, C(O)-heteroaryl, OC(O)-aryl, C(O)O-aryl, OC(O)-heteroaryl, C(O)O-heteroaryl, C(O)N(R5)-aryl, C(O)N(R5)-heteroaryl, N(R5)C(O)-aryl, N(R5)C(O)-heteroaryl, and S(O)2N(R5)-aryl options; and each R9 is independently C1-C20 alkyl, O-C1-C20 alkyl, C1-C20 heteroalkyl, halo, —CN, OH, oxo, aryl, heteroaryl, O-aryl, or O-heteroaryl.
The independent claim broadly covers Formula (I) compounds with purinyl/pyrimidinyl nucleobase pairing, a Z linkage of S or O, independently selected X1/X2 and Y1/Y2 heteroatom positions, optional L1/L2 spacers, and extensive substituent variability through R1-R9.
Stated Advantages
Induces PRR expression and downstream type I interferons via PRR activation, including STING, RIG-I, and NOD2.
Acts as an immune-modulating antiviral described as a small-molecule nucleic acid hybrid.
Documented Applications
Inducing PRR expression in subjects with microbial infection.
Cancer immunomodulation.
Vaccine/adjuvant formulations.
Treating viral infections, including Hepatitis C virus, Norovirus, Junin virus, Respiratory syncytial virus, and Dengue virus.
A referenced outcome includes apoptosis of virus-infected hepatocytes.
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