Pyridopyrazine and pyridotriazine inhibitors of influenza virus replication
Inventors
Jacobson, Irina C. • Lin, Biing Yuan • Sanchez, Emiliano J. • Lee, Sam S K • Xiao, Hong
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Assignees
Merck Sharp and Dohme LLC • Cocrystal Pharma Inc
MemberCocrystal PharmaCocrystal PharmaCocrystal Pharma is a clinical-stage biotechnology company specializing in the discovery and development of novel antiviral therapeutics for serious and chronic viral diseases such as influenza, COVID-19, hepatitis C, norovirus, and other respiratory viruses. The company leverages structure-based drug discovery technology and expertise in structural biology to design direct viral replication inhibitors with broad-spectrum activity. Its pipeline includes candidates in preclinical and clinical development, addressing unmet needs in antiviral medicine.
Cocrystal Pharma is a clinical-stage biotechnology company specializing in the discovery and development of novel antiviral therapeutics for serious and chronic viral diseases such as influenza, COVID-19, hepatitis C, norovirus, and other respiratory viruses. The company leverages structure-based drug discovery technology and expertise in structural biology to design direct viral replication inhibitors with broad-spectrum activity. Its pipeline includes candidates in preclinical and clinical development, addressing unmet needs in antiviral medicine.
Publication Number
US-12037333-B2
Publication Date
2024-07-16
Expiration Date
Abstract
Provided herein are compounds that can inhibit the replication of influenza viruses, reduce the amount of influenza viruses, and/or treat influenza. (I)
Core Innovation
The invention relates to a compound having a structure of Formula (I), or a pharmaceutically acceptable salt thereof, with ring A defined by M being N or CH and with X and X′ independently being CH2, CH2CH2, OCH2, or CH2O. The scaffold further defines multiple variable positions including R1, R2, R3, R4, R5, R6, Q1 through Q6, and a defined substituent group A.
The structural definitions include enumerated substituent options such as halo, CN, OH, CO2H, CHO, NH2, oxo, NO2, alkyl, haloalkyl, alkoxy, alkylthio, carbocyclyl, aryl, and heterocyclyl groups. The disclosure also provides optional Z-linked motifs involving N(RN)(RN), N(RN)SO2, C(O)N, S(O)0-2, and related carbonyl-containing patterns, with Z being a bond or C1-6 alkylene.
The scaffold further permits ring-forming relationships in which R3 and R5 form a 5-7 heterocyclyl having 1-4 total ring heteroatoms selected from N, O, and S, and R5 and R6 form a C3-7 carbocyclyl or 3-7 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S. The compounds are tied to influenza polymerase PA endonuclease-targeting compounds, including substituted pyrido[2,1-f][1,2,4]triazine-4,6-dione derivatives and related indeno-fused analogs.
Claims Coverage
The consolidated claim coverage includes one independent compound claim and one independent use claim. The core inventive features are the Formula (I) scaffold with extensive substituent constraints and the use of the compound to inhibit influenza polymerase PA endonuclease activity.
Formula (I) compound with defined ring A and substituent framework
A compound having a structure of Formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is defined with M being N or CH, X and X′ are independently CH2, CH2CH2, OCH2, or CH2O, and R1, R2, R3, R4, R5, R6, and Q1 through Q6 are selected from enumerated substituent sets including heterocyclyl groups comprising N, O, and S ring heteroatoms.
R3 and R5 heterocycle formation with N/O/S constraints
R3 is selected from the enumerated substituent set and R3 and R5 together form a 5-7 heterocyclyl having 1-4 total ring heteroatoms selected from N, O, and S, optionally substituted with 1-3 of substituent group A.
R5 and R6 formation of carbocyclyl or heterocyclyl
R5 and R6 are independently selected from enumerated substituents and R5 and R6 together form a C3-7 carbocyclyl or 3-7 membered heterocyclyl having 1-3 ring heteroatoms selected from N, O, and S, optionally substituted with 1-3 of substituent group A.
Z-linked nitrogen, sulfonyl, and carbonyl motifs
Optionally one of R1, R2, R3, R5, and R6 is a Z-linked motif such as Z—N(RN)(RN), Z—N(RN)SO2—Rx2, Z—C(O)—N(RN)—SO2—Rx2, Z—N(RN)—C(O)—Rx1, Z—S(O)0-2—Rx2, Z—N(RN)—C(O)O—Rx1, Z—N(RN)—C(O)—N(RN)(RN), or Z—C(O)—N(RN)—C(O)—Rx1, where Z is a bond or C1-6 alkylene.
Influenza polymerase PA endonuclease inhibition by contacting
A method for inhibiting endonuclease activity of influenza polymerase PA in an influenza A or B virus by contacting the virus with the compound or salt of Formula (I).
Overall, the claims cover a tightly defined Formula (I) compound class with enumerated structural variables, heterocycle-forming relationships, and optional Z-linked motifs, together with a method of inhibiting influenza polymerase PA endonuclease activity by contacting influenza A or B virus with the compound.
Stated Advantages
Inhibits influenza polymerase PA endonuclease activity.
Reduces influenza virus replication or viral titer.
Provides treatment or prevention of influenza A or influenza B.
Can be used in combination with a second antiviral agent and optional co-administration with an influenza vaccine.
Supports measurement concepts for viral titer and replication assays.
Documented Applications
Methods of inhibiting endonuclease activity of influenza polymerase PA and reducing influenza virus replication by contacting or administering the compound or salt.
Treatment and prevention of influenza A or influenza B.
Pharmaceutical compositions and medicament manufacturing uses for the compounds or salts.
Combination use with a second antiviral agent, including favipiravir, oseltamivir, influenza neuraminidase inhibitors, influenza PB1 polymerase domain inhibitors, and influenza CAP-binding PB2 domain inhibitors, with optional co-administration with an influenza vaccine.
Pulmonary/inhalation and intranasal delivery formulation approaches, including liquid or gaseous pulmonary delivery, intranasal spray, liposomal, and nanocarrier approaches.
In vitro antiviral evaluation against influenza A and influenza B using an XTT-based CPE inhibition or viability readout.
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