WO2024081318A1 - Anti-viral compounds - Google Patents
Anti-viral compounds Download PDFInfo
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- WO2024081318A1 WO2024081318A1 PCT/US2023/034949 US2023034949W WO2024081318A1 WO 2024081318 A1 WO2024081318 A1 WO 2024081318A1 US 2023034949 W US2023034949 W US 2023034949W WO 2024081318 A1 WO2024081318 A1 WO 2024081318A1
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- compound
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- alkyl
- monocyclic
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- UGZBCXUUYHCFMX-STQMWFEESA-N tert-butyl (4S)-4-[(2S)-3-hydroxy-2-[(2-methylpropan-2-yl)oxycarbonylamino]propyl]-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate Chemical compound CC(C)(C)OC(N[C@@H](C[C@@H](CC(C)(C)N1C(OC(C)(C)C)=O)C1=O)CO)=O UGZBCXUUYHCFMX-STQMWFEESA-N 0.000 description 1
- ICTLTLIZKLSOQI-JTQLQIEISA-N tert-butyl N-[(2S)-1-hydroxy-3-(5-oxo-4-azaspiro[2.4]heptan-6-ylidene)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(N[C@H](CO)C=C(CC1(CC1)N1)C1=O)=O ICTLTLIZKLSOQI-JTQLQIEISA-N 0.000 description 1
- ICTLTLIZKLSOQI-ZKXNXJMVSA-N tert-butyl N-[(2S,3E)-1-hydroxy-3-(5-oxo-4-azaspiro[2.4]heptan-6-ylidene)propan-2-yl]carbamate Chemical compound CC(C)(C)OC(N[C@H](CO)/C=C(\CC1(CC1)N1)/C1=O)=O ICTLTLIZKLSOQI-ZKXNXJMVSA-N 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- VLLMWSRANPNYQX-UHFFFAOYSA-N thiadiazole Chemical compound C1=CSN=N1.C1=CSN=N1 VLLMWSRANPNYQX-UHFFFAOYSA-N 0.000 description 1
- CBDKQYKMCICBOF-UHFFFAOYSA-N thiazoline Chemical compound C1CN=CS1 CBDKQYKMCICBOF-UHFFFAOYSA-N 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- XSROQCDVUIHRSI-UHFFFAOYSA-N thietane Chemical compound C1CSC1 XSROQCDVUIHRSI-UHFFFAOYSA-N 0.000 description 1
- 125000000858 thiocyanato group Chemical group *SC#N 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-M toluene-4-sulfonate Chemical compound CC1=CC=C(S([O-])(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-M 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- YWYZEGXAUVWDED-UHFFFAOYSA-N triammonium citrate Chemical compound [NH4+].[NH4+].[NH4+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O YWYZEGXAUVWDED-UHFFFAOYSA-N 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- 125000004952 trihaloalkoxy group Chemical group 0.000 description 1
- 125000004385 trihaloalkyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
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Definitions
- the present application relates to the fields of chemistry, biochemistry and medicine.
- compounds of Formula (I), or pharmaceutically acceptable salt thereof pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same.
- methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof are also disclosed herein.
- a positive-sense single-stranded RNA virus ((+)ssRNA virus) is a virus that uses positive sense, single stranded, RNA as its genetic material. Positive-sense singlestranded RNA viruses can be enveloped or non-enveloped. Coronaviridae, Picornaviridae and Norviruses are each a (+)ssRNA virus. Each of the aforementioned viruses are known to infect mammals, including humans.
- Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
- Some embodiments described herein relate to a method of treating a coronavirus infection that can include administering to a subject identified as suffering from the coronavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a coronavirus infection.
- Some embodiments disclosed herein relate to a method of inhibiting replication of a coronavirus that can include contacting a cell infected with the coronavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication a coronavirus.
- Some embodiments described herein relate to a method of treating a picornavirus infection that can include administering to a subject identified as suffering from the picornavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof as described herein for the use of treating a picornavirus infection.
- Some embodiments disclosed herein relate to a method of inhibiting replication of a picornavirus that can include contacting a cell infected with the picornavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication a picornavirus.
- Some embodiments described herein relate to a method of treating a norovirus infection that can include administering to a subject identified as suffering from the norovirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a norovirus infection.
- Some embodiments disclosed herein relate to a method of inhibiting replication of a norovirus that can include contacting a cell infected with the norovirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication a norovirus.
- Coronaviridae viruses are a family of enveloped, positive-stranded, singlestranded, spherical RNA viruses. Coronaviruses are named for the crown-like spikes on their surface.
- the Coronaviridae family includes two sub-families, Coronavirus and Torovirus.
- the Coronavirus genus has a helical nucleocapsid
- Torovirus genus has a tubular nucleocapsid.
- the Coronaviridae family of viruses includes Middle East respiratory syndrome coronavirus (MERS-CoV), SARS and SARS-CoV-2.
- Coronavirus disease 2019 (COVID-19) (also referred to as novel coronavirus pneumonia or 2019-nCoV acute respiratory disease) is an infectious disease caused by the virus severe respiratory syndrome coronavirus 2 (SARS-CoV-2) (also referred to as novel coronavirus 2019, or 2019-nCoV).
- SARS-CoV-2 virus severe respiratory syndrome coronavirus 2
- the disease was first identified in December 2019 and spread globally, causing a pandemic.
- Sy mptoms of CO VID-19 include fever, cough, shortness of breath, fatigue, headache, loss of smell, nasal congestion, sore throat, coughing up sputum, pain in muscles or joints, chills, nausea, vomiting, and diarrhea.
- symptoms can include difficulty waking, confusion, blueish face or lips, coughing up blood, decreased white blood cell count, and kidney failure.
- Complications can include pneumonia, viral sepsis, acute respiratory distress syndrome, and kidney failure.
- COVID-19 is especially threatening to public health.
- the virus is highly contagious, and studies currently indicate that it can be spread by asymptomatic carriers or by those who are pre-symptomatic.
- the early stage of the disease is slow-progressing enough that carriers do not often realize they are infected, leading them to expose numerous others to the virus.
- the combination of COVID- 19’ s ease of transmission, its high rate of hospitalization of victims, and its death rate make the virus a substantial public health risk, especially for countries without a healthcare system equipped to provide supportive care to pandemic-level numbers of patients.
- SARS-CoV-2 is not the only coronavirus that causes disease. It is a p- coronavirus, a genus of coronaviruses that includes other human pathogens, including SARS- CoV (the causative agent of SARS), MERS-CoV (the causative agent of MERS), and HCoV- OC43 (a causative agent of the common cold).
- SARS- CoV the causative agent of SARS
- MERS-CoV the causative agent of MERS
- HCoV- OC43 a causative agent of the common cold.
- Pi comaviruses are a family of positive strand RNA, nonenveloped viruses.
- a picornavirus has 60 identical subunits (vertices) which contain five protomers. Each protomer is made up of one copy of four proteins, named VP1, VP2, VP3 and VP4.
- VP1, VP2, VP3 and VP4 proteins that are proteins that are proteins that are proteins that are proteins that are made up of one copy of four proteins.
- VP1, VP2, VP3 and VP4 There are several genera of picornaviruses, including, Enterovirus, Aphthovirus, Cardiovirus and Hepatovirus.
- Enteroviruses known to infect human include, but are not limited to. Rhinovirus A, Rhinovirus B, Rhinovirus C, Coxsackievirus A, Coxsackievirus B and Poliovirus. There is no specific treatment for a picornavirus infection.
- Noroviruses are single-stranded positive-sense RNA, non-enveioped viruses belonging to the Caliciviridae family. Noroviruses are often spread by the fecal-oral route, and are a common cause of gastroenteritis. Infected subjects can experience nausea, non-bloody diarrhea, vomiting and/or abdominal pain. Those suffering from a norovirus infection can become severely dehydrated and require medical attention. As with a picornavirus infection, there is no specific treatment for a norovirus infection. Accordingly, there is a need for compounds that effectively treat or prevent a picornavirus and/or a norovirus infection.
- the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) (such as 1, 2 or 3) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C -amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido(alkyl), isocyanato, thiocyanato, nitro,
- C a to C b or “C a-b ” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group.
- alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms.
- a “C 1 to C 4 alkyl” or “C 1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-.
- alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
- the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
- the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
- the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
- the alkyl group of the compounds may be designated as “C 1 -C 4 alkyl” or similar designations.
- “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
- Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
- alkyl group may be substituted or unsubstituted.
- alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
- the length of an alkenyl can vary.
- the alkenyl can be a C 2-4 alkenyl, C 2-6 alkenyl or C 2-8 alkenyl.
- alkenyl groups include allenyl, vinylmethyl and ethenyl.
- An alkenyl group may be unsubstituted or substituted.
- alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
- alkynyl can vary.
- the alkynyl can be a C 2-4 alkynyl, C 2-6 alkynyl or C 2-8 alkynyl.
- alkynyls include ethynyl and propynyl.
- An alkynyl group may be unsubstituted or substituted.
- cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused- or spiro-fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s).
- a cycloalkyl group may be unsubstituted or substituted.
- Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused- or spiro- fashion.
- a cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s).
- a cycloalkenyl group may be unsubstituted or substituted.
- aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
- the number of carbon atoms in an aryl group can vary.
- the aryl group can be a C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 aryl group.
- Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
- An aryl group may be substituted or unsubstituted.
- heteroaryl refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
- the number of atoms in the ring(s) of a heteroaryl group can vary.
- the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
- heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
- heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4- oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrim
- heteroaryl group may be substituted or unsubstituted.
- heterocyclyl refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
- a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The number of atoms in the ring(s) of a heterocyclyl group can vary.
- the heterocyclyl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
- the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
- a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized.
- Heterocyclyl groups may be unsubstituted or substituted.
- heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5- triazine, imidazoline, imidazolidine, isox
- cycloalkyl(alkyl) refers to a cycloalkyl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and cycloalkyl group of a cycloalkyl(alkyl) may be substituted or unsubstituted.
- a cycloalkyl(alkyl) group may be unsubstituted or substituted.
- aryl(alkyl) refers to an aryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted.
- heteroaryl(alkyl) refers to a heteroaryl group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted.
- heterocyclyl(alkyl) refers to a heterocyclic group connected, as a substituent, via a lower alkylene group.
- the lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted.
- “Lower alkylene groups” are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms.
- alkylene groups can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.” Further, when a lower alkylene group is substituted, the lower alkylene can be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g., [0036]
- alkoxy refers to the formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl(alkyl), an aryl(alkyl), a
- alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzyloxy.
- an alkoxy can be –OR, wherein R is an unsubstituted C 1-4 alkyl.
- An alkoxy may be substituted or unsubstituted.
- acyl refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl) connected, as substituents, via a carbonyl group.
- Examples include formyl, acetyl, propanoyl, benzoyl and acryl.
- An acyl may be substituted or unsubstituted.
- haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl).
- a halogen e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl.
- groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl.
- a haloalkyl may be substituted or unsubstituted.
- haloalkoxy refers to a O-alkyl group and O-monocyclic cycloalkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
- Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2- fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chloro-substituted cyclobutyl and fluoro-substituted cyclobutyl.
- a haloalkoxy can be –OR, wherein R is a C 1-4 alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted.
- a “sulfenyl” group refers to an “–SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl).
- a sulfenyl may be substituted or unsubstituted.
- a sulfinyl may be substituted or unsubstituted.
- a sulfonyl may be substituted or unsubstituted.
- An O-carboxy may be substituted or unsubstituted.
- the term “amino” as used herein refers to a –NH2 group.
- hydroxy refers to a –OH group.
- a “cyano” group refers to a “–CN” group.
- the term “azido” as used herein refers to a –N 3 group.
- An “isocyanato” group refers to a “–NCO” group.
- a “thiocyanato” group refers to a “–SCN” group.
- An “isothiocyanato” group refers to an “–NCS” group.
- a “mercapto” group refers to an “–SH” group.
- An S-sulfonamido may be substituted or unsubstituted.
- R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl).
- An N-sulfonamido may be substituted or unsubstituted.
- An O-carbamyl may be substituted or unsubstituted.
- An N-carbamyl may be substituted or unsubstituted.
- An O-thiocarbamyl may be substituted or unsubstituted.
- An N-thiocarbamyl may be substituted or unsubstituted.
- a C-amido may be substituted or unsubstituted.
- R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl).
- An N-amido may be substituted or unsubstituted.
- a “mono-substituted amine” refers to a “–NHR A ” in which R A can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl).
- a mono-substituted amine may be substituted or unsubstituted.
- a mono-substituted amine can be –NHR A , wherein R A can be an unsubstituted C 1-6 alkyl or an unsubstituted or a substituted benzyl.
- a “di-substituted amine” refers to a “–NR A R B ” in which R A and R B can be independently can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl).
- a mono-substituted amine may be substituted or unsubstituted.
- a mono-substituted amine can be –NR A R B , wherein R A and R B can be independently an unsubstituted C 1-6 alkyl or an unsubstituted or a substituted benzyl.
- a ketoamide may be substituted or unsubstituted.
- halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
- substituents e.g., haloalkyl
- substituents there may be one or more substituents present.
- haloalkyl may include one or more of the same or different halogens.
- C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
- any protective groups, amino acids and other compounds are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.11:942-944 (1972)).
- pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
- the salt is an acid addition salt of the compound.
- Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
- Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid.
- Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
- a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexy
- the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
- the term “comprising” means that the compound or composition includes at least the recited features or components but may also include additional features or components.
- each center may independently be of (R)-configuration or (S)-configuration or a mixture thereof.
- the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
- each double bond may independently be E or Z a mixture thereof.
- a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
- the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium).
- reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
- R 11 can be an optionally substituted monocyclic 4- to 6- membered heterocyclyl, -(NH)m-an optionally substituted 5- to 6-membered monocyclic heteroaryl, -O-an optionally substituted C 1-6 alkyl, -O-an optionally substituted C 3-8 cycloalkyl
- R 1 can be various moieties.
- R 1 can be an unsubstituted ketoamide.
- R 1 can be a substituted ketoamide.
- R 1 can be a substituted acyl.
- R y1 , R y2 and R z1 can be a variety of groups.
- R y1 , R y2 and R z1 can be independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 - 8 cycloalkyl (for example, a monocyclic C 3-8 cycloalkyl), C 3-8 cycloalkenyl (such as a monocyclic C 3-8 cycloalkenyl), aryl (such as phenyl or naphthyl), heteroaryl (including a monocyclic or a bicyclic heteroaryl), heterocyclyl (for example, a monocyclic or a bicyclic heterocyclyl), aryl(alkyl) (such as benzyl), heteroaryl(alkyl) (including a monocyclic heteroaryl(CH 2 )– and a monocyclic (heteroaryl(CH 2 CH 2
- R y1 , R y2 and R z1 can be independently selected from H, C1-8 alkyl, an unsubstituted C 1-4 haloalkyl (including –CF3, –CCl3, –CHF2, –C(CH 3 )F2, –CHCl2, –CH 2 F, –CH(CH 3 )F, –CH 2 CF3, –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F and –CH 2 CH 2 CH 2 Cl), –C 1-4 alkyl(OH) (including –CH 2 OH, –CH 2 CH 2 OH and –CH(CH 3 )OH), – C 1-4 alkyl(C 1-4 alkoxy) (such as –CH 2 O(an unsubstituted C 1-4 alkyl) and –CH 2 CH 2 O(an unsubstituted C 1-4 alkyl)), –C 1-4 alkyl,
- R 6 and R 7 groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained and branched), hexyl (straight-chained and branched), ethenyl, propenyl, butenyl, pentenyl, hexenyl, chloromethyl, fluoromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, an unsubstituted or a substituted phenyl and an unsubstituted or a substituted benzyl.
- R 1 can be cyano. In other embodiments, R 1 can be an unsubstituted C 2-5 alkynyl. In still other embodiments, R 1 can be a substituted C 2-5 alkynyl.
- the C 2-5 alkynyl can have various structures. For example, the C 2-5 alkynyl can have the structure -(CH 2 ) 1 -C 2-4 alkynyl or -(CH 2 )2-C 2-3 alkynyl.
- Ring A 1 can be an unsubstituted .
- Ring A 1 can be a substituted .
- moieties such as 1, 2 or 3 moieties
- moieties such as 1, 2 or 3 moieties
- Ring A 1 examples include halogen (such as F or Cl), an unsubstituted C 1-4 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), an unsubstituted C 1-4 haloalkyl (including –CF 3 , –CCl 3 , –CHF 2 , –C(CH 3 )F 2 , – CHCl 2 , –CH 2 F, –CH(CH 3 )F, –CH 2 CF 3 , –CH 2 Cl, —CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F and —CH 2 CH 2 CH 2 Cl), an unsubstituted C 2-4 alkenyl (such as ethenyl, propenyl and butenyl) and an unsubstituted C 2-4 al
- R 4 can be hydrogen. In other embodiments, R 4 can be deuterium. In still other embodiments, R 4 can be halogen (such as fluoro or chloro).
- R 3 can be a non-hydrogen substituent selected from an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl) and an unsubstituted or a substituted bicyclic nitrogen-containing heterocyclyl(C 1-4 alkyl).
- R 3 can be an unsubstituted monocyclic nitrogen-containing heteroaryl(C 1-4 alkyl).
- R 3 can be a substituted monocyclic nitrogen-containing heteroaryl(C 1-4 alkyl).
- R 3 can be an unsubstituted bicyclic nitrogen- containing heterocyclyl(C 1-4 alkyl).
- R 3 can be a substituted bicyclic nitrogen-containing heterocyclyl(C 1-4 alkyl).
- R 3 is a bicyclic nitrogen- containing heterocyclyl(C 1-4 alkyl)
- the two rings of the bicyclic heterocyclyl can be connected in a fused-fashion (including bridged-fashion) or a spiro-fashion.
- R 3 can be an unsubstituted monocyclic nitrogen-containing heteroaryl(C 1-4 alkyl).
- R 3 can be a substituted monocyclic nitrogen-containing heteroaryl(C 1-4 alkyl).
- rings C1 and C2 are joined in a spiro-fashion.
- the two rings are connected by two or more ring atoms.
- the two rings can be connected by two adjacent ring atoms.
- rings D1 and D1 are connected in a fused-fashion by two adjacent ring atoms .
- two rings described herein can be connected by three or more atoms are shared between the two rings.
- the following structure: is an example of two rings being connected by three or more ring atoms.
- bridging When two rings are connected by three or more ring atoms, the three or more ring atoms connecting the two rings would be referred to by those skilled in the art as “bridging” atoms. Further, those skilled in the art would understand based on the disclosure provided herein that two rings connected in a “bridged” fashion is an example of two rings connected in a fused-fashion. [0089]
- the number of ring atoms for a monocyclic and a bicyclic nitrogen- containing heterocyclyl(C 1-4 alkyl) can vary.
- Non-limiting examples include an unsubstituted or a substituted 5-membered monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl), 6- membered monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl), an unsubstituted or a substituted 9-membered bicyclic nitrogen-containing heterocyclyl(C 1-4 alkyl) and 10- membered bicyclic nitrogen-containing heterocyclyl(C 1-4 alkyl).
- R 3 groups include the following: azepan-2-one(C 1-4 alkyl), imidazolidin-2-one(C 1-4 alkyl), tetrahydropyrimidin-2-one(C 1-4 alkyl), pyrrolidin-2-one(C 1-4 alkyl), piperidin-2-one(C 1-4 alkyl), pyrazolidin-3-one(C 1-4 alkyl), oxazolidin-4-one(C 1-4 alkyl), 1,4-oxazepan-3-one(C 1-4 alkyl), morpholin-3-one(C 1-4 alkyl), , , , , ,
- each m1 can be independently 1, 2, 3 or 4, (including substituted or unsubstituted versions of the aforementioned).
- the R 3 groups provided herein can be substituted with one or more moieties independently selected from those listed for “optionally substituted.”
- a R 3 group provided herein can be substituted with one or more moieties selected from deuterium, halogen, hydroxy, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl an unsubstituted C 1-4 alkoxy, amino, –(an unsubstituted C 1-4 alkyl)- O-P-(OH) 2 (such as –CH 2 -O-P-(OH) 2 ) and –(an unsubstituted C 1-4 alkyl)-O-P-(O(an unsubstituted C 1-4 alkyl))2 (such as –CH 2 -O-P-(OCH 3 ) 2 ).
- R 2 can be hydrogen. In other embodiments, R 2 can be deuterium. In still other embodiments, R 2 can be halogen (for example, fluoro or chloro). O [0092] As provided herein, R 5 can be . In some embodiments, R 9 can be an unsubstituted C 1-6 haloalkyl.
- R 9 can be –CF 3 , –CClF 2, –CCl 3 , –CHF 2 , –C(CH 3 )F 2 , –CHCl 2 , –CH 2 F, –CH(CH 3 )F, –CH 2 CF 3 , –CH(CH 3 )CF 3 , –CH 2 CH 2 CF 3 , – CH 2 CH(CH 3 )CF 3 , –CF 2 CF 3 , –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F and – CH 2 CH 2 CH 2 Cl.
- R 9 can be –CF 3 .
- R 9 can be a substituted C 1-6 haloalkyl where the C 1-6 haloalkyl can be substituted 1 or 2 times with an unsubstituted C 1-4 alkoxy.
- the C 1-6 haloalkyl is substituted with 1 or 2 unsubstituted C1- 4 alkoxys
- one or more hydrogens of the C 1-6 haloalkyl can be replaced with an unsubstituted C 1-4 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy).
- Exemplary C 1-6 haloalkyls substituted with an unsubstituted C 1-4 alkoxy include –C(OCH 3 )F 2 , –C(OCH 3 )Cl 2 , –CH(OCH 3 )F, –C(OCH 3 )(CH 3 )F, –CH(OCH 3 )CF 3 , – C(OCH 3 )(CH 3 )CF 3 , –CH 2 CH(OCH 3 )CF 3 , –CH 2 C(OCH 3 )(CH 3 )CF 3 , –CH(OCH 3 )Cl, – CH 2 CH(OCH 3 )F, –CH 2 CH(OCH 3 )Cl, –CH 2 CH 2 CH(OCH 3 )F and –CH 2 CH 2 CH(OCH 3 )Cl.
- R 9 can be an unsubstituted C 1-6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched).
- R 9 can be a C 1-6 alkyl substituted 1 or 2 times with an unsubstituted C 1-4 alkoxy.
- a hydrogen of the C 1-6 alkyl can be replaced with an unsubstituted C 1-4 alkoxy such as those described herein.
- a non-limiting list of C 1-6 alkyls substituted 1 or 2 times with an unsubstituted C 1-4 alkoxy include –CH 2 (OCH 3 ), –CH(OCH 3 ) 2 , –CH(CH 3 )(OCH 3 ) and –C(CH 3 )2(OCH 3 ).
- R 9 can be an unsubstituted or a substituted monocyclic heteroaryl.
- the heteroaryl can be a 5- or 6- membered heteroaryl that includes 1, 2 or 3 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S).
- exemplary heteroaryls for an unsubstituted or a substituted monocyclic heteroaryl include, but are not limited to, furane, isoxazole, isothiazole pyridine, pyridazine, pyrimidine and pyrazine.
- R 9 can be an unsubstituted or a substituted monocyclic heterocyclyl.
- a non-limiting list of monocyclic heterocyclyls for R 9 include oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine and morpholine.
- Various substituents can be present on a substituted heteroaryl and/or a substituted heterocyclyl of R 9 .
- the heteroaryl can be substituted 1, 2 or 3 times with a moiety selected from halogen, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl and an unsubstituted C 1-6 alkoxy.
- R 9 can be an unsubstituted monocyclic C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In other embodiments, R 9 can be a halogen-substituted monocyclic C 3-6 cycloalkyl.
- R 9 can be a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 1-4 alkyl. In yet still other embodiments, R 9 can be a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 1-4 alkoxy. In some embodiments, R 9 can be a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 2-4 alkenyl. In other embodiments, R 9 can be a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 1-4 haloalkyl.
- R 9 can be a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted monocyclic C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
- R 9 can be an unsubstituted bicyclic C5-6 cycloalkyl.
- R 9 can be a substituted bicyclic C5-6 cycloalkyl.
- the two rings of a bicyclic C5-6 cycloalkyl can be connected in a spiro-fashion or a fused-fashion.
- R 9 can be a halogen- substituted bicyclic C 5-6 cycloalkyl. In still other embodiments, R 9 can be a bicyclic C 5-6 cycloalkyl substituted with an unsubstituted C 1-4 alkyl. In yet still other embodiments, R 9 can be a bicyclic C 5-6 cycloalkyl substituted with an unsubstituted C 1-4 alkoxy. In some embodiments, R 9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C 2-4 alkenyl.
- R 9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C 1-4 haloalkyl.
- R 9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted monocyclic C 3-6 cycloalkyl (including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl).
- a non-liming list of bicyclic C 5-6 cycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, bicyclo[1.1.1]pentane and bicyclo[2.1.1]hexane.
- Suitable halogen-substituted monocyclic C 3-6 cycloalkyls include halogen- substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl and halogen-substituted cyclohexyl.
- Additional monocyclic C 3-6 cycloalkyls include cyclopropyl substituted with an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C1- 4 alkoxy, an unsubstituted C 1-4 haloalkyl and/or an unsubstituted monocyclic C 3-6 cycloalkyl, cyclobutyl substituted with an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 1-4 alkoxy, an unsubstituted C 1-4 haloalkyl and/or an unsubstituted monocyclic C 3-6 cycloalkyl, cyclopentyl substituted with an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 1-4 alkoxy, an unsubsti
- 1, 2, 3 or 4 halogens can be present on a halogen-substituted monocyclic C 3-6 cycloalkyl
- 1, 2, 3 or 4 unsubstituted C 1-4 alkyls can be present on a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 1-4 alkyl
- 1, 2, 3 or 4 unsubstituted C 2-4 alkenyls can be present on a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 2-4 alkenyl
- 1, 2, 3 or 4 unsubstituted C 1-4 alkoxys can be present on a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 1-4 alkoxy
- 1, 2, 3 or 4 unsubstituted C 1-4 haloalkyls can be present on a monocyclic C 3-6 cycloalkyl substituted with an unsubstituted C 1-4
- a monocyclic C 3-6 cycloalkyl can be substituted with 1 or more substituents (such as 1, 2, 3 or 4 substituents) selected from halogen, an unsubstituted C1- 4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 1-4 alkoxy and an unsubstituted C 1-4 haloalkyl.
- substituents such as 1, 2, 3 or 4 substituents
- a bicyclic C 5-6 cycloalkyl can be substituted with 1 or more substituents (such as 1, 2, 3 or 4 substituents) selected from halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 1-4 alkoxy and an unsubstituted C 1-4 haloalkyl.
- substituents such as 1, 2, 3 or 4 substituents
- Suitable halogens that can be present on a substituted monocyclic C 3-6 cycloalkyl include, but are not limited to, fluoro (F) and chloro (Cl).
- R 9 can be an unsubstituted alkoxy. In other embodiments, R 9 can be a substituted alkoxy. Various alkoxys can be present for R 9 .
- –O-(hydrocarbon) such as –O-(C 1-8 alkyl)), –O-(monocyclic C 3-8 cycloalkyl), –O- (bicyclic C5-8 cycloalkyl), –O-(phenyl), –O-(bicyclic aryl), –O-(monocyclic heteroaryl), –O- (bicyclic heteroaryl), –O-(monocyclic heterocyclyl) and –O-(bicyclic heterocyclyl).
- C 1-6 alkoxys are methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched), hexoxy (straight-chained or branched), –O-cyclopropyl, –O-cyclobutyl, –O-cyclopentyl, –O- cyclohexyl and –O-(bicyclo[1.1.1]pentyl).
- a variety of substituents can be present on a substituted alkoxy for R 9 .
- substituents are those provided for “optionally substituted.”
- 1, 2, 3 or 4 substituents can be present on a substituted alkoxy.
- a substituted alkoxy can be substituted 1, 2, 3 or 4 times with substituents independently selected from halogen, hydroxy, an unsubstituted C 1-4 alkyl and an unsubstituted C 1-4 haloalkyl.
- R 5 can be 10 wherein R can be independently selected from an unsubstituted or a substituted C 2-6 alkyl, an unsubstituted or a substituted C 2-6 alkenyl, an unsubstituted or a substituted C 2-6 alkynyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C 5-8 cycloalkyl and an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl, wherein when the C 2-6 alkyl is substituted, the C 2-6 alkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen and an unsubstituted C 1-4 alkoxy; wherein when the C 2-6 alkenyl, the C 2-6 alkynyl, the monocyclic C 3-6 cycloalkyl, the bicyclic
- R 11 can be an optionally substituted monocyclic 4- to 6-membered heterocyclyl.
- heterocyclyls for R 11 include optionally substituted 4- to 6-membered monocyclic heterocyclyls that include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur).
- a non- limiting list of heterocyclyl for R 11 include the following: azetidine, pyrrolidine and piperidine.
- m can be 0; and R 11 can be an unsubstituted 5- to 6-membered monocyclic heteroaryl.
- m can be 0; and R 11 can be a substituted 5- to 6-membered monocyclic heteroaryl.
- m can be 1; and R 11 can be an —(NH)–unsubstituted 5- to 6-membered monocyclic heteroaryl. In other embodiments, m can be 1; and R 11 can be a –(NH)–substituted 5- to 6-membered monocyclic heteroaryl.
- An example of a 5- to 6-membered monocyclic heteroaryl that can be present for R 11 include a 5- to 6-membered monocyclic heteroaryl that includes 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur).
- R 11 can be –O– an optionally substituted C 1-6 alkyl.
- R 11 can be –O–an optionally substituted C 3-8 cycloalkyl.
- R 11 can be –O–an optionally substituted C 3-8 cycloalkyl(C 1-4 alkyl).
- the cycloalkyl of –O–an optionally substituted C 3-8 cycloalkyl and –O–an optionally substituted C 3-8 cycloalkyl(C 1-4 alkyl) can be a monocyclic C 3-6 cycloalkyl or a bicyclic C 5-8 cycloalkyl.
- the C 1-4 alkyl of –O– an optionally substituted cycloalkyl(C 1-4 alkyl) can be –CH 2 –, –CH 2 CH 2 –, –CH 2 CH 2 CH 2 – or –CH 2 CH 2 CH 2 CH 2 —.
- R 11 can be substituted.
- R 11 Exemplary groups that can be present on R 11 include halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-4 alkoxy and an unsubstituted C 1-4 haloalkyl.
- the R 8 and/or R 10 moieties can be a substituted or an unsubstituted version of a C 2-6 alkyl, a C 2-6 alkenyl, a C 2-6 alkynyl, a monocyclic C 3-6 cycloalkyl, a bicyclic C 5-8 cycloalkyl or a monocyclic 4- to 6-membered heterocyclyl.
- R 8 and/or R 10 can be an unsubstituted C 2-6 alkyl. In other embodiments, R 8 and/or R 10 can be a substituted C 2-6 alkyl. Exemplary C 2-6 alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight-chained and branched) and hexyl (straight-chained and branched). In some embodiments, R 8 and/or R 10 can be an unsubstituted C 2-6 alkenyl.
- R 8 and/or R 10 can be a substituted C 2-6 alkenyl. In still other embodiments, R 8 and/or R 10 can be an unsubstituted C 2-6 alkynyl. In yet still other embodiments, R 8 and/or R 10 can be a substituted C 2-6 alkynyl. [0098] Cyclic moieties, including monocyclic and bicyclic moieties, can also be present for R 8 and/or R 10 . In some embodiments, R 8 and/or R 10 can be an unsubstituted monocyclic C 3-6 cycloalkyl. In some embodiments, R 8 and/or R 10 can be a substituted monocyclic C 3-6 cycloalkyl.
- R 8 and/or R 10 can be a substituted or an unsubstituted cyclopropyl, a substituted or an unsubstituted cyclobutyl, a substituted or an unsubstituted cyclopentyl or a substituted or an unsubstituted cyclohexyl.
- R 8 and/or R 10 can be an unsubstituted bicyclic C 5-8 cycloalkyl.
- R 8 and/or R 10 can be an unsubstituted bicyclic C 5-8 cycloalkyl.
- the two rings of the bicyclic C 5-8 cycloalkyl can joined in a fused or a spiro-fashion.
- R 8 and/or R 10 can be an unsubstituted or a substituted bicyclo[1.1.1]pentyl.
- R 8 and/or R 10 can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl.
- R 8 and/or R 10 can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl.
- the number of heteroatoms present in a monocyclic 4- to 6-membered heterocyclyl for R 8 and/or R 10 can vary.
- Suitable heteroatoms include, but are not limited to, O (oxygen), S (sulfur) and N (nitrogen).
- Examples of monocyclic 4- to 6-membered heterocyclyls are oxetane, thietane, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran and piperidine (including unsubstituted or substituted versions of each of the aforementioned).
- R 8 and/or R 10 can be an unsubstituted monocyclic C 3-6 cycloalkyl(CH 2 )–.
- R 8 and/or R 10 can be selected from cyclopropyl(CH 2 )–, cyclobutyl(CH 2 )–, cyclopentyl(CH 2 )– and cyclohexyl(CH 2 )–. [0099] As described herein, R 8 and/or R 10 can be substituted.
- R 8 and/or R 10 when R 8 and/or R 10 is a C 2-6 alkyl that is substituted, the C 2-6 alkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, cyano, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted C 1-4 alkoxy and an unsubstituted C 1-4 haloalkoxy.
- R 8 and/or R 10 can be a C 2-6 alkyl that is substituted 1 to 13 times with deuterium.
- R 8 and/or R 10 can be a C2- 6 alkyl that is substituted 1 to 9 times with deuterium, 1 to 6 times with deuterium, 1 to 5 times with deuterium or 1 to 3 times with deuterium.
- Each halogen can be independently F (fluoro) or Cl (chloro).
- Exemplary unsubstituted and substituted monocyclic C 3-6 cycloalkyls that can be present on a substituted C 2-6 alkyl for R 8 and/or R 10 include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and halogen-substituted monocyclic C 3-6 cycloalkyls.
- Suitable unsubstituted C 1-4 alkoxys that can be substituted on a C 2-6 alkyl of R 8 and/or R 10 include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
- Examples of an unsubstituted C 1-4 haloalkoxy can be substituted on a C 2-6 alkyl of R 8 and/or R 10 include –OCl3, –OCF3, –OCH 2 Cl, –OCH 2 F, –OCHCl 2 and –OCHF2.
- R 8 and/or R 10 when R 8 and/or R 10 is a substituted C 2-6 alkenyl, a substituted C 2-6 alkynyl, a substituted monocyclic C 3-6 cycloalkyl, a substituted bicyclic C 5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl, each of the aforementioned can be substituted 1, 2, 3 or 4 times with a substituents independently selected from halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2-4 alkynyl, an unsubstituted C 1-4 haloalkyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl and an unsubstituted C 1-4 alkoxy.
- Examples of unsubstituted C 1-4 alkyls, an unsubstituted C 2-4 alkenyl and an unsubstituted C 2-4 alkynyl that can be substituted on a substituted C 2-6 alkenyl, a substituted C 2-6 alkynyl, a substituted monocyclic C 3-6 cycloalkyl, a substituted bicyclic C 5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl.
- Suitable halogens and unsubstituted C 1-4 alkoxys that can be present on a substituted C 2-6 alkenyl, a substituted C 2-6 alkynyl, a substituted monocyclic C 3-6 cycloalkyl, a substituted bicyclic C5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl are described herein, such as in this paragraph.
- Non-limiting list of unsubstituted and substituted monocyclic C 3-6 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and halogen-substituted monocyclic C 3-6 cycloalkyls.
- Examples of unsubstituted C 1-6 haloalkyls that can be present on a substituted C 2-6 alkenyl, a substituted C 2-6 alkynyl, a substituted monocyclic C 3-6 cycloalkyl, a substituted bicyclic C 5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl include, but are not limited to, –CF 3 , –CCl 3 , – CHF2, –C(CH 3 )F2, –CHCl2, –CH 2 F, –CH(CH 3 )F, –CH 2 CF3, –CH 2 Cl, —CH 2 CH 2 F, – CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F and —CH 2 CH 2 CH 2 Cl.
- R 5 groups include the following: [0101] As described herein, in some embodiments, R 5 can be a substituted monocyclic C 3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other embodiments, R 5 can be a substituted 4- to 6-membered monocyclic heterocyclyl. For example, R 5 can be a substituted 4- to 6-membered monocyclic heterocyclyl that includes 1, 2 or 3 heteroatoms selected from N (nitrogen), O (oxygen) and S (sulfur).
- the substituted monocyclic C 3-6 cycloalkyl and/or the substituted 4- to 6-membered monocyclic heterocyclyl can be substituted 1, 2 or 3 times with a moiety selected from deuterium, halogen, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl and an unsubstituted C 1-6 alkoxy.
- R 5 is a monocyclic C 3-6 cycloalkyl or a 4- to 6-membered monocyclic heterocyclyl
- the monocyclic C 3-6 cycloalkyl or the 4- to 6-membered monocyclic heterocyclyl can be substituted in a spiro-fashion by an unsubstituted or a substituted bicyclic cycloalkenyl or an unsubstituted or a substituted bicyclic heterocyclyl.
- the bicyclic cycloalkenyl can be an unsubstituted or a substituted 8- to 10-membered bicyclic cycloalkenyl.
- An unsubstituted or a substituted bicyclic heterocyclyl can be an unsubstituted or a substituted 8- to 10-membered bicyclic heterocyclyl, for example, an unsubstituted or a substituted 8- to 10-membered bicyclic heterocyclyl that includes 1, 2 or 3 heteroatoms in the rings selected from N (nitrogen), O (oxygen) and S (sulfur).
- the bicyclic cycloalkenyl and/or the bicyclic heterocyclyl can be substituted one or more times (such as 1, 2, 3 or 4 times) with a moiety independently selected from halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 1-6 haloalkyl (such as –CF 3 , –CCl 3 , –CHF 2 , –C(CH 3 )F 2 , –CHCl2, –CH 2 F, – CH(CH 3 )F, –CH 2 CF 3 , –CH 2 Cl, –CH 2 CH 2 F, –CH 2 CH 2 Cl, –CH 2 CH 2 CH 2 F, –CH 2 CH 2 CH 2 Cl) and an unsubstituted C 1-4 alkoxy.
- R 5 as a monocyclic C 3-6 cycloalkyl or a 4- to 6-membered monocyclic heterocyclyl substituted in a spiro-fashion by an unsubstituted or a substituted bicyclic cycloalkenyl or an unsubstituted or a substituted bicyclic heterocyclyl include the following: [0103]
- Scheme A describes the synthesis of compounds of general Formula (A-6).
- An amino ester of general Formula (A-1) (Alk represents alkyl) with an acid of general Formula (A-2), either by activating the carboxylic acid by converting it to an acid chloride, followed by reaction with the amino acid in the presence of a base, or by activation of the acid with a coupling reagent (such as HATU) followed by coupling with the amino ester in the presence of a base (such as DIPEA), resulting in a compound of general Formula (A-3).
- a coupling reagent such as HATU
- DIPEA such as DIPEA
- the ester functionality of general Formula (A-3) can be hydrolyzed, for example, under basic conditions of -OAlk is -OMe, using LiOH in MeOH, providing in a compound of general Formula (A-4). Further coupling of the carboxylic acid of general Formula (A-4) with an amine of general Formula (A-5) can provide a compound of general Formula (A-6).
- R 1 may be a latent functionality, converted to a functionality as described herein for R 1 .
- Scheme A1 [0107] Alternatively, as described in Scheme A1, a sub-group of amino acids of general Formula (A1-5) can be prepared as described in Scheme A1.
- a protected (PG A1 ) amino acid of general Formula (A1-1) can be coupled with an aminoester of general Formula (A-1) under known amide formation conditions, for example, HATU and iPr 2 NEt.
- the ester of a compound of Formula (A1-2) can be deprotected, for example, by using LiOH in THF/H 2 O, resulting in the acid of general Formula (A1-3).
- the protecting group PG A1 can be removed, for example, by treatment with TFA in case PG A1 being Boc, resulting in a compound of general Formula (A1-4).
- This compound can be converted to a compound of general Formula (A1-5) (for example, by treatment with ethyl 2,2,2-trifluoroacetate in the presence of triethylamine) or alternatively, a compound of general Formula (A1-6) (for example, by treatment of a compound of general Formula (A1-4) with an alkyl trihaloacetate, (such as ethyl 2,2-dichloro-2-fluoroacetate, methyl 2-chloro-2,2-difluoroacetate or ethyl 2-chloro-2,2- difluoroacetate) in the presence of a base like triethylamine (and optionally an additive like and N-methylimidazole), or an alkyl 2,2,3,3,3-pentafluoropropanoate (such as methyl or ethyl 2,2,3,3,3-pentafluoropropanoate) in the presence of a base (for example, triethylamine and an additive, for example, N-
- Scheme B a carboxylic acid of general Formula (A-4) can be coupled with an amino acid of general Formula (B-1), for example, under the influence of a coupling reagent (such as T3P) and a base (for example, DIPEA).
- a coupling reagent such as T3P
- a base for example, DIPEA
- the obtained compound of general Formula (B-2) can be oxidized, providing in a compound of general Formula (B-3).
- R y1 can be part of the ketoamide described herein with respect to R 1 .
- an amino acid of general Formula (B1-1) (with PG B1 a protecting group of the nitrogen, for example, -Boc) can be coupled with a compound of general Formula (B-1), similar as described for the conversion of a compound of general Formula (A-4) to a compound of general Formula (B-2).
- the protecting group can be removed, for example, by treatment with an acid in case of PG B1 being Boc, followed by coupling with a compound of general Formula (A-2), resulting in the formation of a compound of general formula (B-2).
- R 1 can be a substituted acyl, where the possible groups that can be present on the acyl include hydroxy, a substituted or an unsubstituted alkoxy (for example, –O–(an unsubstituted C 1-4 alkyl) and –O–(an unsubstituted C 3-6 cycloalkyl)), an unsubstituted C 1-4 alkyl (such as a heteroaryl substituted with an unsubstituted C 1-4 alkyl), a substituted or an unsubstituted phenoxy or a substituted or an unsubstituted benzyloxy).
- a substituted or an unsubstituted alkoxy for example, –O–(an unsubstituted C 1-4 alkyl) and –O–(an unsubstituted C 3-6 cycloalkyl)
- an unsubstituted C 1-4 alkyl such as a heteroaryl substituted with an unsubsti
- R can represent any of the aforementioned moieties that can be present on a substituted acyl for R 1 .
- Compounds of general Formulae (B2-2) and (B2-3) can be prepared as described in Scheme B2.
- An amino-ketone compound of general Formula (B2-1) can be coupled to a carboxylic acid of general Formula (A-4) or (B1-1) under typical amide coupling conditions.
- a compound of general Formula (B2-2) can be optionally further converted in a hydroxyketone of general Formula (B2-3), for example, in case where R represents a benzyl group, by catalytic hydrogenolysis.
- the PG B1 of a compound of general Formula (B2-4) can be deprotected (for example in the case wherein PG B1 is a Boc-group, by treatment with HCl in Et 2 O).
- the amine can then be coupled with a carboxylic acid of general Formula (A-2) under typical amide bound formation conditions, to provide a compound of general Formula (B2-2).
- Scheme B3 [0112] Similar as described in Scheme B2 for a compound of Formula (B2-2), using an amide of general Formula (B3-1) in place of a compound of general Formula (B2-1). a compound of general Formula (B3-2) can be obtained.
- the compound of general Formula (B4-2) can be converted in a compound of general Formula (B4-3) (for example, by treatment with an alkyl trihaloacetate, such as ethyl 2,2-dichloro-2-fluoroacetate, methyl 2- chloro-2,2-difluoroacetate ethyl 2-chloro-2,2-difluoroacetate or ethyl 2,2,2-trifluoroacetate, in the presence of a base (such as triethylamine and optionally an additive, for example, N- methylimidazole), or an alkyl 2,2,3,3,3-pentafluoropropanoate (such as methyl or ethyl 2,2,3,3,3-pentafluoropropanoate) in the presence of a base (for example, triethylamine and an additive, for example, N-methylimidazole); or a carboxylic acid in the presence of a coupling reagent (such as EDC or HA
- the compound of general Formula (B4-3) can be converted to a compound of general Formula (B4-4), similar as outlined for the conversion of a compound of general Formula (B3-2) to a compound of general Formula (B3- 3).
- a compound of general Formula (B4-2) can be converted to a compound of general Formula (B4-4) (for example, by treatment with T3P and pyridine in the presence of potassium 2,2,3,3,3-pentafluoropropanoate for -R 9 being -CF 2 CF 3 ).
- a compound of general Formula (B4-1) can be obtained by deprotection of PG B1 of a compound of general Formula (B3-4), followed by coupling with a compound of general Formula (A1-1).
- a compound of general Formula (B-1) can be prepared as outlined in Scheme C.
- An aldehyde of general Formula (C-1) (PG 1 can be a nitrogen protecting group, for example -Boc) and an isonitrile of general Formula (C-2), in the presence of a carboxylic acid (for example, benzoic acid), can be condensed in a Passerini-like reaction towards a compound of general Formula (C-3).
- a compound of general Formula (C-4) can be obtained.
- the PG 1 can be removed, for example, by treatment with HCl when PG 1 can be Boc.
- Scheme C1 [0115] An amino ketone of general Formula (B2-1), can be prepared as outline in Scheme C1.
- a protected amino acid of general Formula (C1-1) can be converted to its corresponding Weinreb amide under typical amide coupling conditions. Addition of an organometallic reagent to the Weinreb amide, followed by work-up, can result in a ketone of general Formula (C1-3).
- R can be benzyl
- the protecting group (PG 1 ) can be removed (for example, when PG 1 is Boc, the protecting group can be removed using HCl) resulting in the formation of an amino ketone of general Formula (B2-1).
- a compound of general Formula (B2-1) can be obtained as a HCl salt.
- Examples of a compound of general Formula (C1-1) are (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoic acid and (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid.
- Scheme D1 Scheme D2 [0116] Other conversions for R 1 described herein are shown in Schemes D1 and D2.
- PG 2 represents an appropriate protecting group
- R z1 and R y1 are part of the ketoamide described herein with respect to R 1 .
- Scheme E [0117] A method for preparing a sub-group of amino acids of general Formula (E- 8) are provided in Scheme E.
- a lactam of general Formula (E-1) can be protected with a suitable protecting group, PG E .
- An example of such a PG E group is a Boc-group.
- this protecting group can be removed at any relevant stage; and therefore, PG E present hydrogen for any of compounds of general Formulae (E-4), (E-5), (E- 6), (E-7), (E-8) and (E-9).
- the lactam of general Formula (E-2) can be reacted with an aldehyde of general Formula (E-3) (S or R-garner’s aldehyde).
- the alcohol of general Formula (E-4) can be eliminated to provide an alkene compound of general Formula (E-5) (for example, by sequential conversion of the hydroxy to a corresponding mesylate, followed by elimination under basic conditions).
- the double bond can be reduced (for example, by hydrogenation, under influence of a homogeneous or a heterogenous catalyst, optionally diastereoselective) to provide a compound of general Formula (E-6).
- Removal of the acetonide in a compound of general Formula (E-6) to the Boc-protected amino alcohol of general Formula (E-7) can be followed by the oxidation to the carboxylic acid of general Formula (E-8).
- the acetonide can be deprotected in a compound of general Formula (E-5) to obtain a compound of general Formula (E-9).
- Reduction of the double bond of a compound of general Formula (E-9) (for example, by hydrogenation under influence of a homogeneous or a heterogenous catalyst, optionally diastereoselective) can be used to obtain a compound of general Formula (E-7).
- a compound of general Formula (E-4) can be deoxygenated, for example, by a Barton- type deoxygenation, to provide a compound of general Formula (E-6).
- Scheme F 3 [0118]
- Compounds of Formula (I) can include a prodrug moiety. A method for including a prodrug moiety is depicted in Scheme F.
- an aldehyde of general Formula (F-1) can be transformed into the corresponding bisulfite adduct of general Formula (F-2), by treatment with NaHSO 3 .
- a hydroxyketone of general Formula (F-3) can be transformed to the corresponding phosphate of general Formula (F-5), for example, by treatment with di-tert-butyl N,N-dipropan-2-ylphosphoramidite and tetrazole followed by oxidation with H2O2, that can provide a compound of general Formula (F-4).
- a compound of general Formula (F-4) can be deprotected (for example by treatment with TFA) to provide a compound of general Formula (F-5).
- Scheme J An intermediate, a compound of Formula (J1) (Moody et al., J. Chem. Soc., Perkin Trans.1 (1997) 23:3519-3530), can be used to prepare amino acids of general Formulae (J2) and (J3) using similar procedures as described for Scheme H.
- Pharmaceutical Compositions [0120] Some embodiments described herein relate to a pharmaceutical composition that can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof.
- a pharmaceutical composition described herein is suitable for human and/or veterinary applications.
- a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
- DMSO dimethyl sulfoxide
- a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
- a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
- diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
- an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
- a “diluent” is a type of excipient.
- Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
- compositions will generally be tailored to the specific intended route of administration.
- the liposomes may be targeted to and taken up selectively by the organ.
- the pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
- compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.
- Some embodiments described herein relate to a method of treating a coronavirus infection that can include administering to a subject identified as suffering from the coronavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a coronavirus infection.
- Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a coronavirus infection.
- Some embodiments disclosed herein relate to a method of treating a coronavirus infection that can include contacting a cell infected with the coronavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a coronavirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a coronavirus infection.
- Some embodiments disclosed herein relate to a method of inhibiting replication of a coronavirus that can include contacting a cell infected with the coronavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for inhibiting replication of a coronavirus.
- the coronavirus can be an ⁇ -coronavirus or a ⁇ - coronavirus.
- a compound described herein may be effective against one or more variants of a coronavirus. Examples of variants include, but are not limited, to alpha-variant (B.1.1.7), beta-variant (B.1.351), gamma variant (P.1) and delta-variant (B.1.617.2).
- the coronavirus can be selected from CoV 229E, CoV NL63, CoV OC43, CoV HKU1, Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV, and SARS-CoV-2.
- MERS Middle East Respiratory Syndrome
- SARS Severe Acute Respiratory Syndrome
- SARS-CoV-2 SARS-CoV-2.
- inventions described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a picornavirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a picornavirus infection.
- Some embodiments disclosed herein relate to a method of treating a picornavirus infection that can include contacting a cell infected with the picornavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a picornavirus infection.
- Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a picornavirus infection.
- Some embodiments disclosed herein relate to a method of inhibiting replication of a picornavirus that can include contacting a cell infected with the picornavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- the picornavirus can be a rhinovirus, including rhinovirus A, B and/or C.
- a compound described herein, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be used to treat one or serotypes of a rhinovirus.
- Some embodiments described herein relate to a method of treating a norovirus infection that can include administering to a subject identified as suffering from the norovirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a norovirus infection.
- Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a norovirus infection.
- Some embodiments disclosed herein relate to a method of treating a norovirus infection that can include contacting a cell infected with the norovirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- inventions described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a norovirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a norovirus infection.
- Some embodiments disclosed herein relate to a method of inhibiting replication of a norovirus that can include contacting a cell infected with the norovirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for inhibiting replication of a norovirus.
- Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, for inhibiting replication of a norovirus.
- Some embodiments disclosed herein relate to a method of treating a respiratory condition that is developed because of a coronavirus and/or a picornavirus infection that can include administering to a subject suffering from the respiratory condition and/or contacting a cell infected with the coronavirus and/or the picornavirus in a subject suffering from the respiratory condition with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
- a subject infected with a coronavirus can be asymptotic.
- a coronavirus infection can manifest itself via one or more symptoms.
- symptoms include, but are not limited to, coughing, sore throat, runny nose, sneezing, headache, fever, shortness of breath, myalgia, abdominal pain, fatigue, difficulty breathing, persistent chest pain or pressure, difficulty waking, loss of smell and taste, muscle or joint pain, chills, nausea or vomiting, nasal congestion, diarrhea, haemoptysis, conjunctival congestion, sputum production, chest tightness and/or palpitations.
- a coronavirus infection can cause complications.
- a non-limiting list of complications include, but are not limited to, sinusitis, otitis media, pneumonia, acute respiratory distress syndrome, disseminated intravascular coagulation, pericarditis and/or kidney failure.
- a subject infected with a picornavirus can be asymptotic.
- a subject can exhibit one or more of symptoms. Examples of symptoms of a picornavirus infection include, but are not limited to, aseptic meningitis, rash, conjunctivitis, runny nose a headache a cough a fever a sore throat, chest and/or abdominal pain and paralysis.
- subjects infected with a norovirus can exhibit one or more the symptoms including, but not limited to, nausea, non-bloody diarrhea, vomiting and abdominal pain.
- An example of a complication that can be attributed to a norovirus infection is dehydration, including severe dehydration.
- Various indicators for determining the effectiveness of a method for treating a coronavirus, picornavirus and/or norovirus infection are also known to those skilled in the art.
- suitable indicators include, but are not limited to, a reduction in viral load indicated by reduction in coronavirus (or load) (e.g., reduction ⁇ 10 5 copies/mL in serum), a reduction in plasma viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy a reduction of morbidity or mortality in clinical outcomes, reduction in the need for a ventilator and/or total time on a ventilator, reduction in hospitalization rates and/or reduction in time in an ICU (intensive care unit) and/or hospital.
- a reduction in viral load indicated by reduction in coronavirus (or load) e.g., reduction ⁇ 10 5 copies/mL in serum
- a reduction in plasma viral load e.g., ⁇ 10 5 copies/mL in serum
- a reduction in viral replication e.g., ⁇ 10 5 copies/mL in serum
- a reduction in time to seroconversion virus undetectable in patient serum
- the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
- a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
- “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
- the subject can be human, for example, a human subject that is 60 years old or older.
- the term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent that elicits the biological or medicinal response indicated.
- an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
- This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
- the effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration.
- the dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
- the subject can be asymptomatic, for example, the subject can be infected with coronavirus but does not exhibit any symptoms of the viral infection.
- the subject can be have a pre-existing condition, such as asthma, hypertension, immunocompromised subjects (such as subjects with cancer, HIV and/or genetic immune deficiencies, bone marrow transplant subjects, solid organ transplant subjects, subjects who have had stem cells for cancer treatment and/or subjects who use oral or intravenous corticosteroids or other medicines called immunosuppressants), liver disease, subjects at risk for severe illness, chronic kidney disease being treated with dialysis, chronic lung disease, diabetes, hemoglobin disorders, serious heart conditions (for example, heart failure, coronary artery disease, congenital heart disease, cardiomyopathies, and pulmonary hypertension), severe obesity (such as subjects with a body mass index (BMI) of 40 or above) and people who live in a nursing home or long-term care facility .
- a pre-existing condition such as asthma, hypertension, immunocompromised subjects (such as subjects with cancer, HIV and/or genetic immune deficiencies, bone marrow transplant subjects, solid organ transplant subjects, subjects who have had stem cells for cancer treatment and/or subjects who use oral or
- a compound described herein, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered after a subject is infected with a coronavirus.
- a compound described herein, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be administered prophylactically.
- agents that have been used to treat a coronavirus infection include Remdesivir.
- a coronavirus infection can be treated by inhibiting certain mechanisms.
- a compound described herein such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof
- a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be selective for a coronavirus protease compared to a host protease, for example, one or more host proteases selected from Cathepsin L, Cathepsin B, Cathepsin D, Cathepsin K, Leukocyte Elastase, Chymotrypsin, Trypsin, Thrombin, Pepsin, Caspase 2, Elastase and Calpain.
- the selectivity for a coronavirus protease over a host protease can be > 2-fold.
- the selectivity for a coronavirus protease over a host protease can be > 10-fold. In some embodiments, the selectivity for a coronavirus protease over a host protease (such as those described herein) can be > 100-fold.
- TMPRSS2 transmembrane protease serine 2
- the cathepsin L inhibitor K117777 which lacks an inhibitory effect on the 3CLpro, can result in potent inhibition of SARS-CoV-2 in VeroE6, A549-ACE2 and/or HeLa-ACE2 (Mellott et al., bioRxiv (2020) 2020.2010.2023.347534). It has also been shown that the potent antiviral effect of K117777 is abolished when TMPRSS2 was expressed in A549-ACE2 (Steuten et al., bioRxiv (2020) 2020.2011.2021.392753).
- a compound described herein can have greater selectivity for a coronavirus protease over a host protease, such as cathepsin L.
- the selectivity can be determined by those skilled in the art, for example, using IC 50 and/or Ki values.
- a compound described herein does not significantly inhibit cathepsin L (for example, IC 50 ⁇ 10000 nM or >3.3 ⁇ M), but inhibits a coronavirus protease (for example, SARS-Cov-23Clpro).
- a drawback with anti-viral treatment can be the development of resistance, including cross-resistance. Resistance can be a cause for treatment failure.
- resistance refers to a viral strain displaying a delayed, lessened and/or null response to an anti-viral agent.
- a compound, or a pharmaceutically acceptable salt thereof, as described herein can be provided to a subject infected with a coronavirus strain that is resistant to one or more other anti-viral agents.
- development of coronavirus resistant strains is delayed when a subject is treated with a compound, or a pharmaceutically acceptable salt thereof, as described herein compared to the development of a coronavirus resistant strain when treated with one or more other anti-viral agents.
- Combination Therapies [0151]
- a compound, or a pharmaceutically acceptable salt thereof, as described herein can be used in combination with one or more additional agent(s) for treating and/or inhibiting replication a coronavirus.
- Additional agents include, but are not limited to, an ACE inhibitor, an anticoagulant, an anti-inflammatory, an ARB, an ASO, a Covid-19 convalescent plasma, an entry inhibitor, an H 2 pump antagonist, an H-conducting channel, an HIV protease inhibitor, an HMG-CoA reductase inhibitor, an immune globulin, an immunosuppressant, an immunotherapeutic agent, a monoclonal antibody, a neuraminidase inhibitor, a nucleoside inhibitor, a nucleoside analog inhibitor, a polymerase inhibitor, a protease inhibitor, an siRNA, a statin, a tissue plasminogen activator, an antibiotic, an antimicrobial and a vaccine.
- additional agents include Ascorbic acid, Anakin, Azithromycin, Baloxavir, Baricitinib, Chloroquine Phosphate, Colchicine, a corticosteroid, Epoprostenol, Famotidine, Favipiravir, an IGIV, an interferon (for example, recombinant interferon alpha 2b, IFN-D and/or PEG-IFN- ⁇ -2a),anIVIG,Ivermectin, ⁇ -globulin, lopinavir, Methylprednisolone, Molnupiravir (MK-4482 or EIDD-2801), Niclosamide, Nitazoxanide, Nitric oxide, Oseltamivir, Peramivir, RANTES, ribavirin, Remdesivir, Ruxolitinib, Sarilumab, Siltuximab, Sirolimus, a statin, Tacrolimus, Tocilizumab, Umifenovir
- a compound, or a pharmaceutically acceptable salt thereof can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. Further, the order of administration of a compound, or a pharmaceutically acceptable salt thereof, as described herein with one or more additional agent(s) can vary.
- COMPOUNDS Compounds of Formula (I), along with pharmaceutically acceptable salts thereof, can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
- the crude product was diluted with DCM (150 mL) and made into a slurry with 100 ⁇ 200 silica gel mesh (15 g), and the slurry was loaded to a column chromatography after removing the DCM.
- the sample was purified by column chromatography (Column size 6 x 24 cm, column volume: 600 mL, silica gel size (100 ⁇ 200 mesh) quantity: 330 g) and eluted with MeOH:DCM (0% ⁇ 10% over 30 min).
- the collected fractions 0% MeOH:DCM fractions were chosen as the pure fractions.
- Co- Solvent IPA (0.1%DEA), 10% to 50% in 2.0 min, hold 1.0 min at 50%): Rt: 0.969 min), and tert-butyl (S)-4-(((R*)-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)- 2,2-dimethyloxazolidine-3-carboxylate (1.6 g) as an off-white solid Lux Celloluse-2 4.6*50 mm,3 ⁇ m,35°C.Co-Solvent : IPA (0.1%DEA), 10% to 50% in 2.0 min, hold 1.0 min at 50%): Rt: 1.411 min).
- Chlorosylsodium (1.15 g, 15.4 mmol, 3.5 eq.) was added dropwise at 0 °C. The mixture was stirred at rt overnight, and the reaction was quenched with water (20 mL). The solution was washed with Et2O (2 x 20 mL). The pH value of the aqueous solution was adjusted to 2 with concentrated hydrochloric acid (1 mol/L). The solution was extracted with EtOAc (3 x 50 mL).
- the mixture was stirred overnight at rt, and then concentrated under reduced pressure to remove the MeOH.
- the mixture was diluted with water (20 mL) and the pH was adjusted to 6 with hydrochloric acid (1 M).
- the mixture was extracted with EtOAc (3 x 20 mL).
- TToo aa mixture of (2S)-2- ⁇ [(lR,2S,3S,6R,7S)-4-[(2S)-2-(2-chloro-2,2- difluoroacetamido)-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1 ,0 ⁇ 2,6 ⁇ ]dec-8-en-3- yl]formamido ⁇ -3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (180 mg, 0.323 mmol, 1.0 eq.) in DCM (3 mL) was added pyridine (102 mg, 1.29 mmol, 4.0 eq.) and trifluoroacetic anhydride (122 mg, 0.581 mmol, 1.8 eq.).
- the crude product was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10pm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 70% B in 7 min, 70% B; Wave Length: 254 nm; RT: 5.4 min;) to provide (lR,2S,3S,6R,7S)-4-[(2S)-2-(2-chloro-2,2-difluoroacetamido)-3,3-dimethylbutanoyl]-N- [(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-azatricyclo dec-8-ene-3- carboxamide (41.2 mg, 23%) as a white solid.
- the mixture was stirred at rt for 16 h.
- the mixture was diluted with water (10 mL) and extracted with EA (3 x 10 mL).
- the organic phases were combined, washed with brine (2 x 10 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
- Protease assays were performed in 384- well low volume polypropylene microtiter plates at ambient temperature.
- 3CLpro and HRV3C was added using a Multidrop Combi (Thermo Scientific; Waltham, MA) and preincubated for 30 mins with small molecules. The reactions were initiated by the addition of the two peptide substrates. The reactions were incubated for 30 mins and quenched by the addition of 0.5% formic acid (final) with subsequent neutralization using 1% sodium bicarbonate (final). Internal standard peptides were added in 20 mM Hepes pH 8.0 for quantitation of the protease products.
- SAMDI-MS analysis 2 ⁇ L of each reaction mixture was transferred using a 384- channel automated liquid handler to SAMDI biochip arrays functionalized with a neutravidin-presenting self-assembled monolayer.
- the SAMDI arrays were incubated for 1 h in a humidified chamber to allow the specific immobilization of the biotinylated peptide substrates, cleaved products and internal standards.
- the samples were purified by washing the SAMDI arrays with deionized ultrafiltered water and dried with compressed air.
- a matrix comprising alpha-cyano cinnamic acid in 80% acetonitrile: 20% aqueous ammonium citrate was applied in an automated format by dispensing 50 nL to each spot in the array.
- SAMDI- MS was performed using reflector-positive mode on an AB Sciex TOF-TOF 5800 System (AB Sciex, Framingham, MA) with 400 shots/spot analyzed in a random raster sampling.
- area under the curves (peaks) (AUCs) for the product and internal standard were calculated using the TOF/TOF Series Explorer (AB Sciex), and the amount of product formed was calculated using the equation (AUC product/ AUC internal standard).
- the amount of product generated was calculated using the ratio of product area under the curve (AUC) divided by the AUC of the internal standard.
- Negative controls were pre-quenched with 0.5% formic acid final.
- Assay robustness was determined by Z-Factor.
- the ICsos were determined by fitting the curves using a four-parameter equation in Graphpad Prism 8.
- Table 1 indicates related ICso values for the tested compounds where ‘A’ indicates an EC 50 ⁇ 20 nM, ‘B’ indicates an EC 50 of >20 nM and ⁇ 200 nM, ‘C’ indicates an EC 50 > 200 nM and ⁇ 2000 nM, ‘D’ indicates an ICso > 2000 nM and ⁇ 20000 nM and ‘E’ indicates an ICso > 20000 nM and ⁇ 100000 nM.
- compounds described herein can effectively inhibit and be used to treat a coronavirus and rhinovirus.
- the human beta-coronavirus OC43 is purchased from ATCC (Manassas, VA) and propagated using HCT-8 human colorectal epithelial cells (ATCC).
- ATCC HeLa human cervical epithelial cells (ATCC) are used as susceptible host cell lines and were cultured using EMEM media, supplemented with 10% fetal bovine serum (FBS), 1% (v/v) penicillin/streptomycin (P/S), 1% (v/v) HEPES and 1% (v/v) cellgro glutagroTM supplement (all Coming, Manassas, VA) at 37 °C.
- OC43 antiviral assay 1.5 x 10 4 HeLa cells per well are plated in 100 ⁇ L complete media in white 96- well plates with clear bottoms at 37 °C for up to 24 h to facilitate attachment and allow cells to recover from seeding stresses. Next day, the cell culture medium is removed. Serially diluted compounds in 100 ⁇ L assay media (EMEM, 2% FBS, 1% P/S, 1% cellgro glutagroTM supplement, 1% HEPES) are added to the cells and incubated for 4 H at 37 °C in a humidified 5% CCh incubator. 100 ⁇ L of OC43 virus stock is diluted to a concentration known to produce optimal cytopathic effect, inducing 80- 90% reduction in cell viability.
- EMEM 2% FBS, 1% P/S, 1% cellgro glutagroTM supplement, 1% HEPES
- 96-well plates are incubated for 6 (HeLa) days at 33 °C; each plate contains uninfected control wells as well as virus-infected wells that are not treated with compound. Cytotoxicity plates without the addition of OC43 virus are carried out in parallel. At the end of the incubation period, 100 ⁇ L cell culture supernatant is replaced with 100 ⁇ L cell-titer-glo reagent (Promega, Madison, WI) and incubated for at least 10 min at rt prior to measuring luminescence. Luminescence is measured on a Perkin Elmer (Waltham, MA) Envision plate reader.
- Antiviral % inhibition is calculated as follows: [(Compound treated cells infected sample) -(no compound infected control)]/[(Uninfected control) -(no compound infected control)] *100; Using GraphPad (San Diego, CA) prism software version 8.3.1 , the antiviral dose-response plot is generated as a sigmoidal fit, log(inhibitor) vs response- variable slope (four parameters) model and the EC 50 is calculated which is the predicted compound concentration corresponding to a 50% inhibition of the viral cytopathic effect.
- the SARS-CoV-2 antiviral assay is derived from the previously established SARS-CoV assay (PMID: 15961169). In this assay, fluorescence of Vero E6-eGFP cells declines after infection with SARS-CoV-2 due to the cytopathogenic effect of the virus. In the presence of an antiviral compound, the cytopathogenicity is inhibited and the fluorescent signal rescued. On day -1, the test compounds are serially diluted in assay medium (DMEM supplemented with 2% v/v FCS). The plates are incubated (37 °C, 5% CO2 and 95% relative humidity) overnight.
- assay medium DMEM supplemented with 2% v/v FCS
- the diluted compounds are mixed with Vero E6-eGFP cells (25,000 cells/well), SARS-CoV-2-GHB-03021/2020 (20 TCID50/well) and the MDR1- inhibitor CP-100356 (final concentration 0.5 ⁇ M) in 96-well blackview plates (Greiner Bio- One, Vilvoorde, Belgium).
- the plates are incubated in a humidified incubator at 37 °C and 5% CO 2 .
- the wells are examined for eGFP expression using an argon laser- scanning microscope. The microscope settings are excitation at 488 nm and emission at 510 nm and the fluorescence images of the wells were converted into signal values.
- EC50 values defined as the concentration of compound achieving 50% rescue from the virus-reduced eGFP signals as compared to the untreated virus-infected control cells. Toxicity of compounds in the absence of virus is evaluated in a standard MTS-assay as described previously (PMID: 22575574).
- A549-dual_ACE2_TMPRSS2 cells (InvivoGen Cat #a549 - cov2r) were propagated in the growth medium which was prepared by supplementing DMEM (gibco cat no 41965-039) with 10% v/v heat-inactivated FCS and 10 ⁇ g/mL blasticidin (InvivoGen ant-bl-05), 100 ⁇ g/mL hygromycin (InvivoGen ant-hg-1), 0.5 ⁇ g/mL puromycin (InvivoGen ant-pr-1) and 100 ⁇ g/mL zeocin (InvivoGen ant-zn-05) in a humidified 5% CO2 incubator at 37°C.
- the assay medium was prepared by supplementing DMEM (gibco cat no 41965-039) with 2% v/v heat-inactivated FCS.
- the virus isolate used is from the B.1.1.7 lineage (derived from hCoV- 19/Belgium/rega-12211513/2020; EPI_ISL_791333, 2020-12-21; see Abdelnabi et al, “Comparing infectivity and virulence of emerging SARS-CoV-2 variants in Syrian hamsters” EBioMedicine (2021) Jun;68: 103403. doi: 10.1016/j.ebiom.2021.103403).
- Table 2 indicates related EC 50 and CC 50 values for the tested compounds ‘A’ indicates an EC 50 ⁇ 100 nM, ‘B’ indicates an EC 50 of >100 nM and ⁇ 1000 nM, ‘C* indicates an EC 50 > 1000 nM and ⁇ 10000 nM. For CCso, the values are reported in micromolar (pM). ‘A’ indicates a CCso > 10 pM. ‘B’ indicates a CCso > 1 pM and ⁇ 10 pM.
- Tables 1 and 2 demonstrate that compounds described herein (including pharmaceutically acceptable salts thereof) can effectively inhibit and treat a coronavirus.
Abstract
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Description
ANTI- VIRAL COMPOUNDS
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application No. 63/379,377, filed October 13, 2022.
BACKGROUND
Field
[0002] The present application relates to the fields of chemistry, biochemistry and medicine. Disclosed herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Description
[0003] A positive-sense single-stranded RNA virus ((+)ssRNA virus) is a virus that uses positive sense, single stranded, RNA as its genetic material. Positive-sense singlestranded RNA viruses can be enveloped or non-enveloped. Coronaviridae, Picornaviridae and Norviruses are each a (+)ssRNA virus. Each of the aforementioned viruses are known to infect mammals, including humans.
SUMMARY
[0004] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0006] Some embodiments described herein relate to a method of treating a
coronavirus infection that can include administering to a subject identified as suffering from the coronavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a coronavirus infection.
[0007] Some embodiments disclosed herein relate to a method of inhibiting replication of a coronavirus that can include contacting a cell infected with the coronavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication a coronavirus.
[0008] Some embodiments described herein relate to a method of treating a picornavirus infection that can include administering to a subject identified as suffering from the picornavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof as described herein for the use of treating a picornavirus infection.
[0009] Some embodiments disclosed herein relate to a method of inhibiting replication of a picornavirus that can include contacting a cell infected with the picornavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other
embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication a picornavirus.
[0010] Some embodiments described herein relate to a method of treating a norovirus infection that can include administering to a subject identified as suffering from the norovirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a norovirus infection.
[0011] Some embodiments disclosed herein relate to a method of inhibiting replication of a norovirus that can include contacting a cell infected with the norovirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication a norovirus.
[0012] These are other embodiments are described in greater detail below.
DETAILED DESCRIPTION
[0013] Coronaviridae viruses are a family of enveloped, positive-stranded, singlestranded, spherical RNA viruses. Coronaviruses are named for the crown-like spikes on their surface. The Coronaviridae family includes two sub-families, Coronavirus and Torovirus. The Coronavirus genus has a helical nucleocapsid, and Torovirus genus has a tubular nucleocapsid. The Coronaviridae family of viruses includes Middle East respiratory syndrome coronavirus (MERS-CoV), SARS and SARS-CoV-2.
[0014] Coronavirus disease 2019 (COVID-19) (also referred to as novel coronavirus pneumonia or 2019-nCoV acute respiratory disease) is an infectious disease caused by the virus severe respiratory syndrome coronavirus 2 (SARS-CoV-2) (also referred to as novel coronavirus 2019, or 2019-nCoV). The disease was first identified in December 2019 and spread globally, causing a pandemic. Sy mptoms of CO VID-19 include fever, cough, shortness of breath, fatigue, headache, loss of smell, nasal congestion, sore throat, coughing up sputum, pain in muscles or joints, chills, nausea, vomiting, and diarrhea. In severe cases, symptoms can include difficulty waking, confusion, blueish face or lips, coughing up blood, decreased white blood cell count, and kidney failure. Complications can include pneumonia, viral sepsis, acute respiratory distress syndrome, and kidney failure.
[0015] COVID-19 is especially threatening to public health. The virus is highly contagious, and studies currently indicate that it can be spread by asymptomatic carriers or by those who are pre-symptomatic. Likewise, the early stage of the disease is slow-progressing enough that carriers do not often realize they are infected, leading them to expose numerous others to the virus. The combination of COVID- 19’ s ease of transmission, its high rate of hospitalization of victims, and its death rate make the virus a substantial public health risk, especially for countries without a healthcare system equipped to provide supportive care to pandemic-level numbers of patients. There is not yet a vaccine or specific antiviral treatment for COVID-19 and accordingly, there is a pressing need for treatments or cures.
[0016] SARS-CoV-2 is not the only coronavirus that causes disease. It is a p- coronavirus, a genus of coronaviruses that includes other human pathogens, including SARS- CoV (the causative agent of SARS), MERS-CoV (the causative agent of MERS), and HCoV- OC43 (a causative agent of the common cold). The infectivity of these viruses, and the severity of the diseases they cause, varies widely, p-coronavirus can also manifest as zoonotic infections, spread to and from humans and animals. Additionally, non-human species such as camels, bats, tigers, non-human primates, and rabbits can be susceptible to P-coronavirus. Accordingly, there is a pressing need for treatments or cures to multiple coronaviruses.
[0017] The present disclosure provides molecules useful against coronaviruses, and especially SARS-CoV-2, the causative agent of COVID-19 in humans. Accordingly, the present disclosure fulfills the need in the art for compounds that can be safely and effectively treat or prevent coronavirus infections in humans.
[0018] Pi comaviruses are a family of positive strand RNA, nonenveloped viruses. A picornavirus has 60 identical subunits (vertices) which contain five protomers. Each protomer is made up of one copy of four proteins, named VP1, VP2, VP3 and VP4. There are several genera of picornaviruses, including, Enterovirus, Aphthovirus, Cardiovirus and Hepatovirus. Enteroviruses known to infect human include, but are not limited to. Rhinovirus A, Rhinovirus B, Rhinovirus C, Coxsackievirus A, Coxsackievirus B and Poliovirus. There is no specific treatment for a picornavirus infection.
[0019] Noroviruses are single-stranded positive-sense RNA, non-enveioped viruses belonging to the Caliciviridae family. Noroviruses are often spread by the fecal-oral route, and are a common cause of gastroenteritis. Infected subjects can experience nausea, non-bloody diarrhea, vomiting and/or abdominal pain. Those suffering from a norovirus infection can become severely dehydrated and require medical attention. As with a picornavirus infection, there is no specific treatment for a norovirus infection. Accordingly, there is a need for compounds that effectively treat or prevent a picornavirus and/or a norovirus infection.
Definitions
[0020] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0021] Whenever a group is described as being “optionally substituted’1 that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) (such as 1, 2 or 3) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C -amido,
N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido(alkyl), isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amine and a di-substituted amine. [0022] As used herein, “Ca to Cb” or “Ca-b” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “C1 to C4 alkyl” or “C1-4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed. [0023] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted. [0024] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. The length of an alkenyl can vary. For example, the alkenyl can be a C2-4 alkenyl, C2-6 alkenyl or C2-8 alkenyl.
Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted. [0025] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. The length of an alkynyl can vary. For example, the alkynyl can be a C2-4 alkynyl, C2-6 alkynyl or C2-8 alkynyl. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted. [0026] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused- or spiro-fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s). 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. [0027] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused- or spiro- fashion. A cycloalkenyl can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted. [0028] As used herein, “aryl” refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a C6-C14 aryl group, a C6-C10 aryl group, or a C6 aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. [0029] As used herein, “heteroaryl” refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1 to 5 heteroatoms), that is, an element other than
carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4- oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted. [0030] As used herein, “heterocyclyl” refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The number of atoms in the ring(s) of a heterocyclyl group can vary. For example, the heterocyclyl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5- triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine N-Oxide, piperidine,
piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2- oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl). [0031] As used herein, “cycloalkyl(alkyl)” refers to a cycloalkyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and cycloalkyl group of a cycloalkyl(alkyl) may be substituted or unsubstituted. A cycloalkyl(alkyl) group may be unsubstituted or substituted. [0032] As used herein, “aryl(alkyl)” refers to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2- phenyl(alkyl), 3-phenyl(alkyl), and naphthyl(alkyl). [0033] As used herein, “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaryl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to 2-thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl), and their benzo-fused analogs. [0034] A “heterocyclyl(alkyl)” refer to a heterocyclic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a heterocyclyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro- 2H-thiopyran-4-yl(methyl) and 1,3-thiazinan-4-yl(methyl). [0035] “Lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the definition of “substituted.” Further, when a lower alkylene group is substituted, the lower alkylene can be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g.,
[0036] As used herein, “alkoxy” refers to the formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl(alkyl), an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzyloxy. In some instances, an alkoxy can be –OR, wherein R is an unsubstituted C1-4 alkyl. An alkoxy may be substituted or unsubstituted. [0037] As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted. [0038] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted. [0039] As used herein, “haloalkoxy” refers to a O-alkyl group and O-monocyclic cycloalkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2- fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chloro-substituted cyclobutyl and fluoro-substituted cyclobutyl. In some instances, a haloalkoxy can be –OR, wherein R is a C1-4 alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted. [0040] A “sulfenyl” group refers to an “–SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted. [0041] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.
[0042] A “sulfonyl” group refers to an “S(=O)2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted. [0043] An “O-carboxy” group refers to a “RC(=O)O–” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted. [0044] The terms “ester” and “C-carboxy” refer to a “–C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted. [0045] A “thiocarbonyl” group refers to a “–C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted. [0046] A “trihalomethanesulfonyl” group refers to an “X3CS(=O)2–” group wherein each X is a halogen. [0047] A “trihalomethanesulfonamido” group refers to an “X3CS(=O)2N(RA)–” group wherein each X is a halogen, and RA is hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). [0048] The term “amino” as used herein refers to a –NH2 group. [0049] As used herein, the term “hydroxy” refers to a –OH group. [0050] A “cyano” group refers to a “–CN” group. [0051] The term “azido” as used herein refers to a –N3 group. [0052] An “isocyanato” group refers to a “–NCO” group. [0053] A “thiocyanato” group refers to a “–SCN” group. [0054] An “isothiocyanato” group refers to an “–NCS” group. [0055] A “mercapto” group refers to an “–SH” group. [0056] A “carbonyl” group refers to a –C(=O)– group. [0057] An “S-sulfonamido” group refers to a “–S(=O)2N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.
[0058] An “N-sulfonamido” group refers to a “RS(=O)2N(RA)–” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted. [0059] An “O-carbamyl” group refers to a “–OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted. [0060] An “N-carbamyl” group refers to an “ROC(=O)N(RA)–” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted. [0061] An “O-thiocarbamyl” group refers to a “–OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted. [0062] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)–” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted. [0063] A “C-amido” group refers to a “–C(=O)N(RARB)” group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted. [0064] An “N-amido” group refers to a “RC(=O)N(RA)–” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted. [0065] A “mono-substituted amine” refers to a “–NHRA” in which RA can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). A
mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be –NHRA, wherein RA can be an unsubstituted C1-6 alkyl or an unsubstituted or a substituted benzyl. [0066] A “di-substituted amine” refers to a “–NRARB” in which RA and RB can be independently can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be –NRARB, wherein RA and RB can be independently an unsubstituted C1-6 alkyl or an unsubstituted or a substituted benzyl. [0067] A “ketoamide” group refers to a -C(=O)-C(=O)N(RARB) group in which RA and RB can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl(alkyl), a heteroaryl(alkyl) or a heterocyclyl(alkyl). A ketoamide may be substituted or unsubstituted. [0068] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine. [0069] Where the number of substituents is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms. [0070] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.11:942-944 (1972)). [0071] The term “pharmaceutically acceptable salt” refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic
carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine. [0072] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound or composition, the term "comprising" means that the compound or composition includes at least the recited features or components but may also include additional features or components. [0073] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. [0074] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of (R)-configuration or (S)-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In
addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included. [0075] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium). [0076] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise. [0077] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments. Compounds [0078] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein: Ring A1 can be
, wherein Ring A1 is optionally substituted with one or more moieties independently selected from the group consisting of =O, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl; R1 can be selected from cyano, an unsubstituted or a substituted C2-5 alkynyl, an unsubstituted or a substituted acyl, an unsubstituted or a substituted ketoamide, –CH(OH)-(S(=O)2-O-), – CH(OH)((P=O)(OR6)2) and –C(=O)CH2-O-((P=O)(OR7)2); each R6 and each R7 can be independently hydrogen, an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted C1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C1-4 alkyl); R2 can be hydrogen, deuterium or halogen; R3 can be an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl), an unsubstituted or a substituted bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl) or an unsubstituted or a substituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl); R4 can be hydrogen, deuterium or halogen; R5 can be
a substituted monocyclic C3-6 cycloalkyl or a substituted 4- to 6-membered monocyclic heterocyclyl; R8 and R10 can be independently selected from an unsubstituted or a substituted C2-6 alkyl, an unsubstituted or a substituted C2-6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-8 cycloalkyl, an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl and an unsubstituted monocyclic C3-6 cycloalkyl(CH2)–, wherein when the C2-6 alkyl is substituted, the C2-6 alkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, cyano, an unsubstituted or a substituted monocyclic C3- 6 cycloalkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkoxy, or the C2-6 alkyl is substituted 1 to 13 times with deuterium; wherein when the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted, the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-
6 cycloalkyl, the bicyclic C5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl can be substituted 1 , 2, 3 or 4 times with a substituent independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted C1-4 alkoxy; R9 can be selected from an unsubstituted or a substituted C1-6 alkyl, an unsubstituted or a substituted C1-6 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-6 cycloalkyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl and an unsubstituted or a substituted alkoxy, wherein the substituted C1-6 alkyl is substituted 1 or 2. times with an unsubstituted C1-4 alkoxy, wherein the substituted monocyclic C3-6 cycloalkyl is substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl and an unsubstituted monocyclic C3- 6 cycloalkyl, and wherein the substituted C1-6 haloalkyl is substituted 1 or 2 times with an unsubstituted C1-4 alkoxy; and R11 can be an optionally substituted monocyclic 4- to 6- membered heterocyclyl, -(NH)m-an optionally substituted 5- to 6-membered monocyclic heteroaryl, -O-an optionally substituted C1-6 alkyl, -O-an optionally substituted C3-8 cycloalkyl and -O-an optionally substituted C3-8 cycloalkyl(C1-4 alkyl), wherein m can be 0 or 1.
[ 0079] The substituent R1 can be various moieties. In some embodiments, R1 can be an unsubstituted ketoamide. In some embodiments, R1 can be a substituted ketoamide. The ketoamide can have the structure -C(= O)-C(= O)NRy 1Rz1. In some embodiments, R1 can be an acyl, for example, R1 can be -C(= O)H, -C(= O)(an unsubstituted C1-4 alkyl), -C(= O)(an unsubstituted to a substituted benzyl), -C(= O)(an unsubstituted to a substituted monocyclic heteroaryl) or -C(= O)(an unsubstituted to a substituted bicyclic heteroaryl). In some embodiments, R1 can be a substituted acyl. The acyl for R1 can have the structure -C(= O)Ry 2. When the acyl is substituted, the possible groups that can be present on the acyl include hydroxy, a substituted or an unsubstituted alkoxy (such as -O-(an unsubstituted C1-4 alkyl), - O-(an unsubstituted C3-6 cycloalkyl), a substituted or an unsubstituted phenoxy or a substituted or an unsubstituted benzyloxy) or -O-(C=O)-(an unsubstituted C1-6 alkyl). In some embodiments, R1 can be an unsubstituted can be -C(=O)-N-sulfonamido.
[0080] Ry1, Ry2 and Rz1 can be a variety of groups. In some embodiments, Ry1, Ry2 and Rz1 can be independently selected from hydrogen, C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3- 8 cycloalkyl (for example, a monocyclic C3-8 cycloalkyl), C3-8 cycloalkenyl (such as a monocyclic C3-8 cycloalkenyl), aryl (such as phenyl or naphthyl), heteroaryl (including a monocyclic or a bicyclic heteroaryl), heterocyclyl (for example, a monocyclic or a bicyclic heterocyclyl), aryl(alkyl) (such as benzyl), heteroaryl(alkyl) (including a monocyclic heteroaryl(CH2)– and a monocyclic (heteroaryl(CH2CH2)–) or heterocyclyl(alkyl) (such as a monocyclic heterocyclyl(CH2)– and a monocyclic heterocyclyl(CH2CH2)–), wherein each of the aforementioned Ry1, Ry2 and Rz1 groups can be unsubstituted or substituted. In some embodiments, Ry1, Ry2 and Rz1 can be independently selected from H, C1-8 alkyl, an unsubstituted C1-4 haloalkyl (including –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl), –C1-4 alkyl(OH) (including –CH2OH, –CH2CH2OH and –CH(CH3)OH), – C1-4 alkyl(C1-4 alkoxy) (such as –CH2O(an unsubstituted C1-4 alkyl) and –CH2CH2O(an unsubstituted C1-4 alkyl)), –C1-4 alkyl-O-(a monocyclic C3-6 cycloalkyl) (such as –CH2O(a monocyclic C3-6 cycloalkyl), –CH2CH2O(a monocyclic C3-6 cycloalkyl)), –C1-4 alkyl-O- (phenyl) (for example, –CH2O(phenyl) and –CH2CH2O(phenyl)), –C1-4 alkyl-O-(5- to 6- membered monocyclic heteroaryl) (such as –CH2O(5- to 6-membered monocyclic heteroaryl) and –CH2CH2O(5- to 6-membered monocyclic heteroaryl)), –C1-4 alkyl-O-(5- to 6-membered monocyclic heterocyclyl) (for example, –CH2O(5- to 6-membered monocyclic heterocyclyl) and –CH2CH2O(5- to 6-membered monocyclic heterocyclyl)), –C1-4 alkyl-O-(a monocyclic C3- 6 cycloalkyl(C1-4 alkyl) (such as –C1-4 alkyl-O-CH2-(monocyclic C3-6 cycloalkyl) and –C1-4 alkyl-O-CH2CH2-(monocyclic C3-6 cycloalkyl)), –C1-4 alkyl-O-(benzyl) (for example, –CH2O(benzyl) and –CH2CH2O(benzyl)), –C1-4 alkyl-O-(5- to 6-membered monocyclic heteroaryl(C1-4 alkyl), –C1-4 alkyl-O-(5- to 6-membered monocyclic heterocyclyl(C1-4 alkyl), –C1-4 alkyl-O(C=O)(an unsubstituted C1-6 alkyl) (for example, –CH2O(C=O)(an unsubstituted C1-6 alkyl)), a monocyclic C3-8 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl), a monocyclic heteroaryl (such as imidazole, 1,3,4- oxadiazole and pyridinyl), a monocyclic heterocyclyl (for example, tetrahydrofuran and tetrahydropyran), a bicyclic heteroaryl (for example, benzothiazole, benzoimidazole and benzooxazole), a bicyclic heterocyclyl, a monocyclic C3-6 cycloalkyl(alkyl), aryl(alkyl) (such
as benzyl), heteroaryl(alkyl) (for example, a monocyclic heteroaryl-(CH2)-, such as pyridinyl- (CH2)--) and heterocyclyl(alkyl) (for example, a monocyclic heterocyclyl-(CH2)-), wherein each of the aforementioned Ryl, Ry2 and Rzl groups can be unsubstituted or substituted.
[0081] In some embodiments, R1 can be -C(=O)Ry2, wherein Ry2 can be -C1-4 alkyl(OH) (such as -CH2OH). In some embodiments, R1 can be -C(=O)-C(=O)NRylRzl; wherein Ry1 can be H; and Rz1 can be any of the moieties listed for Rzl in the previous paragraph. In some embodiments, R1 can be -C(=O)-C(=O)NRy1Rz1; wherein Ry1 can be H; and Rz1 can be a monocyclic C3-8 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl).
[0082] Prodrug-type and phosphate-containing moieties can be present at R1. In some embodiments, R1 can be -CH(OH)-(S(=O)2-O ). In other embodiments, R1 can be - CH(OH)((P=O)(OR6)2), wherein each R6 can be independently hydrogen, an unsubstituted Ci- 6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted C1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C1-4 alkyl). In still other embodiments, R1 can be -C(=O)CH2-O-((P=O)(OR7)2), wherein each R7 can be independently hydrogen, an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted C1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C1-4 alkyl). Other examples of R6 and R7 groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained and branched), hexyl (straight-chained and branched), ethenyl, propenyl, butenyl, pentenyl, hexenyl, chloromethyl, fluoromethyl, difluoromethyl, dichloromethyl, trifluoromethyl, trichloromethyl, an unsubstituted or a substituted phenyl and an unsubstituted or a substituted benzyl.
[0083] In some embodiments, R1 can be cyano. In other embodiments, R1 can be an unsubstituted C2-5 alkynyl. In still other embodiments, R1 can be a substituted C2-5 alkynyl. The C2-5 alkynyl can have various structures. For example, the C2-5 alkynyl can have the structure -(CH2)1-C2-4 alkynyl or -(CH2)2-C2-3 alkynyl.
[0084] In some embodiments, Ring A1 can be an unsubstituted . In other
19
embodiments, Ring A1 can be a substituted
. For example, when Ring A1 is substituted, Ring A1 can be substituted with one or more moieties (such as 1, 2 or 3 moieties) independently selected from of =O, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1- 4 alkyl, an unsubstituted C1-4 haloalkyl, an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl. Those skilled in the art understand that the nitrogen shown in each of the ring structures for Ring A1 corresponds to the ring nitrogen shown in Formula (I), and the carbon adjacent to the ring nitrogen with the
corresponds to the carbon to which R4 is attached. For example, those skilled in the art understand that when Ring A1 is
, then a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the following structure:
. [0085] As provided herein, Ring A1 can be substituted with one or more moieties (such as 1, 2 or 3 moieties) independently selected from =O, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl. Example of suitable substituents that can be present in Ring A1 include halogen (such as F or Cl), an unsubstituted C1-4 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), an unsubstituted C1-4 haloalkyl (including –CF3, –CCl3, –CHF2, –C(CH3)F2, –
CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl), an unsubstituted C2-4 alkenyl (such as ethenyl, propenyl and butenyl) and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl). When Ring A1 is substituted by an unsubstituted or a substituted C3-6 monocyclic cycloalkyl, the unsubstituted or a substituted C3-6 monocyclic cycloalkyl can replace one hydrogen. [0086] In some embodiments, R4 can be hydrogen. In other embodiments, R4 can be deuterium. In still other embodiments, R4 can be halogen (such as fluoro or chloro). [0087] As provided herein R3 can be a non-hydrogen substituent selected from an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl) and an unsubstituted or a substituted bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl). In some embodiments, R3 can be an unsubstituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl). In other embodiments, R3 can be a substituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl). In still other embodiments, R3 can be an unsubstituted bicyclic nitrogen- containing heterocyclyl(C1-4 alkyl). In yet still other embodiments, R3 can be a substituted bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl). When R3 is a bicyclic nitrogen- containing heterocyclyl(C1-4 alkyl), the two rings of the bicyclic heterocyclyl can be connected in a fused-fashion (including bridged-fashion) or a spiro-fashion. In some embodiments, R3 can be an unsubstituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl). In other embodiments, R3 can be a substituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl). [0088] Those skilled in the art understand that when two rings are connected in a spiro-fashion, the two rings are connected by a single ring atom. For example, in the structure
rings C1 and C2 are joined in a spiro-fashion. When two rings described herein are connected in a fused-fashion, the two rings are connected by two or more ring atoms. In some instances, the two rings can be connected by two adjacent ring atoms. As an example, rings D1 and D1 are connected in a fused-fashion by two adjacent ring atoms
. In some instances, two rings described herein can be connected by three or more atoms are shared
between the two rings. The following structure:
is an example of two rings being connected by three or more ring atoms. When two rings are connected by three or more ring atoms, the three or more ring atoms connecting the two rings would be referred to by those skilled in the art as “bridging” atoms. Further, those skilled in the art would understand based on the disclosure provided herein that two rings connected in a “bridged” fashion is an example of two rings connected in a fused-fashion. [0089] The number of ring atoms for a monocyclic and a bicyclic nitrogen- containing heterocyclyl(C1-4 alkyl) can vary. Non-limiting examples include an unsubstituted or a substituted 5-membered monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl), 6- membered monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl), an unsubstituted or a substituted 9-membered bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl) and 10- membered bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl). Examples of suitable R3 groups include the following: azepan-2-one(C1-4 alkyl), imidazolidin-2-one(C1-4 alkyl), tetrahydropyrimidin-2-one(C1-4 alkyl), pyrrolidin-2-one(C1-4 alkyl), piperidin-2-one(C1-4 alkyl), pyrazolidin-3-one(C1-4 alkyl), oxazolidin-4-one(C1-4 alkyl), 1,4-oxazepan-3-one(C1-4 alkyl), morpholin-3-one(C1-4 alkyl),
, , , ,
wherein each m1 can be independently 1, 2, 3 or 4, (including substituted or unsubstituted versions of the aforementioned). The R3 groups provided herein can be substituted with one or more moieties independently selected from those listed for “optionally substituted.” In some embodiments, a R3 group provided herein can be substituted with one or more moieties selected from deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl an unsubstituted C1-4 alkoxy, amino, –(an unsubstituted C1-4 alkyl)- O-P-(OH)2 (such as –CH2-O-P-(OH)2) and –(an unsubstituted C1-4 alkyl)-O-P-(O(an unsubstituted C1-4 alkyl))2 (such as –CH2-O-P-(OCH3)2). [0090] Non-limiting examples of R3 moieties include the following:
[0091] In some embodiments, R2 can be hydrogen. In other embodiments, R2 can be deuterium. In still other embodiments, R2 can be halogen (for example, fluoro or chloro). O [0092] As provided herein, R5 can be
. In some embodiments, R9 can be an unsubstituted C1-6 haloalkyl. For example, R9 can be –CF3, –CClF2, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH(CH3)CF3, –CH2CH2CF3, – CH2CH(CH3)CF3, –CF2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and – CH2CH2CH2Cl. In some embodiments, R9 can be –CF3. In other embodiments, R9 can be a substituted C1-6 haloalkyl where the C1-6 haloalkyl can be substituted 1 or 2 times with an unsubstituted C1-4 alkoxy. When the C1-6 haloalkyl is substituted with 1 or 2 unsubstituted C1- 4 alkoxys, one or more hydrogens of the C1-6 haloalkyl can be replaced with an unsubstituted C1-4 alkoxy (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy). Exemplary C1-6 haloalkyls substituted with an unsubstituted C1-4 alkoxy include –C(OCH3)F2, –C(OCH3)Cl2, –CH(OCH3)F, –C(OCH3)(CH3)F, –CH(OCH3)CF3, –
C(OCH3)(CH3)CF3, –CH2CH(OCH3)CF3, –CH2C(OCH3)(CH3)CF3, –CH(OCH3)Cl, – CH2CH(OCH3)F, –CH2CH(OCH3)Cl, –CH2CH2CH(OCH3)F and –CH2CH2CH(OCH3)Cl. In still other embodiments, R9 can be an unsubstituted C1-6 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched). In yet still other embodiments, R9 can be a C1-6 alkyl substituted 1 or 2 times with an unsubstituted C1-4 alkoxy. When the C1-6 alkyl is substituted with an unsubstituted C1-4 alkoxy, a hydrogen of the C1-6 alkyl can be replaced with an unsubstituted C1-4 alkoxy such as those described herein. A non-limiting list of C1-6 alkyls substituted 1 or 2 times with an unsubstituted C1-4 alkoxy include –CH2(OCH3), –CH(OCH3)2, –CH(CH3)(OCH3) and –C(CH3)2(OCH3). In some embodiments, R9 can be an unsubstituted or a substituted monocyclic heteroaryl. A variety of an unsubstituted or a substituted monocyclic heteroaryls can be present for R9. For example, the heteroaryl can be a 5- or 6- membered heteroaryl that includes 1, 2 or 3 heteroatoms selected from nitrogen (N), oxygen (O) and sulfur (S). Exemplary heteroaryls for an unsubstituted or a substituted monocyclic heteroaryl include, but are not limited to, furane, isoxazole, isothiazole pyridine, pyridazine, pyrimidine and pyrazine. In yet still other embodiments, R9 can be an unsubstituted or a substituted monocyclic heterocyclyl. A non-limiting list of monocyclic heterocyclyls for R9 include oxetane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine and morpholine. Various substituents can be present on a substituted heteroaryl and/or a substituted heterocyclyl of R9. For example, the heteroaryl can be substituted 1, 2 or 3 times with a moiety selected from halogen, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 haloalkyl and an unsubstituted C1-6 alkoxy. Suitable halogens, unsubstituted C1-6 alkyls, unsubstituted C1-6 haloalkyls and unsubstituted C1-6 alkoxys are described herein. [0093] In some embodiments, R9 can be an unsubstituted monocyclic C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In other embodiments, R9 can be a halogen-substituted monocyclic C3-6 cycloalkyl. In still other embodiments, R9 can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C1-4 alkyl. In yet still other embodiments, R9 can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C1-4 alkoxy. In some embodiments, R9 can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C2-4 alkenyl. In other embodiments, R9 can be a monocyclic
C3-6 cycloalkyl substituted with an unsubstituted C1-4 haloalkyl. In still other embodiments, R9 can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted monocyclic C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In some embodiments, R9 can be an unsubstituted bicyclic C5-6 cycloalkyl. In other embodiments, R9 can be a substituted bicyclic C5-6 cycloalkyl. The two rings of a bicyclic C5-6 cycloalkyl can be connected in a spiro-fashion or a fused-fashion. In some embodiments, R9 can be a halogen- substituted bicyclic C5-6 cycloalkyl. In still other embodiments, R9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 alkyl. In yet still other embodiments, R9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 alkoxy. In some embodiments, R9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C2-4 alkenyl. In other embodiments, R9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 haloalkyl. In still other embodiments, R9 can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted monocyclic C3-6 cycloalkyl (including cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl). A non-liming list of bicyclic C5-6 cycloalkyls include spiro[2.2]pentane, spiro[2.3]hexane, bicyclo[1.1.1]pentane and bicyclo[2.1.1]hexane. [0094] Suitable halogen-substituted monocyclic C3-6 cycloalkyls include halogen- substituted cyclopropyl, halogen-substituted cyclobutyl, halogen-substituted cyclopentyl and halogen-substituted cyclohexyl. Additional monocyclic C3-6 cycloalkyls include cyclopropyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1- 4 alkoxy, an unsubstituted C1-4 haloalkyl and/or an unsubstituted monocyclic C3-6 cycloalkyl, cyclobutyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl and/or an unsubstituted monocyclic C3-6 cycloalkyl, cyclopentyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl and/or an unsubstituted monocyclic C3-6 cycloalkyl and cyclohexyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl and/or an unsubstituted monocyclic C3-6 cycloalkyl. The number halogens on a halogen-substituted monocyclic C3-6 cycloalkyl and/or a bicyclic C5-6 cycloalkyl, the number of unsubstituted C1-4 alkyls on a monocyclic C3-6 cycloalkyl and/or a bicyclic C5-6 cycloalkyl, the number of unsubstituted C2-4 alkenyls on a monocyclic C3-6 cycloalkyl and/or a bicyclic C5-6 cycloalkyl, the number of unsubstituted C1-4 haloalkyls on a monocyclic C3-6 cycloalkyl and/or a bicyclic
C5-6 cycloalkyl, the number of unsubstituted C1-4 alkoxys on a monocyclic C3-6 cycloalkyl and/or a bicyclic C5-6 cycloalkyl and the number of unsubstituted monocyclic C3-6 cycloalkyls on a monocyclic C3-6 cycloalkyl and/or a bicyclic C5-6 cycloalkyl can vary. For example, 1, 2, 3 or 4 halogens can be present on a halogen-substituted monocyclic C3-6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C1-4 alkyls can be present on a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C1-4 alkyl, 1, 2, 3 or 4 unsubstituted C2-4 alkenyls can be present on a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C2-4 alkenyl, 1, 2, 3 or 4 unsubstituted C1-4 alkoxys can be present on a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C1-4 alkoxy, 1, 2, 3 or 4 unsubstituted C1-4 haloalkyls can be present on a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C1-4 haloalkyl, 1 or 2 unsubstituted monocyclic C3-6 cycloalkyls can be present on a monocyclic C3-6 cycloalkyl, 1, 2, 3 or 4 halogens can be present on a halogen-substituted bicyclic C5-6 cycloalkyl, 1, 2, 3 or 4 unsubstituted C1-4 alkyls can be present on a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 alkyl, 1, 2, 3 or 4 unsubstituted C2-4 alkenyls can be present on a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C2-4 alkenyl, 1, 2, 3 or 4 unsubstituted C1-4 alkoxys can be present on a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C2-4 alkoxy, 1, 2, 3 or 4 unsubstituted C1-4 haloalkyls can be present on a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 haloalkyl and 1 or 2 unsubstituted monocyclic C3-6 cycloalkyls can be present on a bicyclic C5- 6 cycloalkyl. In some embodiments, a monocyclic C3-6 cycloalkyl can be substituted with 1 or more substituents (such as 1, 2, 3 or 4 substituents) selected from halogen, an unsubstituted C1- 4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl. In other embodiments, a bicyclic C5-6 cycloalkyl can be substituted with 1 or more substituents (such as 1, 2, 3 or 4 substituents) selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl. Suitable halogens that can be present on a substituted monocyclic C3-6 cycloalkyl include, but are not limited to, fluoro (F) and chloro (Cl). Examples of unsubstituted C1-4 haloalkyls include, but are not limited to, –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F and – CH2CH2CH2Cl. [0095] In some embodiments, R9 can be an unsubstituted alkoxy. In other embodiments, R9 can be a substituted alkoxy. Various alkoxys can be present for R9. For
example, –O-(hydrocarbon) (such as –O-(C1-8 alkyl)), –O-(monocyclic C3-8 cycloalkyl), –O- (bicyclic C5-8 cycloalkyl), –O-(phenyl), –O-(bicyclic aryl), –O-(monocyclic heteroaryl), –O- (bicyclic heteroaryl), –O-(monocyclic heterocyclyl) and –O-(bicyclic heterocyclyl). A non- limiting list of examples of C1-6 alkoxys are methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched), hexoxy (straight-chained or branched), –O-cyclopropyl, –O-cyclobutyl, –O-cyclopentyl, –O- cyclohexyl and –O-(bicyclo[1.1.1]pentyl). A variety of substituents can be present on a substituted alkoxy for R9. Examples of suitable substituents are those provided for “optionally substituted.” In some embodiments, 1, 2, 3 or 4 substituents can be present on a substituted alkoxy. For example, a substituted alkoxy can be substituted 1, 2, 3 or 4 times with substituents independently selected from halogen, hydroxy, an unsubstituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl. [0096] In some embodiments, R5 can be 10
wherein R can be independently selected from an unsubstituted or a substituted C2-6 alkyl, an unsubstituted or a substituted C2-6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-8 cycloalkyl and an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl, wherein when the C2-6 alkyl is substituted, the C2-6 alkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen and an unsubstituted C1-4 alkoxy; wherein when the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted, the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 haloalkyl and an unsubstituted C1-4 alkoxy; and R11 can be –(NH)m–an optionally substituted 5- to 6-membered monocyclic heteroaryl, wherein m can be 0 or 1. In some embodiments, R11 can be an optionally substituted monocyclic 4- to 6-membered heterocyclyl. Examples of heterocyclyls for R11 include optionally substituted 4- to 6-membered monocyclic heterocyclyls that include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). A non-
limiting list of heterocyclyl for R11 include the following: azetidine, pyrrolidine and piperidine. In other embodiments, m can be 0; and R11 can be an unsubstituted 5- to 6-membered monocyclic heteroaryl. In other embodiments, m can be 0; and R11 can be a substituted 5- to 6-membered monocyclic heteroaryl. In still other embodiment, m can be 1; and R11 can be an –(NH)–unsubstituted 5- to 6-membered monocyclic heteroaryl. In other embodiments, m can be 1; and R11 can be a –(NH)–substituted 5- to 6-membered monocyclic heteroaryl. An example of a 5- to 6-membered monocyclic heteroaryl that can be present for R11 include a 5- to 6-membered monocyclic heteroaryl that includes 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). Examples of suitable 5- to 6-membered monocyclic heteroaryls include, but are not limited to, imidazole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, 1,3,4-oxadiazole and 1,3,4-thiadiazole. In still other embodiments, R11 can be –O– an optionally substituted C1-6 alkyl. In yet still other embodiments, R11 can be –O–an optionally substituted C3-8 cycloalkyl. In some embodiments, R11 can be –O–an optionally substituted C3-8 cycloalkyl(C1-4 alkyl). The cycloalkyl of –O–an optionally substituted C3-8 cycloalkyl and –O–an optionally substituted C3-8 cycloalkyl(C1-4 alkyl) can be a monocyclic C3-6 cycloalkyl or a bicyclic C5-8 cycloalkyl. The C1-4 alkyl of –O– an optionally substituted cycloalkyl(C1-4 alkyl) can be –CH2–, –CH2CH2–, –CH2CH2CH2– or –CH2CH2CH2CH2–. As described herein, R11 can be substituted. Exemplary groups that can be present on R11 include halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkyl. [0097] The R8 and/or R10 moieties can be a substituted or an unsubstituted version of a C2-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a monocyclic C3-6 cycloalkyl, a bicyclic C5-8 cycloalkyl or a monocyclic 4- to 6-membered heterocyclyl. In some embodiments, R8 and/or R10 can be an unsubstituted C2-6 alkyl. In other embodiments, R8 and/or R10 can be a substituted C2-6 alkyl. Exemplary C2-6 alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight-chained and branched) and hexyl (straight-chained and branched). In some embodiments, R8 and/or R10 can be an unsubstituted C2-6 alkenyl. In other embodiments, R8 and/or R10 can be a substituted C2-6 alkenyl. In still other embodiments, R8 and/or R10 can be an unsubstituted C2-6 alkynyl. In yet still other embodiments, R8 and/or R10 can be a substituted C2-6 alkynyl. [0098] Cyclic moieties, including monocyclic and bicyclic moieties, can also be
present for R8 and/or R10. In some embodiments, R8 and/or R10 can be an unsubstituted monocyclic C3-6 cycloalkyl. In some embodiments, R8 and/or R10 can be a substituted monocyclic C3-6 cycloalkyl. For example, R8 and/or R10 can be a substituted or an unsubstituted cyclopropyl, a substituted or an unsubstituted cyclobutyl, a substituted or an unsubstituted cyclopentyl or a substituted or an unsubstituted cyclohexyl. In some embodiments, R8 and/or R10 can be an unsubstituted bicyclic C5-8 cycloalkyl. In other embodiments, R8 and/or R10 can be an unsubstituted bicyclic C5-8 cycloalkyl. The two rings of the bicyclic C5-8 cycloalkyl can joined in a fused or a spiro-fashion. Examples of rings connected in a fused and a spiro-fashion are provided herein. In some embodiments, R8 and/or R10 can be an unsubstituted or a substituted bicyclo[1.1.1]pentyl. In still other embodiments, R8 and/or R10 can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl. In yet still other embodiments, R8 and/or R10 can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl. The number of heteroatoms present in a monocyclic 4- to 6-membered heterocyclyl for R8 and/or R10 can vary. Suitable heteroatoms include, but are not limited to, O (oxygen), S (sulfur) and N (nitrogen). Examples of monocyclic 4- to 6-membered heterocyclyls are oxetane, thietane, azetidine, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran, tetrahydrothiopyran and piperidine (including unsubstituted or substituted versions of each of the aforementioned). In some embodiments, R8 and/or R10 can be an unsubstituted monocyclic C3-6 cycloalkyl(CH2)–. Various monocyclic C3-6 cycloalkyl are described herein. As examples, R8 and/or R10 can be selected from cyclopropyl(CH2)–, cyclobutyl(CH2)–, cyclopentyl(CH2)– and cyclohexyl(CH2)–. [0099] As described herein, R8 and/or R10 can be substituted. In some embodiments, when R8 and/or R10 is a C2-6 alkyl that is substituted, the C2-6 alkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, cyano, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkoxy. In some embodiments, R8 and/or R10 can be a C2-6 alkyl that is substituted 1 to 13 times with deuterium. In some embodiments, R8 and/or R10 can be a C2- 6 alkyl that is substituted 1 to 9 times with deuterium, 1 to 6 times with deuterium, 1 to 5 times with deuterium or 1 to 3 times with deuterium. Each halogen can be independently F (fluoro) or Cl (chloro). Exemplary unsubstituted and substituted monocyclic C3-6 cycloalkyls that can be present on a substituted C2-6 alkyl for R8 and/or R10 include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl and halogen-substituted monocyclic C3-6 cycloalkyls. Suitable unsubstituted C1-4 alkoxys that can be substituted on a C2-6 alkyl of R8 and/or R10 include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy. Examples of an unsubstituted C1-4 haloalkoxy can be substituted on a C2-6 alkyl of R8 and/or R10 include –OCl3, –OCF3, –OCH2Cl, –OCH2F, –OCHCl2 and –OCHF2. In some embodiments, when R8 and/or R10 is a substituted C2-6 alkenyl, a substituted C2-6 alkynyl, a substituted monocyclic C3-6 cycloalkyl, a substituted bicyclic C5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl, each of the aforementioned can be substituted 1, 2, 3 or 4 times with a substituents independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted C1-4 alkoxy. Examples of unsubstituted C1-4 alkyls, an unsubstituted C2-4 alkenyl and an unsubstituted C2-4 alkynyl that can be substituted on a substituted C2-6 alkenyl, a substituted C2-6 alkynyl, a substituted monocyclic C3-6 cycloalkyl, a substituted bicyclic C5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, ethenyl, propenyl, butenyl, ethynyl, propynyl and butynyl. Suitable halogens and unsubstituted C1-4 alkoxys that can be present on a substituted C2-6 alkenyl, a substituted C2-6 alkynyl, a substituted monocyclic C3-6 cycloalkyl, a substituted bicyclic C5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl are described herein, such as in this paragraph. Non-limiting list of unsubstituted and substituted monocyclic C3-6 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and halogen-substituted monocyclic C3-6 cycloalkyls. Examples of unsubstituted C1-6 haloalkyls that can be present on a substituted C2-6 alkenyl, a substituted C2-6 alkynyl, a substituted monocyclic C3-6 cycloalkyl, a substituted bicyclic C5-8 cycloalkyl or a substituted monocyclic 4- to 6-membered heterocyclyl include, but are not limited to, –CF3, –CCl3, – CHF2, –C(CH3)F2, –CHCl2, –CH2F, –CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, – CH2CH2Cl, –CH2CH2CH2F and –CH2CH2CH2Cl. [0100] Exemplary R5 groups include the following:
[0101] As described herein, in some embodiments, R5 can be a substituted monocyclic C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In other embodiments, R5 can be a substituted 4- to 6-membered monocyclic heterocyclyl. For example, R5 can be a substituted 4- to 6-membered monocyclic heterocyclyl that includes 1, 2 or 3 heteroatoms selected from N (nitrogen), O (oxygen) and S (sulfur). The substituted monocyclic C3-6 cycloalkyl and/or the substituted 4- to 6-membered monocyclic heterocyclyl can be substituted 1, 2 or 3 times with a moiety selected from deuterium, halogen, an unsubstituted C1-6 alkyl, an unsubstituted C1-6 haloalkyl and an unsubstituted C1-6 alkoxy. [0102] Further, when R5 is a monocyclic C3-6 cycloalkyl or a 4- to 6-membered monocyclic heterocyclyl, the monocyclic C3-6 cycloalkyl or the 4- to 6-membered monocyclic heterocyclyl can be substituted in a spiro-fashion by an unsubstituted or a substituted bicyclic cycloalkenyl or an unsubstituted or a substituted bicyclic heterocyclyl. The bicyclic cycloalkenyl can be an unsubstituted or a substituted 8- to 10-membered bicyclic cycloalkenyl. An unsubstituted or a substituted bicyclic heterocyclyl can be an unsubstituted or a substituted 8- to 10-membered bicyclic heterocyclyl, for example, an unsubstituted or a substituted 8- to 10-membered bicyclic heterocyclyl that includes 1, 2 or 3 heteroatoms in the rings selected from N (nitrogen), O (oxygen) and S (sulfur). In some embodiments, the bicyclic cycloalkenyl and/or the bicyclic heterocyclyl can be substituted one or more times (such as 1, 2, 3 or 4 times) with a moiety independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-6 haloalkyl (such as –CF3, –CCl3, –CHF2, –C(CH3)F2, –CHCl2, –CH2F, – CH(CH3)F, –CH2CF3, –CH2Cl, –CH2CH2F, –CH2CH2Cl, –CH2CH2CH2F, –CH2CH2CH2Cl) and an unsubstituted C1-4 alkoxy. Examples of R5 as a monocyclic C3-6 cycloalkyl or a 4- to 6-membered monocyclic heterocyclyl substituted in a spiro-fashion by an unsubstituted or a substituted bicyclic cycloalkenyl or an unsubstituted or a substituted bicyclic heterocyclyl include the following:
[0103] Examples of a compound of Formula (I), include the following:
a pharmaceutically acceptable salt of any of the foregoing. [0104] Additional examples of a compound of Formula (I) (along with pharmaceutically acceptable salts thereof) include the following:
a pharmaceutically acceptable salt of any of the foregoing. Synthesis [0105] Compounds of Formula (I) along with those described herein may be prepared in various ways. General synthetic routes for preparing compounds of Formula (I) are shown and described herein along with some examples of starting materials used to synthesize compounds described herein. Additionally, for the purpose of the general synthetic routes, the structures depicted are appropriately protected, as known by one skilled in the art and the generic structures are meant to include these protecting groups. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims. Scheme A
[0106] Scheme A describes the synthesis of compounds of general Formula (A-6). An amino ester of general Formula (A-1) (Alk represents alkyl) with an acid of general Formula (A-2), either by activating the carboxylic acid by converting it to an acid chloride,
followed by reaction with the amino acid in the presence of a base, or by activation of the acid with a coupling reagent (such as HATU) followed by coupling with the amino ester in the presence of a base (such as DIPEA), resulting in a compound of general Formula (A-3). The ester functionality of general Formula (A-3) can be hydrolyzed, for example, under basic conditions of -OAlk is -OMe, using LiOH in MeOH, providing in a compound of general Formula (A-4). Further coupling of the carboxylic acid of general Formula (A-4) with an amine of general Formula (A-5) can provide a compound of general Formula (A-6). For the purpose of the generic synthesis, R1 may be a latent functionality, converted to a functionality as described herein for R1. Scheme A1
[0107] Alternatively, as described in Scheme A1, a sub-group of amino acids of general Formula (A1-5) can be prepared as described in Scheme A1. A protected (PGA1) amino acid of general Formula (A1-1) can be coupled with an aminoester of general Formula (A-1) under known amide formation conditions, for example, HATU and iPr2NEt. The ester of a
compound of Formula (A1-2) can be deprotected, for example, by using LiOH in THF/H2O, resulting in the acid of general Formula (A1-3). The protecting group PGA1 can be removed, for example, by treatment with TFA in case PGA1 being Boc, resulting in a compound of general Formula (A1-4). This compound can be converted to a compound of general Formula (A1-5) (for example, by treatment with ethyl 2,2,2-trifluoroacetate in the presence of triethylamine) or alternatively, a compound of general Formula (A1-6) (for example, by treatment of a compound of general Formula (A1-4) with an alkyl trihaloacetate, (such as ethyl 2,2-dichloro-2-fluoroacetate, methyl 2-chloro-2,2-difluoroacetate or ethyl 2-chloro-2,2- difluoroacetate) in the presence of a base like triethylamine (and optionally an additive like and N-methylimidazole), or an alkyl 2,2,3,3,3-pentafluoropropanoate (such as methyl or ethyl 2,2,3,3,3-pentafluoropropanoate) in the presence of a base (for example, triethylamine and an additive, for example, N-methylimidazole)). [0108] General methodology for the synthesis of amino acids of general Formula (A1-1), or precursors that could be converted to an amino acid of general Formula (A1-1) by one skilled in the art, are described in the literature, and include the following examples:
Scheme B
[0109] In Scheme B, a carboxylic acid of general Formula (A-4) can be coupled with an amino acid of general Formula (B-1), for example, under the influence of a coupling reagent (such as T3P) and a base (for example, DIPEA). The obtained compound of general Formula (B-2) can be oxidized, providing in a compound of general Formula (B-3). In Scheme B, Ry1 can be part of the ketoamide described herein with respect to R1. Scheme B1
[0110] Alternatively, as depicted in Scheme B1, an amino acid of general Formula (B1-1) (with PGB1 a protecting group of the nitrogen, for example, -Boc) can be coupled with a compound of general Formula (B-1), similar as described for the conversion of a compound of general Formula (A-4) to a compound of general Formula (B-2). The protecting group can be removed, for example, by treatment with an acid in case of PGB1 being Boc, followed by coupling with a compound of general Formula (A-2), resulting in the formation of a compound of general formula (B-2).
Scheme B2
[0111] As described herein, R1 can be a substituted acyl, where the possible groups that can be present on the acyl include hydroxy, a substituted or an unsubstituted alkoxy (for example, –O–(an unsubstituted C1-4 alkyl) and –O–(an unsubstituted C3-6 cycloalkyl)), an unsubstituted C1-4 alkyl (such as a heteroaryl substituted with an unsubstituted C1-4 alkyl), a substituted or an unsubstituted phenoxy or a substituted or an unsubstituted benzyloxy). In Scheme B2, R can represent any of the aforementioned moieties that can be present on a substituted acyl for R1. Compounds of general Formulae (B2-2) and (B2-3) can be prepared as described in Scheme B2. An amino-ketone compound of general Formula (B2-1) can be coupled to a carboxylic acid of general Formula (A-4) or (B1-1) under typical amide coupling conditions. A compound of general Formula (B2-2) can be optionally further converted in a hydroxyketone of general Formula (B2-3), for example, in case where R represents a benzyl group, by catalytic hydrogenolysis. The PGB1 of a compound of general Formula (B2-4) can be deprotected (for example in the case wherein PGB1 is a Boc-group, by treatment with HCl in Et2O). The amine can then be coupled with a carboxylic acid of general Formula (A-2) under typical amide bound formation conditions, to provide a compound of general Formula (B2-2).
Scheme B3
[0112] Similar as described in Scheme B2 for a compound of Formula (B2-2), using an amide of general Formula (B3-1) in place of a compound of general Formula (B2-1). a compound of general Formula (B3-2) can be obtained. Conversion of a compound of general Formula (B3-2) to a compound of general Formula B3-3 can, for example, occur under the influence of trifluoroacetic anhydride (TFAA) and pyridine in CH2Cl2, or by application of the Burgess reagent. Scheme B4
[0113] For the purpose of the generic synthesis the transformations described in Scheme B3 include transformations as described in Scheme B4, where a compound of general Formula (A1-3) can be coupled with amine of general Formula (B3-1), resulting in a compound of general Formula (B4-1), where PGA1 can be a protecting group which can be removed (for example, in case PGA1 is Boc, by treatment with HCl or TFA). The compound of general Formula (B4-2) can be converted in a compound of general Formula (B4-3) (for example, by treatment with an alkyl trihaloacetate, such as ethyl 2,2-dichloro-2-fluoroacetate, methyl 2- chloro-2,2-difluoroacetate ethyl 2-chloro-2,2-difluoroacetate or ethyl 2,2,2-trifluoroacetate, in the presence of a base (such as triethylamine and optionally an additive, for example, N- methylimidazole), or an alkyl 2,2,3,3,3-pentafluoropropanoate (such as methyl or ethyl 2,2,3,3,3-pentafluoropropanoate) in the presence of a base (for example, triethylamine and an additive, for example, N-methylimidazole); or a carboxylic acid in the presence of a coupling reagent (such as EDC or HATU) and a base (such as NEt3). The compound of general Formula (B4-3) can be converted to a compound of general Formula (B4-4), similar as outlined for the conversion of a compound of general Formula (B3-2) to a compound of general Formula (B3- 3). Alternatively, a compound of general Formula (B4-2) can be converted to a compound of general Formula (B4-4) (for example, by treatment with T3P and pyridine in the presence of potassium 2,2,3,3,3-pentafluoropropanoate for -R9 being -CF2CF3). A compound of general
Formula (B4-1) can be obtained by deprotection of PGB1 of a compound of general Formula (B3-4), followed by coupling with a compound of general Formula (A1-1). Scheme C
[0114] A compound of general Formula (B-1) can be prepared as outlined in Scheme C. An aldehyde of general Formula (C-1) (PG1 can be a nitrogen protecting group, for example -Boc) and an isonitrile of general Formula (C-2), in the presence of a carboxylic acid (for example, benzoic acid), can be condensed in a Passerini-like reaction towards a compound of general Formula (C-3). After hydrolysis, a compound of general Formula (C-4) can be obtained. The PG1 can be removed, for example, by treatment with HCl when PG1 can be Boc. Scheme C1
[0115] An amino ketone of general Formula (B2-1), can be prepared as outline in Scheme C1. A protected amino acid of general Formula (C1-1) can be converted to its corresponding Weinreb amide under typical amide coupling conditions. Addition of an organometallic reagent to the Weinreb amide, followed by work-up, can result in a ketone of general Formula (C1-3). An example, wherein R can be benzyl, is the formation of an
organometallic reagent by mixing Mg, HgCl2 and benzylchloromethyl ether, followed by addition to a Weinreb amide of general Formula (C1-2), followed by work-up with saturated ammonium chloride. The protecting group (PG1) can be removed (for example, when PG1 is Boc, the protecting group can be removed using HCl) resulting in the formation of an amino ketone of general Formula (B2-1). When HCl is used for the deprotection, a compound of general Formula (B2-1) can be obtained as a HCl salt. Examples of a compound of general Formula (C1-1) are (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopiperidin-3-yl)propanoic acid and (S)-2-((tert-butoxycarbonyl)amino)-3-((S)-2-oxopyrrolidin-3-yl)propanoic acid. Scheme D1
Scheme D2
[0116] Other conversions for R1 described herein are shown in Schemes D1 and D2. In Schemes D1 and D2, PG2 represents an appropriate protecting group, and Rz1 and Ry1 are part of the ketoamide described herein with respect to R1.
Scheme E
[0117] A method for preparing a sub-group of amino acids of general Formula (E- 8) are provided in Scheme E. A lactam of general Formula (E-1) can be protected with a suitable protecting group, PGE. An example of such a PGE group is a Boc-group. For the purpose of the Scheme E, this protecting group can be removed at any relevant stage; and therefore, PGE present hydrogen for any of compounds of general Formulae (E-4), (E-5), (E- 6), (E-7), (E-8) and (E-9). The lactam of general Formula (E-2) can be reacted with an aldehyde of general Formula (E-3) (S or R-garner’s aldehyde). The alcohol of general Formula (E-4) can be eliminated to provide an alkene compound of general Formula (E-5) (for example, by sequential conversion of the hydroxy to a corresponding mesylate, followed by elimination under basic conditions). The double bond can be reduced (for example, by hydrogenation, under influence of a homogeneous or a heterogenous catalyst, optionally diastereoselective) to provide a compound of general Formula (E-6). Removal of the acetonide in a compound of general Formula (E-6) to the Boc-protected amino alcohol of general Formula (E-7) can be followed by the oxidation to the carboxylic acid of general Formula (E-8). Alternatively, the acetonide can be deprotected in a compound of general Formula (E-5) to obtain a compound of general Formula (E-9). Reduction of the double bond of a compound of general Formula (E-9) (for example, by hydrogenation under influence of a homogeneous or a heterogenous catalyst, optionally diastereoselective) can be used to obtain a compound of general Formula
(E-7). A compound of general Formula (E-4) can be deoxygenated, for example, by a Barton- type deoxygenation, to provide a compound of general Formula (E-6). Scheme F 3
[0118] Compounds of Formula (I) can include a prodrug moiety. A method for including a prodrug moiety is depicted in Scheme F. For example, an aldehyde of general Formula (F-1) can be transformed into the corresponding bisulfite adduct of general Formula (F-2), by treatment with NaHSO3. A hydroxyketone of general Formula (F-3), can be transformed to the corresponding phosphate of general Formula (F-5), for example, by treatment with di-tert-butyl N,N-dipropan-2-ylphosphoramidite and tetrazole followed by oxidation with H2O2, that can provide a compound of general Formula (F-4). A compound of general Formula (F-4) can be deprotected (for example by treatment with TFA) to provide a compound of general Formula (F-5).
Scheme J
[0119] An intermediate, a compound of Formula (J1) (Moody et al., J. Chem. Soc., Perkin Trans.1 (1997) 23:3519-3530), can be used to prepare amino acids of general Formulae (J2) and (J3) using similar procedures as described for Scheme H. Pharmaceutical Compositions [0120] Some embodiments described herein relate to a pharmaceutical composition that can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof. A pharmaceutical composition described herein is suitable for human and/or veterinary applications. [0121] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject. [0122] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood. [0123] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.
[0124] Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection, inhalation and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. Pharmaceutical compositions will generally be tailored to the specific intended route of administration. [0125] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes may be targeted to and taken up selectively by the organ. [0126] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. As described herein, compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions. Methods of Use [0127] Some embodiments described herein relate to a method of treating a coronavirus infection that can include administering to a subject identified as suffering from the coronavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a coronavirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a coronavirus infection.
[0128] Some embodiments disclosed herein relate to a method of treating a coronavirus infection that can include contacting a cell infected with the coronavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a coronavirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a coronavirus infection. [0129] Some embodiments disclosed herein relate to a method of inhibiting replication of a coronavirus that can include contacting a cell infected with the coronavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for inhibiting replication of a coronavirus. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, for inhibiting replication of a coronavirus. [0130] In some embodiments, the coronavirus can be an α-coronavirus or a β- coronavirus. A compound described herein may be effective against one or more variants of a coronavirus. Examples of variants include, but are not limited, to alpha-variant (B.1.1.7), beta-variant (B.1.351), gamma variant (P.1) and delta-variant (B.1.617.2). In some embodiments, the coronavirus can be selected from CoV 229E, CoV NL63, CoV OC43, CoV HKU1, Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV, and SARS-CoV-2. [0131] Some embodiments described herein relate to a method of treating a picornavirus infection that can include administering to a subject identified as suffering from
the picornavirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a picornavirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a picornavirus infection. [0132] Some embodiments disclosed herein relate to a method of treating a picornavirus infection that can include contacting a cell infected with the picornavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a picornavirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a picornavirus infection. [0133] Some embodiments disclosed herein relate to a method of inhibiting replication of a picornavirus that can include contacting a cell infected with the picornavirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for inhibiting replication of a picornavirus. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, for inhibiting replication of a picornavirus.
[0134] In some embodiments, the picornavirus can be a rhinovirus, including rhinovirus A, B and/or C. In some embodiments, a compound described herein, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be used to treat one or serotypes of a rhinovirus. [0135] Some embodiments described herein relate to a method of treating a norovirus infection that can include administering to a subject identified as suffering from the norovirus infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a norovirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a norovirus infection. [0136] Some embodiments disclosed herein relate to a method of treating a norovirus infection that can include contacting a cell infected with the norovirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a norovirus infection. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a norovirus infection. [0137] Some embodiments disclosed herein relate to a method of inhibiting replication of a norovirus that can include contacting a cell infected with the norovirus with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described
herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for inhibiting replication of a norovirus. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, for inhibiting replication of a norovirus. [0138] Some embodiments disclosed herein relate to a method of treating a respiratory condition that is developed because of a coronavirus and/or a picornavirus infection that can include administering to a subject suffering from the respiratory condition and/or contacting a cell infected with the coronavirus and/or the picornavirus in a subject suffering from the respiratory condition with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein. Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating a respiratory condition due to a coronavirus infection and/or a picornavirus infection with an effective amount of the compound, or a pharmaceutically acceptable salt thereof. Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating a respiratory condition due to a coronavirus infection and/or a picornavirus infection. [0139] A subject infected with a coronavirus can be asymptotic. A coronavirus infection can manifest itself via one or more symptoms. Examples of symptoms include, but are not limited to, coughing, sore throat, runny nose, sneezing, headache, fever, shortness of breath, myalgia, abdominal pain, fatigue, difficulty breathing, persistent chest pain or pressure, difficulty waking, loss of smell and taste, muscle or joint pain, chills, nausea or vomiting, nasal congestion, diarrhea, haemoptysis, conjunctival congestion, sputum production, chest tightness and/or palpitations. A coronavirus infection can cause complications. A non-limiting list of complications include, but are not limited to, sinusitis, otitis media, pneumonia, acute respiratory distress syndrome, disseminated intravascular coagulation, pericarditis and/or
kidney failure. [0140] As with a coronavirus, a subject infected with a picornavirus can be asymptotic. Alternatively, a subject can exhibit one or more of symptoms. Examples of symptoms of a picornavirus infection include, but are not limited to, aseptic meningitis, rash, conjunctivitis, runny nose a headache a cough a fever a sore throat, chest and/or abdominal pain and paralysis. As provided herein, subjects infected with a norovirus can exhibit one or more the symptoms including, but not limited to, nausea, non-bloody diarrhea, vomiting and abdominal pain. An example of a complication that can be attributed to a norovirus infection is dehydration, including severe dehydration. [0141] Various indicators for determining the effectiveness of a method for treating a coronavirus, picornavirus and/or norovirus infection are also known to those skilled in the art. Examples of suitable indicators include, but are not limited to, a reduction in viral load indicated by reduction in coronavirus (or load) (e.g., reduction <105 copies/mL in serum), a reduction in plasma viral load, a reduction in viral replication, a reduction in time to seroconversion (virus undetectable in patient serum), an increase in the rate of sustained viral response to therapy a reduction of morbidity or mortality in clinical outcomes, reduction in the need for a ventilator and/or total time on a ventilator, reduction in hospitalization rates and/or reduction in time in an ICU (intensive care unit) and/or hospital. [0142] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance. [0143] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human, for example, a human subject that is 60 years old or older. [0144] The term “effective amount” is used to indicate an amount of an active
compound, or pharmaceutical agent that elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. [0145] In some embodiments, the subject can be asymptomatic, for example, the subject can be infected with coronavirus but does not exhibit any symptoms of the viral infection. In some embodiments, the subject can be have a pre-existing condition, such as asthma, hypertension, immunocompromised subjects (such as subjects with cancer, HIV and/or genetic immune deficiencies, bone marrow transplant subjects, solid organ transplant subjects, subjects who have had stem cells for cancer treatment and/or subjects who use oral or intravenous corticosteroids or other medicines called immunosuppressants), liver disease, subjects at risk for severe illness, chronic kidney disease being treated with dialysis, chronic lung disease, diabetes, hemoglobin disorders, serious heart conditions (for example, heart failure, coronary artery disease, congenital heart disease, cardiomyopathies, and pulmonary hypertension), severe obesity (such as subjects with a body mass index (BMI) of 40 or above) and people who live in a nursing home or long-term care facility . Additional examples and/or further information is provided by the CDC (https://www.cdc.gov/coronavirus/2019- ncov/need-extra-precautions/groups-at-higher-risk.html). [0146] A compound described herein, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered after a subject is infected with a coronavirus. In addition and/or alternatively, a compound described herein, including a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be administered prophylactically. [0147] Examples of agents that have been used to treat a coronavirus infection
include Remdesivir. However, there can be drawbacks associated with compounds being used to treat a coronavirus including, but not limited to, one or more adverse side effects, the need for subcutaneous administration and/or high cost. Potential advantages of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be less adverse side effects, delay in the onset of an adverse side effect and/or reduction in the severity of an adverse side effect. [0148] A coronavirus infection can be treated by inhibiting certain mechanisms. In some embodiments, a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can be selective for a coronavirus protease. For example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be selective for a coronavirus protease compared to a host protease, for example, one or more host proteases selected from Cathepsin L, Cathepsin B, Cathepsin D, Cathepsin K, Leukocyte Elastase, Chymotrypsin, Trypsin, Thrombin, Pepsin, Caspase 2, Elastase and Calpain. In some embodiments, the selectivity for a coronavirus protease over a host protease (such as those described herein) can be > 2-fold. In some embodiments, the selectivity for a coronavirus protease over a host protease (such as those described herein) can be > 10-fold. In some embodiments, the selectivity for a coronavirus protease over a host protease (such as those described herein) can be > 100-fold. [0149] Studies have shown that the entry of SARS-CoV-2 into the target cells is a process that can be mediated by multiple proteases including cysteine cathepsins L and/or transmembrane protease serine 2 (TMPRSS2) (Shang et al., PNAS (2020) 117:11727, and Hoffmann et al., Cell (2020) 181:271-280). The cathepsin L inhibitor K117777, which lacks an inhibitory effect on the 3CLpro, can result in potent inhibition of SARS-CoV-2 in VeroE6, A549-ACE2 and/or HeLa-ACE2 (Mellott et al., bioRxiv (2020) 2020.2010.2023.347534). It has also been shown that the potent antiviral effect of K117777 is abolished when TMPRSS2 was expressed in A549-ACE2 (Steuten et al., bioRxiv (2020) 2020.2011.2021.392753). Off target activity of 3CLpro inhibitors, for example, on cathepsin L, may lead to an inaccurate assessment of the 3CLpro component of a compound’s cellular potency. As an example, a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) can have greater selectivity for a coronavirus protease over a host protease, such as cathepsin L. The selectivity can be determined by those skilled in the art, for
example, using IC50 and/or Ki values. In some embodiments, a compound described herein does not significantly inhibit cathepsin L (for example, IC50 ≥10000 nM or >3.3 μ M), but inhibits a coronavirus protease (for example, SARS-Cov-23Clpro). [0150] A drawback with anti-viral treatment can be the development of resistance, including cross-resistance. Resistance can be a cause for treatment failure. The term “resistance” as used herein refers to a viral strain displaying a delayed, lessened and/or null response to an anti-viral agent. In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be provided to a subject infected with a coronavirus strain that is resistant to one or more other anti-viral agents. In some embodiments, development of coronavirus resistant strains is delayed when a subject is treated with a compound, or a pharmaceutically acceptable salt thereof, as described herein compared to the development of a coronavirus resistant strain when treated with one or more other anti-viral agents. Combination Therapies [0151] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be used in combination with one or more additional agent(s) for treating and/or inhibiting replication a coronavirus. Additional agents include, but are not limited to, an ACE inhibitor, an anticoagulant, an anti-inflammatory, an ARB, an ASO, a Covid-19 convalescent plasma, an entry inhibitor, an H2 pump antagonist, an H-conducting channel, an HIV protease inhibitor, an HMG-CoA reductase inhibitor, an immune globulin, an immunosuppressant, an immunotherapeutic agent, a monoclonal antibody, a neuraminidase inhibitor, a nucleoside inhibitor, a nucleoside analog inhibitor, a polymerase inhibitor, a protease inhibitor, an siRNA, a statin, a tissue plasminogen activator, an antibiotic, an antimicrobial and a vaccine. Examples of additional agents include Ascorbic acid, Anakin, Azithromycin, Baloxavir, Baricitinib, Chloroquine Phosphate, Colchicine, a corticosteroid, Epoprostenol, Famotidine, Favipiravir, an IGIV, an interferon (for example, recombinant interferon alpha 2b, IFN-D and/or PEG-IFN-α-2a),anIVIG,Ivermectin,γ-globulin, lopinavir, Methylprednisolone, Molnupiravir (MK-4482 or EIDD-2801), Niclosamide, Nitazoxanide, Nitric oxide, Oseltamivir, Peramivir, RANTES, ribavirin, Remdesivir, Ruxolitinib, Sarilumab, Siltuximab, Sirolimus, a statin, Tacrolimus, Tocilizumab, Umifenovir, Zanamivir,
Casirivimab, imdevimab, bamlanivimab, etesevimab and AT-527 (Good et al., Antimicrobial Agents and Chemotherapy (2021) 65(4):e02479-20) [0152] In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, as described herein can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound, or a pharmaceutically acceptable salt thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. Further, the order of administration of a compound, or a pharmaceutically acceptable salt thereof, as described herein with one or more additional agent(s) can vary. EXAMPLES [0153] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims. COMPOUNDS [0154] Compounds of Formula (I), along with pharmaceutically acceptable salts thereof, can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.
Synthesis of Intermediates
[0155] To a solution of 1,2-di-tert-butyl (2S,4R)-4-hydroxypyrrolidine-1,2- dicarboxylate (15 g, 52.2 mmol, 1.0 eq.) in DCM (250 mL) was added triethylamine (9.51 g, 93.9 mmol, 1.8 eq.) and DMAP (1.91 g, 15.7 mmol, 0.3 eq.). MsCl (8.97 g, 78.3 mmol, 1.5 eq.) was added dropwise at 0 °C. The mixture was stirred at room temperature (rt) for 2 h, and the reaction was quenched with water (100 mL). The solution was extracted with DCM (3 x 150 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:10) to provide 1,2-di-tert-butyl (2S,4R)-4-(methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (17.8 g, 89%) as a colorless oil. LC-MS (ESI, m/z): 366 [M+H]+. [0156] To a solution of 1,2-di-tert-butyl (2S,4R)-4- (methanesulfonyloxy)pyrrolidine-1,2-dicarboxylate (17.8 g, 48.7 mmol, 1.0 eq.) in MeOH (400 mL) was added (phenyldiselanyl)benzene (9.12 g, 29.2 mmol, 0.6 eq.). Sodium borohydride (2.4 g, 63.3 mmol, 1.3 eq.) was added at 0 °C in several portions. The mixture was refluxed overnight and then concentrated under reduced pressure. Water (100 mL) was added, and the mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:5) to provide 1,2-di-tert-butyl (2S,4S)-4-(phenylselanyl)pyrrolidine-1,2- dicarboxylate (7.5 g, 32%) as a colorless oil. LC-MS (ESI, m/z): 428 [M+H]+.
[0157] To a solution of 1,2-di-tert-butyl (2S,4S)-4-(phenylselanyl)pyrrolidine-1,2- dicarboxylate (7.5 g, 17.6 mmol, 1.0 eq.) in DCM (100 mL) was added pyridine (2.4 mL, 30.5 mmol, 1.7 eq.) and 30% aqueous H2O2 (5.6 mL, 71.6 mmol, 4.0 eq.). The mixture was stirred at rt for 12 h, and the reaction was quenched with water (20 mL). The solution was extracted with DCM (3 x 150 mL). The organic layers were combined, washed with 1 M citric acid (80 mL), sat. aq. Na2SO3 (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:9) to provide 1,2-di-tert-butyl (2S)-2,5-dihydropyrrole-1,2- dicarboxylate (2.8 g, 53%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6^^į^6.02-6.09 (m, 1H), 5.76-5.83 (m, 1H), 4.72-4.78 (m, 1H), 4.05-4.09 (m, 2H), 1.17-1.42 (m, 18H). LC-MS (ESI, m/z): 270 [M+H]+. [0158] A solution of 1,2-di-tert-butyl (2S)-2,5-dihydropyrrole-1,2-dicarboxylate (2.8 g, 10.4 mmol, 1.0 eq.) in dicyclopentadiene (60 mL) was stirred at 170 °C for 48 h under nitrogen and then resolved with DCM (200 mL). After removal of the solvent, the residue was chromatographed on a silica gel column with EA:PE (1:9) to provide the product (2.5 g, crude) as a yellow oil. The crude oil was chromatographed on a C18 column with H2O:MeCN (2:1) to provide di-tert-butyl (1S,3aR,4S,7R,7aS)-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindole-1,2-dicarboxylate (690 mg, 19%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 6.14-6.21 (m, 2H), 3.55-3.60 (m, 1H), 3.23-3.27 (m, 1H), 2.95-3.02 (m, 2H), 2.74-2.87 (m, 3H), 1.24-1.48 (m, 20H). LC-MS (ESI, m/z): 270 [M+H]+. [0159] To a solution of i-tert-butyl (1S,3aR,4S,7R,7aS)-1,3,3a,4,7,7a-hexahydro- 2H-4,7-methanoisoindole-1,2-dicarboxylate (690 mg, 2.1 mmol, 1.0 eq.) in dioxane (10 mL) was added hydrochloric acid (10 mL, 9M). The mixture was stirred at rt overnight and then concentrated under reduced pressure to provide (1S,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro- 1H-4,7-methanoisoindole-1-carboxylic acid (320 mg, crude) as a black solid. LC-MS (ESI, m/z): 180 [M+H]+. [0160] To a solution of (1S,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-1H-4,7- methanoisoindole-1-carboxylic acid (320 mg, 1.79 mmol, 1.0 eq.) in DCM (8 mL) was added di-tert-butyl dicarbonate (429 mg, 1.97 mmol, 1.1 eq.) and triethylamine (542 mg, 5.34 mmol, 3.0 eq.). The mixture was stirred at rt for 3 h and then concentrated under reduced pressure to provide (1S,3aR,4S,7R,7aS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-
methanoisoindole-1-carboxylic acid (430 mg, crude) as a brown solid. LC-MS (ESI, m/z): 280 [M+H]+.
[0161] A mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-[(3S)-2- oxopyrrolidin-3-yl]propanoate (10.0 g, 34.9 mmol, 1.00 eq.) in ammonia (150 mL, 7 M in MeOH) was stirred overnight at 80 °C and concentrated under reduced pressure to afford tert- butyl N-[(1S)-1-carbamoyl-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]carbamate (10.0 g, crude) as a light brown solid. 1H NMR (400 MHz, DMSO-d6^^į 7.65 (s, 1H), 7.29 (s, 1H), 7.01 (s, 1H), 6.88-6.95 (m, 1H), 3.84-4.15 (m, 1H), 3.09-3.21 (m, 2H), 2.08-2.26 (m, 2H), 1.84-1.96 (m, 1H), 1.60-1.74 (m, 1H), 1.44-1.54 (m, 1H), 1.38 (s, 9H). LC-MS (ESI, m/z): 272 [M+H]+. O
[0162] A solution of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate (710 mg, 2.62 mmol, 1.0 eq.) in hydrochloric acid in ether (12 mL, 2 mol/L) was stirred at rt for 2 h and concentrated under reduced pressure to provide (S)-2- amino-3-((S)-2-oxopyrrolidin-3-yl)propenamide (500 mg, crude) as a white solid. LC-MS (ESI, m/z): 172 [M+H]+.
[0163] To a solution of (1S,3aR,4S,7R,7aS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a- hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (979 mg, 3.5 mmol, 1.2 eq.) in DMF (2 mL) was added N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (1.44 g, 3.8 mmol, 1.3 eq.) and N,N-diisopropylethylamine (2.64 g, 20.4 mmol, 7.0 eq.). The mixture was stirred at 0 °C for 30 min and then (S)-2-amino-3-((S)-2- oxopyrrolidin-3-yl)propanamide (500 mg, 2.92 mmol, 1.0 eq.) was added. The mixture was stirred at rt for 2 h, and the reaction was quenched with water (5 mL). The mixture was extracted with EA (3 x 10 mL). The organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a C18 column with water:MeCN (2:1) to provide tert- butyl (1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-2-carboxylate (1.05 g, 75%) as a brown yellow solid. LC-MS (ESI, m/z): 433 [M+H]+. [0164] A solution of tert-butyl (1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)- 2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindole-2-carboxylate (300 mg, 0.69 mmol, 1.0 eq.) in hydrochloric acid in ether (5 mL, 2 mol/L) was stirred at rt for 2 h and then concentrated under reduced pressure to provide (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)- 2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (200 mg, crude) as a white solid. LC-MS (ESI, m/z): 333 [M+H]+.
[0165] To a stirred mixture of tert-butyl (2S)-2-amino-3,3-dimethylbutanoate hydrochloride (6.00 g, 26.8 mmol, 1.0 eq.) and ethyl 2,2,2-trifluoroacetate (7.62 g, 53.6 mmol, 2.0 eq.) in MeOH (100 mL) was added triethylamine (5.43 g, 53.7 mmol, 2.0 eq.) at 0 °C. The mixture was stirred for 5 h at 30 °C and then concentrated under reduced pressure to afford the crude product. The crude product was diluted with DCM (150 mL) and made into a slurry with 100 ~ 200 silica gel mesh (15 g), and the slurry was loaded to a column chromatography after removing the DCM. The sample was purified by column chromatography (Column size
6 x 24 cm, column volume: 600 mL, silica gel size (100 ~ 200 mesh) quantity: 330 g) and eluted with MeOH:DCM (0% ~ 10% over 30 min). The collected fractions: 0% MeOH:DCM fractions were chosen as the pure fractions. and those fractions were combined and concentrated under reduced pressure to provide tert-butyl (2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoate (7.20 g, 90%) as a white solid. 1H NMR (300 MHz, CDCl3^^į^ 6.78-6.90 (m, 1H), 4.32-4.38 (m, 1H), 1.50 (s, 9H), 1.01 (s, 9H). LC-MS (ESI, m/z): 282 [M- H]-. [0166] To a mixture of tert-butyl (2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoate (1.03 g, 3.64 mmol, 1.0 eq.) in DCM (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred for 1 h at rt and then concentrated under reduced pressure to (2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoic acid (826 mg, crude) as a yellow oil. LC-MS (ESI, m/z): 226 [M-H]-.
[0167] To a solution of 1,2-di-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate 1,2-di-tert-butyl (2S)-5-oxopyrrolidine-1,2-dicarboxylate (50 g, 175 mmol, 1.0 eq.) in toluene
(500 mL) was added [tert-butoxy(dimethylamino)methyl]dimethylamine (36.7 g, 210 mmol, 1.2 eq.). The mixture was stirred at 115 °C for 3 h under nitrogen and concentrated under reduced pressure to provide di-tert-butyl (S,Z)-4-((dimethylamino)methylene)-5- oxopyrrolidine-1,2-dicarboxylate (46g, crude) as an orange oil. LC-MS (ESI, m/z): 341 [M+H]+. [0168] To a solution of di-tert-butyl (S,Z)-4-((dimethylamino)methylene)-5- oxopyrrolidine-1,2-dicarboxylate (46 g, 135 mmol, 1.0 eq.) in THF (900 mL) was added DIBAl-H (203 mL, 1M in toluene, 203 mmol, 1.5 eq.) dropwise at -78 °C under N2. The mixture was stirred at -78 °C for 2 h, and was then poured into hydrochloric acid (800 mL, 2 mol/L) slowly at 0 °C. The solution was extracted with EA (3 x 600 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:5) to provide di-tert-butyl (S)-4- methylene-5-oxopyrrolidine-1,2-dicarboxylate (16 mg, 36%) as a colorless oil. 1H NMR (300 MHz, DMSO-d6^^į^^^^^-6.00(m, 1H), 5.58-5.59 (m, 1H), 4.50-4.54 (m, 1H), 3.04-3.34 (m, 1H), 2.57-2.64 (m, 1H), 1.36-1.44 (m, 18H). LC-MS (ESI, m/z): 298 [M+H]+. [0169] To a solution of di-tert-butyl (S)-4-methylene-5-oxopyrrolidine-1,2- dicarboxylate (12 g, 40.4 mmol, 1.0 eq.) in THF (200 mL) was added methoxylithium (22 mL, 2.2M in methanol, 48.4 mmol, 1.2 eq.) at -40 °C under N2. The mixture was stirred at -40 °C for 30 min. The reaction quenched with sat. aq. sodium chloride (100 mL). The solution was extracted with EA (3 x 100 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:4) to provide 1-(tert-butyl) 5-methyl (S)-2-((tert-butoxycarbonyl)amino)-4-methylenepentanedioate (12 g, 81%) as a colorless viscous oil. LC-MS (ESI, m/z): 330 [M+H]+. [0170] To a solution of 1-(tert-butyl) 5-methyl (S)-2-((tert- butoxycarbonyl)amino)-4-methylenepentanedioate (7 g, 21 mmol, 1.0 eq.) in MeCN (70 mL) and DMSO (70 mL) was added 2H-pyrazol-3-amine (2.1 g, 25.5 mmol, 1.2 eq.), K2CO3 (2.94 mg, 21 mmol, 1.0 eq.). The mixture was stirred at 60 °C overnight and then concentrated under reduced pressure. The residue was chromatographed on a C18 column with MeCN:H2O (3:2) to provide tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7-
tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoate (1.7 g, 19%) as a brown yellow oil. 1H NMR (300 MHz, DMSO-d6)δ10.76(s,1H),7.18 -7.27 (m, 2H), 5.56-5.57 (m, 1H), 4.26-4.36 (m, 1H), 3.89-4.13 (m, 1H), 2.75-2.79 (m, 1H), 2.10-2.25 (m, 1H), 1.61-1.80 (m, 1H), 1.27- 1.53 (m, 18H). LC-MS (ESI, m/z): 381 [M+H]+. [0171] To a solution of tert-butyl (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo- 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoate (800 mg, 3.55 mmol, 1.0 eq.) in dioxane (8 mL) was added hydrochloric acid (8 mL, 9M). The mixture was stirred at rt for 2 h and then concentrated under reduced pressure to provide (2S)-2-amino-3-(5-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoic acid (400 mg, crude) as an off-white semi- solid. LC-MS (ESI, m/z): 225 [M+H]+. [0172] To a solution of (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-6-yl)propanoic acid (400 mg, 1.78 mmol, 1.0 eq.) in DCM (6 mL) was added di- tert-butyl dicarbonate (430 mg, 1.96 mmol, 1.1 eq.) and triethylamine (180 mg, 5.36 mmol, 3.0 eq.). The mixture was stirred at rt for 3 h and then concentrated under reduced pressure to provide (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-6-yl)propanoic acid (530 mg, crude) as a brown yellow semi-solid. LC-MS (ESI, m/z): 325 [M+H]+. [0173] To a solution of (2S)-2-((tert-butoxycarbonyl)amino)-3-(5-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propanoic acid (530 mg, 1.63 mmol, 1.0 eq.) in DMF (8 mL) was added N,N,N,N-tetramethylchloroformamidinium hexafluorophosphate (550 mg, 1.96 mmol, 1.2 eq.), NMI (671 mg, 8.17 mmol, 5.0 eq.) and NH3 in dioxane (40 mL, 10.0 eq., 0.4 mol/L). The mixture was stirred at rt for 2 h and then chromatographed on a C18 column with MeCN:H2O (1:4) to provide tert-butyl ((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (280 mg, 48%) as a brown yellow oil. LC-MS (ESI, m/z): 324 [M+H]+. [0174] To a solution of tert-butyl ((2S)-1-amino-1-oxo-3-(5-oxo-4,5,6,7- tetrahydropyrazolo[1,5-a]pyrimidin-6-yl)propan-2-yl)carbamate (280 mg, 0.87 mmol, 1.0 eq.) in hydrochloric acid (4 mL, 2 mol/L in dioxane) was stirred at rt for 2 h and then concentrated under reduced pressure to provide (2S)-2-amino-3-(5-oxo-4,5,6,7-tetrahydropyrazolo[1,5- a]pyrimidin-6-yl)propanamide (180 mg, crude) as an off-white semi-solid. LC-MS (ESI, m/z): 224 [M+H]+.
(S)-3-((R*)-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)-2-((tert- butoxycarbonyl)amino)propanoic acid
The chiral center noted with “*” is tentatively assigned. [0175] A 100 mL round-bottom flask was charged with 5,5-dimethylpyrrolidin-2- one (3.5 g, 30.9 mmol, 1.0 eq.), DCM (50 mL), di-tert-butyl dicarbonate (10.8 g, 49.5 mmol, 1.6 eq.), triethylamine (6.24 g, 61.8 mmol, 2.0 eq.) and DMAP (0.38 g, 3.09 mmol, 0.1 eq.). The solution was stirred overnight at 40 °C, and the reaction was quenched with water (150 mL). The solution was extracted with EA (5 x 300 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (13:87) to provide tert-butyl 2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (4.0 g, 58%) as a white solid. LC-MS (ESI, m/z): 214 [M+H]+.
[0176] A 100 mL round-bottom flask was charged with tert-butyl 2,2-dimethyl-5- oxopyrrolidine-1-carboxylate (3.6 g, 16.9 mmol, 1.00 eq.) and THF (50 mL). The solution was cooled to -78 °C and LiHMDS (20.2 mL, 1M in THF, 20.2 mmol, 1.2 eq.) was added. The mixture was stirred for 1 h at -78 °C, and a solution of tert-butyl (4R)-4-formyl-2,2- dimethyl-1,3-oxazolidine-3-carboxylate (5.81 g, 25.3 mmol, 1.5 eq.) in THF (10 mL) was added under Ar. Stirring was continued at -78 °C for 1 h. The reaction was quenched with a sat. ammonium chloride solution (50 mL). The solution was extracted with dichloromethane (3 x 150 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:4) to provide tert-butyl (4R)-4-{[1- (tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](hydroxy)methyl}-2,2-dimethyl- 1,3-oxazolidine-3-carboxylate (7.2 g, 89%) as a colorless oil. LC-MS (ESI, m/z): 443 [M+H]+. [0177] A 100 mL round-bottom flask was charged with tert-butyl (4R)-4-{[1-(tert- butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](hydroxy)methyl}-2,2-dimethyl-1,3- oxazolidine-3-carboxylate (1 g, 2.26 mmol, 1.00 eq.), DCM (10 mL), triethylamine (1.14 g, 11.3 mmol, 5.0 eq.) and MsCl (0.31 g, 4.52 mmol, 2.0 eq.). The mixture was stirred overnight at rt, and the reaction was quenched with water (30 mL). The solution was extracted with dichloromethane (4 x 50 mL). The organic layers were combined, washed with brine (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl (4R)-4-{[1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3- yl](methanesulfonyloxy)methyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (960 mg, crude) as a yellow oil. LC-MS (ESI, m/z): 521 [M+H]+. [0178] A 100 mL round-bottom flask was charged with tert-butyl (4R)-4-{[1-(tert- butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl](methanesulfonyloxy)methyl}-2,2- dimethyl-1,3-oxazolidine-3-carboxylate (900 mg, 1.73 mmol, 1.0 eq.), DCM (20 mL) and DBU (1.32 g, 8.64 mmol, 5.0 eq.). The mixture was stirred overnight at rt, and the reaction was quenched with water (30 mL). The solution was extracted with dichloromethane (3 x 80 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:4) to provide tert-butyl (4S)-4-{[1- (tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-ylidene]methyl}-2,2-dimethyl-1,3-
oxazolidine-3-carboxylate (635 mg, 82%) as a colorless oil. LC-MS (ESI, m/z): 425 [M+H]+. [0179] A 250 mL round-bottom flask was charged with tert-butyl (4S)-4-{[1-(tert- butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-ylidene]methyl}-2,2-dimethyl-1,3- oxazolidine-3-carboxylate (4.4 g, 10.4 mmol, 1.0 eq.), EA (50 mL) and 10% palladium on activated carbon (5.51 g). The contents of the flask were placed under an atmosphere of hydrogen (3 atm). The mixture was stirred overnight at rt. The solids were filtered off. The organic layer was concentrated under reduced pressure to provide tert-butyl (4S)-4-{[1-(tert- butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl]methyl}-2,2-dimethyl-1,3-oxazolidine-3- carboxylate (4.3 g, 78%) as a colorless oil. LC-MS (ESI, m/z): 427 [M+H]+. [0180] Tert-butyl (4S)-4-((1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin- 3-yl)methyl)-2,2-dimethyloxazolidine-3-carboxylate (3.6g) was purified by prep-SFC using the following gradient conditions: Column: Lux 5um Cellulose-2, 3*25 cm,5 μm; Mobile Phase A: CO2, Mobile Phase B: IPA(0.5% 2M NH3-MeOH); Flow rate: 60 mL/min; Gradient: isocratic 10% B; Column Temperature(°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 (min): 4.81; RT2(min): 6.43; Sample Solvent: MeOH--Preparative; Injection Volume: 1.5 mL; Number Of Runs: 27. Purification resulted in tert-butyl (S)-4-(((S*)-1-(tert- butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyloxazolidine-3- carboxylate (990 mg) as an off-white solid (Lux Celloluse-2 4.6*50 mm, 3μm,35°C. Co- Solvent : IPA (0.1%DEA), 10% to 50% in 2.0 min, hold 1.0 min at 50%): Rt: 0.969 min), and tert-butyl (S)-4-(((R*)-1-(tert-butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)- 2,2-dimethyloxazolidine-3-carboxylate (1.6 g) as an off-white solid Lux Celloluse-2 4.6*50 mm,3μm,35°C.Co-Solvent : IPA (0.1%DEA), 10% to 50% in 2.0 min, hold 1.0 min at 50%): Rt: 1.411 min). [0181] A 40 mL vial was charged with tert-butyl (S)-4-(((R*)-1-(tert- butoxycarbonyl)-5,5-dimethyl-2-oxopyrrolidin-3-yl)methyl)-2,2-dimethyloxazolidine-3- carboxylate (1.6 g, 3.75 mmol, 1.0 eq.), para-toluene sulfonate (64.6 mg, 0.375 mmol, 0.1 eq.) and MeOH (20 mL). The mixture was stirred overnight at rt. The reaction was quenched with water (20 mL). The solution was extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl(S)-4-((S)-2-((tert- butoxycarbonyl)amino)-3-hydroxypropyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate
(1.47 g, crude) as an off-white semi-solid. LC-MS (ESI, m/z): 387 [M+H]+. [0182] To a solution of tert-butyl (S)-4-((R*)-2-((tert-butoxycarbonyl)amino)-3- hydroxypropyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (1.7 g, 4.40 mmol, 1.0 eq.) in acetone (22 mL) was added 5% sodium bicarbonate solution (22 mL, 13.1 mmol, 3.0 eq.) and 2,2,6,6-Tetramethylpiperidinooxy (0.14 g, 0.88 mmol, 0.2 eq.). Chlorosylsodium (1.15 g, 15.4 mmol, 3.5 eq.) was added dropwise at 0 °C. The mixture was stirred at rt overnight, and the reaction was quenched with water (20 mL). The solution was washed with Et2O (2 x 20 mL). The pH value of the aqueous solution was adjusted to 2 with concentrated hydrochloric acid (1 mol/L). The solution was extracted with EtOAc (3 x 50 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide (S)-3-((R*)-1-(tert-butoxycarbonyl)-5,5- dimethyl-2-oxopyrrolidin-3-yl)-2-((tert-butoxycarbonyl)amino)propanoic acid (1.2 g, 61%) as a white solid. tert-butyl ((S)-1-hydroxy-3-((S*)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate
The absolute configuration of the chiral center noted with “*” is tentatively assigned. [0183] To a solution of methyl 3-cyanopropanoate (10 g, 88.4 mmol, 1.0 eq.) in Et2O (100 mL) was added Ti(OiPr)4 (5.03 g, 17.7 mmol, 0.2 eq.). EtMgBr (194 mL, 1M in THF, 194 mmol, 2.2 eq.) was then added dropwise under N2. The mixture was stirred at rt for 2h, and the reaction was quenched with water (20 mL). The mixture was extracted with EA (3 x 60 mL). The organic layers were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with PE:MeOH (12:1) to provide 4- azaspiro[2.4]heptan-5-one (8.5 g, 69%) as a colorless oil. LC-MS (ESI, m/z): 112 [M+H]+. [0184] A 250 mL round-bottom flask was charged with 4-azaspiro[2.4]heptan-5- one (8.5 g, 76.5 mmol, 1.0 eq.) , DCM (100 mL), di-tert-butyl dicarbonate (26.7 g, 122 mmol, 1.6 eq.) , triethylamine (0.77 g, 7.65 mmol, 0.1 eq.) and DMAP (0.93 g, 7.65 mmol, 0.1 eq.). The solution was stirred overnight at 40 °C, and the reaction was quenched with water (70 mL). The solution was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:12) to provide tert-butyl 5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (11 g, 58%) as a white solid. LC-MS (ESI, m/z): 212 [M+H]+. [0185] A 500 mL round-bottom flask was charged with tert-butyl 5-oxo-4- azaspiro[2.4]heptane-4-carboxylate (11 g, 52.1 mmol, 1.0 eq.) and THF (150 mL). The solution was cooled to -78 °C and LiHMDS (62.5 mL, 1M in THF, 62.5 mmol, 1.2 eq.) was added. The mixture was stirred for 1 h at -78 °C and a solution of tert-butyl (4R)-4-formyl- 2,2-dimethyl-1,3-oxazolidine-3-carboxylate (17.9 g, 78.1 mmol, 1.5 eq.) in THF (50 mL) under Ar was added. Stirring was continued at -78 °C for 1h. The reaction was quenched with sat. ammonium chloride solution (100 mL). The solution was extracted with EA (3 x 200 mL). The organic layers were combined, washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:8) to provide tert-butyl (4R)-4-((4-(tert-butoxycarbonyl)- 5-oxo-4-azaspiro[2.4]heptan-6-yl)(hydroxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (19.7 g, 69%) as a colorless oil. LC-MS (ESI, m/z): 441 [M+H]+. [0186] A 500 mL round-bottom flask was charged with tert-butyl (4R)-4-((4-(tert-
butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan-6-yl)(hydroxy)methyl)-2,2- dimethyloxazolidine-3-carboxylate (19.7 g, 44.7 mmol, 1.0 eq.), DCM (250 mL), triethylamine (27.2 g, 268 mmol, 6.0 eq.) and MsCl (20.5 g, 179 mmol, 4.0 eq.). The mixture was stirred overnight at rt, and the reaction was quenched with water (100 mL). The solution was extracted with DCM (4 x 150 mL). The organic layers were combined, washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide tert-butyl (4R)-4-((4-(tert-butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan- 6-yl)((methylsulfonyl)oxy)methyl)-2,2-dimethyloxazolidine-3-carboxylate (22 g, crude) as an orange oil. LC-MS (ESI, m/z): 519 [M+H]+. [0187] A 500 mL round-bottom flask was charged with tert-butyl (4R)-4-((4-(tert- butoxycarbonyl)-5-oxo-4-azaspiro[2.4]heptan-6-yl)((methylsulfonyl)oxy)methyl)-2,2- dimethyloxazolidine-3-carboxylate (22 g, 42.4 mmol, 1.0 eq.), DCM (200 mL) and DBU (14.2 g, 93.3 mmol, 2.2 eq.). The mixture was stirred overnight at rt, and the reaction was quenched with water (80 mL). The solution was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:12) to provide tert-butyl 6-{[(4S)-3-(tert-butoxycarbonyl)-2,2-dimethyl-1,3- oxazolidin-4-yl]methylidene}-5-oxo-4-azaspiro[2.4]heptane-4-carboxylate (11.3 g,57%) as a colorless oil. LC-MS (ESI, m/z): 423 [M+H]+. [0188] A 250 mL vial was charged with tert-butyl 6-{[(4S)-3-(tert- butoxycarbonyl)-2,2-dimethyl-1,3-oxazolidin-4-yl]methylidene}-5-oxo-4- azaspiro[2.4]heptane-4-carboxylate (11.3 g, 26.7 mmol, 1.0 eq.), 4-methylbenzenesulfonic acid (5.53 g, 32.1 mmol, 1.2 eq.) and MeOH (120 mL). The mixture was stirred overnight at rt, and then concentrated under reduced pressure to provide 6-[(2S)-2-amino-3- hydroxypropylidene]-4-azaspiro[2.4]heptan-5-one (5.8 g, crude) as an orange oil. LC-MS (ESI, m/z): 183 [M+H]+. [0189] To a solution of 6-[(2S)-2-amino-3-hydroxypropylidene]-4- azaspiro[2.4]heptan-5-one (5.8 g, 31.829 mmol, 1.00 eq.) in DCM (90 mL) was added triethylamine (25.8 g, 255 mmol, 8.0 eq.) and di-tert-butyl dicarbonate (20.8 g, 95.5 mmol, 3.0 eq.). The mixture was stirred at rt overnight, and the reaction was quenched with water (30 mL). The mixture was extracted with CDCl3:isopropyl alcohol = 3:1 (3 x 50 mL). The organic
layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with MeOH:DCM (1:25) to provide tert-butyl N-[(2S)-1-hydroxy-3-[(6E)-5-oxo-4-azaspiro[2.4]heptan-6- ylidene]propan-2-yl]carbamate (3.9 g, 39%) as a brown yellow solid. LCMS (ESI, m/z): 283 [M+H]+. [0190] To a solution of tert-butyl N-[(2S)-1-hydroxy-3-[5-oxo-4- azaspiro[2.4]heptan-6-ylidene]propan-2-yl]carbamate (3.9 g, 13.8 mmol, 1.0 eq.) in THF (30 mL) and MeOH (90 mL) was added NiCl2•6H2O (23 g, 96.7 mmol, 7.0 eq.). NaBH4 (11 g, 290 mmol, 21.0 eq.) was added in several portions at 0°C. The mixture was stirred at rt overnight, and the reaction was quenched with water (30 mL). The mixture was extracted with CDCl3:isopropyl alcohol = 3:1 (3 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a C18 column with MeCN:H2O (4:1) to provide tert-butyl N-[(2S)-1- hydroxy-3-{5-oxo-4-azaspiro[2.4]heptan-6-yl}propan-2-yl]carbamate (1.7 g, 39%) as a brown yellow solid. LCMS (ESI, m/z): 285 [M+H]+. [0191] Tert-butyl N-[(2S)-1-hydroxy-3-{5-oxo-4-azaspiro[2.4]heptan-6- yl}propan-2-yl]carbamate (1.7 g) was purified by SFC using the following gradient conditions: Column: NB-Lux 5um i-Cellulose-5, 2.12*25 cm, 5 μm; Mobile Phase A: CO2, Mobile Phase B: MeOH(0.1% 2M NH3-MeOH); Flow rate: 100 mL/min; Gradient: isocratic 25% B; Column Temperature(ć): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RT1 (min): 3.37; RT2(min): 4.02; Sample Solvent: MeOH--Preparative; Injection Volume: 1 mL; Number Of Runs: 40. Purification resulted in 590 mg of first eluding tert-butyl ((S)-1-hydroxy-3-((R*)-5- oxo-4-azaspiro[2.4]heptan-6-yl)propan-2-yl)carbamate as a brown yellow solid and 640 mg of last eluding tert-butyl ((S)-1-hydroxy-3-((S*)-5-oxo-4-azaspiro[2.4]heptan-6-yl)propan-2- yl)carbamate as a brown yellow solid.
(3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide
[0192] To a stirred mixture of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3- [(3S)-2-oxopyrrolidin-3-yl]propanoate (3.0 g, 10.5 mmol, 1.0 eq.) in tetrahydrofuran (50 mL) was added lithium borohydride (26.2 mL, 52.4 mmol, 5.0 eq.) dropwise at 0 °C. The mixture was stirred for 1 h at 0 °C and then concentrated under reduced pressure. The mixture was diluted with water (20 mL), and then extracted with isopropanol:trichloromethane (1:5, 4 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane:methanol (19:1) to afford tert-butyl N-[(2S)-1- hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (2.6 g, crude) as a white solid. The crude product was precipitated by the addition of PE:EA (4:1, 40 mL) to afford tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (2.4 g, 79%) as a white solid. LC-MS (ESI, m/z): 259 [M+H]+. [0193] To a stirred mixture of tert-butyl N-[(2S)-1-hydroxy-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamate (2.4 g, 9.29 mmol, 1.0 eq.) in dimethyl sulfoxide (40 mL) was added 2-iodoxybenzoic acid (7.80 g, 27.8 mmol, 3.0 eq.) in portions at rt. The mixture was stirred for 3 h at rt, and then basified to pH = 8 with sat. sodium bicarbonate (aq.). The mixture was diluted with water (20 mL) and extracted with EA (4 x 200 mL). The organic layers were combined, washed with brine (3 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl N-[(2S)-1-oxo-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamate (1.5 g, 63%) as a yellow solid. LC-MS (ESI, m/z):
257 [M+H]+. [0194] To a stirred mixture of tert-butyl N-[(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3- yl]propan-2-yl]carbamate (900 mg, 3.51 mmol, 1.0 eq.) in dichloromethane (10 mL) were added isocyanocyclopropane (471 mg, 7.02 mmol, 2.0 eq.) and acetic acid (633 mg, 10.5 mmol, 3.0 eq.) dropwise at 0 °C. The mixture was stirred for 5 h at rt and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with dichloromethane:methanol (49:1) to afford (2S)-2-[(tert-butoxycarbonyl)amino]-1- (cyclopropylcarbamoyl)-3-[(3S)-2-oxopyrrolidin-3-yl]propyl acetate (820 mg, 55%) as a yellow solid. LC-MS (ESI, m/z): 384 [M+H]+. [0195] To a stirred mixture of (2S)-2-[(tert-butoxycarbonyl)amino]-1- (cyclopropylcarbamoyl)-3-[(3S)-2-oxopyrrolidin-3-yl]propyl acetate (810 mg, 2.11 mmol, 1.0 eq.) in tetrahydrofuran (8 mL) was added lithium hydroxide (253 mg, 10.5 mmol, 5.0 eq., in water 8 mL) at 0 °C. The mixture was stirred for 1 h at 0 °C. The mixture was acidified to pH = 6 with hydrochloric acid (2M). The mixture was extracted with EA (4 x 60 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl N-[(2S)-1-(cyclopropylcarbamoyl)-1-hydroxy-3-[(3S)-2- oxopyrrolidin-3-yl]propan-2-yl]carbamate (680 mg, 94%) as a yellow solid. LCMS (ESI, m/z): 342 [M+H]+. [0196] To a stirred mixture of tert-butyl N-[(2S)-1-(cyclopropylcarbamoyl)-1- hydroxy-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl]carbamate (400 mg, 1.17 mmol, 1.0 eq.) in dichloromethane (6 mL) was added trifluoroacetic acid (2 mL) dropwise at rt. The mixture was stirred for 1 h at rt and then concentrated under reduced pressure to afford (3S)-3-amino- N-cyclopropyl-2-hydroxy-4-[(3S)-2-oxopyrrolidin-3-yl]butanamide (290 mg, crude) as a brown solid. LC-MS (ESI, m/z): 242 [M+H]+. tert-butyl (1S,3aR,4S,7R,7aS)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1-((S)-2- oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-
methanoisoindole-2-carboxylate
[0197] A solution of tert-butyl ((2S)-4-(cyclopropylamino)-3-hydroxy-4-oxo-1- ((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamate (800 mg, 2.34 mmol, 1.0 eq.) in hydrochloric acid (14 mL, 4 M in dioxane) was stirred at rt for 2 h and then concentrated under reduced pressure to provide (3S)-3-amino-N-cyclopropyl-2-hydroxy-4-((S)-2-oxopyrrolidin-3- yl)butanamide (550 mg, crude) as an off-white solid. LC-MS (ESI, m/z): 242 [M+H]+. [0198] To a solution of (1S,3aR,4S,7R,7aS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a- hexahydro-1H-4,7-methanoisoindole-1-carboxylic acid (700 mg, 2.5 mmol, 1.1 eq.) in DMF (8 mL) were added N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospate (1.13 g, 2.96 mmol, 1.3 eq.) and N,N-diisopropylethylamine (2.06 g, 16 mmol, 7.0 eq.). The mixture was stirred at 0 °C for 30 min and (3S)-3-amino-N-cyclopropyl- 2-hydroxy-4-((S)-2-oxopyrrolidin-3-yl)butanamide (550 mg, 2.28 mmol, 1.0 eq.) was added. The mixture was stirred at rt for 2 h, and the reaction was quenched with water (10 mL). The mixture was extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (3 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with MeOH:DCM (1:12) to provide tert-butyl (1S,3aR,4S,7R,7aS)-1-(((2S)-4-(cyclopropylamino)-3-hydroxy-4- oxo-1-((S)-2-oxopyrrolidin-3-yl)butan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindole-2-carboxylate (900 mg, 70%) as a brown yellow solid. LC-MS (ESI, m/z): 503 [M+H]+.
[0199] To a solution of tert-butyl (2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoate (118 mg, 0.42 mmol, 1.2 eq.) in DMF (2 mL) was added N,N,N',N'-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophospate (171 mg, 0.45 mmol, 1.3 eq.) and N,N-diisopropylethylamine (313 mg, 2.42 mmol, 7.0 eq.). The mixture was stirred at 0 °C for 30 min and then (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1- carboxamide (115 mg, 0.35 mmol, 1.0 eq.) was added. The mixture was stirred at rt for 2 h, and the reaction was quenched with water (3 mL). The mixture was extracted with EA (3 x 5 mL). The organic layers were combined, washed with brine (3 x 5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on a C18 column with water:MeCN (2:1) to provide (1S,3aR,4S,7R,7aS)-N- ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1- carboxamide (150 mg, yield 72%) as a brown yellow solid. LC-MS (ESI, m/z): 542 [M+H]+. [0200] To a solution of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)- 2,3,3a,4,7,7a-hexahydro-1H-4,7-methanoisoindole-1-carboxamide (120 mg, 0.22 mmol, 1.0 eq.) in DCM (3 mL) was added TFAA (88.4 mg, 0.42 mmol, 1.9 eq.) and pyridine (61.3mg,
0.78 mmol, 3.5 eq.). The mixture was stirred at 0 °C for 4 h, and the reaction was quenched with water (4 mL). The mixture was extracted with DCM (3 x 5 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by Prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19*150 mm, 5μm, Mobile Phase A: Water (0.05% TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 30% B to 50% B in 7 min, 50% B; Wave Length: 254 nm; RT1 (min): 5.55;) to provide (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3- yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro- 1H-4,7-methanoisoindole-1-carboxamide (53.2 mg, yield 45%) as a white solid. 1H NMR (400 MHz, DMSO-d6,80°C) δ 8.66--8.95 (m, 2H), 7.28-7.37 (m, 1H), 5.96-6.23 (m, 2H), 4.87-4.93 (m, 1H), 4.41-4.68 (m, 1H), 3.86-4.17 (m, 1H), 3.58-3.71 (m, 1H), 3.20-3.51 (m, 2H), 2.83- 3.06 (m, 4H), 2.59-2.79 (m, 1H), 2.29-2.38 (m, 1H), 2.03-2.28 (m, 2H), 1.61-1.84 (m, 2H), 1.31-1.42 (m, 2H), 0.79-0.90 (m, 9H). LC-MS (ESI, m/z): 524 [M+H]+.
[0201] To a mixture of (2S)-2-{[(1R,2S,3S,6R,7S)-4-[(2S)-2-amino-3,3- dimethylbutanoyl]-4-azatricyclo[5.2.1.0^{2,6}]dec-8-en-3-yl]formamido}-3-[(3S)-2- oxopyrrolidin-3-yl]propanamide hydrochloride (177 mg, 0.367 mmol, 1.0 eq.) in MeOH (5 mL) was added triethylamine (446 mg, 4.40 mmol, 12.0 eq.) and ethyl 2-chloro-2,2- difluoroacetate (582 mg, 3.67 mmol, 10.0 eq.). The mixture was stirred overnight at rt, and
then concentrated under reduced pressure to remove the MeOH. The mixture was diluted with water (20 mL) and the pH was adjusted to 6 with hydrochloric acid (1 M). The mixture was extracted with EtOAc (3 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide (2S)-2-{[(lR,2S,3S,6R,7S)-4-[(2S)-2-(2-chloro-2,2-difluoroacetamido)- 3,3-dimethylbutanoyl]-4-azatricyclo dec-8-en-3-yl]formamido}-3-[(3S)-2-
oxopyrrolidin-3-yl]propanamide (180 mg, 80%) as a light yellow solid. LC-MS (ESI, m/z): 558 [M+H]+.
[0202] TToo aa mixture of (2S)-2-{[(lR,2S,3S,6R,7S)-4-[(2S)-2-(2-chloro-2,2- difluoroacetamido)-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1 ,0 {2,6} ]dec-8-en-3- yl]formamido}-3-[(3S)-2-oxopyrrolidin-3-yl]propanamide (180 mg, 0.323 mmol, 1.0 eq.) in DCM (3 mL) was added pyridine (102 mg, 1.29 mmol, 4.0 eq.) and trifluoroacetic anhydride (122 mg, 0.581 mmol, 1.8 eq.). The mixture was stirred for 1 h at rt. The reaction was quenched with water (20 mL). The mixture was extracted with DCM (3 x20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by prep-HPLC (Column: XBridge Shield RP18 OBD Column, 19 x 250 mm, 10pm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 70% B in 7 min, 70% B; Wave Length: 254 nm; RT: 5.4 min;) to provide (lR,2S,3S,6R,7S)-4-[(2S)-2-(2-chloro-2,2-difluoroacetamido)-3,3-dimethylbutanoyl]-N- [(lS)-l-cyano-2-[(3S)-2-oxopyrrolidin-3-yl]ethyl]-4-azatricyclo
dec-8-ene-3- carboxamide (41.2 mg, 23%) as a white solid. NMR (400 MHz, 80 °C, DMSO-d6) δ 8.65- 8.90 (m, 1H), 8.40-8.64 (m, 1H), 7.30-7.62 (m, 1H), 5.95-6.25 (m, 2H), 4.83-5.01 (m, 1H), 4.40-4.75 (m, 1H), 3.95-4.20 (m, 1H), 3.56-3.75 (m, 1H), 3.32-3.55 (m, 1H), 3.06-3.30 (m, 2H), 3.01-3.05 (m, 1H), 2.80-3.00 (m, 2H), 2.60-2.79 (m, 1H), 2.21-2.40 (m, 1H), 2.00-2.20 (m, 2H), 1.60-1.95 (m, 2H), 1.30-1.48 (m, 2H), 0.72-1.10 (m, 9H). LC-MS (ESI, m/z): 540 [M+H]+.
[0203] A mixture of tert-butyl ((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3- yl)propan-2-yl)carbamate (1.04 g, 3.83 mmol, 1.0 eq.) in hydrogen chloride (10 mL, 2 M in Et2O) was stirred for 1 h at rt. The mixture was concentrated under reduced pressure to afford (S)-2-amino-3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (0.650 g, crude) as a yellow oil. LC-MS (ESI, m/z): 172 [M+H]+. [0204] To a mixture of (1S,3aR,4S,7R,7aS)-2-((S)-2-((tert- butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7- methanoisoindole-1-carboxylic acid (1.50 g, 3.82 mmol, 1.0 eq.) in N,N-dimethylformamide
(15 mL) was added o-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.74 g, 4.58 mmol, 1.2 eq.) and N-ethyl-N-isopropylpropan-2-amine (3.95 g, 30.5 mmol, 8.0 eq.) at 0 °C. The mixture was stirred for 20 min at 0 °C. (S)-2-amino- 3-((S)-2-oxopyrrolidin-3-yl)propanamide hydrochloride (650 mg, 3.82 mmol, 1.0 eq.) was added at 0 °C. The mixture was stirred for 2 h at rt. The reaction was quenched with water (50 mL). The mixture was extracted with EtOAc (3 x 80 mL). The organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was chromatographed on a silica gel column with MeOH:DCM (7:93) to provide tert-butyl ((S)-1- ((1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo-3-((S)-2-oxopyrrolidin-3-yl)propan-2- yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)-3,3-dimethyl-1- oxobutan-2-yl)carbamate (1.46 g, 70%) as a light yellow solid. LC-MS (ESI, m/z): 546 [M+H]+. [0205] A mixture of tert-butyl ((S)-1-((1S,3aR,4S,7R,7aS)-1-(((S)-1-amino-1-oxo- 3-((S)-2-oxopyrrolidin-3-yl)propan-2-yl)carbamoyl)-1,3,3a,4,7,7a-hexahydro-2H-4,7- methanoisoindol-2-yl)-3,3-dimethyl-1-oxobutan-2-yl)carbamate (150 mg, 0.275 mmol, 1.0 eq.) in hydrogen chloride (2mL, 2 M in Et2O) was stirred for 1 h at rt. The mixture was concentrated under reduced pressure to afford (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3- ((S)-2-oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a- hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (133 mg, crude) as a yellow oil. LC-MS (ESI, m/z): 446 [M+H]+. [0206] To a suspension of potassium trimethylsilanolate (67 mg, 0.522 mmol, 1.0 eq.) in Et2O (1 mL) cooled at 0°C was added dropwise a solution of ethyl 2,2,3,3,3- pentafluoropropanoate (100 mg, 0.521 mmol, 1.0 eq.) in Et2O (1 mL). The mixture stirred at rt for 16 h and then concentrated under reduced pressure. The residue was triturated with Et2O. The solid was filtered and dried under reduced pressure to afford potassium 2,2,3,3,3- pentafluoropropanoate (85 mg, 80%) as an off-white solid. [0207] To a mixture of (1S,3aR,4S,7R,7aS)-N-((S)-1-amino-1-oxo-3-((S)-2- oxopyrrolidin-3-yl)propan-2-yl)-2-((S)-2-amino-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a- hexahydro-1H-4,7-methanoisoindole-1-carboxamide hydrochloride (60 mg, 0.124 mmol, 1.0 eq.), potassium 2,2,3,3,3-pentafluoropropanoate (25 mg, 0.195 mmol, 1.6 eq.) and 50% T3P
in EA (0.390 g, 1.25 mmol, 10.0 eq.) cooled at 0°C was added pyridine (0.050 mL, 0.620 mmol, 5.0 eq.). The mixture was stirred at rt for 16 h. The mixture was diluted with water (10 mL) and extracted with EA (3 x 10 mL). The organic phases were combined, washed with brine (2 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (1 to 10%) in DCM and by prep-HPLC (Column: YMC-TRIART-C18, 25*150 mm, 10μm; Mobile Phase A: 10 mM NH4HCO3 in water, Mobile Phase B: ACN; Flow rate: 22 mL/min; Gradient: 20% B to 80% B in 8 min) to afford (1S,3aR,4S,7R,7aS)-N-((S)-l-cyano-2-((S)-2- oxopyrrolidin-3-yl)ethyl)-2-((S)-3,3-dimethyl-2-(2,2,3,3,3-pentafluoropropanamido) butanoyl)-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxamide (30 mg, 40%) as an off-white solid. 1H NMR (400 MHz, 363K, DMSO-d6) 58.49-8.83 (m, 2H), 7.29-7.46 (m, 1H), 5.91-6.22 (m, 2H), 4.60-4.97 (m, 1H), 4.55 (s, 1H), 4.00-4.16 (m, 1H), 3.65 (m, 1H), 3.36-3.51 (m, 1H), 3.03-3.23 (m, 3H), 2.88-2.96 (m, 2H), 2.72 (m, 1H), 2.37 (m, 1H), 2.15 (m, 2H), 1.64-1.94 (m, 2H), 1.35-1.46 (m, 2H), 0.82-1.00 (m, 9H). LCMS (ESI, m/z): 574 [M+H]+.
[0208] To aa solution ooff (lR,2S,3S,6R,7S)-4-[(2S)-2-(2-chloro-2,2- difluoroacetamido)-3,3-dimethy Ibutanoyl] -N-[( 1 S)- 1 -cyano-2- [(3 S)-2-oxopyrrolidin-3 - yl]ethyl]-4-azatricyclo dec-8-ene-3-carboxamide (155 mg, 0.287 mmol) in
DCM (3 mL) was added mCPBA (96.5 mg 77%, 0.43 mmol). The reaction was allowed to proceed overnight at rt. After completion, the excess of mCPBA was quenched with a small amount of aqueous solution of sodium sulfite. The mixture was diluted with ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate and brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Compound 2 (115
mg, 72%) was isolated as a white foam by silica gel column chromatography in 1 to 10% methanol-DCM. LC-MS (ESI, m/z): 556 [M+H]+ . EXAMPLE 2 Compound 2
[0209] Compound 2 (117 mg 85%) was prepared using the procedure for preparing Compound 1 using (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7- methanoisoindole-1-carboxamide (135 mg). LC-MS (ESI, m/z): 540 [M+H]+. EXAMPLE 3 Compound 3
[0210] Compound 3 (107 mg 86%) was prepared using the procedure for preparing Compound 1 using (1S,3aR,4S,7R,7aS)-N-((S)-1-cyano-2-((S)-2-oxopyrrolidin-3-yl)ethyl)-2- ((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-2,3,3a,4,7,7a-hexahydro-1H-4,7- methanoisoindole-1-carboxamide (121 mg). LC-MS (ESI, m/z): 590 [M+H]+.
EXAMPLE 3 Additional Compounds [0211] Additional compounds of Formula (I) can be prepared using similar materials and methods described herein, such as those described herein.
including pharmaceutically acceptable salts thereof.
EXAMPLE A SARS-Cov-23CLpro and HRV3C Duplex assay
[0212] Protease assays were performed in 384- well low volume polypropylene microtiter plates at ambient temperature. For the duplex assay, 3CLpro and HRV3C was added using a Multidrop Combi (Thermo Scientific; Waltham, MA) and preincubated for 30 mins with small molecules. The reactions were initiated by the addition of the two peptide substrates. The reactions were incubated for 30 mins and quenched by the addition of 0.5% formic acid (final) with subsequent neutralization using 1% sodium bicarbonate (final). Internal standard peptides were added in 20 mM Hepes pH 8.0 for quantitation of the protease products. For SAMDI-MS analysis, 2 μ L of each reaction mixture was transferred using a 384- channel automated liquid handler to SAMDI biochip arrays functionalized with a neutravidin-presenting self-assembled monolayer. The SAMDI arrays were incubated for 1 h in a humidified chamber to allow the specific immobilization of the biotinylated peptide substrates, cleaved products and internal standards. The samples were purified by washing the SAMDI arrays with deionized ultrafiltered water and dried with compressed air. A matrix comprising alpha-cyano cinnamic acid in 80% acetonitrile: 20% aqueous ammonium citrate was applied in an automated format by dispensing 50 nL to each spot in the array. SAMDI- MS was performed using reflector-positive mode on an AB Sciex TOF-TOF 5800 System (AB Sciex, Framingham, MA) with 400 shots/spot analyzed in a random raster sampling. For data analysis, area under the curves (peaks) (AUCs) for the product and internal standard were calculated using the TOF/TOF Series Explorer (AB Sciex), and the amount of product formed was calculated using the equation (AUC product/ AUC internal standard). The amount of product generated was calculated using the ratio of product area under the curve (AUC) divided by the AUC of the internal standard. Negative controls were pre-quenched with 0.5% formic acid final. Assay robustness was determined by Z-Factor. The ICsos were determined by fitting the curves using a four-parameter equation in Graphpad Prism 8.
[0213] Table 1 indicates related ICso values for the tested compounds where ‘A’ indicates an EC50 < 20 nM, ‘B’ indicates an EC50 of >20 nM and < 200 nM, ‘C’ indicates an EC50 > 200 nM and < 2000 nM, ‘D’ indicates an ICso > 2000 nM and < 20000 nM and ‘E’ indicates an ICso > 20000 nM and < 100000 nM. As shown by the data in Table 1 , compounds described herein (including pharmaceutically acceptable salts thereof) can effectively inhibit
and be used to treat a coronavirus and rhinovirus.
EXAMPLE B CORONAVIRUS ASSAY
OC43 Coronavirus Assay in HeLa cells
[0214] The human beta-coronavirus OC43 is purchased from ATCC (Manassas, VA) and propagated using HCT-8 human colorectal epithelial cells (ATCC). HeLa human cervical epithelial cells (ATCC) are used as susceptible host cell lines and were cultured using EMEM media, supplemented with 10% fetal bovine serum (FBS), 1% (v/v) penicillin/streptomycin (P/S), 1% (v/v) HEPES and 1% (v/v) cellgro glutagro™ supplement (all Coming, Manassas, VA) at 37 °C. For the OC43 antiviral assay, 1.5 x 104 HeLa cells per well are plated in 100 μL complete media in white 96- well plates with clear bottoms at 37 °C for up to 24 h to facilitate attachment and allow cells to recover from seeding stresses. Next day, the cell culture medium is removed. Serially diluted compounds in 100 μL assay media (EMEM, 2% FBS, 1% P/S, 1% cellgro glutagro™ supplement, 1% HEPES) are added to the cells and incubated for 4 H at 37 °C in a humidified 5% CCh incubator. 100 μL of OC43 virus stock is diluted to a concentration known to produce optimal cytopathic effect, inducing 80- 90% reduction in cell viability. 96-well plates are incubated for 6 (HeLa) days at 33 °C; each plate contains uninfected control wells as well as virus-infected wells that are not treated with compound. Cytotoxicity plates without the addition of OC43 virus are carried out in parallel. At the end of the incubation period, 100 μL cell culture supernatant is replaced with 100 μL cell-titer-glo reagent (Promega, Madison, WI) and incubated for at least 10 min at rt prior to measuring luminescence. Luminescence is measured on a Perkin Elmer (Waltham, MA) Envision plate reader. Antiviral % inhibition is calculated as follows: [(Compound treated cells infected sample) -(no compound infected control)]/[(Uninfected control) -(no compound infected control)] *100; Using GraphPad (San Diego, CA) prism software version 8.3.1 , the antiviral dose-response plot is generated as a sigmoidal fit, log(inhibitor) vs response-
variable slope (four parameters) model and the EC50 is calculated which is the predicted compound concentration corresponding to a 50% inhibition of the viral cytopathic effect. SARS-CoV-2 infection model in VeroE6 cells [0215] The SARS-CoV-2 antiviral assay is derived from the previously established SARS-CoV assay (PMID: 15961169). In this assay, fluorescence of Vero E6-eGFP cells declines after infection with SARS-CoV-2 due to the cytopathogenic effect of the virus. In the presence of an antiviral compound, the cytopathogenicity is inhibited and the fluorescent signal rescued. On day -1, the test compounds are serially diluted in assay medium (DMEM supplemented with 2% v/v FCS). The plates are incubated (37 °C, 5% CO2 and 95% relative humidity) overnight. On day 0, the diluted compounds are mixed with Vero E6-eGFP cells (25,000 cells/well), SARS-CoV-2-GHB-03021/2020 (20 TCID50/well) and the MDR1- inhibitor CP-100356 (final concentration 0.5 μM) in 96-well blackview plates (Greiner Bio- One, Vilvoorde, Belgium). The plates are incubated in a humidified incubator at 37 °C and 5% CO2. At 4 days p.i., the wells are examined for eGFP expression using an argon laser- scanning microscope. The microscope settings are excitation at 488 nm and emission at 510 nm and the fluorescence images of the wells were converted into signal values. The results are expressed as EC50 values defined as the concentration of compound achieving 50% rescue from the virus-reduced eGFP signals as compared to the untreated virus-infected control cells. Toxicity of compounds in the absence of virus is evaluated in a standard MTS-assay as described previously (PMID: 22575574). B.1.1.7 infection model in A549-dual_ACE2_TMPRSS2 cells [0216] The A549-dual_ACE2_TMPRSS2 cells (InvivoGen Cat #a549 - cov2r) were propagated in the growth medium which was prepared by supplementing DMEM (gibco cat no 41965-039) with 10% v/v heat-inactivated FCS and 10 μg/mL blasticidin (InvivoGen ant-bl-05), 100 μg/mL hygromycin (InvivoGen ant-hg-1), 0.5 μg/mL puromycin (InvivoGen ant-pr-1) and 100 μg/mL zeocin (InvivoGen ant-zn-05) in a humidified 5% CO2 incubator at 37°C. The assay medium was prepared by supplementing DMEM (gibco cat no 41965-039) with 2% v/v heat-inactivated FCS. [0217] The virus isolate used is from the B.1.1.7 lineage (derived from hCoV-
19/Belgium/rega-12211513/2020; EPI_ISL_791333, 2020-12-21; see Abdelnabi et al, “Comparing infectivity and virulence of emerging SARS-CoV-2 variants in Syrian hamsters" EBioMedicine (2021) Jun;68: 103403. doi: 10.1016/j.ebiom.2021.103403).
[0218] For antiviral testing, cells were seeded in 96-well plates (Falcon) at a density of 15,000 cells per well in assay medium. After overnight growth, cells were treated with the indicated compound concentrations and infected with a MOI of 0.001 TCID50/cell (final volume 200 pL/well in assay medium). On day 4 p.i. differences in cell viability caused by virus-induced CPE or by compound-specific side effects is analyzed using MTS as described previously (PMID: 22575574).
[0219] For toxicity testing, the same experimental setup was used except that assay medium without virus was added to the cells and that an additional control of well without cells was added to the plate.
[0220] Table 2 indicates related EC50 and CC50 values for the tested compounds ‘A’ indicates an EC50 < 100 nM, ‘B’ indicates an EC50 of >100 nM and < 1000 nM, ‘C* indicates an EC50 > 1000 nM and < 10000 nM. For CCso, the values are reported in micromolar (pM). ‘A’ indicates a CCso > 10 pM. ‘B’ indicates a CCso > 1 pM and <10 pM.
[0221] Tables 1 and 2 demonstrate that compounds described herein (including pharmaceutically acceptable salts thereof) can effectively inhibit and treat a coronavirus.
EXAMPLE C PICORNAVTRUS & NOROVIRUS ASSAYS
[0222] Compounds of Formula (I), including pharmaceutically acceptable salts thereof, are tested following a protocol similar to the protocol described in one of the following articles: Kim et al., Journal of Virology (2012) 86(21): 11754-11762, Zhang et al, JACS (2020)
106
(https://dx.doi.org/10.1021/acs.jmedchem.9b01828), and U.S. Patent No.9,603,864. [0223] The protocols of Kim et al., and Zhang et al., can be used to test for activity against a picornavirus and norovirus. EXAMPLE D [0224] For the cathepsin L assay, 10 pM of human cathepsin L (R&D Systems; Minneapolis, MN) is preincubated for 30 mins with test compounds. Reactions are initiated by the addition of a peptide substrate Z-FR-AMC (final concentration 2 μM, Anaspec; Fremont, CA). Fluorescence is measured at 2-minute intervals for 30 mins using a 355/460 excitation/emission filter module on an Envision plate reader (Perkin Elmer; Waltham, MA). The IC50 values are calculated for each assay by fitting the curves using a four-parameter equation in GraphPad Prism. [0225] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.
Claims
WHAT IS CLAIMED IS: 1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein: Ring A1 is
, wherein Ring A1 is optionally substituted with one or more moieties independently selected from the group consisting of =O, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl; R1 is selected from the group consisting of cyano, an unsubstituted or a substituted C2- 5 alkynyl, an unsubstituted or a substituted acyl, an unsubstituted or a substituted ketoamide, – CH(OH)-(S(=O)2-O-), –CH(OH)((P=O)(OR6)2) and –C(=O)CH2-O-((P=O)(OR7)2); each R6 and each R7 are independently hydrogen, an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted C1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C1-4 alkyl); R2 is hydrogen, deuterium or halogen; R3 is an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C1- 4 alkyl), an unsubstituted or a substituted bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl), an unsubstituted or a substituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl); R4 is hydrogen, deuterium or halogen;
R5 is
a substituted monocyclic C3-6 cycloalkyl or a substituted 4- to 6-membered monocyclic heterocyclyl; R8 and R10 are independently selected from the group consisting of an unsubstituted or a substituted C2-6 alkyl, an unsubstituted or a substituted C2-6 alkenyl, an unsubstituted or a substituted C2-6 alkynyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-8 cycloalkyl, an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl and an unsubstituted monocyclic C3-6 cycloalkyl(CH2)–, wherein when the C2-6 alkyl is substituted, the C2-6 alkyl is substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, cyano, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted C1-4 alkoxy and an unsubstituted C1-4 haloalkoxy, or the C2-6 alkyl is substituted 1 to 13 times with deuterium; wherein when the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted, the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl and the monocyclic 4- to 6- membered heterocyclyl are substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted C1-4 alkoxy; and R9 is selected from the group consisting of an unsubstituted or a substituted C1-6 alkyl, an unsubstituted or a substituted C1-6 haloalkyl, a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-6 cycloalkyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl and an unsubstituted or a substituted alkoxy, wherein the substituted C1-6 alkyl is substituted 1 or 2 times with an unsubstituted C1-4 alkoxy, wherein the substituted monocyclic C3-6 cycloalkyl is substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an
unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl and an unsubstituted monocyclic C3- 6 cycloalkyl, and wherein the substituted C1-6 haloalkyl is substituted 1 or 2 times with an unsubstituted C1-4 alkoxy; and R11 is an optionally substituted monocyclic 4- to 6-membered heterocyclyl, –(NH)m– an optionally substituted 5- to 6-membered monocyclic heteroaryl, –O–an optionally substituted C1-6 alkyl, –O–an optionally substituted C3-8 cycloalkyl and –O–an optionally substituted C3-8 cycloalkyl(C1-4 alkyl), wherein m is 0 or 1.
2. The compound of Claim 1, wherein R1 is an unsubstituted or a substituted ketoamide.
3. The compound of Claim 1, wherein R1 is an unsubstituted or a substituted acyl.
4. The compound of Claim 1, wherein R1 is –CH(OH)-(S(=O)2-O-).
5. The compound of Claim 1, wherein R1 is –CH(OH)((P=O)(OR6)2), wherein each R6 are independently hydrogen, an unsubstituted C1-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted C1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C1-4 alkyl).
6. The compound of Claim 1, wherein R1 is –C(=O)CH2-O-((P=O)(OR7)2), wherein each R7 are independently hydrogen, an unsubstituted C1-6 alkyl, an unsubstituted C2- 6 alkenyl, an unsubstituted C1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C1-4 alkyl).
7. The compound of Claim 1, wherein R1 is cyano.
8. The compound of Claim 1, wherein R1 is an unsubstituted or a substituted C2-5 alkynyl.
10. The compound of any one of Claims 1-8, wherein Ring A1 is a substituted
with one or more moieties independently selected from the group consisting of =O, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl.
12. The compound of Claim 11, wherein R8 is an unsubstituted C2-6 alkyl.
13. The compound of Claim 11, wherein R8 is a substituted C2-6 alkyl.
14. The compound of Claim 11, wherein R8 is an unsubstituted C2-6 alkenyl.
15. The compound of Claim 11, wherein R8 is a substituted C2-6 alkenyl.
16. The compound of Claim 11, wherein R8 is an unsubstituted C2-6 alkynyl.
17. The compound of Claim 11, wherein R8 is a substituted C2-6 alkynyl.
18. The compound of Claim 11, wherein R8 is an unsubstituted monocyclic C3-6 cycloalkyl.
19. The compound of Claim 11, wherein R8 is a substituted monocyclic C3-6 cycloalkyl.
20. The compound of Claim 11, wherein R8 is an unsubstituted bicyclic C5-8 cycloalkyl.
21. The compound of Claim 11, wherein R8 is a substituted bicyclic C5-8 cycloalkyl.
22. The compound of Claim 11, wherein R8 is an unsubstituted monocyclic 4- to 6- membered heterocyclyl.
23. The compound of Claim 11, wherein R8 is a substituted monocyclic 4- to 6- membered heterocyclyl.
24. The compound of Claim 11, wherein R8 is an unsubstituted monocyclic C3-6 cycloalkyl(CH2)–.
25. The compound of any one of Claims 11-24, wherein R9 is an unsubstituted C1- 6 alkyl.
26. The compound of any one of Claims 11-24, wherein R9 is a substituted C1-6 alkyl.
27. The compound of any one of Claims 11-24, wherein R9 is an unsubstituted C1- 6 haloalkyl.
28. The compound of any one of Claims 11-24, wherein R9 is a substituted C1-6 haloalkyl.
29. The compound of any one of Claims 11-24, wherein R9 is an unsubstituted or substituted monocyclic C3-6 cycloalkyl.
30. The compound of any one of Claims 11-24, wherein R9 is an unsubstituted or a substituted bicyclic C5-6 cycloalkyl.
31. The compound of any one of Claims 11-24, wherein R9 is an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted monocyclic heterocyclyl.
32. The compound of any one of Claims 11-24, wherein R9 is an unsubstituted or a substituted alkoxy.
34. The compound of Claim 33, wherein R10 is an unsubstituted C2-6 alkyl.
35. The compound of Claim 33, wherein R10 is a substituted C2-6 alkyl.
36. The compound of Claim 33, wherein R10 is an unsubstituted C2-6 alkenyl.
37. The compound of Claim 33, wherein R10 is a substituted C2-6 alkenyl.
38. The compound of Claim 33, wherein R10 is an unsubstituted C2-6 alkynyl.
39. The compound of Claim 33, wherein R10 is a substituted C2-6 alkynyl.
40. The compound of Claim 33, wherein R10 is an unsubstituted monocyclic C3-6 cycloalkyl.
41. The compound of Claim 33, wherein R10 is a substituted monocyclic C3-6 cycloalkyl.
42. The compound of Claim 33, wherein R10 is an unsubstituted bicyclic C5-8 cycloalkyl.
43. The compound of Claim 33, wherein R10 is a substituted bicyclic C5-8 cycloalkyl.
44. The compound of Claim 33, wherein R10 is an unsubstituted monocyclic 4- to 6-membered heterocyclyl.
45. The compound of Claim 33, wherein R10 is a substituted monocyclic 4- to 6- membered heterocyclyl.
46. The compound of Claim 33, wherein R8 is an unsubstituted monocyclic C3-6 cycloalkyl(CH2)–.
47. The compound of any one of Claims 33-46, wherein R11 is –an optionally substituted 5- to 6-membered monocyclic heteroaryl.
48. The compound of any one of Claims 33-46, wherein R11 is –(NH)–an optionally substituted 5- to 6-membered monocyclic heteroaryl.
49. The compound of any one of Claims 33-46, wherein R11 is an optionally substituted monocyclic heterocyclyl.
50. The compound of any one of Claims 33-46, wherein R11 is –O–an optionally substituted alkyl.
51. The compound of any one of Claims 33-46, wherein R11 is –O–an optionally substituted cycloalkyl.
52. The compound of any one of Claims 33-46, wherein R11 is –O–an optionally substituted cycloalkyl(C1-4 alkyl).
53. The compound of any one of Claims 1-10, wherein R5 is a substituted monocyclic C3-6 cycloalkyl.
54. The compound of any one of Claims 1-10, wherein R5 is a substituted 4- to 6- membered monocyclic heterocyclyl.
57. The compound of any one of Claims 1-56, wherein R3 is an unsubstituted monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
58. The compound of any one of Claims 1-56, wherein R3 is a substituted monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
59. The compound of Claim 57 or 58, wherein the monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl) is a 5-membered monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
60. The compound of Claim 57 or 58, wherein the monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl) is a 6-membered monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
61. The compound of Claim 57 or 58, wherein the monocyclic nitrogen-containing heterocyclyl(C1-4 alkyl) is azepan-2-one(C1-4 alkyl), imidazolidin-2-one(C1-4 alkyl), tetrahydropyrimidin-2-one(C1-4 alkyl), pyrrolidin-2-one(C1-4 alkyl), piperidin-2-one(C1-4 alkyl), pyrazolidin-3-one(C1-4 alkyl), morpholin-3-one(C1-4 alkyl), oxazolidin-4-one(C1-4 alkyl) 1,4-oxazepan-3-one(C1-4 alkyl) or morpholin-3-one(C1-4 alkyl).
62. The compound of any one of Claims 1-56, wherein R3 is an unsubstituted bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
63. The compound of any one of Claims 1-56, wherein R3 is a substituted bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
64. The compound of Claim 62 or 63, wherein the bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl) is a 9-membered or 10-membered bicyclic nitrogen-containing heterocyclyl(C1-4 alkyl).
66. The compound of any one of Claims 1-56, wherein R3 is an unsubstituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl).
67. The compound of any one of Claims 1-56, wherein R3 is a substituted monocyclic nitrogen-containing heteroaryl(C1-4 alkyl).
71. The compound of any one of Claims 1-70, wherein R2 is hydrogen.
72. The compound of any one of Claims 1-70, wherein R2 is deuterium.
73. The compound of any one of Claims 1-70, wherein R2 is halogen.
74. The compound of any one of Claims 1-73, wherein R4 is hydrogen.
75. The compound of any one of Claims 1-73, wherein R4 is deuterium.
76. The compound of any one of Claims 1-73, wherein R4 is halogen.
79. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, and excipient.
80. Use of the compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a coronavirus infection.
81. The use of Claim 80, wherein the use further comprises the use of an additional agent selected from the group consisting of an ACE inhibitor, an anticoagulant, an anti- inflammatory, an ARB, an ASO, a Covid-19 convalescent plasma, an entry inhibitor, an H2 pump antagonist, an H-conducting channel, an HIV protease inhibitor, an HMG-CoA
reductase inhibitor, an immune globulin, an immunosuppressant, an immunotherapeutic agent, a neuraminidase inhibitor, a nucleoside inhibitor, a nucleoside analog inhibitor, a polymerase inhibitor, a protease inhibitor, an siRNA, a statin, a tissue plasminogen activator, an antibiotic, an antimicrobial and a vaccine.
82. The use of Claim 81, wherein the additional agent selected from the group consisting of Ascorbic acid, Anakinra, Azithromycin, Baloxavir, Baricitinib, Chloroquine Phosphate, Colchicine, a corticosteroid, Epoprostenol, Famotidine, Favipiravir, an IGIV, an interferon, an IVIG, Ivermectin, y-globulin, lopinavir, Methylprednisolone, Niclosamide, Molnupiravir (MK-4482 or EIDD-2801), Nitazoxanide, Nitric oxide, Oseltamivir, Peramivir, RANTES, ribavirin, Remdesivir, Ruxolitinib, Sarilumab, Siltuximab, Sirolimus, a statin, Tacrolimus, Tocilizumab, Umifenovir, Zanamivir, Casirivimab, imdevimab, bamlanivimab, etesevimab and AT-527.
83. The use of any one of Claims 80-82, wherein the coronavirus is P-coronavirus.
84. The use of any one of Claims 80-82, wherein the coronavirus is coronavirus selected from the group consisting of CoV 229E, CoV NL63, CoV OC43, CoV HKU1 , Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV, and SARS-CoV-2.
85. Use of the compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a picomavirus infection.
86. The use of Claim 85, wherein the picomavirus infection is a rhinovirus infection.
87. Use of the compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a norovirus infection.
88. A compound of any one of Claims 1 -78, or a pharmaceutically acceptable salt thereof, for use in treating a coronavirus infection.
89. The compound of Claim 88, wherein the compound is used in combination with an additional agents selected from the group consisting of an ACE inhibitor, an anticoagulant, an anti-inflammatory, an ARB, an ASO, a Covid-19 convalescent plasma, an entry inhibitor, an Hi pump antagonist, an H-conducting channel, an HIV protease inhibitor, an HMG-CoA
reductase inhibitor, an immune globulin, an immunosuppressant, an immunotherapeutic agent, a neuraminidase inhibitor, a nucleoside inhibitor, a nucleoside analog inhibitor, a polymerase inhibitor, a protease inhibitor, an siRNA, a statin, a tissue plasminogen activator, an antibiotic, an antimicrobial and a vaccine.
90. The compound of Claim 89, wherein the additional agent is selected from the group consisting of Ascorbic acid, Anakinra, Azithromycin, Baloxavir, Baricitinib, Chloroquine Phosphate, Colchicine, a corticosteroid, Epoprostenol, Famotidine, Favipiravir, an KHV, an interferon, an IVIG, Ivermectin, y-globulin, lopinavir, Methylprednisolone, Molnupiravir (MK-4482 or EIDD-2801), Niclosamide, Nitazoxanide, Nitric oxide, Oseltamivir, Peramivir, RANTES, ribavirin, Remdesivir, Ruxolitinib, Sarilumab, Siltuximab, Sirolimus, a statin, Tacrolimus, Tocilizumab, Umifenovir, Zanamivir, Casirivimab, imdevimab, bamlanivimab, etesevimab and AT-527.
91. The compound of any one of Claims 88-90, wherein the coronavirus is 0- coronavirus.
92. The compound of any one of Claims 88-90, wherein the coronavirus is coronavirus selected from the group consisting of CoV 229E, CoV NL63, CoV OC43, CoV HKU1, Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (SARS)-CoV, and SARS-CoV-2.
93. A compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, for use in treating a picomavirus infection.
94. The compound of Claim 93, wherein the picomavirus infection is a rhinovirus infection.
95. A compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, for use in treating a norovirus infection.
96. A method for treating a coronavirus infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof.
97. The method of Claim 96, further comprising administering an additional agent selected from the group consisting of an ACE inhibitor, an anticoagulant, an antiinflammatory, an ARB, an ASO, a Covid- 19 convalescent plasma, an entry inhibitor, an Hz pump antagonist, an H-conducting channel, an HIV protease inhibitor, an HMG-CoA
reductase inhibitor, an immune globulin, an immunosuppressant, an immunotherapeutic agent, a neuraminidase inhibitor, a nucleoside inhibitor, a nucleoside analog inhibitor, a polymerase inhibitor, a protease inhibitor, an siRNA, a statin, a tissue plasminogen activator, an antibiotic, an antimicrobial and a vaccine.
98. The method of Claim 97, wherein the additional agent selected from the group consisting of Ascorbic acid, Anakinra, Azithromycin, Baloxavir, Baricitinib, Chloroquine Phosphate, Colchicine, a corticosteroid, Epoprostenol, Famotidine, Favipiravir, an IGIV, an interferon, an IVIG, Ivermectin, y-globulin, lopinavir, Methylprednisolone, Molnupiravir (MK-4482 or EIDD-2801), Niclosamide, Nitazoxanide, Nitric oxide, Oseltamivir, Peramivir, RANTES, ribavirin, Remdesivir, Ruxolitinib, Sarilumab, Siltuximab, Sirolimus, a statin, Tacrolimus, Tocilizumab, Umifenovir, Zanamivir, Casirivimab, imdevimab, bamlanivimab, etesevimab and AT-527.
99. The method of any one of Claims 96-98, wherein the coronavirus is 0- coronavirus.
100. The method of any one of Claims 96-98, wherein the coronavirus is coronavirus selected from the group consisting of CoV 229E, CoV NL63, CoV OC43, CoV HKU1 , Middle East Respiratory Syndrome (MERS)-CoV, Severe Acute Respiratory Syndrome (S ARS)-CoV, and SARS-CoV-2.
101. A method for treating a picomavirus infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof.
102. The method of Claim 101, wherein the picomavirus infection is a rhinovirus infection.
103. A method for treating a norovirus infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof.
104. The use of any one of Claims 80-87, the compound of any one of Claims 88- 95, or the method of any one of Claims 96-103, wherein the subject is a human.
105. The use, compound or method of Claim 104, wherein the subject is 60 years old or older.
106. The use, compound or method of Claim 104, wherein the subject is a non-
human primate.
107. The use, compound or method of Claim 104, wherein the subject is a cat.
108. The use, compound or method of Claim 104, wherein the subject is a camel.
109. The use of any one of Claims 80-87, the compound of any one of Claims 88- 95, or the method of any one of Claims 96-103, wherein the coronavirus causes one or more symptoms selected from the group consisting of coughing, sore throat, runny nose, sneezing, headache, fever, shortness of breath, myalgia, abdominal pain, fatigue, difficulty breathing, persistent chest pain or pressure, difficulty waking, loss of smell and taste, muscle or joint pain, chills, nausea or vomiting, nasal congestion, diarrhea, haemoptysis, conjunctival congestion, sputum production, chest tightness and palpitations.
110. The use of any one of Claims 80-87, the compound of any one of Claims 88- 95, or the method of any one of Claims 96-103, wherein the coronavirus causes a complication selected from the group consisting of sinusitis, otitis media, pneumonia, acute respiratory distress syndrome, disseminated intravascular coagulation, pericarditis and kidney failure.
111. The use of any one of Claims 80-87, the compound of any one of Claims 88- 95, or the method of any one of Claims 96-103, wherein the compound is administered intravenously, subcutaneously, orally or via inhalation.
112. The use of Claim 82, the compound of Claim 90, or the method of Claim 98, wherein the interferon is selected from the group consisting of recombinant interferon alpha 2b, IFN-D and PEG-IFN-D-2a.
113. A method for inhibiting a coronavirus protease comprising contacting a cell infected with a coronavirus with an effective amount of a compound of any one of Claims 1- 78, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of Claims 1-78, or a pharmaceutically acceptable salt thereof, selectively inhibits the coronavirus protease compared to a host protease.
114. The method of Claim 113, wherein the compound of formula (I) selectively inhibits the coronavirus protease over the host protease that is selected from the group consisting of Cathepsin L, Cathepsin B, Cathepsin D, Cathepsin K, Leukocyte Elastase, Chymotrypsin, Trypsin, Thrombin, Pepsin, Caspase 2, Elastase and Calpain.
115. The method of Claim 113 or 114, wherein the host protease is selected from Cathepsin L and Cathepsin B.
116. The method of any one of Claims 113-115, wherein the selectively is > 2-fold.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US202263379377P | 2022-10-13 | 2022-10-13 | |
US63/379,377 | 2022-10-13 |
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WO2024081318A1 true WO2024081318A1 (en) | 2024-04-18 |
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PCT/US2023/034949 WO2024081318A1 (en) | 2022-10-13 | 2023-10-11 | Anti-viral compounds |
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WO (1) | WO2024081318A1 (en) |
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2023
- 2023-10-11 WO PCT/US2023/034949 patent/WO2024081318A1/en unknown
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