WO2020117794A1 - Compounds for the treatment of arenavirus infection - Google Patents
Compounds for the treatment of arenavirus infection Download PDFInfo
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- WO2020117794A1 WO2020117794A1 PCT/US2019/064223 US2019064223W WO2020117794A1 WO 2020117794 A1 WO2020117794 A1 WO 2020117794A1 US 2019064223 W US2019064223 W US 2019064223W WO 2020117794 A1 WO2020117794 A1 WO 2020117794A1
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- 0 CC(*)(CCC1)CCC1N Chemical compound CC(*)(CCC1)CCC1N 0.000 description 9
- DYVLKIPPQZCJRT-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(C(N)=O)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(C(N)=O)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C DYVLKIPPQZCJRT-UHFFFAOYSA-N 0.000 description 2
- BENBXQBGALFKST-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(C(O)=O)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(C(O)=O)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C BENBXQBGALFKST-UHFFFAOYSA-N 0.000 description 2
- GTXAMTPJUFOZGK-UHFFFAOYSA-N CC(C)(C)Oc(cc1)ccc1-[n]1c(cc(c(C)c2)-c3ccc(C(C)(C)O)cc3)c2nc1 Chemical compound CC(C)(C)Oc(cc1)ccc1-[n]1c(cc(c(C)c2)-c3ccc(C(C)(C)O)cc3)c2nc1 GTXAMTPJUFOZGK-UHFFFAOYSA-N 0.000 description 1
- KYAONFCHAPKAKK-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-[n]1nnc(cc2C(OC)=O)c1cc2Br Chemical compound CC(C)Oc(cc1)ccc1-[n]1nnc(cc2C(OC)=O)c1cc2Br KYAONFCHAPKAKK-UHFFFAOYSA-N 0.000 description 1
- AZYFBCANAVISJH-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(C(OC)=O)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(C(OC)=O)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C AZYFBCANAVISJH-UHFFFAOYSA-N 0.000 description 1
- TWUXCBSMDFLDBC-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(C)c1)c[n]2c1ncc2-c(cc1)ccc1OC(C)(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(C)c1)c[n]2c1ncc2-c(cc1)ccc1OC(C)(C)C TWUXCBSMDFLDBC-UHFFFAOYSA-N 0.000 description 1
- PLPIVXKAFAVFHK-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(C)c1)c[n]2c1ncc2-c1ccc(C(C)(C)O)cc1 Chemical compound CC(C)Oc(cc1)ccc1-c(c(C)c1)c[n]2c1ncc2-c1ccc(C(C)(C)O)cc1 PLPIVXKAFAVFHK-UHFFFAOYSA-N 0.000 description 1
- BTCFKVDIOVXQAY-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(C)c1)cc2c1nc[n]2-c(cc1)ccc1OC(C)(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(C)c1)cc2c1nc[n]2-c(cc1)ccc1OC(C)(C)C BTCFKVDIOVXQAY-UHFFFAOYSA-N 0.000 description 1
- INKPEUODFNQWRE-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(CN)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(CN)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C INKPEUODFNQWRE-UHFFFAOYSA-N 0.000 description 1
- IPNMFYNCUIVXJD-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(CO)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(CO)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C IPNMFYNCUIVXJD-UHFFFAOYSA-N 0.000 description 1
- CWMQCQSWHAOJFN-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(Cl)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(Cl)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C CWMQCQSWHAOJFN-UHFFFAOYSA-N 0.000 description 1
- VVNCIEBRMQLOBC-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(c(N)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C Chemical compound CC(C)Oc(cc1)ccc1-c(c(N)c1)cc2c1nn[n]2-c(cc1)ccc1OC(C)C VVNCIEBRMQLOBC-UHFFFAOYSA-N 0.000 description 1
- ANVLQXYEQHHXCE-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c(ccc1c2[n](-c(cc3)ccc3OC(C)C)nn1)c2F Chemical compound CC(C)Oc(cc1)ccc1-c(ccc1c2[n](-c(cc3)ccc3OC(C)C)nn1)c2F ANVLQXYEQHHXCE-UHFFFAOYSA-N 0.000 description 1
- IQYKBLJKDWXZIU-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1-c1cnc2[n]1cc(-c(cc1)ccc1OC(C)C)c(C#N)c2 Chemical compound CC(C)Oc(cc1)ccc1-c1cnc2[n]1cc(-c(cc1)ccc1OC(C)C)c(C#N)c2 IQYKBLJKDWXZIU-UHFFFAOYSA-N 0.000 description 1
- URTXLCZMUNVDCG-UHFFFAOYSA-N CC(C)Oc(cc1)ccc1Nc(cc(c(Cl)c1)Br)c1N Chemical compound CC(C)Oc(cc1)ccc1Nc(cc(c(Cl)c1)Br)c1N URTXLCZMUNVDCG-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4192—1,2,3-Triazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Definitions
- the present invention relates to the use of heterocyclic compounds for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to methods of reducing the amount of arenaviruses, and to compositions that can be employed for such methods.
- arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers
- Arenaviridae comprise a diverse family of 29 (and growing) negative stranded enveloped RNA viruses. Arenaviruses are divided into two groups, Old and New World, based on serological, genetic and geographical data. Old World viruses are found primarily throughout South and West Africa and include the prototypic lymphocytic choriomeningitis virus (LCMV), along with Lassa (LASV), Lujo (LUJV), Mopeia (MOPV), Ippy and Mobala (MOBV) viruses. Both LASV and LUJV can cause lethal hemorrhagic fever (HF), while LCMV infection is associated with aseptic meningitis.
- LCMV prototypic lymphocytic choriomeningitis virus
- LASV Lassa
- LJV Lujo
- MOPV Mopeia
- Ippy and Mobala MOBV
- Lassa alone is estimated to cause over 300,000 disease cases each year in West Africa, of which 15-20% of hospitalized patients die and survivors often suffer sequelae, including permanent bilateral hearing damage.
- Clade B HF viruses include, Junin (JUNV), Machupo (MACV), Guanarito (GTOV), Sabia (SABV) and Chapare, along with non-HF viruses such as Tacaribe (TCRV) and Amapari (AMPV).
- Arenaviruses consist of a nucleocapsid (NP) surrounded by an envelope membrane, and the NP contains two ambisense RNA genome segments L and S that direct the synthesis of two polypeptides.
- the L segment encodes the RNA-dependent-RNA polymerase (RdRp) and a small Ring Finger protein Z.
- the S segment encodes for nucleoprotein and a glycoprotein precursor GPC that is cleaved by host proteases and undergoes post-translational modification into a mature complex composed of glycoproteins GP1 (binds host protein at the cell surface), GP2 (directs pH dependent membrane fusion and release of genomic material in the cytoplasm) and a stable signal peptide (SSP1).
- GP1 binds host protein at the cell surface
- GP2 directs pH dependent membrane fusion and release of genomic material in the cytoplasm
- SSP1 stable signal peptide
- the mature glycoprotein complex (GP, or referred to as glycoprotein) is formed in the viral envelope and is responsible for mediating viral entry.
- the Old World arenaviruses bind to host a-dystroglycan while New World arenaviruses bind to transferrin receptor 1 for entry/endocytosis into cells.
- the virus Upon binding to cell surface receptors, the virus is endocytosed and directed to acidic late endosomes whereby, GP2 mediates pH dependent membrane fusion and release of genomic material into the cytoplasm for viral replication and transcription. Therefore, viral entry inhibitors (e.g. small molecules) that target virus GP complex or host factors are a potential therapeutic/prophylactic approach in treating patients infected with arenavirus infection.
- VSV vesicular stomatitis virus
- GP pseudotype VSV viruses The cell entry and infectivity properties of GP pseudotype VSV viruses have been shown for multiple viruses including HIV, Hepatitis B and C, Ebola, Lassa, Hanta and others [Qqino, M.. et al. Use of vesicular stomatitis virus pseudotypes bearing hantaan or seoul virus envelope proteins in a rapid and safe neutralization test. Clin. Diagn. Lab. Immunol. (2003) 10(1):154-60; Saha, M.N., et al. Formation of vesicular stomatitis virus pseudotypes bearing surface proteins of hepatitis B virus. J. Virol. (2005) 79(19):12566-74; Takada, A., et al.
- The“pseudoviruses” may therefore be used to screen chemical compound libraries to identify inhibitors of arenavirus cell entry while avoiding the complications of working with highly pathogenic BSL-4 agents.
- deuterium is a stable, nontoxic, nonradioactive isotope of hydrogen. Due to the greater atomic mass, deuterium forms a stronger bond with carbon than hydrogen, making the carbon-deuterium bond much harder to break. In cases where the breaking of a carbon-hydrogen bond is partially or wholly rate-limiting step in the cytochrome P450- mediated drug metabolism, replacing hydrogen atom(s) with deuterium may slow the rate of metabolism, resulting in improved half-life, greater tolerability, improved efficacy and dosing regimen, lower side effects, and decreased toxicity [Foster, A. B.
- entry inhibitors described were identified using an arenavirus GP pseudovirus screen and selected compounds were tested against native non-HF virus TCRV to confirm activity against replicative arenavirus. Selected top compounds were then tested against native LASV to confirm activity against the native highly pathogenic human (HF) arenaviruses, and initial drug-like properties were assessed.
- HF highly pathogenic human
- the present invention relates to the use of heterocyclic compounds for inhibiting arenavirus infection in humans, other mammals, or in cell culture, to methods of treating arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers, to methods of inhibiting the replication of arenaviruses, to methods of reducing the amount of arenaviruses, and to compositions that can be employed for such methods.
- arenavirus infection such as Lassa, Venezuelan, Argentine, Venezuelan, Brazilian, Chapare and Lujo hemorrhagic fevers
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I
- A is independently selected from C and N;
- G is independently selected from CH, CD, and N;
- E is independently selected from CH, CD, and N;
- R 2 is independently selected from H, D, -OR 3 , -R 4 , -NHR 10 , -CONHR 10 ;
- R 3 is independently selected from H, D, Ci to C6 alkyl, C2 to C6 alkenyl, (C3 to C10) cycloalkyl, (C2 to Cg) cycloheteroalkyl, -NHC(0)R 4 , -C(0)NHR 10 , and -C(0)R 10 , wherein each Ci to C6 alkyl is optionally substituted with D, halogen, -OH, -OR 4 , -NHR 10 ;
- R 4 is independently selected from Ci to C6 alkyl and (C2to Cg) cycloheteroalkyl optionally substituted with D, halogen, -OH, -OR 10 , and NHR 10 ;
- R 5 is independently selected from H, D, Ci to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogen, -OR 3 , -CO2R 10 , -NHC(0)R 4 , -C(0)NHR 10 , -NHR 10 , -CHNHR 10 , -CN, -CR 4 , and -C(0)R 10 , wherein each Ci to C6 alkyl is optionally substituted with D;
- R 6 is independently selected from H, D, halogen, -OR 3 , and R 4 ;
- R 9 is independently selected from H, D, halogen, Ci to Ob alkyl, and -OR 10 ;
- R 10 is independently selected from H, D, -OH, Ci to Ob alkyl and C2 to Ob alkenyl;
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I
- A is independently selected from C and N;
- G is independently selected from CH, CD, and N;
- E is independently selected from CH, CD, and N;
- R 2 is independently selected from H, D, -OR 3 , -R 4 , -NHR 10 , -CONHR 10 ;
- R 3 is independently selected from H, D, Ci to C6 alkyl, C2 to C6 alkenyl, (C3 to C10) cycloalkyl, (C2 to Cg) cycloheteroalkyl, -NHC(0)R 4 , -C(0)NHR 10 , and -C(0)R 10 , wherein each Ci to C6 alkyl is optionally substituted with D, halogen, -OH, -OR 4 , -NHR 10 ;
- R 4 is independently selected from Ci to C6 alkyl and (C2to Cg) cycloheteroalkyl optionally substituted with D, halogen, -OH, -OR 10 , and NHR 10 ;
- R 5 is independently selected from H, D, Ci to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogen, -OR 3 , -CO2R 10 , -NHC(0)R 4 , -C(0)NHR 10 , -NHR 10 , -CHNHR 10 , -CN, -CR 4 , and -C(0)R 10 , wherein each Ci to C6 alkyl is optionally substituted with D;
- R 6 is independently selected from H, D, halogen, -OR 3 , and R 4 ;
- R 9 is independently selected from H, D, halogen, -OR 10 , and Ci to Ob alkyl;
- R 10 is independently selected from H, D, -OH, Ci to Ob alkyl, and C2 to Ob alkenyl;
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, J, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- E is CH or CD.
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein E, G, J, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- A is C.
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein E, G, J, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- A is N.
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 , and R 10 are defined as above and wherein
- the method comprises administering to humans, other mammals, cell culture, or biological sample an effective amount of a compound represented by Structural Formula I, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 , and R 10 are defined as above and wherein
- the method comprises of administering to humans, other mammals, cell culture, or biological sample a pharmaceutically effective amount of a pharmaceutical composition comprising a compound selected from the group of compounds described as Examples A1 to A3, B4 to B9, C10 to C26, D27 to D29, and E30 with a pharmaceutically acceptable carrier, dilutant, or vehicle.
- the method comprises of administering a pharmaceutically effective amount of a pharmaceutical composition comprising a compound selected of Structural Formula I or a compound as shown above with a pharmaceutically acceptable carrier, dilutant, or vehicle, with an additional therapeutically effective amount of a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.
- a therapeutic agent selected from the group consisting of Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors.
- the invention relates to compounds of Structural Formula I
- A is independently selected from C and N;
- G is independently selected from CH, CD, and N;
- E is independently selected from CH, CD, and N;
- R 2 is independently selected from H, D, -OR 3 , -R 4 , -NHR 10 , -CONHR 10 ;
- R 3 is independently selected from H, D, Ci to C6 alkyl, C2 to C6 alkenyl, (C3 to C10) cycloalkyl, (C2 to Cg) cycloheteroalkyl, -NHC(0)R 4 , -C(0)NHR 10 , and -C(0)R 10 , wherein each Ci to C6 alkyl is optionally substituted with D, halogen, -OH, -OR 4 , -NHR 10 ;
- R 4 is independently selected from Ci to C6 alkyl and (C2to Cg) cycloheteroalkyl optionally substituted with D, halogen, -OH, -OR 10 , and NHR 10 ;
- R 5 is independently selected from H, D, Ci to C6 alkyl, C2 to C6 alkenyl, C2 to C6 alkynyl, halogen,
- Ci to C6 alkyl is optionally substituted with D;
- R 6 is independently selected from H, D, halogen, -OR 3 , and R 4 ;
- R 9 is independently selected from H, D, halogen, -OR 10 , and Ci to C6 alkyl;
- R 10 is independently selected from H, D, -OH, Ci to C6 alkyl and C2 to C6 alkenyl;
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, J, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- E is CH or CD.
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein E, G, J, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- A is C.
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein E, G, J, R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 are defined as above and wherein
- A is N.
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 , and R 10 are defined as above and wherein
- the invention relates to compounds of Structural Formula I or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, wherein A, G, E, R 2 , R 3 , R 4 , R 5 , R 9 , and R 10 are defined as above and wherein
- the invention relates to compounds, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, selected from the group consisting of the compounds described as examples A1 to A3, B4 to B9, C10 to C26, D27 to D29, and E30.
- the invention relates to compounds, or a pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier, diluent, or vehicle thereof, selected from the group consisting of:
- halo and/or“halogen” refer to fluorine, chlorine, bromine or iodine.
- (Ci to Ob) alkyl refers to a saturated aliphatic hydrocarbon radical including straight chain and branched chain groups of 1 to 6 carbon atoms.
- Examples of (Ci to Ob) alkyl groups include methyl, ethyl, propyl, 2-propyl, n-butyl, /so-butyl, fe/f-butyl, pentyl, and the like.
- (C2 to Cs) alkenyl means an alkyl moiety comprising 2 to 8 carbons having at least one carbon-carbon double bond.
- the carbon-carbon double bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound.
- Such groups include both the E and Z isomers of said alkenyl moiety. Examples of such groups include, but are not limited to, ethenyl, propenyl, butenyl, allyl, and pentenyl.
- the term“(C2to Cs) alkynyl” means an alkyl moiety comprising from 2 to 8 carbon atoms and having at least one carbon-carbon triple bond.
- the carbon-carbon triple bond in such a group may be anywhere along the 2 to 8 carbon chain that will result in a stable compound. Examples of such groups include, but are not limited to, ethyne, propyne, 1 -butyne, 2-butyne, 1-pentyne, 2-pentyne, 1- hexyne, 2-hexyne, and 3-hexyne.
- (Ci to Cs) alkoxy means an O-alkyl group wherein said alkyl group contains from 1 to 8 carbon atoms and is straight, branched, or cyclic. Examples of such groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, iso-propyloxy, n-butoxy, iso-butoxy, tert-butoxy, cyclopentyloxy, and cyclohexyloxy.
- (C6to C10) aryl means a group derived from an aromatic hydrocarbon containing from 6 to 10 carbon atoms. Examples of such groups include, but are not limited to, phenyl or naphthyl.
- (C 2 to Cg) heteroaryl means an aromatic heterocyclic group having a total of from 5 to 10 atoms in its ring, and containing from 2 to 9 carbon atoms and from one to four heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
- the heterocyclic groups include benzo-fused ring systems.
- aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinox
- the (C2 to Cg) heteroaryl groups may be C-attached or N-attached where such is possible.
- a group derived from pyrrole may be pyrrol-1 -yl (N-attached) or pyrrol-3-yl (C-attached).
- a group derived from imidazole may be imidazol-1-yl (N-attached) or imidazol-3-yl (C-attached).
- (C 2 to Cg) cycloheteroalkyl means a non-aromatic, monocyclic, bicyclic, tricyclic, spirocyclic, or tetracyclic group having a total of from 4 to 13 atoms in its ring system, and containing from 5 to 9 carbon atoms and from 1 to 4 heteroatoms each independently selected from O, S and N, and with the proviso that the ring of said group does not contain two adjacent O atoms or two adjacent S atoms.
- such C 2 to Cg cycloheteroalkyl groups may contain an oxo substituent at any available atom that will result in a stable compound.
- such a group may contain an oxo atom at an available carbon or nitrogen atom. Such a group may contain more than one oxo substituent if chemically feasible.
- a C2 to C9 cycloheteroalkyl group contains a sulfur atom, said sulfur atom may be oxidized with one or two oxygen atoms to afford either a sulfoxide or sulfone.
- An example of a 4 membered cycloheteroalkyl group is azetidinyl (derived from azetidine).
- An example of a 5 membered cycloheteroalkyl group is pyrrolidinyl.
- An example of a 6 membered cycloheteroalkyl group is piperidinyl.
- An example of a 9 membered cycloheteroalkyl group is indolinyl.
- An example of a 10 membered cycloheteroalkyl group is 4/-/-quinolizinyl.
- C2 to C9 cycloheteroalkyl groups include, but are not limited to, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3, 6-tet ra h yd ro py rid i n y 1 , 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4 H pyranyl, dioxanyl, di
- (C3 to C10) cycloalkyl group means a saturated, monocyclic, fused, spirocyclic, or polycyclic ring structure having a total of from 3 to 10 carbon ring atoms.
- Examples of such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cycloheptyl, and adamantyl.
- spirocyclic as used herein has its conventional meaning, that is, any compound containing two or more rings wherein two of the rings have one ring carbon in common.
- Non-limiting examples of a spirocyclic compound include spiro[3.3]heptane, spiro[3.4]octane, and spiro[4.5]decane.
- (Csto Cs) cycloalkenyl means an unsaturated, monocyclic, fused, spirocyclic ring strucures having a total of from 5 to 8 carbon ring atoms. Examples of such groups include, but are not limited to, cyclopentenyl, cyclohexenyl.
- aldehyde refers to a carbonyl group, -C(0)R, where R is hydrogen.
- alkoxy refers to both an -O-alkyl and an -O-cycloalkyl group, as defined herein.
- alkoxycarbonyl refers to a -C(0)0R.
- alkylaminoalkyl refers to an -alkyl-NR-alkyl group.
- alkylsulfonyl refer to a -SO2 alkyl.
- amino refers to an -NH2 or an -NRR' group.
- aminoalkyl refers to an -alkyl-NRR' group.
- aminocarbonyl refers to a -C(0)NRR'.
- arylalkyl refers to -alkylaryl, where alkyl and aryl are defined herein.
- aryloxy refers to both an -O-aryl and an -O-heteroaryl group, as defined herein.
- aryloxycarbonyl refers to -C(0)0 aryl.
- arylsulfonyl refers to a -SO2 aryl.
- a "C-amido” group refers to a -C(0)NRR' group.
- a “carbonyl” group refers to a -C(0)R.
- a "C-carboxyl” group refers to a -C(0)0R groups.
- a “carboxylic acid” group refers to a C-carboxyl group in which R is hydrogen.
- a "cyano" group refers to a -CN group.
- dialkylaminoalkyl refers to an—(a I ky I) N (a I ky I) 2 group.
- halo or halogen group refers to fluorine, chlorine, bromine or iodine.
- haloalkyl group refers to an alkyl group substituted with one or more halogen atoms.
- heteroaryloxyl refers to a heteroaryl-O group with heteroaryl as defined herein.
- a "hydroxy” group refers to an -OH group.
- N-amido refers to a -R'C(0)NR group.
- N-carbamyl refers to a -R0C(0)NR- group.
- a "nitro” group refers to a -NO2 group.
- N-Sulfonamido refers to a -NR-S(0) 2 R group.
- N-thiocarbamyl refers to a ROC(S)NR' group.
- An "O-carbamyl” group refers to a -0C(0)NRR' group.
- An "O-carboxyl” group refers to a RC(0)0 group.
- O-thiocarbamyl refers to a -OC(S)NRR' group.
- An“oxo” group refers to a carbonyl moiety such that alkyl substituted by oxo refers to a ketone group.
- a “perfluoroalkyl group” refers to an alkyl group where all of the hydrogen atoms have been replaced with fluorine atoms.
- a “phosphonyl” group refers to a -P(0)(0R) 2 group.
- sil refers to a -S1R3 group.
- S-sulfonamido refers to a -S(0) 2 NR- group.
- a “sulfinyl” group refers to a -S(0)R group.
- a “sulfonyl” group refers to a -S(0) 2 R group.
- a "trihalomethanecarbonyl” group refers to a ⁇ 3CC(0) group, where Z is halogen.
- a "trihalomethanesulfonamido" group refers to a ⁇ 3CS(0) 2 NR- group, where Z is halogen.
- a "trihalomethanesulfonyl” group refers to a ⁇ 3CS(0) 2 group, where Z is halogen.
- a "trihalomethyl” group refers to a -CZ3 group, where Z is halogen.
- a "C-carboxyl” group refers to a -C(0)0R groups.
- substituted means that the specified group or moiety bears one or more substituents.
- unsubstituted means that the specified group bears no substituents.
- optionally substituted means that the specified group is unsubstituted or substituted by one or more substituents. It is to be understood that in the compounds of the present invention when a group is said to be“unsubstituted,” or is“substituted” with fewer groups than would fill the valencies of all the atoms in the compound, the remaining valencies on such a group are filled by hydrogen.
- a C6 aryl group also called“phenyl” herein
- phenyl substituted with one additional substituent
- one of ordinary skill in the art would understand that such a group has 4 open positions left on carbon atoms of the C6 aryl ring (6 initial positions, minus one to which the remainder of the compound of the present invention is bonded, minus an additional substituent, to leave 4). In such cases, the remaining 4 carbon atoms are each bound to one hydrogen atom to fill their valencies.
- a Ob aryl group in the present compounds is said to be“disubstituted,” one of ordinary skill in the art would understand it to mean that the Ob aryl has 3 carbon atoms remaining that are unsubstituted. Those three unsubstituted carbon atoms are each bound to one hydrogen atom to fill their valencies.
- solvate is used to describe a molecular complex between compounds of the present invention and solvent molecules.
- examples of solvates include, but are not limited to, compounds of the invention in combination water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO), ethyl acetate, acetic acid, ethanolamine, or mixtures thereof.
- DMSO dimethylsulfoxide
- hydrate can be used when said solvent is water. It is specifically contemplated that in the present invention one solvent molecule can be associated with one molecule of the compounds of the present invention, such as a hydrate. Furthermore, it is specifically contemplated that in the present invention, more than one solvent molecule may be associated with one molecule of the compounds of the present invention, such as a dihydrate.
- solvates of the present invention are contemplated as solvates of compounds of the present invention that retain the biological effectiveness of the non-hydrate form of the compounds.
- pharmaceutically acceptable salt means a salt of a compound of the present invention that retains the biological effectiveness of the free acids and bases of the specified derivative and that is not biologically or otherwise undesirable.
- pharmaceutically acceptable formulation means a combination of a compound of the invention, or a salt or solvate thereof, and a carrier, diluent, and/or excipient(s) that are compatible with a compound of the present invention, and is not deleterious to the recipient thereof.
- Pharmaceutical formulations can be prepared by procedures known to those of ordinary skill in the art.
- the compounds of the present invention can be formulated with common excipients, diluents, or carriers, and formed into tablets, capsules, and the like.
- excipients, diluents, and carriers that are suitable for such formulations include the following: fillers and extenders such as starch, sugars, mannitol, and silicic derivatives; binding agents such as carboxymethyl cellulose and
- compositions of the present invention can contain more than one active ingredient.
- such formulations may contain more than one compound according to the present invention.
- such formulations may contain one or more compounds of the present invention and one or more additional agents that inhibit arenavirus.
- Arenavirus GP-inhibiting amount refers to the amount of a compound of the present invention, or a salt or solvate thereof, required to inhibit the cell entry of Arenaviruses in vivo, such as in a mammal, birds or in vitro.
- the amount of such compounds required to cause such inhibition can be determined without undue experimentation using methods described herein and those known to those of ordinary skill in the art.
- a therapeutically effective amount means an amount of a compound of the present invention, or a salt thereof, that, when administered to a mammal in need of such treatment, is sufficient to effect treatment, as defined herein.
- a therapeutically effective amount of a compound of the present invention, or a salt thereof is a quantity sufficient to modulate or inhibit the activity of the Arenavirus GP protein such that cell entry and replication of arenaviruses that is mediated by activity of the Arenavirus GP protein is reduced or alleviated.
- treat with reference to arenavirus infection, in mammals, particularly a human, include: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the condition, such that the treatment constitutes prophylactic treatment for the pathologic condition; (ii) modulating or inhibiting the disease or condition, i.e., arresting its development; (iii) relieving the disease or condition, i.e., causing regression of the disease or condition; or (iv) relieving and/or alleviating the disease or condition or the symptoms resulting from the disease or condition.
- references herein to the inventive compounds include references to salts, solvates, and complexes thereof, including polymorphs, stereoisomers, tautomers, and isotopically labeled versions thereof.
- compounds of the present invention can be pharmaceutically acceptable salts and/or pharmaceutically acceptable solvates.
- stereoisomers refers to compounds that have identical chemical constitution, but differ with regard to the arrangement of their atoms or groups in space.
- enantiomers refers to two stereoisomers of a compound that are non-superimposable mirror images of one another. A pure enantiomer can be contaminated with up to about 10% of the opposite enantiomer.
- racemic or“racemic mixture,” as used herein, refer to a 1 :1 mixture of enantiomers of a particular compound.
- diastereomers refers to the relationship between a pair of stereoisomers that comprise two or more asymmetric centers and are not mirror images of one another.
- the symbol is used in structural formulas herein to depict the bond that is the point of attachment of the moiety or substituent to the core or backbone structure.
- the carbon atoms and their bound hydrogen atoms are not explicitly depicted, e.g., * 3 ⁇ 4 ⁇ represents a methyl group,
- the compounds of the present invention may have asymmetric carbon atoms.
- the carbon carbon bonds of the compounds of the present invention may be depicted herein using a solid line (— ), a solid wedge (— ⁇ ), or a dotted wedge ( . ).
- the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers (e.g. specific enantiomers, racemic mixtures, etc.) at that carbon atom are included.
- the use of either a solid or dotted wedge to depict bonds to asymmetric carbon atoms is meant to indicate that only the stereoisomer shown is meant to be included.
- compounds of the invention may contain more than one asymmetric carbon atom.
- the use of a solid line to depict bonds to asymmetric carbon atoms is meant to indicate that all possible stereoisomers are meant to be included.
- the compounds of the present invention can exist as enantiomers and diastereomers or as racemates and mixtures thereof.
- the use of a solid line to depict bonds to one or more asymmetric carbon atoms in a compound of the invention and the use of a solid or dotted wedge to depict bonds to other asymmetric carbon atoms in the same compound is meant to indicate that a mixture of
- a substituent“R” may reside on any atom of the ring system, assuming replacement of a depicted, implied, or expressly defined hydrogen from one of the ring atoms, so long as a stable structure is formed.
- racemate or a racemic precursor
- HPLC high pressure liquid chromatography
- the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenyl ethyl amine.
- a suitable optically active compound for example, an alcohol, or, in the case where the compound contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenyl ethyl amine.
- the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to one skilled in the art.
- Chiral compounds of the invention (and chiral precursors thereof) may be obtained in enantiomerically-enriched form using chromatography, typically HPLC, on an asymmetric resin with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluate affords the enriched mixture.
- Stereoisomeric conglomerates may be separated by conventional techniques known to those skilled in the art. See, e.g. “Stereochemistry of Organic Compounds” by E L Eliel (Wiley, New York, 1994), the disclosure of which is incorporated herein by reference in its entirety.
- a compound of the invention contains an alkenyl or alkenylene group
- geometric cis/trans (or Z/E) isomers are possible.
- the compound contains, for example, a keto or oxime group or an aromatic moiety
- tautomeric isomerism (‘tautomerism’) can occur.
- tautomerism include keto and enol tautomers.
- a single compound may exhibit more than one type of isomerism. Included within the scope of the invention are all stereoisomers, geometric isomers and tautomeric forms of the inventive compounds, including compounds exhibiting more than one type of isomerism, and mixtures of one or more thereof.
- Cis/trans isomers may be separated by conventional techniques well known to those skilled in the art, for example, chromatography and fractional crystallization.
- the compounds of the present invention may be administered as prodrugs.
- certain derivatives of compounds of Formula I which may have little or no pharmacological activity themselves can, when administered to a mammal, be converted into a compound of Formula (I) having the desired activity, for example, by hydrolytic cleavage.
- Such derivatives are referred to as“prodrugs”.
- Prodrugs can, for example, be produced by replacing appropriate functionalities present in the compounds of Formula I with certain moieties known to those skilled in the art. See, e.g.“Pro-drugs as Novel Delivery Systems”, Vol. 14, ACS Symposium Series (T Higuchi and W Stella) and“Bioreversible Carriers in Drug Design”, Pergamon Press, 1987 (ed.
- prodrugs include: an ester moiety in the place of a carboxylic acid functional group; an ether moiety or an amide moiety in place of an alcohol functional group; and an amide moiety in place of a primary or secondary amino functional group.
- replacement groups are known to those of skill in the art. See, e.g. “Design of Prodrugs” by H Bundgaard (Elsevier, 1985), the disclosure of which is incorporated herein by reference in its entirety. It is also possible that certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I.
- Salts of the present invention can be prepared according to methods known to those of skill in the art.
- Examples of salts include, but are not limited to, acetate, acrylate, benzenesulfonate, benzoate (such as chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, and methoxybenzoate), bicarbonate, bisulfate, bisulfite, bitartrate, borate, bromide, butyne-1 ,4-dioate, calcium edetate, camsylate, carbonate, chloride, caproate, caprylate, clavulanate, citrate, decanoate, dihydrochloride,
- dihydrogenphosphate edetate, edislyate, estolate, esylate, ethylsuccinate, formate, fumarate, gluceptate, gluconate, glutamate, glycollate, glycollylarsanilate, heptanoate, hexyne-1 ,6-dioate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, g-hydroxybutyrate, iodide, isobutyrate, isothionate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, mesylate, metaphosphate,
- methanesulfonate methyls ulfate, monohydrogenphosphate, mucate, napsylate, naphthalene-1 -sulfonate, naphthalene-2-sulfonate, nitrate, oleate, oxalate, pamoate (embonate), palmitate, pantothenate, phenylacetates, phenylbutyrate, phenylpropionate, phthalate, phospate/diphosphate, polygalacturonate, propanesulfonate, propionate, propiolate, pyrophosphate, pyrosulfate, salicylate, stearate, subacetate, suberate, succinate, sulfate, sulfonate, sulfite, tannate, tartrate, teoclate, tosylate, triethiodode, and valerate salts.
- the compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be
- the acid addition salts of the base compounds of this invention can be prepared by treating the base compound with a substantially equivalent amount of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon evaporation of the solvent, the desired solid salt is obtained.
- the desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding an appropriate mineral or organic acid to the solution.
- Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations.
- such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
- the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention.
- Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
- salts can be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
- they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
- stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
- the desired salt may be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha-hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.
- an inorganic acid such as hydrochloric acid, hydrobro
- the desired salt may be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
- an inorganic or organic base such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like.
- suitable salts include organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary, and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.
- the invention also includes isotopically-labeled compounds of the invention, wherein one or more atoms is replaced by an atom having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
- isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as 11 C, 13 C and 14 C, chlorine, such as 36 CI, 35 CI, and 37 CI, fluorine, such as 18 F, iodine, such as 123 l and 125 l, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 32 P, and sulfur, such as 35 S.
- Certain isotopically-labeled compounds of the invention are useful in drug and/or substrate tissue distribution studies.
- the radioactive isotopes tritium, 3 H, and carbon-14, 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
- Substitution with heavier isotopes such as deuterium, 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, 35 S increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
- Substitution with positron emitting isotopes, such as 11 C, 18 F, 15 0 and 13 N can be useful in Positron Emission Tomography (PET) studies for examining substrate receptor occupancy.
- PET Positron Emission Tomography
- deuterated refers to the replacement of one or more hydrogen atoms with a corresponding number of deuterium atoms.
- a particular position in a compound of this invention is designated specifically as“D”,“deuterium”, being“deuterated”, or“having deuterium” (the element deuterium is represented by the letter“D” in chemical structures and formulas and indicated with a lower case“d” in chemical names), the position is understood to have deuterium at an abundance that is at least 3000 times greater than the natural abundance of deuterium, which is 0.015% (i.e., the term“D”,“d” or“deuterium” indicates at least 45% incorporation of deuterium).
- isotopic enrichment factor means the ratio between the isotopic abundance and the natural abundance of a specified isotope.
- a compound of this invention has an isotopic enrichment factor for each deuterium present at a site designated as a potential site of deuteration on the compound of at least 3500 (52.5% deuterium incorporation), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium
- the compounds of the present invention may be formulated into pharmaceutical compositions as described below in any pharmaceutical form recognizable to the skilled artisan as being suitable.
- compositions of the invention comprise a therapeutically effective amount of at least one compound of the present invention and an inert, pharmaceutically acceptable carrier or diluent.
- a pharmaceutical composition of the invention is administered in a suitable formulation prepared by combining a therapeutically effective amount (i.e., an arenavirus GP modulating, regulating, or inhibiting amount effective to achieve therapeutic efficacy) of at least one compound of the present invention (as an active ingredient) with one or more pharmaceutically suitable carriers, which may be selected, for example, from diluents, excipients and auxiliaries that facilitate processing of the active compounds into the final pharmaceutical preparations.
- the pharmaceutical carriers employed may be either solid or liquid. Exemplary solid carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
- Exemplary liquid carriers are syrup, peanut oil, olive oil, water and the like.
- inventive compositions may include time-delay or time-release material known in the art, such as glyceryl monostearate or glyceryl distearate alone or with a wax, ethylcellulose, hydroxypropylmethylcellulose, methylmethacrylate or the like.
- Further additives or excipients may be added to achieve the desired formulation properties.
- a bioavailability enhancer such as Labrasol, Gelucire or the like, or formulator, such as CMC (carboxy-methylcellulose), PG (propyleneglycol), or PEG (polyethyleneglycol)
- Gelucire® a semi-solid vehicle that protects active ingredients from light, moisture and oxidation, may be added, e.g., when preparing a capsule formulation.
- the preparation can be tableted, placed in a hard gelatin capsule in powder or pellet form, or formed into a troche or lozenge.
- the amount of solid carrier may vary, but generally will be from about 25 mg to about 1 g.
- the preparation may be in the form of syrup, emulsion, soft gelatin capsule, sterile injectable solution or suspension in an ampoule or vial or non-aqueous liquid suspension.
- a semi-solid carrier is used, the preparation may be in the form of hard and soft gelatin capsule formulations.
- the inventive compositions are prepared in unit-dosage form appropriate for the mode of administration, e.g. parenteral or oral administration.
- a salt of a compound of the present invention may be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3 M solution of succinic acid or citric acid.
- the agent may be dissolved in a suitable co-solvent or combinations of co-solvents.
- suitable co-solvents include alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like in concentrations ranging from 0 to 60% of the total volume.
- the composition may also be in the form of a solution of a salt form of the active ingredient in an appropriate aqueous vehicle such as water or isotonic saline or dextrose solution.
- the agents of the compounds of the present invention may be formulated into aqueous solutions, preferably in physiologically compatible buffers such as Hanks solution, Ringer's solution, or physiological saline buffer.
- penetrants appropriate to the barrier to be permeated are used in the formulation.
- penetrants are generally known in the art.
- the compounds can be formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art.
- Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject to be treated.
- Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture, and processing the mixture of granules after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
- Suitable excipients include: fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; and cellulose preparations, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum, methyl cellulose, hydroxypropylmethyl-cellulose, sodium
- polyvinylpyrrolidone PVP
- disintegrating agents may be added, such as crosslinked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
- Dragee cores are provided with suitable coatings.
- suitable coatings For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, polyvinyl pyrrolidone, Carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
- Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active agents.
- compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
- the push-fit capsules can contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
- the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
- stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
- the compositions may take the form of tablets or lozenges formulated in conventional manner.
- the compounds for use according to the present invention may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane,
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- Capsules and cartridges of gelatin for use in an inhaler or insufflator and the like may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
- the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
- Formulations for injection may be presented in unit-dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
- the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
- compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
- the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
- a suitable vehicle e.g. sterile pyrogen-free water
- the compounds of the present invention may also be formulated as a depot preparation.
- Such long-acting formulations may be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.
- the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion-exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
- a pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase.
- the co-solvent system may be a VPD co-solvent system.
- VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the non-polar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
- the VPD co-solvent system (VPD: 5W) contains VPD diluted 1 :1 with a 5% dextrose in water solution. This co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
- the proportions of a co-solvent system may be suitably varied without destroying its solubility and toxicity characteristics.
- co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of polysorbate 80; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may be substituted for dextrose.
- hydrophobic pharmaceutical compounds may be employed.
- Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs.
- Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity due to the toxic nature of DMSO.
- the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
- sustained-release materials have been established and are known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
- additional strategies for protein stabilization may be employed.
- the pharmaceutical compositions also may comprise suitable solid- or gel-phase carriers or excipients.
- These carriers and excipients may provide marked improvement in the bioavailability of poorly soluble drugs.
- Examples of such carriers or excipients include calcium carbonate, calcium phosphate, sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
- additives or excipients such as Gelucire®, Capryol®, Labrafil®, Labrasol®, Lauroglycol®, Plurol®, Peceol®, Transcutol® and the like may be used.
- the pharmaceutical composition may be incorporated into a skin patch for delivery of the drug directly onto the skin.
- an exemplary daily dose generally employed will be from about 0.001 to about 1000 mg/kg of body weight, with courses of treatment repeated at appropriate intervals.
- the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount of about 10 mg to about 2000 mg, or from about 10 mg to about 1500 mg, or from about 10 mg to about 1000 mg, or from about 10 mg to about 750 mg, or from about 10 mg to about 500 mg, or from about 25 mg to about 500 mg, or from about 50 to about 500 mg, or from about 100 mg to about 500 mg.
- the pharmaceutically acceptable formulations of the present invention may contain a compound of the present invention, or a salt or solvate thereof, in an amount from about 0.5 w/w% to about 95 w/w%, or from about 1 w/w% to about 95 w/w%, or from about 1 w/w% to about 75 w/w%, orfrom about 5 w/w% to about 75 w/w%, or from about 10 w/w% to about 75 w/w%, or from about 10 w/w% to about 50 w/w%.
- the compounds of the present invention may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus or any virus expressing arenavirus glycoprotein, either alone or in combination with one or more compounds selected from Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors as part of a pharmaceutically acceptable formulation, once a day, twice a day, three times a day, four times a day, or even more frequently.
- a mammal such as a human, suffering from a condition or disease mediated by arenavirus or any virus expressing arenavirus glycoprotein, either alone or in combination with one or more compounds selected from Ribavirin, polymerase inhibitors, Favipiravir, Triazavirin, small interfering RNAs (siRNAs), vaccines, monoclonal antibodies, immunomodulators, and other arenavirus inhibitors as part of
- the compounds of the present invention may be administered to a mammal, such as a human, suffering from a condition or disease mediated by arenavirus in combination with at least one other agent used for treatment of arenavirus selected from the group consisting of Ribavirin, viral RNA-dependent-RNA-polymerase inhibitors as shown by Ng KK, Arnold JJ and Cameron CE, Structure-Function Relationships Among RNA-Dependent RNA Polymerases, Curr Top Microbiol Immunol, 2008; 320: 137-156, incorporated herein by reference in its entirety, Favipiravir , a broad- spectrum inhibitor of viral RNA-Dependent RNA Polymerases, Triazavirin, a broad-spectrum inhibitor of viral RNA-Dependent RNA Polymerases, small interfering RNAs (siRNAs) and microRNAs as shown by Carthew RW and Sontheimer EJ, Origins and Mechanisms ofmiRNAs and
- the compounds of the present invention are useful for modulating or inhibiting arenavirus glycoprotein (GP) both in vitro and in vivo.
- GP arenavirus glycoprotein
- these compounds are useful for the prevention and/or treatment of disease states associated with arenavirus infection or treating viruses expressing the arenavirus glycoprotein.
- This invention also relates to a method for the treatment of arenavirus infection in mammals including a human comprising administering to said mammal an amount of a compound of the Formula I, as defined above, or a salt or solvate thereof, that is effective in treating disease states associated with Arenavirus infection or viruses expressing the arenavirus glycoprotein.
- Scheme 1 shows a method useful for the synthesis of compounds of structural Formula I wherein G is CH, J is N, E is CH, and A is C.
- Reduction of the nitro group using a reducing agent such as Fe or SnCh in a solvent such as THF or methanol can provide aniline 1 -3 which can be reacted with formic acid HCO2H or orthoester HC(OR)3to form 1 -4.
- Coupling of 1 -4 with a boronic acid or boronic ester R 1 B(OR)2 using a catalyst such as [1 ,T-bis(diphenylphosphino)ferrocene]palladium(ll) dichloride in the presence of a base such as K2CO3 in a solvent such as dimethoxyethane can provide compound of structural Formula I.
- Scheme 2 depicts a method of synthesis of deuterated aniline 2-4 useful in preparing deuterated intermediates 1 -2 for the synthesis of deuterated compounds of the invention as described in Scheme 1 above.
- Reduction of the nitro group using a reducing agent such as hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as methanol can provide aniline 2-4.
- Scheme 3 depicts a method of synthesis of deuterated aniline 3-4 useful in preparing deuterated intermediates 1 -2 for the synthesis of deuterated compounds of the invention as described in Scheme 1 above.
- Arylation of alcohol 3-1 with diaryliodonium salt 3-2 in the presence of a base such as NaHMDS in a solvent such as pentane can provide compound 3-3 [Lindstedt, E.; Stridfeldt, E.; Olofsson, B. Mild synthesis of sterically congested alkyl aryl ethers. Org. Lett. (2016) 18: 4234-4237]
- the above paper is herein incorporated by reference in its entirety for all purposes.
- Reduction of the nitro group using a reducing agent such as hydrogen gas in the presence of a catalyst such as palladium on carbon in a solvent such as methanol can provide aniline 3-4.
- Scheme 4 depicts a method useful for the synthesis of compounds of structural Formula I wherein A is N, E is CH, and J is C.
- a halogenation reagent such as bromine or /V-bromosuccinimide (NBS), or iodine or A/-iodosuccinimide
- Treatment of 4-3 with a boronic acid or boronic ester R 2 B(OR) 2 using a catalyst such as tetrakis(triphenylphosphine)palladium in the presence of a base such as K 2 CO3 in a solvent such as dioxane can provide a compound of Structural Formula I.
- a catalyst such as tetrakis(triphenylphosphine) palladium in the presence of a base such as K 2 CO3 in a solvent such as dioxane
- a catalyst such as [1 ,1’-bis(diphenylphos
- Scheme 5 depicts a method useful for the synthesis of compounds of structural Formula I wherein G is CH, A is C, J is N, and E is N.
- Reduction of the nitro groups using a reducing agent such as Fe or SnCh in a solvent such as THF or methanol can provide aniline 5-3 which can be reacted with nitrous acid to form 5-4.
- Coupling of 5-4 with a boronic acid or boronic ester R 1 B(OR)2 using a catalyst such as [1 ,1 - bis(diphenylphosphino)ferrocene]palladium(ll) dichloride in the presence of a base such as K2CO3 in a solvent such as dimethoxyethane can provide compound of structural Formula I.
- Reaction Schemes 6-8 illustrate methods of synthesis of borane reagents 6-4, 7-4, and 8-4 useful in preparing deuterated intermediates and final compounds of the invention as described in Schemes 1 , 4, and 5 above, to introduce R 1 and/or R 2 substituents.
- Compound 6-3 can be converted to a boronic acid or ester 6-4 using standard borylation reaction conditions well known to those skilled in the art.
- Scheme 7 depicts a method useful for the synthesis of deuterated boronic acid or ester 7-4.
- Compound 7-3 can be converted to a boronic acid or ester 7-4 using standard borylation reaction conditions well known to those skilled in the art.
- organolithium reagent such as n-Butyllithium
- Scheme 8 depicts a method useful for the synthesis of deuterated boronic acid or ester 8-4.
- Compound 8-3 can be converted to a boronic acid or ester 8-4 using standard borylation reaction conditions well known to those skilled in the art.
- Examples A2 to A3 were prepared in the same manner as described above for 2-(4-(1 -(4-(tert- butoxy)phenyl)-5-methyl-1 H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1), using the appropriate aryl halide described above and the appropriate commercially available boronic acid.
- 6-bromoimidazo[1 ,2-a]pyridine-7-carbonitrile To a solution of 2-amino-5-bromoisonicotinonitrile (150 mg, 0.76 mmol) in i-PrOH (2ml_) is added 0.6 ml_ (1 .5 eq) of 2-chloro-1 ,1 -dimethoxyethane. The solution is capped tightly and heated in a microwave reactor to 160°C for 30 minutes. The mixture is cooled and evaporated in vacuo, the residue dissolved in ethyl acetate, washed with saturated aq. NaHCC>3, and evaporated in vacuo to give 0.47 g of the title compound, pure enough for further use. LC/MS m/z: 221 .10 (M+H) + 6-bromo-3-iodo-7-methylimidazo[1 ,2-a]pyridine
- Examples B4 to B9 were prepared in the same manner as described above for 2-(4-(1 -(4-(tert- butoxy)phenyl)-5-methyl-1 H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1) using the appropriate aryl halide and commercially available boronic acids. In the case of compounds which have identical substitutions of the aryl halide, 2 equivalents of the boronic acid are used.
- the title compound was prepared from 4-bromo-2-fluoro-1 -nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-A/ 1 -(4-isopropoxyphenyl)-4-methylbenzene-1 ,2-diamine.
- LCMS m/z; 321 .20 ( 79 Br, M+H) + , 323.19 ( 81 Br, M+H) + , 362.20 ( 79 Br, M+H+CH 3 CN) + , 364.24( 81 Br, M+H+CH 3 CN) + .
- the title compound was prepared from 1 -bromo-2,3-difluoro-4-nitrobenzene and 4-isopropoxyaniline in the same manner as described for 5-bromo-A/ 1 -(4-isopropoxyphenyl)-4-methylbenzene-1 ,2-diamine.
- the title compound was prepared from 5-bromo-N1 -(4-isopropoxyphenyl)-4-methoxybenzene-1 ,2-diamine in the same manner as described for 6-bromo-1 -[4-(propan-2-yloxy)phenyl]-1 /-/-1 ,2,3-benzotriazole.
- Examples C10 to C18 were prepared in the same manner as described above for 2-(4-(1 -(4-(tert- butoxy)phenyl)-5-methyl-1 H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1), using the appropriate aryl halide described above and the appropriate commercially available boronic acid.
- Example C20 1 ,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1 ,2,3]triazole-5-carboxylic acid
- Example C22 (1 ,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1 ,2,3]triazol-5-yl)methanamine
- Example C23 1 ,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1 ,2,3]triazol-5-amine
- Example C25 1 ,6-bis(4-isopropoxyphenyl)-5-vinyl-1 H-benzo[d][1 ,2,3]triazole
- Step 1 1 ,6-bis(4-isopropoxyphenyl)-1 H-benzo[d][1 ,2,3]triazole-5-carbaldehyde
- Step 2 1 ,6-bis(4-isopropoxyphenyl)-5-vinyl-1 H-benzo[d][1 ,2,3]triazole
- Step 1 6-bromo-7-methylimidazo[1 ,2-a]pyrimidine
- Step 2 6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyrimidine
- the title compound was prepared from 6-bromo-7-methylimidazo[1 ,2-a]pyrimidine and 4- isopropoxyphenylboronic acid in the same manner as described for 2-(4-(1 -(4-(tert-butoxy)phenyl)-5- methyl-1 H-benzo[d]imidazol-6-yl)phenyl)propan-2-ol (Example A1).
- Step 3 3-iodo-6-(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyrimidine
- Step 4 3,6-bis(4-isopropoxyphenyl)-7-methylimidazo[1 ,2-a]pyrimidine
- Example E30 3-(4-(tert-butoxy)phenyl)-6-(4-(isopropoxy-d7)phenyl)-7-methylimidazo[1 ,2-a]pyridine
- Step 1 4-(3-(4-(tert-butoxy)phenyl)-7-methylimidazo[1 ,2-a]pyridin-6-yl)phenol
- the resulting mixture is diluted with ethyl acetate and the aqueous layer extracted 3X with ethyl acetate, followed by drying over Na 2 SC> 4 and evaporation to yield the crude product.
- the crude material is purified using silica gel flash chromatography with 100% ethyl acetate as eluent to give 20 mg of the title compound as a light brown oil. LC/MS m/z ⁇ 373.35
- Step 2 3-(4-(tert-butoxy)phenyl)-6-(4-(isopropoxy-d7)phenyl)-7-methylimidazo[1 ,2-a]pyridine
- VSV pseudotype system expressing arenavirus glycoproteins prseudotyped viruses here to referred to as LASV-p, MACV-p, JUNV-p, GTOV-p and TCRV-p
- Renilla luciferase reporter gene heterocyclic compounds were screened to identify individual compounds that inhibit infectivity of the pseudotyped viruses but not the native VSV virus expressing the VSV glycoprotein.
- VSV viruses expressing the VSV glycoprotein or pseudotyped with LASV, MACV, JUNV, GTOV and TCRV glycoproteins were generated in cultured HEK-293T cells (ATCC CRL-3216), which were grown in 10 cm dishes in DMEM supplemented with 10% FBS, 1X Pen-Strep, non-essential amino acids and L-glutamine.
- cells When cells reached approximately 80% confluency, they were transfected with a mixture of 15 pg of the pCAGGS plasmid encoding the desired glycoprotein and 45 pi of PEI (polyethylenimine) transfection reagent (PEI MAX, Polysciences Inc., #24765). The cells were incubated with the solution for 5 hours at 37°C at 5% CO2 then washed and the mixture replaced with supplemented DMEM and incubated at 37°C at 5% CO2 for approximately 16-18 hours. Subsequently cells were infected with approximately 50 pi of VSV reporter virus whereby the VSV glycoprotein was replaced with a luciferase reporter gene.
- PEI polyethylenimine
- Vero cells were infected for 1 hour, then washed 1X with PBS and incubated in supplemented media. 24 hours post-infection, supernatant was collected, clarified by centrifugation and filtration through a 0.45um filter, aliquoted and stored at -80°C. Both VSV-Luciferase and arenavirus glycoproteins pseudotypes were titrated for luminescence activity in Vero cells as described in the Luciferase assay protocol (below). Vero cells (ATCC: CCL-81) were grown in clear 384 well plates (3000 cells/well) in supplemented DMEM media. After incubating overnight at 37°C and 5% CO2, cells were treated with compounds at desired concentrations and pseudotyped virus in assay media.
- Assay media consisted of 50% Opti-MEM, 50% DMEM, with 1 % FBS, Pen-Strep, non- essential amino acids and L-glutamine. Each of the viral supernatants generated was diluted (from 1 :100 to 1 :2000) to give similar luminescence signal / background values of > 200. Final DMSO concentration in the compound testing wells was kept ⁇ 1 % and control wells were treated with assay media and 1 % DMSO. Cells were incubated for 24 hours at 37°C and 5% CO 2 . The compound-virus mixture was aspirated off the cells 24 hours post-infection and washed 1X with PBS.
- Luminescence signals were obtained for compound containing and control wells to determine % activity (inhibition of luciferase signal) for each compound.
- Active compounds in the pseudotype assays were also evaluated for cytotoxicity over a period of 3 days.
- Compounds were serially diluted and added to Vero cells (4000 cells/well) with final DMSO concentration maintained at 1 % in growth media consisting of minimal essential media (MEM) with 1 % FBS.
- the plates were incubated at 37 °C for 3 days, and then dead cells were removed by washing with Phosphate buffered saline (PBS).
- CPE was assessed by staining cells with neutral red dye for 1 hour and then de-staining with a solution of 50% ethanol/ 1 % acetic acid solution.
- Absorbances were read at 540 nm and 690 nm on a Spectramax Plus 384 spectrophotometer. Data were analyzed as (540 nm - 690 nm) and then compared to untreated controls to obtain % cell survival.
- Confluent or near-confluent cell culture monolayers in 12-well disposable cell culture plates were prepared. Cells were maintained in MEM or DMEM supplemented with 10% FBS. For antiviral assays the same medium was used but with FBS reduced to 2% or less and supplemented with 1 % penicillin/streptomycin. The test compounds were prepared at seven half log 10 final concentrations, (01 -10 mM) in 2X MEM or 2X DMEM. Test compounds and positive control compounds (favipiravir or ribavirin) were run in parallel in biological triplicates.
- the assay was initiated by first removing growth media from the 12-well plates of cells, which was challenged with compound at a given concentration and 0.01 MOI of virus or about 50 to 100 plaque forming units (pfu). Cells were incubated for 60 min: 100 pL inoculum/ well, at 37°C, 5% C0 2 with constant gentle rocking. Virus inoculum was removed, cells washed and overlaid with either 1 % agarose or 1 % methylcellulose diluted 1 :1 with 2X MEM and supplemented with 2% FBS and 1 %
- SI selectivity index
- the VYR test is a direct determination of the concentration of the test compound that inhibits virus replication. Compound and virus were added to Vero cells for 3-4 days at which point the supernatant was removed and tested for infectious particles. The supernatant was titrated log 10 dilutions of virus using 3 or 4 microwells per dilution on fresh monolayers of Vero cells in 96- well plates. Wells were scored for presence or absence of virus after distinct CPE is observed.
- TCRV native replicating Tacaribe virus
- TRVL-11573 native replicating Tacaribe virus
- BEI Resources native replicating Tacaribe virus
- Vero cells ATCC: CCL-81
- Vero cells ATCC: CCL-81
- MEM media 5000 cells/well
- FBS 1 % FBS
- Final DMSO concentration in the compound testing wells was kept ⁇ 1 % and control wells were treated with TCRV or media and 1 % DMSO. After 5 days of incubation at 37°C in 5% CO2, cells were fixed with 2%
- compounds In addition to the ability of compounds to demonstrate broad inhibitory activity against arenaviruses in vitro, compounds must also have certain drug-like properties for them to be used to inhibit arenaviruses and provide methods of treatment for arenavirus infection in mammals in vivo.
- Such compounds may exhibit drug-like properties including but not limited to chemical stability against metabolic degradation by liver microsomal CYP p450 enzymes, cell permeability and oral bioavailability (if the drug is to delivered orally) and lack of inhibition of the hERG ion channel, which is associated with cardiac safety [Kerns, E.H. Li, D. Drug-like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization, (2008) Academic Press, Burlington MA] The above publication is herein incorporated by reference for all purposes.
- reaction premixture was set up, containing 1 uM compound of interest, 1 mg/mL liver microsomes of desired species, 2.1 mM MgCh and 0.1 M sodium phosphate buffer, pH 7.4. This premixture was incubated at 37°C for 30 minutes with gentle agitation to allow the compound to be completely dissolved in the mixture. Then freshly made NADPH solution in 0.1 M sodium phosphate buffer was added at a concentration of 2mM to start the reaction. A Time 0’ sample (30 uL) was taken out immediately after addition of NADPH and added to 140uL cold acetonitrile containing 1 uM of pre-decided internal standard. The rest of the reaction mixture was incubated at 37°C for the remaining time period.
- Test compounds were left in the reaction mixture for 60 minutes before Time 60’ sample was added to acetonitrile with internal standard.
- the control compound (Verapamil for human, monkey and dog LM, Lidocaine for Guinea pig LM, and diphenhydramine for rat and mouse LM) was incubated in reaction mixture for 15 m inutes before Time 15’ samples were collected and added to cold acetonitrile with internal standard. The samples were then spun in a centrifuge for 10 minutes at 4000 rpm, supernatant was collected and mixed with equal parts distilled water. These were then analyzed on a Varian 500-MS. hERG Channel Assay
- Drugs belonging to different classes have been shown to be associated with QT prolongation and in some cases serious ventricular arrhythmias.
- the most common mechanism for these adverse events is the inhibition of one or more cardiac potassium channels, in particular hERG.
- This current is important for cardiac myocyte repolarization and is a common target for drugs that prolong the QT interval.
- Test articles in this study were therefore, characterized to determine their ability to inhibit the hERG channel.
- Ion channel activity was measured using a stably transfected Chinese Hamster Ovary (CHO) cell line expressing the hERG mRNA. The pharmacology of this cloned channel expressed in the CHO cell line is very similar to that observed in native tissue.
- test articles were applied. Test article solutions were added to cells in 4 separate additions. Cells were kept in test solution until effect of the test article reached steady state, to a maximum of 12 min. Next, 1 mM cisapride (positive control) was added. Finally, washout with External Solution was performed until the recovery current reached steady state. Data analysis was performed using DataXpress (Axon Instruments), Clampfit (Axon Instruments) and Origin (OriginLab Corporation) software.
- Example compounds and their observed inhibitory activities are shown as ECso values for LASV-p, MACV-p, JUNV-p, TCRV-p and GTOV-p (VSV-p EC50 values were all > 10 uM) and CC50 for cytotoxicity; nd: not determined.
- Vd volume of distribution
- Table 7 Compound Concentrations 24 Hours Post Final Administration Taken together the results show that the compounds of the invention exhibit potent, broad-spectrum inhibition of HF arenaviruses and attractive drug-like properties for utilization as treatments for viral infections that are mediated by arenavirus glycoproteins.
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Abstract
Description
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KR1020217017726A KR20210106997A (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infections |
MX2021005234A MX2021005234A (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infection. |
EA202191001A EA202191001A1 (en) | 2018-12-06 | 2019-12-03 | COMPOUNDS FOR TREATMENT OF ARENAVIRAL INFECTION |
JP2021525159A JP2022509763A (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infections |
CA3118765A CA3118765A1 (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infection |
AU2019393784A AU2019393784A1 (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infection |
CN201980080594.2A CN113329750A (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infections |
EP19892030.8A EP3890731A4 (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infection |
US17/299,270 US20220193038A1 (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infection |
BR112021010909-9A BR112021010909A2 (en) | 2018-12-06 | 2019-12-03 | Compounds for the treatment of arenavirus infection |
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US20150023916A1 (en) * | 2012-02-17 | 2015-01-22 | Siga Technologies Inc. | Antiviral drugs for treatment of arenavirus infection |
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US20150023916A1 (en) * | 2012-02-17 | 2015-01-22 | Siga Technologies Inc. | Antiviral drugs for treatment of arenavirus infection |
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JP2022509763A (en) | 2022-01-24 |
CA3118765A1 (en) | 2020-06-11 |
EP3890731A1 (en) | 2021-10-13 |
MX2021005234A (en) | 2021-08-11 |
AU2019393784A1 (en) | 2021-05-27 |
KR20210106997A (en) | 2021-08-31 |
EP3890731A4 (en) | 2022-08-17 |
CN113329750A (en) | 2021-08-31 |
AR117228A1 (en) | 2021-07-21 |
BR112021010909A2 (en) | 2021-08-24 |
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