Anti-viral compounds

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 COMPOUNDSINCORPORATION 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 Nos. 63 / 634,012, filed April 15, 2024 and 63 / 680,236, filed August 7, 2024, each of which is incorporated by reference in their entireties.BACKGROUNDField

[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 acompound, 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 picorna virus.

[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 (CO VID- 19) (also referred to as novel coronavirus pneumonia or 2019-nCoV acute respiratory disease) is an infectious disease caused by the virus severe acute 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. Symptoms of COVID-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 effectivelytreat or prevent coronavirus infections in humans.

[0018] Picornaviruses 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-enveloped 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, nonbloody 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” 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, “Cato Cb”, “Ca-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 “Ci 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 Ce-Cio aryl group, or a Ce 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 thancarbon, 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-l,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 A-Oxide, piperidine,piperazine, pyrrolidine, pyrrolidone, pyrrolidinone, 4-piperidone, pyrazoline, pyrazolidine, 2- oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., 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 l,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 acycloalkyl group (e.g., -C- ).

[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 Ci-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, l-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, l-chloro-2- fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropoxy, fluoro-substituted cyclopropoxy, chloro-substituted cyclobutoxy and fluoro-substituted cyclobutoxy. In some instances, a haloalkoxy can be -OR, wherein R is a CM 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 “R0C(=0)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(=0)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). Amono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be -NHRA, wherein RA can be an unsubstituted Ci-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 Ci-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] As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “spiro” refers to two rings which have one atom in common. As used herein, the term “bridged refers to two rings which contains a linkage of one or more atoms connecting non-adjacent atoms.

[0070] Where the numbers of substituents are 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.

[0071] 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)).

[0072] 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.

[0073] 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.

[0074] 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.

[0075] It is understood that, in any compound described herein having one or morechiral 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.

[0076] 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).

[0077] 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.

[0078] 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

[0079] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:wherein: Ring A1can be a monocyclic moiety selected from:wherein each can be optionally substituted with one or more moieties independently selected from =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl, an unsubstituted or a substituted C3-6 monocyclic cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted -O-aryl and an unsubstituted or a substituted-O-benzyl; or Ring A1can be a multicyclic moiety selected fromoptionally substituted with one or more moieties independently selected from =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl and an unsubstituted or awherein each can be optionally substituted with one or more moieties independently selected from halogen, cyano, hydroxy, an unsubstituted Ci-6 alkyl, an unsubstituted -O(Ci-6 alkyl), an unsubstituted C1-4 haloalkyl, an unsubstituted C1-4 haloalkoxy, an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted benzyl, an unsubstituted or a substituted 5- or 6-membered heteroaryl, -S(=O)2(an unsubstituted C1-4 alkyl), -NRN1RN2and -C(=O)-NRN1RN2, wherein RN1and RN2are independently hydrogen or an unsubstituted C1-4 alkyl, or RN1and RN2can be taken together to form a monocyclic heterocyclyl; R2can be hydrogen, deuterium or halogen; R3can beor R12; R4can be selected from cyano, an unsubstituted or a substituted C2-5 alkynyl, an unsubstituted or a substituted acyl, an unsubstituted or a substituted ketoamide,-C(=O)NH2, -CH(OH)-(S(=O)2-OH), -CH(OH)-(S(=O)2-O ), -CH(OH)((P=O)(OR6)2) and -C(=O)CH2-O-((P=O)(OR7)2); R5acan be selected from hydrogen, an unsubstituted or a substituted C1-4 alkyl, an unsubstituted or a substituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 cycloalkyl; Z1can be -C(=O)- or -S(=O)2-; each R6and each R7can be independently hydrogen, an unsubstituted Ci-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(Ci-4 alkyl); R8and R10can be independently selected from an unsubstituted or a substituted Ci-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 or a substituted bicyclic 5- to 8-membered heterocyclyl, wherein when the Ci-6 alkyl is substituted, the Ci-6 alkyl can be substituted 1 , 2, 3 or 4 times with a substituent independently selected from halogen, cyano, -NH2, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic 5- or 6-membered heteroaryl, an unsubstituted or a substituted monocyclic 4-6 membered heterocyclyl, an unsubstituted C1-4 alkoxy (e.g., -O-(an unsubstituted C1-4 alkyl)), an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted -O-(CH2)-phenyl and an unsubstituted C1-4 haloalkoxy (e.g., -O-(an unsubstituted CM haloalkyl)), or the Ci-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, the monocyclic 4- to 6-membered heterocyclyl and the bicyclic 5- to 8- membered heterocyclyl are substituted, the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl, the monocyclic 4- to 6-membered heterocyclyl and the bicyclic 5- to 8-membered heterocyclyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, an unsubstituted CM alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 haloalkyl, an unsubstituted or a substitutedmonocyclic C3-6 cycloalkyl and an unsubstituted C1-4 alkoxy (e.g., -O-(an unsubstituted C1-4 alkyl)); R8acan be hydrogen or an unsubstituted C1-4 alkyl; or R8and R8acan be taken together to form an unsubstituted monocyclic C3-6 cycloalkyl or a halogen- substituted monocyclic C3-6 cycloalkyl; R9can be selected from an unsubstituted or a substituted Ci-6 alkyl, an unsubstituted or a substituted Ci-6 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-12 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted alkoxy and - NR17R18, wherein the substituted Ci-6 alkyl can be substituted 1 or 2 times with a substituent selected from hydroxy and an unsubstituted C1-4 alkoxy (such as -O-(an unsubstituted C1-4 alkyl)), or the Ci-6 alkyl is substituted 1 to 13 times with deuterium, wherein the substituted monocyclic C3-6 cycloalkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy (such as -O-(an unsubstituted C1-4 alkyl)), an unsubstituted C1-4 haloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl and an unsubstituted or a substituted phenyl, wherein when the phenyl is substituted it is substituted with one or more substituents selected from -F, -Cl, - CH3 and -CF3, and wherein the substituted Ci-6 haloalkyl can be substituted 1 or 2 times with a substituent independently selected from the group consisting of an unsubstituted C1-4 alkoxy (for example, -O-(an unsubstituted C1-4 alkyl)) and an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; R11can be an unsubstituted or a substituted monocyclic 4- to 6- membered heterocyclyl, -(NH)-(an unsubstituted or a substituted 5- to 10-membered heteroaryl), -O-(an unsubstituted or a substituted Ci-6 alkyl), -O-(an unsubstituted or a substituted C3-8 cycloalkyl) or -O-(Ci-4 alkyl)-(an unsubstituted or a substituted C3-8 cycloalkyl); R12can be an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 12-membered monocyclic heterocyclyl, an unsubstituted or a substituted 5- to 12-membered bicyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl), an unsubstituted or a substituted heteroaryl(alkyl), an unsubstituted or a substituted heterocyclyl(alkyl), an unsubstituted or a substituted C- carboxy, -OR13, -NR14R15or -C(=O)-NR16AR16B; R13can be an unsubstituted or a substitutedC1-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted3- to 8-membered monocyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl) or an unsubstituted or a substituted heteroaryl(alkyl); R14are R15can be independently selected from hydrogen, an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl) and an unsubstituted or a substituted heteroaryl(alkyl); R16Acan be hydrogen or an unsubstituted C1-3 alkyl; R16Bcan be an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl; and R17and R18can be independently selected from hydrogen, an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted C3-8 cycloalkyl, an unsubstituted or a substituted 3-8 membered heterocyclyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted aryl(alkyl) and an unsubstituted or a substituted heteroaryl(alkyl); or R17and R18can be taken together along with the nitrogen to which they are connected to form an unsubstituted or a substituted 3-8 membered heterocyclyl.

[0080] Ring A1can be a variety of monocyclic or multicyclic ring moiety. In some embodiments, Ring A1can be a monocyclic ring selected from:,wherein each can be optionally substituted with one or more moieties independently selected from =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted CM haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl, an unsubstituted or a substituted C3-6 monocyclic cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted -O-aryl and anunsubstituted or a substituted -O-benzyl.

[0081] In other embodiments, Ring A1can be a multicyclic ring moiety selected from the group consistingwherein each is optionally substituted with one or more moieties independently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted CM haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl.

[0082] In some embodiments, Ring A1can be a multicyclic moiety selected fromwherein each is optionally substituted with one or more moieties independently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted CM haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl.

[0083] In some embodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedIn still other embodiments, Ring A1can be an unsubstituted or a substitutedstill embodiments, Ring A1can be an unsubstituted or a substitutedsome embodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedIn still other embodiments, Ring A1can be an unsubstituted or a substitutedIn yet still other embodiments, Ring A1can be an unsubstituted or a substitutedIn someembodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedIn still other embodiments, Ring A1can be an unsubstituted or a substituted. In yet still other embodiments, Ring A1can be an unsubstitutedsome embodiments, Ring A1can be an unsubstituted orother embodiments, Ring A1can be an unsubstituted or aother embodiments, Ring A1can be an unsubstituted or a substitutedIn yet still other embodiments, Ring A1can be an unsubstituted or a substitutedsome embodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedIn still otherembodiments, Ring A1can be an unsubstituted or a substituted. In yet still other embodiments, Ring A1can be an unsubstituted or a substitutedsome embodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedIn still other embodiments, Ring A1can be an unsubstituted or a substitutedIn yet still other embodiments, Ring A1can be an unsubstituted or a substitutedIn some embodiments, Ring A1can be an unsubstituted or a substitutedother embodiments, Ring A1can be an unsubstituted or a substituted. In still otherembodiments, Ring A1can be an unsubstituted or a substitutedIn yet still other embodiments, Ring A1can be an unsubstituted or a substitutedIn some embodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedIn still other, embodiments, Ring A1can be an unsubstitutedIn other embodiments, Ring A1can be an unsubstituted or a substitutedother embodiments, Ring A1can be an unsubstituted or a substituted. In yet still otherembodiments, Ring A1can be an unsubstituted or a substitutedIn some embodiments, Ring A1can be an unsubstituted or a substitutedIn other embodiments, Ring A1can be an unsubstituted or a substituted. Those skilled in the art understand that the nitrogen shown in each of the ring structures for Ring A1corresponds to the ring nitrogen shown in Formula (I), and the carbon adjacent to the ring nitrogen with thecorresponds to the carbon to which R2is attached. For example, those skilled in the art understand that when Ringthen a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure

[0084] As provided herein, Ring A1can be substituted with one or more moieties(such as 1, 2 or 3 moieties) independently selected from =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted CM alkyl, an unsubstituted Ci-4 haloalkyl, -O(unsubstituted Ci-4 alkyl), an unsubstituted C2-4 alkenyl, an unsubstituted or a substituted C3-6 monocyclic cycloalkyl and an unsubstituted or a substituted aryl, an unsubstituted or a substituted -O-aryl and an unsubstituted or a substituted -O-benzyl. Example of suitable substituents that can be present in Ring A1include =0, =CH2, deuterium, F, Cl, methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, sec -butyl, tert-butyl, -CF3, -CCIF2, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F,-CH2CF3, -CH(CH3)CF3, -CH2CH2CF3, -CH2CH(CH3)CF3, -CF2CF3, -CH2CH2F, -CH2CH2CH2F, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec -butoxy, tert-butoxy, ethenyl, propenyl, butenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted -O-phenoxy and an unsubstituted or a substituted -O-benzyl. When Ring A1is substituted by an unsubstituted or a substituted C3-6 monocyclic cycloalkyl, the unsubstituted or a substituted C3-6 monocyclic cycloalkyl can replace one hydrogen. In some embodiments, an unsubstituted or a substituted C3-6 monocyclic cycloalkyl can replace two hydrogens of Ring A1such that the unsubstituted or a substituted C3-6 monocyclic cycloalkyl is connected to Ring A1in a spiro-fashion. Examples of an unsubstituted or a substituted C3-6 monocyclic cycloalkyl replacing twounsubstituted or substituted as described herein.

[0085] Examples of Ring A1include, but are not limited to, the following:each is optionally substituted with one or more moieties independently selected from the group consisting of halogen, cyano, hydroxy, an unsubstituted Ci-6 alkyl, an unsubstituted -O(Ci-6 alkyl), an unsubstituted C1-4 haloalkyl, an unsubstituted C1-4 haloalkoxy, an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted benzyl, an unsubstituted or a substituted 5- or 6-membered heteroaryl, -S(=O)2(an unsubstituted C1-4 alkyl), -NRN1RN2and -C(=O)-NRN1RN2, wherein RN1and RN2are independently hydrogen or an unsubstituted C1-4 alkyl or RN1and RN2are taken together to form a monocyclic heterocyclyl.

[0088] In some embodiments, R5acan be hydrogen. As provided herein, R5acan be a non-hydrogen moiety. For example, R5acan be an unsubstituted or a substituted C1-4 alkyl, an unsubstituted or a substituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 cycloalkyl. In some embodiments, R5acan be an unsubstituted C1-4 alkyl. In other embodiments, R5acan be a substituted CM alkyl. In still other embodiments, R5acan be an unsubstituted C2-4 alkenyl. In yet still other embodiments, R5acan be a substituted C2-4 alkenyl. In some embodiments, R5acan be an unsubstituted C3-6 cycloalkyl. In other embodiments, R5acan be a substituted C3-6 cycloalkyl. For example, R5acan be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. In some embodiments, R5acan be methyl. In some embodiments, R5acan be cyclopropyl.

[0089] As provided herein, R1can be optionally substituted with one or more moieties (such as 1, 2 or 3 moieties) selected from halogen, cyano, hydroxy, an unsubstituted C1-6 alkyl, an unsubstituted -O(Ci-6 alkyl), an unsubstituted CM haloalkyl, an unsubstitutedCi-4 haloalkoxy, an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted benzyl, an unsubstituted or a substituted 5- or 6-membered heteroaryl, -S(=O)2(an unsubstituted C1-4 alkyl), -NRN1RN2and -C(=O)-NRN1RN2, wherein RN1and RN2are independently hydrogen or an unsubstituted C1-4 alkyl or RN1and RN2are taken together to form a monocyclic heterocyclyl. Exemplary groups that can be present on R1can be selected from bromo, chloro, fluoro, cyano, hydroxy, methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (straight-chained and / or branched), hexyl (straight-chained and / or branched), methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, secbutoxy, tert-butoxy, pentoxy (straight-chained and / or branched), hexoxy (straight-chained and / or branched), -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F, -CH2CH2CH2F, -O(an unsubstituted CM haloalkyl) (such as -OCF3, -OCHF2, -OC(CH3)F2, -OCH2F, -OCH(CH3)F, -OCH2CF3, -OCH2CH2F and -OCH2CH2CH2F), an unsubstituted phenoxy, a substituted phenoxy, an unsubstituted phenyl, a substituted phenyl, an unsubstituted benzyl, a substituted benzyl, an unsubstituted 5- or 6-membered monocyclic heteroaryl, a substituted 5- or 6-membered monocyclic heteroaryl, -S(=O)2(an unsubstituted C1-4 alkyl), -NRN1RN2and -C(=O)-NRN1RN2, wherein RN1and RN2are independently hydrogen or an unsubstituted C1-4 alkyl or RN1and RN2are taken together to form a monocyclic heterocyclyl (such as a 5- or 6-membered heterocyclyl that includes, but is not limited to, pyrrolidinyl, piperidinyl and morpholinyl).

[0090] In some embodiments, the unsubstituted or a substituted C3-6 cycloalkyl that can be present on R1can be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, the unsubstituted or a substituted C3-6 cycloalkyl that can be present on R1can be an unsubstituted or a substituted bicyclic C3-6 cycloalkyl. For example, when R1is substituted with an unsubstituted or a substituted bicyclic C3-6 cycloalkyl, the unsubstituted or a substituted bicyclic C3-6 cycloalkyl can be an unsubstituted or a substituted spiro [2.2]pentane, an unsubstituted or a substituted spiro[2.3]hexane, an unsubstituted or a substituted bicyclo[l.l.l]pentane or an unsubstituted or a substituted bicyclo[2.1.1]hexane. The monocyclic C3-6 cycloalkyl and bicyclic C3-6 cycloalkyl that can be substituted on R1can beconnected via 1 ring carbon of the C3-6 cycloalkyl (for example,or a fused-fashionvia 2 ring carbons of the C3-6 cycloalkyl (for example, * * , wherein the asterisks indicate the points of attachment) or spiro-fashion via 1 ring carbon of the C3-6 cycloalkyl (for example,, wherein the asterisk indicates the point of attachment). Examples of a C3-6 cycloalkyl

[0091] In some embodiments, R1can be substituted with an unsubstituted phenyl.In other embodiments, R1can be substituted with a substituted phenyl, such as a monosubstituted phenyl, a di-substituted phenyl or a phenyl substituted with 3 to 5 substituents. A non-limiting list of moieties that can be present on substituted phenyl that is substituted on R1include halogen (such as bromo, chloro and fluoro), cyano, an unsubstituted C1-4 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), hydroxy, an unsubstituted C1-4 alkoxy (for example, -O(Ci-4 alkyl) such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec -butoxy and tert-butoxy), an unsubstituted C1.4 haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, CH(CH3)F, -CH2CF3, -CH2CH2Fand -CH2CH2CH2F), an unsubstituted C1-4 haloalkoxy (for example, -0(Ci-4 haloalkyl) such as -OCF3, -OCHF2, -OC(CH3)F2, -OCH2F, -OCH(CH3)F, -OCH2CF3, -OCH2CH2F and -OCH2CH2CH2F), an unsubstituted monocyclic C3-6 cycloalkyl, a substituted monocyclic C3. 6 cycloalkyl, an unsubstituted phenyl, a substituted phenyl, an unsubstituted 5- or 6-membered heteroaryl and a substituted 5- or 6-membered heteroaryl (for example, a substituted monocyclic C3-6 cycloalkyl, a substituted phenyl and / or a substituted 5- or 6-membered heteroaryl can be substituted 1, 2, 3, 4 or 5 times with a substituent selected from halogen (for example, F, Cl and Br), an unsubstituted CM alkyl (for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl and tert-butyl), an unsubstituted C1-4 alkoxy (for example -O(Ci-4 alkyl) such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, secbutoxy and tert-butoxy), an unsubstituted C1-4 haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F), an unsubstituted -O(an unsubstituted C1-4 haloalkyl) (for example, -OCF3, -OCHF2, -OC(CH3)F2, -OCH2F, -OCH(CH3)F, -OCH2CF3, -OCH2CH2F and -OCH2CH2CH2F) and -S(=O)2(an unsubstitutedCi-4 alkyl.

[0092] Exemplary R1groups include the following:wherein each can be unsubstituted or substituted, including the replacement of the hydrogen on a nitrogen. Examples of substituted version include the following:or substituted. In some embodiments, R1can be an unsubstituted. In other embodiments, R1can be a substituted. in some embodiments, R1can be

[0094] The substituent R4can be various moieties. In some embodiments, R4can be an unsubstituted ketoamide. In some embodiments, R4can be a substituted ketoamide. The ketoamide can have the structure -C(=O)-C(=O)NRylRzl. In some embodiments, R4can be -C(=O)NH2. In some embodiments, R4can be an acyl, for example, R4can be -C(=O)H, -C(=O)(an unsubstituted C1-4 alkyl), -C(=O)(an unsubstituted or a substituted benzyl), -C(=O)(an unsubstituted or a substituted monocyclic heteroaryl) or -C(=O)(an unsubstituted or a substituted bicyclic heteroaryl). In some embodiments, R4can be a substituted acyl. The acyl for R4can have the structure -C(=O)Ry2. 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 Ci-6 alkyl).

[0095] Ryl, Ry2and Rzlcan be a variety of groups. In some embodiments, Ryl, Ry2and Rzlcan be independently selected from hydrogen, Ci-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 ofthe aforementioned Ryl, Ry2and Rzlgroups can be unsubstituted or substituted. In some embodiments, Ryl, Ry2and Rzlcan be independently selected from H, Ci-8 alkyl, an unsubstituted C1-4 haloalkyl (including -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F), -C1.4 alkyl(OH) (including -CH2OH, -CH2CH2OH and -CH(CH3)0H), -C1-4 alkyl(Ci-4 alkoxy) (such as -CH20(an unsubstituted C1-4 alkyl) and -CH2CH2O(an unsubstituted C1-4 alkyl)), -C1-4 alkyl-O-(a monocyclic C3-6 cycloalkyl) (such as -CH20(a monocyclic C3-6 cycloalkyl), -CH2CH2O(a monocyclic C3-6 cycloalkyl)), -CM 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)), -Ci- 4 alkyl-O-(a monocyclic C3-6 cycloalkyl(Ci-4 alkyl) (such as -CM 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(Ci-4 alkyl), -C1-4 alkyl-O-(5- to 6-membered monocyclic heterocyclyl(Ci-4 alkyl), -C1-4 alkyl-O(C=O)(an unsubstituted Ci-6 alkyl) (for example, -CH20(C=0)(an unsubstituted Ci-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, THF 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, Ry2and Rzlgroups can be unsubstituted or substituted.

[0096] In some embodiments, R4can be -C(=O)Ry2, wherein Ry2can be -C1-4 alkyl(OH) (such as -CH2OH). In some embodiments, R4can be -C(=O)-C(=O)NRylRzl; wherein Rylcan be H; and Rzlcan be any of the moieties listed for Rzlin the previous paragraph. In some embodiments, R4can be -C(=O)-C(=O)NRylRzl; wherein Rylcan be H; and Rzlcan be a monocyclic C3-8 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl).

[0097] Prodrug-type and phosphate-containing moieties can be present at R4. In some embodiments, R4can be -CH(OH)-(S(=O)2-OH) or -CH(OH)-(S(=O)2-O ). Those skilled in the art understand that when R4is -CH(OH)-(S(=O)2-O ), the negative charge can be balanced with a positive ion and form a salt. For example, R4can be -CH(OH)-(S(=O)2-O" )(Na+). In other embodiments, R4can be -CH(OH)((P=O)(OR6)2), wherein each R6can be independently hydrogen, an unsubstituted Ci-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(Ci-4 alkyl). In still other embodiments, R4can be -C(=0)CH2-0- ((P=O)(OR7)2), wherein each R7can be independently hydrogen, an unsubstituted Ci-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(Ci-4 alkyl). Other examples of R6and R7groups 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.

[0098] In some embodiments, R4can be cyano. In other embodiments, R4can be an unsubstituted C2-5 alkynyl. In still other embodiments, R4can 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)I-C2-4 alkynyl or -(CH2)2-C2-3 alkynyl.

[0099] As provided herein, R3can be . In some embodiments,4R can be;wherein Z is -C(=O)- such that R can be . In3 1 3 some embodiments, R can be,wherein Z is -S(=O)2- such that R can be. Depending upon R8, the carbon to which R8is attached can be a chiralJ WW zi>R8aR9^ Nr8, center. In some embodiments, R can be H . In other embodiments, R can be

[0100] In some embodiments, R9can be an unsubstituted Ci-6 haloalkyl. For example, R9can be -CF3, -CCIF2, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH(CH3)CF3, -CH2CH2CF3, -CH2CH(CH3)CF3, -CF2CF3, -CH2CH2F, -CF2CF2CF3and -CH2CH2CH2F. In some embodiments, R9can be -CF3. In other embodiments, R9can be a substituted Ci-6 haloalkyl where the Ci-6 haloalkyl can be substituted 1 or 2 times with an unsubstituted C1-4 alkoxy (such as -O-(an unsubstituted C1-4 alkyl)). When the Ci-6 haloalkyl is substituted with 1 or 2 unsubstituted CM alkoxys, one or more hydrogens of the Ci-6 haloalkyl (for example, 1, 2 or 3 hydrogens) can be replaced with an unsubstituted C1-4 alkoxy (for example -O(Ci-4 alkyl) such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy). Exemplary Ci-6 haloalkyls substituted with an unsubstituted CM alkoxy include -C(OCH3)F2, -CH(OCH3)F, -C(OCH3)(CH3)F, -CH(OCH3)CF3, -C(OCH3)(CH3)CF3, -CH2CH(OCH3)CF3, -CH2C(OCH3)(CH3)CF3, -CH2CH(OCH3)F and -CH2CH2CH(OCH3)F. In still other embodiments, R9can be a substituted Ci-6 haloalkyl where the Ci-6 haloalkyl can be substituted with an unsubstituted or substituted C3-6 monocyclic cycloalkyl (for example, an unsubstituted C3-6 monocyclic cycloalkyl or a C3-6 monocyclic cycloalkyl substituted by one or more (such as 1, 2, 3 or 4 times) with a moiety selected from halogen, an unsubstituted C1-4 alkyl or an unsubstituted Ci- 4 haloalkyl).

[0101] In some embodiments, R9can be an unsubstituted Ci-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, R9can be a C1-6 alkyl substituted 1 or 2 times with an unsubstituted C1-4 alkoxy (such as a -O-(an unsubstituted C1-4 alkyl)) and / or hydroxy. When the Ci-6 alkyl is substituted with an unsubstituted C1-4 alkoxy and / or hydroxy, a hydrogen of the Ci-6 alkyl can be replaced with an unsubstituted C1-4 alkoxy and / or hydroxy 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-CH(OH)(CH3)3, -CH2(OCH3), -CH(OCH3)2, -CH(CH3)(OCH3) and -C(CH3)2(OCH3). In some embodiments, R9can be a Ci-6 alkyl substituted with 1 to 13 times with deuterium. For example, R9can be -CD3or -CD2CD3.

[0102] In some embodiments, R9can be an unsubstituted phenyl. In some embodiments, R9can be a substituted phenyl. When the phenyl is substituted, a variety of substituents can be present, and the number of substituents can vary. In some embodiments, R9can be a phenyl substituted 1 , 2, 3 or 4 times with a moiety independently selected from halogen, an unsubstituted Ci-6 alkyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted Ci-6 alkoxy (for example, -O-(an unsubstituted Ci-4 alkyl)) and an unsubstituted or a substituted monocyclic heteroaryl. For example, R9can be a phenyl substituted 1 , 2, 3 or 4 times with a moiety independently selected from F, Cl, Br, as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, pentyl (straight-chained or branched), hexyl (straight-chained or branched), -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F, -CH2CH2CH2F, -O(an unsubstituted Ci-6 alkyl) (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched), hexoxy (straight-chained or branched)), and an unsubstituted or a substituted 5- to 6-membered monocyclic heteroaryl, wherein the heteroaryl can include 1 , 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen. Exemplary monocyclic heteroaryls include furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine and pyrazine.

[0103] In some embodiments, R9can 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, furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, imidazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine and pyrazine. In yet still other embodiments, R9can be an unsubstituted or a substituted monocyclic heterocyclyl. A non-limiting list of monocyclic heterocyclyls for R9include azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene,pyrrolidine, oxazolidin-2-one, imidazolidin-2-one, tetrahydropyran, tetrahydrothiopyran, piperidine, piperazine, morpholine and thiomorpholine. Various substituents can be present on a substituted heteroaryl and / or a substituted heterocyclyl of R9. For example, the heteroaryl and / or heterocyclyl of R9can be substituted 1, 2 or 3 times with a moiety selected from halogen, an unsubstituted Ci-6 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, isobutyl, sec -butyl, tert-butyl, pentyl (straight-chained or branched) and hexyl (straight-chained or branched)), an unsubstituted Ci-6 haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F, -CH2CH2CH2F), an unsubstituted Ci-6alkoxy (e.g., -O-(an unsubstituted C1-4 alkyl)), an unsubstituted or a substituted monocyclic C3-6 cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) and an unsubstituted or a substituted phenyl. Suitable halogens, unsubstituted Ci-6 alkyls, unsubstituted Ci-6 haloalkyls and unsubstituted Ci-6 alkoxys are described herein, including those that can be present on a phenyl of R9. An unsubstituted or a substituted phenyl that can be substituted on a heteroaryl or a heterocyclyl of R9can substituted 1, 2, 3, 4 or 5 times. A non-limiting list of examples of substituents that can be substituted on a phenyl that is substituted on a heteroaryl or heterocyclyl of R9include F, Cl, Br, as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, pentyl (straight-chained or branched), hexyl (straight-chained or branched), -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F, -CH2CH2CH2F, -O(an unsubstituted Ci-6 alkyl) (such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (straight-chained or branched), hexoxy (straight-chained or branched)), and an unsubstituted or a substituted 5- to 6-membered monocyclic heteroaryl, wherein the heteroaryl can include 1 , 2 or 3 heteroatoms selected from oxygen, sulfur and nitrogen. Examples of monocyclic heteroaryls include furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine and pyrazine.

[0104] In some embodiments, R9can be an unsubstituted monocyclic C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In other embodiments, R9can be a halogen-substituted monocyclic C3-6 cycloalkyl. In still other embodiments, R9can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted CM alkyl. In yet still other embodiments, R9can be a monocyclic C3-6 cycloalkyl substituted withan unsubstituted C1-4 alkoxy (e.g., -O-(an unsubstituted C1-4 alkyl)). In some embodiments, R9can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C2-4 alkenyl. In other embodiments, R9can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted CM haloalkyl. In still other embodiments, R9can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted monocyclic C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. In yet still other embodiments, R9can be a monocyclic C3-6 cycloalkyl substituted with an unsubstituted or a substituted phenyl, wherein when the phenyl is substituted it can be substituted with one or more substituents selected from halogen (such as -F and -Cl), an unsubstituted C1-4 alkyl (e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl) and an unsubstituted CM haloalkyl (for example, -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F, -CH2CH2CH2F).

[0105] In some embodiments, R9can be an unsubstituted bicyclic C5-6 cycloalkyl. In other embodiments, R9can be a substituted bicyclic C5-6 cycloalkyl. The two rings of a bicyclic C5-6 cycloalkyl can be connected in a spiro-fashion, a fused-fashion or a bridged- fashion. In some embodiments, R9can be a halogen- substituted bicyclic C5-6 cycloalkyl. In still other embodiments, R9can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 alkyl. In yet still other embodiments, R9can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 alkoxy (such as -O-(an unsubstituted C1-4 alkyl)). In some embodiments, R9can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C2-4 alkenyl. In other embodiments, R9can be a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 haloalkyl. In still other embodiments, R9can 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 [l.l.l]pentane and bicyclo [2.1.1 ]hexane.

[0106] Suitable halogen-substituted monocyclic C3-6 cycloalkyls include halogensubstituted 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 Ci- 4 alkoxy (for example, -O-(an unsubstituted C1-4 alkyl)), an unsubstituted C1-4 haloalkyl and / or an unsubstituted monocyclic C3-6 cycloalkyl, cyclobutyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4haloalkyl and / or an unsubstituted monocyclic C3-6 cycloalkyl, cyclopentyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy, an unsubstituted C2-4 alkenyl, an unsubstituted C1-4 haloalkyl and / or an unsubstituted monocyclic C3-6 cycloalkyl and cyclohexyl substituted with an unsubstituted C1-4 alkyl, an unsubstituted C1-4 alkoxy, an unsubstituted C2-4 alkenyl, 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 CM alkoxys 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 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 CM alkyls can be present on a monocyclic C3-6 cycloalkyl substituted with an unsubstituted C1-4 alkyl, 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 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 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 C1-4 alkoxys can be present on a bicyclic C5-6 cycloalkyl substituted with an unsubstituted C1-4 alkoxy, 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 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 C1-4 alkoxy, an unsubstituted C2-4 alkenyl, and an unsubstituted C1-4haloalkyl. 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 C1-4 alkoxy an unsubstituted C2-4 alkenyl, 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, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F.

[0107] In some embodiments, R9can be an unsubstituted alkoxy. In other embodiments, R9can be a substituted alkoxy. Various alkoxys can be present for R9. For example, -O-(hydrocarbon) (such as -O-(Ci-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), -O-(bicyclic heterocyclyl), -O- ((C1-4 alkyl)-monocyclic C3-8 cycloalkyl), -O-((Ci-4 alkyl)-bicyclic C5-8 cycloalkyl), -O-((Ci- 4 alkyl)-phenyl), -O-((Ci-4 alkyl)-bicyclic aryl), -O-((Ci-4 alkyl)-monocyclic heteroaryl), -O-((Ci-4 alkyl)-bicyclic heteroaryl), -O-((Ci-4 alkyl)-monocyclic heterocyclyl) and -O- ((C1-4 alkyl)-bicyclic heterocyclyl). A non-limiting list of examples of Ci-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[l.l.l]pentyl). In some embodiments, R9can be -O-(an unsubstituted or a substituted Ci-8 alkyl). In some embodiments, R9can be -O-(an unsubstituted C1-4 alkyl). For example, R9can be -O-CH3, -O-CH2CH3, -O-CH2CH2CH3, -O-CH(CH3)2, -O-CH2CH2CH2CH3, -O-CH(CH3)CH2CH3, -O-CH2CH(CH3)2 and -O-C(CH3)3, In some embodiments, R9can be an unsubstituted or substituted alkoxy selected from methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, -O-cyclopropyl, -O-cyclobutyl, -O-cyclopentyl, -O- cyclohexyl, -O-(bicyclic C5-8 cycloalkyl) (for example, -O-(bicyclo[l.l.l]pentyl)), -O- (phenyl), -O-(monocyclic 5-6 membered heteroaryl), -O-(monocyclic 4-6 membered heterocyclyl), -O-((Ci-4 alkyl)-monocyclic C3-6 cycloalkyl) (such as -O-C IE-monocyclic C3- 6 cycloalkyl), -O-((Ci-4 alkyl)bicyclic C5-8 cycloalkyl) (for example, -O-CH2- (bicyclo[l.l.l]pentyl)), -O-((Ci-4 alkyl)-phenyl) (for example, -O-(benzyl)), -O-((Ci-4 alkyl)-monocyclic heteroaryl) (such as -O-CIE-(5- or 6-membered monocyclic heteroaryl))and -O-((Ci-4alkyl)-monocyclic heterocyclyl) (such as -O-CH2-(4- to 6-membered monocyclic heterocyclyl)), wherein each can be unsubstituted or substituted. Various heteroatoms and number of heteroatoms can be present in a heteroaryl and heterocyclyl described herein for an alkoxy. For example, the heteroaryl and / or heterocyclyl that is part of the alkoxy for R9can include 1, 2, 3 or 4 heteroatoms independently selected from O (oxygen), S (sulfur) and N (nitrogen). Examples of heteroaryls and heterocyclyls that can be part of an unsubstituted or a substituted alkoxy include those described herein and include furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine, pyrazine, indole, quinoline, isoquinoline, quinazoline, azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidin-2-one, imidazolidin-2-one, tetrahydropyran, tetrahydrothiopyran, piperidine, piperazine, morpholine and thiomorpholine.

[0108] 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, 4, 5 or 6 times with substituents independently selected from halogen (for example, F or Cl), hydroxy, an unsubstituted CM alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl and tert-butyl), an unsubstituted CM haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F), an unsubstituted C alkoxy (e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec -butoxy and tert-butoxy), an unsubstituted or a substituted monocyclic C3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl) and an unsubstituted or a substituted bicyclic C5-8 cycloalkyl (for example, bicyclo[l.l.l]pentyl). When an alkoxy is substituted with an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, the unsubstituted or a substituted monocyclic C3-6 cycloalkyl can replace one hydrogen or two hydrogen. When the unsubstituted or a substituted monocyclic C3-6 cycloalkyl replaces two hydrogen, the unsubstituted or a substituted monocyclic C3-6 cycloalkyl is spiro-connected. When the alkoxy is -O-((Ci-4 alkyl)-monocyclic C3-s cycloalkyl), -O-((Ci-4 alkyl)-bicyclic C5-8 cycloalkyl), -O-((Ci-4 alkyl)-phenyl), -O-((Ci-4 alkyl)-bicyclic aryl), -O-((Ci-4 alkyl)-monocyclic heteroaryl), -O-((Ci-4 alkyl)-bicyclic heteroaryl), -O-((Ci-4 alkyl)-monocyclic heterocyclyl) or -O-((Ci-4 alkyl)-bicyclicheterocyclyl), the cyclic group and / or (C1-4 alkyl) portion can be substituted. The following are examples of the (C1-4 alkyl) portionbeing substituted. In other embodiments, R9can be an alkoxy (such as -O-(Ci-8 alkyl)) substituted 1 to 13 times with deuterium. Examples of deuterium substituted alkoxys include -OCD3 and -OCD2CD3

[0109] In some embodiments, R9can be an amino or an amine, such as -NR17R18, wherein R17and R18can be independently selected from hydrogen, an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted C3-8 cycloalkyl, an unsubstituted or a substituted 3-8 membered heterocyclyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted aryl(alkyl) and an unsubstituted or a substituted heteroaryl(alkyl). In other embodiments, R9can be -NR17R18, wherein R17and R18are taken together along with the nitrogen to which they are connected to form an unsubstituted or a substituted 3-8 membered heterocyclyl.

[0110] In some embodiments, R17and / or R18can be an unsubstituted Ci-8 alkyl. In other embodiments, R17and / or R18can be a substituted Ci-8 alkyl. In still other embodiments, R17and / or R18can be an unsubstituted C2-8 alkenyl. In yet still other embodiments, R17and / or R18can be a substituted C2-8 alkenyl. In some embodiments, R17and / or R18can be an unsubstituted C2-8 alkynyl. In other embodiments, R17and / or R18can be a substituted C2-8 alkynyl. In still other embodiments, R17and / or R18can be an unsubstituted C3-8 cycloalkyl, for example an unsubstituted monocyclic C3-8 cycloalkyl. In yet still other embodiments, R17and / or R18can be a substituted C3-8 cycloalkyl, for example a substituted monocyclic C3-8 cycloalkyl. Various cyclic moieties can be present for R17and / or R18. In some embodiments, R17and / or R18can be an unsubstituted aryl. In other embodiments, R17and / or R18can be a substituted aryl. In still other embodiments, R17and / or R18can be an unsubstituted heteroaryl. In yet still other embodiments, R17and / or R18can be a substituted heteroaryl. In some embodiments, R17and / or R18can be an unsubstituted 3- to 8-membered monocyclic heterocyclyl. In other embodiments, R17and / or R18can be a substituted 3- to 8-membered monocyclic heterocyclyl. In still other embodiments, R17and / or R18can be an unsubstituted aryl(alkyl). In yet still other embodiments, R17and / or R18can be a substituted aryl(alkyl). Insome embodiments, R17and / or R18can be an unsubstituted heteroaryl(alkyl). In other embodiments, R17and / or R18can be a substituted heteroaryl(alkyl). The aryl, heteroaryl and heterocyclyl can be monocyclic or bicyclic, and the heteroaryl and heterocyclyl can include 1 , 2, 3, 4 or 5 heteroatoms independently selected from O (oxygen), S (sulfur) and N (nitrogen). When R17and / or R18is aryl(alkyl) or heteroaryl(alkyl), the alkyl linker can be 1, 2 or 3 alkylene groups, such as -CH2-, -CH2CH2- and -CH2CH2CH2-. In some embodiments, R9can be -NHR18, wherein R18can be as provided herein. For example, In some embodiments, R9can be -NHR18, wherein R18can be an unsubstituted Ci-8 alkyl.

[0111] In some embodiments, R3can be, wherein R10can be independently selected from an unsubstituted or a substituted Ci-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 Ci-6 alkyl is substituted, the Ci-6 alkyl can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, cyano, -NH2, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic 4-6 membered heterocyclyl, an unsubstituted or a substituted monocyclic 5- or 6- membered heteroaryl, an unsubstituted C1-4 alkoxy (e.g., -O-(an unsubstituted C1-4 alkyl)), an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted -O-(CH2)-phenyl and an unsubstituted C1-4 haloalkoxy (e.g., -O-(an unsubstituted C1-4 haloalkyl)); 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 CM alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted C2-4 alkynyl, an unsubstituted C1-4 haloalkyl and an unsubstituted C1-4 alkoxy (such as -O-(an unsubstituted C1-4 alkyl)); and R11can be -(NH)-(an unsubstituted or a substituted 5- to 10-membered heteroaryl). In some embodiments, R11can be an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl. Examples ofheterocyclyls for R11include unsubstituted or a 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 R11include the following: azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidin-2- one, imidazolidin-2-one, tetrahydropyran, tetrahydrothiopyran, piperidine, piperazine, morpholine and thiomorpholine. In some embodiment, R11can be an -(NH)-(unsubstituted 5- to 6-membered monocyclic heteroaryl). In other embodiments, R11can be a -(NH)- (substituted 5- to 6-membered monocyclic heteroaryl). In still other embodiment, R11can be an -(NH)-(unsubstituted 8- to 10-membered bicyclic heteroaryl). In other embodiments, R11can be a -(NH)-(substituted 8- to 10-membered bicyclic heteroaryl). An example of a 5- to 10-membered heteroaryl that can be present for R11include a 5- to 10-membered 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, furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine, pyrazine, indole, quinoline, isoquinoline and quinazoline. In still other embodiments, R11can be -O-(an unsubstituted or a substituted Ci-6 alkyl). In yet still other embodiments, R11can be -O-(an unsubstituted or a substituted C3-8 cycloalkyl). In some embodiments, R11can be -O-(Ci-4 alkyl)-(an unsubstituted or a substituted C3-8 cycloalkyl). The cycloalkyl of -O-(an unsubstituted or a substituted C3-8 cycloalkyl) and -O-(Ci-4 alkyl)- (an unsubstituted or a substituted C3-8 cycloalkyl)can be a monocyclic C3-6 cycloalkyl or a bicyclic C5-8 cycloalkyl. The CM alkyl of -O-(Ci-4 alkyl)-(an unsubstituted or a substituted C3-8 cycloalkyl)can be -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-.

[0112] As described herein, R11can be substituted. Exemplary groups that can be present on R11include halogen, an unsubstituted CM alkyl (for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl), an unsubstituted monocyclic C3-6 cycloalkyl (such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), an unsubstituted C1-4 alkoxy (for example -O(Ci-4 alkyl), such as methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, iso-butoxy, sec-butoxy and tert-butoxy), an unsubstituted C1-4 haloalkyl (for example, -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F), an unsubstituted phenyl, a substituted phenyl, an unsubstituted 5- or 6-membered heteroaryland a substituted 5- or 6-membered heteroaryl (for example wherein a substituted phenyl and / or substituted 5- or 6-membered heteroaryl can be substituted 1, 2, 3, 4 or 5 times with a substituent independently selected from halogen (for example, F, Cl and Br), an unsubstituted Ci-4 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl), an unsubstituted CM alkoxy (for example -0(Ci-4 alkyl) such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec -butoxy and tert-butoxy), an unsubstituted Ci-4 haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F), an unsubstituted -O(an unsubstituted CM haloalkyl) (for example, -O(Ci-4haloalkyl) such as -OCF3, -OCHF2, -OC(CH3)F2, -OCH2F, -OCH(CH3)F, -OCH2CF3, -OCH2CH2F and -OCH2CH2CH2F) and -S(=O)2(an unsubstituted Ci-4 alkyl).

[0113] The R8and R10moieties can be a substituted or an unsubstituted version of a Ci-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a monocyclic C3-6 cycloalkyl, a bicyclic C5-8 cycloalkyl, a monocyclic 4- to 6-membered heterocyclyl or a bicyclic 5- to 8-membered heterocyclyl. In some embodiments, R8and / or R10can be an unsubstituted Ci-6 alkyl. In other embodiments, R8and / or R10can be a substituted Ci-6 alkyl. Exemplary Ci-6 alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, pentyl (straight- chained and branched) and hexyl (straight-chained and branched). In some embodiments, R8and / or R10can be an unsubstituted C2-6 alkenyl. In other embodiments, R8and / or R10can be a substituted C2-6 alkenyl. In still other embodiments, R8and / or R10can be an unsubstituted C2. 6 alkynyl. In yet still other embodiments, R8and / or R10can be a substituted C2-6 alkynyl.

[0114] Cyclic moieties, including monocyclic and bicyclic moieties, can also be present for R8and / or R10. In some embodiments, R8and / or R10can be an unsubstituted monocyclic C3-6 cycloalkyl. In other embodiments, R8and / or R10can be a substituted monocyclic C3-6 cycloalkyl. For example, R8and / or R10can 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, R8and / or R10can be an unsubstituted bicyclic C5-8 cycloalkyl. In other embodiments, R8and / or R10can be an unsubstituted bicyclic C5-8 cycloalkyl. The two rings of the bicyclic C5-8 cycloalkyl can joined in a fused-fashion, a spiro-fashion or a bridged- fashion. Examples of rings connected in a fused and a spiro-fashion are provided herein. In some embodiments, R8and / or R10can be an unsubstituted or a substituted bicyclo[l.1. l]pentyl.In still other embodiments, R8and / or R10can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl. In yet still other embodiments, R8and / or R10can be an unsubstituted monocyclic 4- to 6-membered heterocyclyl. In some embodiments, R8and / or R10can be an unsubstituted bicyclic 5- to 8-membered heterocyclyl. In other embodiments, R8and / or R10can be an unsubstituted bicyclic 5- to 8-membered heterocyclyl. As with a bicyclic C5-8 cycloalkyl, the two rings of a bicyclic 5- to 8-membered heterocyclyl can be connected in a fused-fashion, a spiro-fashion or a bridged-fashion. The number of heteroatoms present in a monocyclic 4- to 6-membered heterocyclyl and a bicyclic 5- to 8-membered for R8and / or R10can 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 azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidin-2-one, imidazolidin-2-one, tetrahydropyran, tetrahydrothiopyran, piperidine, piperazine, morpholine and thiomorpholine (including unsubstituted or substituted versions of each of the aforementioned); examples of bicyclic 5- to 8-membered heterocyclyls are 2-oxabicyclo[2.1.1]hexane, bicyclo [1.1.1] pentane, bicyclo[3.1.1]heptane and bicyclo[2.2.2]octane (including unsubstituted or substituted versions of each of the aforementioned).

[0115] As described herein, R8and / or R10can be substituted. In some embodiments, when R8and / or R10is a Ci-6 alkyl that is substituted, the Ci-6 alkyl can be substituted 1 , 2, 3 or 4 times with a substituent independently selected from halogen, cyano, -NH2, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic 5- to 6-membered heteroaryl, an unsubstituted or a substituted monocyclic 4-6 membered heterocyclyl, an unsubstituted C1-4 alkoxy (for example, -O-(an unsubstituted C1-4 alkyl)), an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted -O-(CH2)-phenyl and an unsubstituted CM haloalkoxy (such as -O-(an unsubstituted C1-4 haloalkyl)). In some embodiments, R8and / or R10can be a Ci-6 alkyl that is substituted 1 to 13 times with deuterium. In some embodiments, R8and / or R10can be a Ci-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 that can be substituted on R8and / or R10moiety can be independently F (fluoro) or Cl (chloro). In other embodiment, R8and / or R10can be a Ci-6 alkyl that is substituted with -NH2. For example, R8and / or R10canbe - (CH2)I-6- NH2. Exemplary unsubstituted and substituted monocyclic C3-6 cycloalkyls and unsubstituted and substituted bicyclic C5-6 cycloalkyls that can be present on a substituted Ci- 6 alkyl for R8and / or R10include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, halogensubstituted monocyclic C3-6 cycloalkyls, (an unsubstituted C1-4 alkyl)-substituted monocyclic C3-6 cycloalkyls, bicyclofl. l.l]pentyl and spiro[2.2]pentyl. A phenyl that can be substituted on a C1-6 alkyl of R8and / or R10. The phenyl can be unsubstituted or substituted. In some embodiments, R8and / or R10can be a Ci-6 alkyl that is substituted with an unsubstituted or a substituted monocyclic 5- to 6-membered heteroaryl. The monocyclic 5- to 6-membered heteroaryl can include various heteroatoms (such as nitrogen, oxygen and sulfur), and the number of heteroatoms can also vary. Exemplary monocyclic heteroaryls include furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine and pyrazine. In other embodiments, R8and / or R10can be a Ci-6 alkyl that is substituted with an unsubstituted or a substituted monocyclic 4-6 membered heterocyclyl. Examples of monocyclic 4- to 6-membered heterocyclyls are azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidin-2-one, imidazolidin-2-one, tetrahydropyran, tetrahydrothiopyran, piperidine, piperazine, morpholine and thiomorpholine (including unsubstituted or substituted versions of each of the aforementioned).

[0116] The phenyl, monocyclic 5- to 6-membered heteroaryl and / or monocyclic 4- 6 membered heterocyclyl that can be substituted on a Ci-6 alkyl of R8and / or R10can be substituted one or more times (1, 2, 3 or 4 times) with a substituent independently selected from halogen (such as bromo, chloro and fluoro), cyano, an unsubstituted C1-4 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), hydroxy, an unsubstituted C1-4 alkoxy (for example, -O(Ci-4 alkyl) such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec -butoxy and tert-butoxy), an unsubstituted C1.4 haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F) and an unsubstituted C1-4 haloalkoxy (for example, -O(Ci-4 haloalkyl), such as -OCF3, -OCHF2, -OC(CH3)F2, -OCH2F, -OCH(CH3)F, -OCH2CF3, -OCH2CH2F and -OCH2CH2CH2F).

[0117] Suitable unsubstituted CM alkoxys that can be substituted on a Ci-6 alkyl of R8and / or R10include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy. In some embodiments, a Ci-6 alkyl of R8and / or R10can be substituted with an unsubstituted or a substituted phenoxy. In other embodiments, a Ci-6 alkyl of R8and / or R10can be substituted with an unsubstituted or a substituted -O-(CH2)-phenyl. In other embodiments, a Ci-6 alkyl of R8and / or R10can be substituted with an unsubstituted Ci-4 haloalkoxy. Examples of an unsubstituted C1-4 haloalkoxy can be substituted on a Ci-6 alkyl of R8and / or R10include -OCF3, -OCH2F and -OCHF2. In some embodiments, R8and / or R10can be an unsubstituted monocyclic C3-6 cycloalkyl(CH2)-. Various monocyclic C3-6 cycloalkyl are described herein. As examples, R8and / or R10can be selected from cyclopropyl(CH2)-, cyclobutyl(CH2)-, cyclopentyl(CH2)- and cyclohexyl(CH2)-. In other embodiments, R8and / or R10can be (an unsubstituted or a substituted bicyclic C5-6 cycloalkyl)- (CH2)-. In still other embodiments, R8and / or R10can be (an unsubstituted or a substituted phenyl)-(CH2)-. In still other embodiments, R8and / or R10can be (an unsubstituted or a substituted monocyclic 5- or 6-membered heteroaryl)-(CH2)-. In yet still other embodiments, R8and / or R10can be (an unsubstituted or a substituted monocyclic 4-6 membered heterocyclyl)-(CH2)-.

[0118] In some embodiments, when R8and / or R10is 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 CM 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 the previous paragraph. Non-limiting list of unsubstituted and substituted monocyclic C3-6 cycloalkylsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and halogen-substituted monocyclic C3-6 cycloalkyls. Examples of unsubstituted Ci-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, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F.

[0119] In some embodiments, R8acan be hydrogen. In other embodiments, R8acan be an unsubstituted CM alkyl. For example, R8acan be methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl or sec -butyl. In some embodiments, R8and R8acan be taken together to form an unsubstituted monocyclic C3-6 cycloalkyl. In some embodiments, R8and R8acan be taken together to form a halogen-substituted monocyclic C3-6 cycloalkyl, where 1, 2, 3 or 4 halogens can be present. As an example, R8and R8acan be taken together to form a fluoro-substituted monocyclic C3-6 cycloalkyl.

[0120] In some embodiments, R3can be R12. As described herein, R12can be an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 8 -membered monocyclic heterocyclyl, an unsubstituted or a substituted 5- to 8-membered bicyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl), an unsubstituted or a substituted heteroaryl(alkyl), an unsubstituted or a substituted C-carboxy, -OR13, -NR14R15or -C(=O)-NR16AR16B. In some embodiments, R12can be an unsubstituted Ci-8 alkyl. In other embodiments, R12can be a substituted Ci-8 alkyl. In still other embodiments, R12can be an unsubstituted C2-8 alkenyl. In yet still other embodiments, R12can be a substituted C2-8 alkenyl. In some embodiments, R12can be an unsubstituted C2-8 alkynyl. In other embodiments, R12can be a substituted C2-8 alkynyl.

[0121] A variety of cyclic moieties can be present for R12. In some embodiments, R12can be an unsubstituted C3-8 cycloalkyl. In other embodiments, R12can be a substituted C3-8 cycloalkyl. For example, R12can be an unsubstituted or a substituted monocyclic C3-8 cycloalkyl. In still other embodiments, R12can be an unsubstituted aryl. In yet still other embodiments, R12can be a substituted aryl. As an example, R12can be an unsubstituted or a substituted phenyl. In some embodiments, R12can be an unsubstituted heteroaryl. In otherembodiments, R12can be a substituted heteroaryl. In some embodiments, R12can be an unsubstituted 3- to 12-membered monocyclic heterocyclyl. In other embodiments, R12can be a substituted 3- to 12-membered monocyclic heterocyclyl. In still other embodiments, R12can be an unsubstituted or a substituted 5- to 12-membered bicyclic heterocyclyl. In yet still other embodiments, R12can be an unsubstituted or a substituted 5- to 12-membered bicyclic heterocyclyl. In some embodiments, R12can be an unsubstituted or a substituted 3- to 12- membered monocyclic heterocyclyl. In other embodiments, R12can be an unsubstituted or a substituted 5- to 8-membered bicyclic heterocyclyl. In some embodiments, R12can be an unsubstituted aryl(alkyl). In other embodiments, R12can be a substituted aryl(alkyl). For example, R12can be an unsubstituted or a substituted benzyl. In some embodiments, R12can be an unsubstituted heteroaryl(alkyl). In other embodiments, R12can be a substituted heteroaryl(alkyl). In some embodiments, R12can be an unsubstituted heterocyclyl(alkyl). In other embodiments, R12can be a substituted heterocyclyl(alkyl). The aryl, heteroaryl and heterocyclyl, including that those of an aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl)) can be monocyclic or bicyclic (unless stated otherwise), and include 1, 2, 3, 4 or 5 heteroatoms independently selected from O (oxygen), S (sulfur) and N (nitrogen). Exemplary heteroaryls for R12include, but are not limited to, furan, isoxazole, isothiazole, pyrrole, pyrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole, imidazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, pyridine, pyridazine, pyrimidine, pyridazine, pyrazine, indole, benzo[d]imidazole, pyrrolo[2,3- b]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, thieno[2,3-b]pyrrole, benzofuran, benzo[b]thiophene, benzo[d]oxazole and benzo [d] thiazole. Examples of heterocyclyls for R12include azetidine, oxetane, thietane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, oxazolidin-2-one, imidazolidin-2-one, tetrahydropyran, tetrahydrothiopyran, piperidine, piperazine, pyridin-2(lH)-one, pyridazin-3(2H)-one, morpholine, thiomorpholine, isoquinolin- l(2H)-one and 5-azaspiro[2.4]heptane. When R12is aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), the alkyl linker can be 1, 2 or 3 alkylene groups, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -C(CH3)3- and -CH2-(CH3)3-. The alkyl linker of an aryl(alkyl), a heteroaryl(alkyl) and a heterocyclyl(alkyl) can be also substituted. Possible substituents that take the place of one or more of the hydrogens (such as 1 , 2, 3 or 4 hydrogens) of the alkyl linker include, but are not limited to, halogen, hydroxy and cyclopropyl (for example, -CH-(cyclopropyl)-), or two hydrogen on the same carbon can be replaced with aVXZ54 spiro-connected monocyclic C3-4 cycloalkyl (for example,fand * ).

[0122] As provided herein, R12can be substituted. For example, R12can be substituted 1, 2, 3 or 4 times with a substituent independently selected from halogen, hydroxy, an unsubstituted CM alkyl, an unsubstituted C1-4 alkoxy (for example -O(Ci-4 alkyl), such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec -butoxy and tert-butoxy), an unsubstituted C1-4 haloalkyl, -C(=O)(an unsubstituted C1-4 alkyl), -C(=O)(an unsubstituted C1-4 haloalkyl), an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted phenyl, a substituted phenyl, an unsubstituted 5- or 6-membered heteroaryl, a substituted 5- or 6- membered heteroaryl, an unsubstituted 5- or 6-membered heterocyclyl and a substituted 5- or 6-membered heterocyclyl (for example a substituted phenyl, as substituted 5- or 6-membered heteroaryl and / or a substituted 5- or 6-membered heterocyclyl, which can be substituted 1, 2, 3, 4 or 5 times with a substituent selected from halogen (for example, F, Cl and Br), 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 alkoxy (for example -O(Ci-4 alkyl) such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec -butoxy and tert-butoxy), an unsubstituted CM haloalkyl (such as -CF3, -CHF2, -C(CH3)F2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CH2F and -CH2CH2CH2F), an unsubstituted -O(an unsubstituted C1-4 haloalkyl) (for example, -OCF3, -OCHF2, -OC(CH3)F2, -OCH2F, -OCH(CH3)F, -OCH2CF3, -OCH2CH2F and -OCH2CH2CH2F) and -S(=O)2(an unsubstituted C1-4 alkyl). The alkyl linker of an aryl(alkyl), a heteroaryl(alkyl) and a heterocyclyl(alkyl) can be also substituted. Possible substituents that take the place of one or more of the hydrogens (such as 1 , 2, 3 or 4 hydrogens) include, but are not limited to, halogen and hydroxy. The 5- or 6-membered heteroaryl and 5- or 6-membered heterocyclyl can include 1, 2 or 3 heteroatoms selected from O (oxygen), S (sulfur) and N (nitrogen).

[0123] In some embodiments, R12can be an unsubstituted C-carboxy. In other embodiments, R12can be a substituted C-carboxy. In still other embodiments, R12can be an alkoxy. For example, in some embodiments, R12can be -OR13, wherein R13can be an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstitutedor a substituted 3- to 8-membered monocyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl) or an unsubstituted or a substituted heteroaryl(alkyl). In still other embodiments, R12can be amino, mono- substituted amine or a di-substituted amine. In some embodiments, the amine can be -NR14R15, wherein R14and R15can be independently selected from hydrogen, an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl) or an unsubstituted or a substituted heteroaryl(alkyl). In yet still other embodiments, R12can be C-amido. In some embodiments, R12can be -C(=O)-NR16AR16B, wherein R16Acan be hydrogen or an unsubstituted C1-3 alkyl; and R16Bcan be an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl. In some embodiments, R16Acan be hydrogen; and R16Bcan be an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic 5- or 6-membered heteroaryl or an unsubstituted or a substituted 3- to8-membered monocyclic heterocyclyl.

[0124] Various examples of R12groups include the following:wherein each is unsubstituted or substituted (including the nitrogen). Otherexamples of R12groups include the following:wherein each is unsubstituted or substituted(including the nitrogen). When R12is substituted, R12can be substituted with a variety of substituents. For example, R12can be substituted 1, 2, 3, or more than 3 times with a substituent independently selected from halogen, (such as F and Cl), an unsubstituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl, hydroxy, an unsubstituted CM alkoxy, -C(=O)(an unsubstituted Ci-4 alkyl), -C(=O)(an unsubstituted CM haloalkyl) and an unsubstituted or a substituted phenyl (for example, an unsubstituted phenyl or a phenyl substituted with 1 , 2 or 3 substituents independently selected from halogen, an unsubstituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl and an unsubstituted Ci-4 alkoxy).HO

[0125] Examples of substituted R12groups include the following:Further examples of R12include the following:

[0126] Exemplary R3groups include the following:VLwherein each phenyl and can be substituted or unsubstituted as described herein. As examples, the phenyl can be substituted with 1, 2 or 3 substituents independently selected from halogen for example, fluoro and / or chloro, an unsubstituted CM alkyl, an unsubstituted Ci-4 haloalkyl and an unsubstituted C alkoxy.Examples of substituted phenyls within R9include

[0127] Further examples of R3groups include:wherein each moiety is unsubstituted or substituted.

[0128] In some embodiments, R3can be selected from

[0130] In some embodiments, R2can be hydrogen. In other embodiments, R2can be deuterium. In still other embodiments, R2can be halogen (such as fluoro or chloro).

[0131] Examples of compounds of Formula (I), include the following:pharmaceutically acceptable salt of any of the foregoing.

[0132] Further examples of compounds of Formula (I), can be selected from:pharmaceutically acceptable salt of any of the foregoing.

[0133] Additional examples of compounds of Formula (I), include the following:acceptable salt of any of the foregoing.

[0134] Examples of compounds of Formula (I), can be selected from:pharmaceutically acceptable salt of any of the foregoing.

[0135] In some embodiments, Ring A1cannot be an unsubstituted or a substitutedembodiments, Ring A1cannot be an unsubstituted or a substitutedIn some embodiments, Ring A1cannot be an unsubstituted or a substitutedIn some embodiments, Ring A1cannot be an unsubstituted or aSynthesis

[0136] 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

[0137] Scheme A describes the synthesis of compounds of general Formula (A-6). An amino ester of general Formula (A- 1 , Aik represents alkyl) reacts 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 a compound of general Formula (A-4). Further coupling of the carboxylic acid of general Formula (A-4) with an amine R1can provide compounds of Formula A-5.Scheme Al

[0138] Alternatively, as described in Scheme Al, a sub-group of amino acids of general Formula (Al-5) can be prepared as described in Scheme Al. A protected (PGA1) amino acid of general Formula (Al- 1) can be coupled with an aminoester of general Formula (A-l) under known amide formation conditions, for example, HATU and iPr2NEt. The ester of a compound of Formula (A 1-2) can be deprotected, for example, by using LiOH in THF / H2O, resulting in the acid of general Formula (Al-3). The protecting group PGA1can be removed, for example, by treatment with TFA in case PGA1being Boc, resulting in a compound of general Formula (A 1-4). This compound can be converted to a compound of general Formula (Al-5) (for example, by treatment with ethyl 2,2,2-trifluoroacetate in the presence of triethylamine) a compound of general Formula (A 1-6) (for example, by treatment of a compound of general Formula (A 1-4) 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)).. Alternatively, compounds of the general Formula (A 1-4) can be reacted with a different electrophile by either an amino acid coupling reaction, reaction with an acid chloride or reaction with a chloroformate to afford compounds of the Formula (A 1-6).

[0139] General methodology for the synthesis of amino acids of general Formula(Al-1), or precursors that could be converted to an amino acid of general Formula (Al-1) by one skilled in the art, are described in the literature, and include the following examples:Scheme BG4

[0140] Intermediates are described in Scheme B. The intermediate of general Formula (Gl) can undergo a Diels- Alder reaction with cyclopentadiene to afford compounds of the general Formula (G2). Compounds of Formula (G2) can be subjected to catalytic hydrogenation conditions to afford the saturated intermediate analog compounds of general Formula (G3). The compounds of general Formula (G2) can react in a Simmons-Smith reaction to form compounds of general Formula (G4), containing a cyclopropyl ring.Scheme C

[0141] Other intermediates are described in Scheme C. The intermediate of general Formula (G2), can be selectively hydroxylated, for example, by hydrosilylation with trichlorosilane in the presence of a chiral Pd-catalyst, followed by SiCh / OH exchange (for example, Breuning et al, Beilstein Journal of Organic Chemistry 2009, 5(81), 1-5). Oxidation of the alcohol of general Formula (Hl) can provide a ketone of general Formula (H2). The ketone of general Formula (H2) can be converted to an alkene of general Formula (H3), for example, by using a Wittig or a Tebbe reagent. Transformation of the double bond towards the cyclopropyl can be done by treatment with CH2N2 in the presence of Pd(OAc)2, or other methods described in the literature and known to those skilled in the art, and can result in a compound of general Formula (H4). A similar approach can be accomplished with the isomer of a compound of general Formula (Hl), a compound of general Formula (H5) can be obtainedby using an enantiomeric chiral Pd-catalyst. A compound of general Formula (H5) can then be converted to a compound of general Formula (H6), similar as outlined for the conversion of a compound of general Formula (Hl) to a compound of general Formula (H4). Alternatively, the ketone of compound of general Formula (H2) can be converted to a compound of general Formula (H2’) by fluorination, for example by application of the DAST reagent. The isomeric compound of general Formula (H7) can be obtained starting from a related isomer. The alcohols of general Formulae (Hl) and (H5) can be converted to the related fluoro derivatives of general Formulae (HF) and (H5’), by treatment with a fluorination reagent like DAST (Diethylaminosulfur trifluoride).Scheme D

[0142] Other compounds of general Formulae (II), (12) (Johnson et al., Synthetic Communications (2011) 41(18):2769-2793), (13), (14), (15), (16), (17), (18), (19), (110), (Il l) and (112) as depicted in Scheme D can be obtained by methods described in literature (for example, de Graaff et al., Org. Biomol. Chem. (2015) 13: 10108-10112; and Johnson et al.,Synthetic Communications (2011) 41(18):2769-2793) and / or by applying methodologies as described herein. Compounds general Formulae (II), (12), (13), (14), (15), (16), (17), (18), (19), (110), (Il l) and (112) can be used to obtain compounds of Formula (I), along with pharmaceutically acceptable salts, using similar methods as described herein.Scheme EL4 L5

[0143] The synthesis of spriobenzoxazinones of Formula (L5), depicted in Scheme E, can prepared with the conversion of a ketone of Formula (LI) to the protected cyanohydrin of Formula (E2) with the use of a silyl cyanide, such as TMSCN. Deprotection of the alcohol and alcoholysis of the CN group of compounds of Formula (E2) (for example, in HC1, CH3OH) can lead to the formation of hydroxy-ester compounds of Formula (E3). Reaction with orthonitrophenols using typical Mitsunobu conditions can afford ether compounds of Formula (E4). Reduction of the nitro group of compounds of Formula (E4) can be accomplished under conditions known to those skilled in the art (e.g., Fe, NH4CI) in an alcoholic / aqueous solvent to afford the amine and concomitant ring closure to generate spirobenzoxazinones of Formula (E5), wherein the spirobenzoxazinone can be unsubstituted or substituted.Scheme Fl

[0144] An alternative general synthetic method towards the compound series depicted in Scheme E is provided in Scheme Fl. Compounds of Formula (E10) can be converted to compounds of Formula (E20) by reaction with an optionally substituted phenol in the presence of a base (such as NaOH) in an appropriate solvent (e.g., acetone). The two alkyl ester groups of Formula (E20) can be converted to the primary amides of Formula (E21) by heating with ammonia in a sealed vessel (facilitated when Aik is methyl or ethyl). Compounds of Formula (E21) can be reacted under copper catalysis conditions (e.g., Cui, DMEDA, CS2CO3) to afford cyclization and provide compounds of Formula (E22), wherein the ring(s) can be unsubstituted or substituted.Scheme F2

[0145] Similar to Scheme Fl, Scheme F2 depicts a synthetic pathway towards seven-membered spiro rings. Compounds of Formula (E10) can be converted to compounds of Formula (MIO) by reaction with an optionally substituted, optionally protected, 2-(aminomethyl)phenol in the presence of a base (such as NaOH) in an appropriate solvent (e.g., acetone) with excess base resulting in the diacid of Formula (MIO). Alkylation of the acid groups utilizing an alkyl halide and base (e.g., CH3I, K2CO3, DMF) can result in a diester ofFormula (Mi l). The removal of the protecting group (PG2) either selectivity or unselectively over PGi can afford a primary amine that, upon heating with base (e.g. triethylamine), will cyclize to form spirocyclyls of Formula (M12), wherein the spirocyclyls can be unsubstituted or substituted..Scheme GQ-4 Q-5

[0146] A spirolactam derivative of Formula (Q-5) can be prepared as provided in Scheme G. Pyrrolidinone of Formula (Q-l) when n is 1, Aik is Et and PG1is Boc can be prepared as described in Cowley et al., Org. Biomol. Chem. (2011) 9:7042-7056. Pyrrolidinone of Formula (Q-l) when n is 2, Aik is Et and PG1is Boc can be prepared by Michael reaction with acrylonitrile and 1 -( / -butyl) 2,4-diethyl (2S)-5-oxopyrrolidine- 1,2,4- tricarboxylate synthesized as described in Cowley et al., Org. Biomol. Chem. (2011) 9:7042- 7056. Selective reduction of a pyrrolidinone of Formula (Q-l) (with PG1representing a suitable nitrogen protecting group, for example, -Boc) using lithium triethylborohydride followed by further reduction of the hemiaminal intermediate with triethysilane and boron trifluoride etherate (Dorta et al., Tetrahedron Lett. (1994) 35(13):2053-2056) can provide a pyrrolidine of Formula (Q-2). Nitrile reduction (for example, with CoCh and NaBFL), and subsequent cyclisation in-situ can provide a lactam of Formula (Q-3). Alternatively, a nitrile of Formula (Q-2) can be converted via a Kulinkovich-Szymoniak reaction into a cyclopropyl amine, which can react with the ethyl ester in-situ to afford a lactam of Formula (Q-3). A primary amide of Formula (Q-4) can be prepared by aminolysis of an ester of Formula (Q-3),when Aik is methyl or ethyl, or by ester hydrolysis in basic conditions followed by the reaction with ammonia under typical amide coupling conditions. Protecting group removal (for example, when PG1is Boc, by treatment with HC1) can provide an amine of Formula (Q-5). The spirolactam intermediates can be resolved using various techniques (such as purification by chromatography).Scheme Hl

[0147] Alternatively, lactams of Formula (Q-3) when n is 1, RzlObis H and PG1is Boc can be prepared as provided in Scheme Hl. Alkylation of a pyrrolidinone of Formula (Q2-1) (synthesized as described in Cowley et al., Org. Biomol. Chem. (2011) 9:7042-7056) with an allyl halide in presence of a base (such as sodium hydride) can provide allyl of Formula (Q2-2). A pyrrolidine of Formula (Q2-3) can be prepared by reduction using lithium triethylborohydride followed by treatment with triethysilane and boron trifluoride etherate as described for the pyrrolidine of Formula (Q-2). A ketone of Formula (Q2-4) can be prepared by oxidative cleavage using, for example, osmium tetroxide and sodium periodate. Reductive amination with ammonium acetate and a reducing agent (such as sodium cyanoborohydride followed by cyclisation in-situ) can provide a lactam of Formula (Q-3).Scheme I

[0148] A general synthesis towards spiropyridazinones is provided in Scheme I. Acetophenones can be converted to an enol ether of Formula (Tl) using methods know to those skilled in the art (for example, TBSC1, Nal, triethylamine in CH2CI2). In parallel, a compound of Formula (L50) can be prepared using a similar procedure for the formation of a compound of Formula (LIO) with the exception that bromoform can be used instead of chloroform. Compounds of Formula (L50) can be transformed into compounds of Formula (L51) using a base in an alcoholic solvent (such as DBU in methanol). Compounds of Formula (L51) can react with an enol ether of Formula (Tl) using a copper catalyst and base to form compounds of Formula (T2). Deprotection of the enol ether, for example, with TBAF in THF, can afford a ketone of Formula (T3), which can be reacted with hydrazine (in an organic solvent, with optional heating) to afford a compound of Formula (T4). The ester of Formula (T4) can beconverted to a primary amide of Formula (T5) via addition of concentrated ammonia in an organic solvent, optionally heated under pressure.

[0149] A general synthesis to prepare spirolactams is shown in Scheme J. Starting bromides of Formula (L51) can be reacted with a (2-bromobenzyl) zinc bromide via a cobalt catalyst in an organic solvent to afford a compound of Formula (VI). Subsequent conversion of a compound of Formula (VI) to the bis-acid of Formula (V2) can be accomplished via basic hydrolysis. A bis-amide of Formula (V3) can be formed by reacting the bis acid of Formula (V2) with ammonia and a coupling catalyst. Ring closure via copper catalysis can afford a compound of Formula (V4).Scheme K

[0150] Scheme K provides a general synthesis of phenyl substituted spirolactams. The alcohol of a compound of Formula (W5) can be exchanged for a halogen (for example, iodine) via the Appel reaction using iodine and triphenylphosphine. An alkyl iodide of Formula (XI) can undergo a Suzuki reaction with a phenyl borane or phenyl boronic acid, using procedures described known to those skilled in the art to afford a compound of Formula (X3). Alternatively, the halogen of a compound of Formula (XI) can be eliminated to form a double bond compound of Formula (X2). Compounds of Formula (X2) can undergo a Hecktype coupling reaction using methods known to those skilled in the art to afford a compound of Formula (X4).Scheme L

[0151] Depicted in Scheme L is a synthesis towards spirolactams of Formula (Y5). Commercially available protected serine esters can be converted to an alkyl chloride of Formula (Yl) using the Appel reaction (PPI13, CCI4). A compound of Formula (Yl) can undergo a cycloaddition with an aryl acrylate of Formula (Y2) to afford a cyclic compound of Formula (Y3). Subsequent formation of a compound of Formula (Y4) can be accomplished via a Suzuki coupling of a vinyl potassium trifluoroborate with the aryl bromide of Formula (Y3). Alternatively, formation of a compound of Formula (Y4) can be accomplished by reaction of the aryl bromide of Formula (Y3) with Zn(CN)2 with the aid of a Pd catalyst, followed by reduction of the CN group to afford a compound of Formula (Y4) where PG is hydrogen. Compounds of Formula (Y 4) can be cyclized by deprotection of the amine, followed by heating, or alternatively, deprotection of the amine and the ester using a coupling agent to afford a spirocyclic lactam of Formula (Y5).Scheme M

[0152] Depicted in Scheme M is a general synthetic pathway towards spirolactams of Formula (Z4) and Formula (Z5) where R can be Ci-Ce alkyl, Ci-Ce alkoxy, aryl or heteroaryl. Compounds of the Formula (L51) can react with an acetylene, mediated by copper (e.g. CuBr) in the presence of a base (such as triethylamine) to afford compounds of Formula (Zl). Subsequent conversion of the ester groups to primary amides can be affected by the addition of ammonia in methanol (MeOH) in a sealed reactor to give compounds of Formula (Z2). Ring closure, to form compounds of Formula (Z3), can be mediated by copper or palladium catalysis (for example, Xphos Pd G3). Compounds of Formula (Z3) can be subjected to hydrogen and a palladium catalyst (such as Pd / C) to reduce the double bond to afford compounds of Formula (Z4). Alternatively, compounds of Formula (Z3) can be further derivatized in a Simmons-Smith reaction or carbene insertion to afford compounds of the Formula (Z5).Scheme N

[0153] Scheme N depicts a general synthetic method to form an aldehyde of Formula (B105) where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. An ester of Formula (B101) can be reduced to the alcohol of Formula (B 102) using methods provided in the literature (e.g., LiBFU). Removal of the protecting group (PG) can afford a compound of the Formula (B103) (e.g., HC1 when PG is Boc). The amine of Formula (B 103) can be coupled to a carboxylic acid of Formula (A 104) using known coupling agents (e.g., HATU) to afford a compound of Formula (B104). Oxidation of the alcohol group of Formula (B104) can be accomplished using an oxidizing reagent described in the literature (such as IBX or Dess-Martin periodinane) and provide an aldehyde of Formula (B105).Scheme N2

[0154] Scheme N2 depicts a general method to synthesize the hydroxyketones of Formula (Cl 06) where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. An ester of Formula (B101) can be hydrolyzed, for example, with LiOH when Aik is methyl, to afford a carboxylic acid of Formula (C101). Conversion of compounds of Formula (C101) to an amide of Formula (C102) can be accomplished by using a coupling agent (e.g., BOP, HATU, etc.) in the presence of N,O-dimethylhydroxyamine and a base (such as triethylamine) in an appropriate solvent (e.g., DMF). Addition of an organometallic reagent to the Weinreb amide of Formula (C102), followed by work-up, can result in a ketone of Formula (C103). An example, wherein R is benzyl, is the formation of an organometallic reagent by mixing Mg, HgCh and benzylchloromethyl ether, followed by addition to a Weinreb amide of Formula (C102), followed by work-up with saturated ammonium chloride, (See Evans et al., Journal of the American Chemical Society (1988) 110(11):3560-3578 and Mendonca et al., Bioorganic & Medicinal Chemistry Letters (2002) 12(20):2887-2891) to afford an ether of the Formula (C103). Removal of the nitrogen protecting group (PG), (for example, using HC1 or pTSA when PG is Boc) can afford a compound of Formula (Cl 04). Subsequent coupling of a compound of Formula (C104) with a carboxylic acid of a compound of Formula (A104), using a coupling agent (e.g., TCFH, HBTU, etc.) can afford a compound of Formula (C105). The R group can be selectively removed (for example, by catalytic hydrogenation conditions (whenR is benzyl (Bn), in Pd / C in a hydrogen atmosphere)) and provide a hydroxyketone of Formula (C106).Scheme N3C201 C202

[0155] Another method for preparing an intermediate that can be used to prepare R1is shown in Scheme N3 where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. In Scheme N3, the Weinreb amide of Formula (C201) can be converted to a heterocyclic ketone of Formula (C202) using methods known to those skilled in the art (for example, Nahm et al., Tetrahedron Lett. (1981) 22(39), 3815-3818 and Balasubramaniam et al., Synthesis (2008) 23:3707-3738).Scheme N4C101

[0156] A general synthetic method to afford chloromethylketones of Formula (DI 03) is depicted in Scheme N4 where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. Compoundsof Formula (B101) can be converted to a chloromethylketones of Formula (D101), for example, when Aik is methyl or ethyl, via methods known in the art (e.g., Pace et al., Advanced Synthesis & Catalysis (2013) 355(5):919-926 and Concellon et al., Journal of Organic Chemistry (2001) 66(25): 8661-8665) using chloroiodomethane, or bromoiodomethane, and a strong base (such as LDA). An ester of Formula (B 101) can be hydrolyzed to a compound of Formula (C101) and then converted to a chloromethylketone employing a variety of methods known in the art, including, but not limited to, the following: isopropyl chloroformate, 4- methylmorpholine, then diazomethane (See Sun et al., J. Med. Chem. 2006, 49(11):3153- 3158). The protecting group of compounds of Formula (D101) can be cleaved to afford an amine of Formula (DI 02). Subsequent coupling of an amine of Formula (DI 02) with a carboxylic acid of Formula (A 104) can be utilized using known coupling agents to provide chloromethylketones of Formula (D103).

[0157] A general synthesis towards fluoromethylketone compounds of Formula (E104) is provided in Scheme N5 where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. The benzyl ether of Formula (C103) can be cleaved by Pd catalyzed hydrogenolysis (for example Pd / C in methanol) to afford a compound of Formula (E101). Subsequent conversion of an alcohol of Formula (E101) can be converted to a fluoromethylketone using fluorinating reagents that are known to those skilled in the art (e.g., a sulfonyl fluoride / HF-EtsN) to afford afluoromethylketone of Formula (E102). Deprotection of the protecting group (PG) (for example, with HC1 if PG is Boc) can afford compounds of Formula (E103). Compound of Formula (El 03) can be then coupled with a carboxylic acid of Formula (A 104) using a wide variety of commercially available coupling agents (such as TCFH in DMF with A-methyl imidazole) to afford a fluoromethylketone of Formula (E104). Alternatively, fluoromethylketone compounds of Formula (El 02) can be obtained from a carboxylic acid of Formula (C101) via a modified Daikin-West reaction using fluoroacetic anhydride, triethylamine and DMAP in benzene (See Rasnick, D., Anal. Biochem. (1985) 149:461-465).Scheme N6

[0158] A general synthesis method towards a-ketoamides of Formula (Fl 02) is described in Scheme N6 where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. The starting aldehyde of Formula (B105) can be treated with an isocyanide under conditions described in the literature to afford an alpha-hydroxy amide of Formula (F101). Subsequent oxidation of the alcohol group of a compound of Formula (F101) utilizing procedures know in the literature (such as Swern oxidation or Dess-Martin periodinane oxidation) can afford the alphaketoamide of Formula (Fl 02).Scheme N7G104 G105

[0159] Scheme N7 illustrates a general method to synthesize nitrile compounds of Formula (G102) where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. An aldehyde of Formula (B105) can be condensed with hydroxyamine HC1 in an appropriate solvent (e.g., HMPA, DMSO) to afford oxime compound of Formula (G101). Subsequent reaction with Cu(OAc)2 in HCI / CH3CN, for example, provides a nitrile of Formula (G102). Alternatively, an aldehyde of Formula (B105) can react with O-(4-(trifluoromethyl)benzoyl)hydroxylamine and L-(-)- camphorsulfonic acid (10%) in methanol to afford a nitrile of Formula (G102) (See An et al., Org. Lett. (2015) 17(20):5064-5067).

[0160] An additional method to prepare compounds of Formula (G102) is to start with a protected ester of Formula (B101) and then convert it directly to an amide of Formula (G103) by reaction with ammonia in THF or methanol in a sealed reactor. An ester of Formula (B101) can also be transformed into an amide of Formula (G103) via a two-step process wherethe ester of Formula (B 101) is first hydrolyzed to a carboxylic acid (for example, using LiOH, water and THF when Aik is methyl) to a compound of Formula (C101). Subsequent transformation of the carboxylic acid of Formula (C101) to Formula (G103) can be carried out using a coupling agent (e.g., COMU, EDC) in the presence of ammonia, in an appropriate solvent (such as DMF or CH3CN). Deprotection of the nitrogen protecting group of Formula (G103), for example, with HC1 when PG is Boc, can generate the free amine which can be coupled with a compound of Formula (A 104) (using a readily available amino acid coupling agent) to afford a compound of Formula (G105). Dehydration of the amide group of Formula (G105) using methods described in the literature, for example the Burgess reagent, or trifluoroacetic anhydride (TFAA) can provide the cyano compound of Formula (G102).Scheme N8

[0161] Compounds of Formula (I), or a pharmaceutically acceptable salt thereof, can include a prodrug-type and phosphate-containing moieties at R4. An example of a method is depicted in Scheme N8 where a sub-structure of R1is depicted and the chemical modifications described here can be applied to other R1groups described herein. For example, an aldehyde of Formula (B 105) can be transformed into the bisulfite adduct of Formula (H101), by treatment with NaHSCh. A hydroxyketone of Formula (C106) can be transformed to the phosphate of Formula (H102), for example, by treatment with di- / -butyl N,N-dipropan-2- ylphosphoramidite and tetrazole followed by oxidation with H2O2. A compound of Formula (Hl 02) can be deprotected (for example, by treatment with TFA) to provide a compound of Formula (H103).Scheme N9J113

[0162] Scheme N9 describes the transformation of compounds of Formula (Al l i) to compounds of formulae (J 112) and (J 113). Compounds of Formula (Al l i) can be coupled to carboxylic acids using a variety of readily available peptide coupling agents (e.g., HATU, COMU, etc.). Compounds of Formula (JI 10) can be deprotected to provide an amine group. The amine group of compounds of Formula (Ji l l) can be reacted with a chloroformate, in the presence of a base to form the carbamate compounds of Formula (JI 12). Alternatively, the amine group of Formula (Ji l l) can be reacted with a sulfonyl chloride, in the presence of a base, to afford sulfonamides of Formula (JI 13).Pharmaceutical Compositions

[0163] 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.

[0164] 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 organiccompounds into cells or tissues of a subject.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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

[0170] 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.

[0171] 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.

[0172] 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, ora 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.

[0173] In some embodiments, the coronavirus can be an a-coronavirus or a P- 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.l) 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.

[0174] Some embodiments described herein relate to a method of treating a picorna virus 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.

[0175] 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.

[0176] 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.

[0177] 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.

[0178] 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.

[0179] 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, ora 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.

[0180] 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.

[0181] 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 aneffective 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.

[0182] 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.

[0183] 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.

[0184] 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 <105copies / 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.

[0185] 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.

[0186] 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.

[0187] 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.

[0188] 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, chroniclung 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).

[0189] 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.

[0190] 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.

[0191] 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.

[0192] Studies have shown that the entry of SARS-CoV-2 into the target cells is aprocess 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 KI 17777, 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 KI 17777 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 pM), but inhibits a coronavirus protease (for example, SARS-Cov-2 3Clpro).

[0193] 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

[0194] 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, aCovid- 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-Ol and / or PEG-IFN-0l-2a), 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, GS-5245 (Obeldesivir) and AT-527 (Good et al., Antimicrobial Agents and Chemotherapy (2021) 65(4):e02479-20)

[0195] 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.EXAMPEES

[0196] 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

[0197] 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(lS,3AR,4S,7R,7AS)-2-(tert-butoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid

[0198] To a solution of 1 ,2-di-tert-butyl (2S,4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (15 g, 52.2 mmol) in DCM (250 mL) were added NEta (9.51 g, 93.9 mmol) and DMAP (1.91 g, 15.7 mmol,). MsCI (8.97 g, 78.3 mmol,) 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) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate (EA): petroleum ether (PE) (1: 10) to provide 1 ,2-di-tert-butyl (2S,4R)-4-(methanesulfonyloxy)pyrrolidine-l,2- dicarboxylate (17.8 g, 89%) as a colorless oil. LC-MS (ESI, m / z): 366 [M+H]+.

[0199] To a solution of 1,2-di-tert-butyl (2S,4R)-4- (methanesulfonyloxy)pyrrolidine- 1 ,2-dicarboxylate (17.8 g, 48.7 mmol) in MeOH (400 mL) was added (phenyldiselanyl)benzene (9.12 g, 29.2 mmol). Sodium borohydride (2.4 g, 63.3 mmol) was added at 0 °C in several portions. The mixture was refluxed overnight and thenconcentrated 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, the solids were removed by filtration and the filtrate was 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]+.

[0200] To a solution of 1 ,2-di-tert-butyl (2S,4S)-4-(phenylselanyl)pyrrolidine-l,2- dicarboxylate (7.5 g, 17.6 mmol) in DCM (100 mL) was added pyridine (2.4 mL, 30.5 mmol) and 30% aqueous H2O2 (5.6 mL, 71.6 mmol). 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. Na2SOs (100 mL) and brine (100 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (1:9) to provide 1,2-di-Lbutyl (2S)-2,5- dihydropyrrole- 1 ,2-dicarboxylate (2.8 g, 53%) as a colorless oil. ’H NMR (300 MHz, DMSO- d6) 8 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]+.

[0201] A solution of 1,2-di-Lbutyl (2S)-2,5-dihydropyrrole-l,2-dicarboxylate (2.8 g, 10.4 mmol) 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-Lbutyl (lS,3aR,4S,7R,7aS)-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole- 1 ,2-dicarboxylate (690 mg, 19%) as a white solid. 'H NMR (300 MHz, DMSO-de) 8 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]+.

[0202] To a solution of di-Lbutyl (lS,3aR,4S,7R,7aS)-l,3,3a,4,7,7a-hexahydro- 2H-4,7-methanoisoindole-l,2-dicarboxylate (690 mg, 2.1 mmol) in dioxane (10 mL) was added HC1 (10 mL, 9M). The mixture was stirred at rt overnight and then concentrated under reduced pressure to provide (lS,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (320 mg, crude) as a black solid. LC-MS (ESI, m / z) 180[M+H]+.

[0203] To a solution of (lS,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (320 mg, 1.79 mmol) in DCM (8 mL) was added di-L butyl dicarbonate (429 mg, 1.97 mmol) and NEta (542 mg, 5.34 mmol). The mixture was stirred at rt for 3 h and then concentrated under reduced pressure to provide (lS,3aR,4S,7R,7aS)-2-(Lbutoxycarbonyl)-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (430 mg, crude) as a brown solid. LC-MS (ESI, m / z) 280 [M+H]+.(lS,3aR,4S,7R,7aS)-2-((S)-2-(( / -butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylic acid

[0204] To a mixture of l -r-butyl 2-methyl (2S,4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (30.0 g, 122 mmol), NEta (22.3 g, 220 mmol) and N,N-dimethylpyridin-4-amine (4.48 g, 36.7 mmol) in DCM (500 mL) was added dropwise methanesulfonyl chloride (21.0 g,183 mmol) at 0 °C. The mixture was stirred for 2 h at 0 °C. The reaction was quenched with water (500 mL). The mixture was extracted with DCM (3 x 500 mL). The organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the crude product that was chromatographed on a silica gel column with EA:PE (1 : 1) to provide 1-Lbutyl 2-methyl (2S,4R)-4-(methanesulfonyloxy)pyrrolidine-l,2-dicarboxylate (35.0 g, 85%) as a light yellow solid. LC-MS (ESI, m / z): 224 [M+H-Boc]+.

[0205] To a mixture of 1-Lbutyl 2-methyl (2S,4R)-4- (methanesulfonyloxy)pyrrolidine- 1 ,2-dicarboxylate (25.0 g, 77.3 mmol) and diphenyl diselenide (24.1 g, 77.3 mmol) in MeOH (600 mL) was added sodium borohydride (3.80 g, 100 mmol) at 0 °C. The mixture was stirred overnight at 70 °C and then concentrated under reduced pressure to remove the MeOH. Water (600 mL) was added, and the mixture was extracted with EA (3 x 600 mL). The organic layers were combined, washed with brine (600 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (1:8) to provide 1-Lbutyl 2-methyl (2S,4S)-4- (phenylselanyl)pyrrolidine-l,2-dicarboxylate (26.8 g, 84%) as a yellow oil. LC-MS (ESI, m / z): 286 [M-100+H]+.

[0206] To a mixture of 1-Lbutyl 2-methyl (2S,4S)-4-(phenylselanyl)pyrrolidine- 1,2-dicarboxylate (26.8 g, 69.7 mmol) and pyridine (9.38 g, 118 mmol) in DCM (300 mL) was added hydrogen peroxide (31.6 mL, 279 mmol, 30% in water). The mixture was stirred for 5 h at rt. The reaction was quenched with water (500 mL). The mixture was extracted with DCM (3 x 400 mL). The organic layers were combined, washed with citric acid (500 mL, 1 M), saturated aqueous sodium sulfite (500 mL), washed with brine (500 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (1:5) to provide 1-Lbutyl 2-methyl (2S)-2,5-dihydropyrrole-l,2- dicarboxylate (10.5 g, 62%) as a yellow oil. ’H NMR (300 MHz, CDCI3) 85.91-5.04 (m, 1H), 5.67-5.79 (m, 1H), 4.92-5.09 (m, 1H), 4.17-4.35 (m, 2H), 3.71-3.79 (m, 3H), 1.42-1.52 (m, 9H). LC-MS (ESI, m / z): 128 [M+H-Boc]+.

[0207] A mixture of 1-Lbutyl 2-methyl (2S)-2,5-dihydropyrrole-l,2-dicarboxylate(3.68 g, 16.2 mmol) in dicyclopentadiene (40 mL) was stirred overnight at 170 °C. The mixture was diluted with DCM (500 mL) and made into a slurry with 100-200 silica gel mesh (50 g). The mixture was loaded to a column. After removed the DCM under reduced pressure, 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 EA:PE (0%~50% over 30 min). The crude product was purified by C18 column with CH3CN: Water (0.05% TFA). The compound fraction was concentrated under reduced pressure to provide 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3,4-dicarboxylate (1.70 g, 32%) as a yellow oil. 'H NMR (300 MHz, CDCI3) 8 6.12-6.30 (m, 2H), 3.78-3.98 (m, 1H), 3.72 (s, 3H), 3.38-3.51 (m, 1H), 3.04-3.21 (m, 2H), 2.77-2.96 (m, 3H), 1.50-1.58 (m, 1H), 1.32-1.46 (m, 10H). LC-MS (ESI, m / z): 194 [M+H-Boc]+.

[0208] A mixture of 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S)-4- azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3,4-dicarboxylate (500 mg, 1.70 mmol) in hydrogen chloride (10 mL, 2 M in Et20) was stirred for 2 h at rt. The mixture was concentrated under reduced pressure to afford methyl (lR,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3- carboxylate hydrochloride (391 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 194 [M+H]+.

[0209] To a mixture of methyl (lR,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0A{2,6]]dec- 8-ene-3 -carboxylate hydrochloride (391 mg, 1.70 mmol), (2S)-2-[(Lbutoxycarbonyl)amino]- 3,3-dimethylbutanoic acid (394 mg, 1.70 mmol) and o-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) (777 mg, 2.04 mmol.) in DMF (10 mL) was added N-ethyl-N-isopropylpropan-2-amine (DIPEA) (1.32 g, 10.2 mmol) at 0 °C. The mixture was stirred for 1 h at rt. The reaction was quenched with water (20 mL). The mixture was extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (8:92) to provide methyl (lR,2S,3S,6R,7S)-4-[(2S)-2-[(L butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0A{2,6]]dec-8-ene-3- carboxylate (490 mg, 69%) as an off-white semi-solid. ’H NMR (300 MHz, CDCI3) 8 6.03- 6.27 (m, 2H), 5.11-5.26 (m, 1H), 4.18-4.36 (m, 2H), 3.72-3.78 (m, 3H), 3.54-3.70 (m, 2H), 2.97-3.14 (m, 2H), 2.86-2.94 (m, 2H), 1.49-1.54 (m, 1H), 1.41-1.48 (m, 9H), 1.33-1.39 (m, 1H), 0.92-1.00 (m, 9H). LC-MS (ESI, m / z) 407 [M+H]+.

[0210] To a mixture of methyl (lR,2S,3S,6R,7S)-4-[(2S)-2-[(L butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3- carboxylate (490 mg, 1.205 mmol) in THF (5 mL) / water (5 mL) was added LiOH (144 mg, 6.03 mmol). The mixture was stirred for 3 h at rt. The mixture was concentrated under reduced pressure to removed then THF and the pH was adjusted to 5 with HC1 (2 M). The mixture was extracted with EA (3 x 10 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to provide (lR,2S,3S,6R,7S)-4-[(2S)-2-[(L butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3- carboxylic acid (465 mg, 97%) as a white solid. ’H NMR (300 MHz, CDCI3) 8 6.04-6.30 (m, 2H), 5.21-5.29 (m, 1H), 4.22-4.32 (m, 2H), 3.52-3.79 (m, 2H), 3.06-3.24 (m, 2H), 2.91-3.04 (m, 2H), 1.51-1.56 (m, 1H), 1.37-1.47 (m, 10H), 0.95-1.00 (m, 9H). LC-MS (ESI, m / z): 393 [M+H]+.(lS,3aR,4R,7S,7aS)-2-((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydro-1 H-4,7-methanoisoindole- 1 -carboxylic acid

[0211] To a mixture of (lS,3aR,4S,7R,7aS)-2-((S)-2-((Lbutoxycarbonyl)amino)- 3,3-dimethylbutanoyl)-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylic acid (170 mg, 0.434 mmol) in EA (5 mL) was added 10% palladium on activated carbon (65.0 mg). The mixture was stirred for 2 h at rt under hydrogen. The mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure to afford (lS,3aR,4R,7S,7aS)-2- ((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)octahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (170 mg, crude) as an off-white solid. LC-MS (ESI, m / z) 395 [M+H]+.(lS,3aR,4S,4aS,5aR,6R,6aS)-2-(Lbutoxycarbonyl)decahydro-4,6- methanocyclopropa[f]isoindole- 1 -carboxylic acid

[0212] To a solution of 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S)-4- azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3,4-dicarboxylate (300 mg, 1.02 mmol) in Et20 (2.5 mL) at -30 °C was added diazomethane (30 mL) and palladium(II) acetate (45.9 mg, 0.205 mmol). The mixture was stirred for 1 h at rt and then filtered. The filter cake was washed with diethyl ether (3 x 50 mL). The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (1:8) to provide 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S,8S,10R)-4-azatetracyclo[5.3.1.0A{2,6}.0A{8,10}]undecane-3,4- dicarboxylate (200 mg, 58%) as a light yellow solid. 'H NMR (400 MHz, DMSO-de) 8 4.25- 4.50 (m, 1H), 3.53-3.72 (m, 4H), 3.22-3.30 (m, 1H), 2.52-2.64 (m, 2H), 2.22-2.42 (m, 2H), 1.21-1.47 (m, 9H), 1.03-1.16 (m, 1H), 0.70-0.95 (m, 3H), 0.39-0.54 (m, 1H), -0.09-0.05 (m, 1H). LC-MS (ESI, m / z): 208 [M+H-Boc]+.

[0213] To a stirred mixture of 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S,8S,10R)-4- azatetracyclo[5.3.1.0A{2,6].0A{8,10]]undecane-3,4-dicarboxylate (245 mg, 0.797 mmol) in MeOH (3 mL) and H2O (3 mL) were added LiOH (95.4 mg, 3.98 mmol). The mixture was stirred for 2 h at rt. The mixture was acidified to pH 4 with HC1 (IM) and then extracted with EA (3 x 10 mL). The mixture was concentrated under reduced pressure to afford (lR,2S,3S,6R,7S,8S,10R)-4-(Lbutoxycarbonyl)-4- azatetracyclo[5.3.1.0A{2,6].0A{8,10]]undecane-3-carboxylic acid (200 mg, 85%) as a light yellow solid. 'H NMR (400 MHz, DMSO-de) 8 12.57 (s, 1H), 4.17-4.39 (m, 1H), 3.47-3.76 (m, 1H), 3.12-3.31 (m, 1H), 2.51-2.59 (m, 2H), 2.20-2.44 (m, 2H), 1.27-1.49 (m, 9H), 1.05- 1.22 (m, 1H), 0.69-0.93 (m, 3H), 0.40-0.51 (m, 1H), -0.06-0.00 (m, 1H). LC-MS (ESI, m / z):238 [M+H-56]+.(lS,3aR,4R,4aR,5aS,6S,6aS)-2-(Lbutoxycarbonyl)-5,5-difluorodecahydro-4,6- methanocyclopropa[f]isoindole- 1 -carboxylic acid

[0214] To a stirred mixture of 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S)-4- azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3,4-dicarboxylate (1 g, 3.40 mmol) in toluene (4 mL) was added sodium fluoride (50.0 mg, 1.19 mmol). Trimethylsilyl 2, 2-difluoro-2-sulfoacetate (4.27 g, 17.0 mmol) was added slowly for 2 h at 115 °C under nitrogen. The reaction was quenched with water (30 mL). The mixture was extracted with EA(3 x 30 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 column with CHsCbhWater (0.05% FA). The desired fraction was concentrated under reduced pressure to provide 4-Lbutyl 3-methyl (lS,2S,3S,6R,7R,8R,10S)-9,9-difluoro-4-azatetracyclo[5.3.1.0A{2,6}.0A{8,10}]undecane- 3,4-dicarboxylate (180 mg, 13%) as a light yellow oil. LC-MS (ESI, m / z) 288 [M-56+H]+.

[0215] To a stirred mixture of 4-Lbutyl 3-methyl (lS,2S,3S,6R,7R,8R,10S)-9,9- difhroro-4-azatetracyclo[5.3.1.0A{2,6}.0A{8,10}]undecane-3,4-dicarboxylate (180 mg, 0.524 mmol) in THF (3 mL) and H2O (1 mL) was added LiOH (37.6 mg, 1.57 mmol) at rt. The mixture was stirred for 1 h at rt. The mixture was acidified to pH=4 with HC1 (2M) and then extracted with EA(3 x 10 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to afford (lS,2S,3S,6R,7R,8R,10S)-4-(Lbutoxycarbonyl)-9,9-difluoro-4- azatetracyclo[5.3.1.0A{2,6].0A{8,10]]undecane-3-carboxylic acid (150 mg, crude) as a light yellow oil. LC-MS (ESI, m / z) 328 [M-H]’.(lS,3aR,4S,7S,7aS)-2-(Lbutoxycarbonyl)-6-(trifluoromethyl)octahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid

[0216] To a solution of 2-(Lbutyl) 1-methyl (!S,3aR,4S,6R,7S,7aR)-6- hydroxyoctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (300 mg, 0.964 mmol) and 4- dimethylaminopyridine (235 mg, 1.93 mmol) in MeCN (10 mL) was added O-phenyl carbonochloridothioate (332 mg, 1.92 mmol). The mixture was stirred overnight at rt and the reaction was quenched with water (20 mL). The mixture was extracted with EtOAc (3 x 20 mL), washed with brine / 1 M HC1 (3: 1, 2 x 20 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 EtOAc:PE (1:3) to provide 2-(t- butyl) 1-methyl (lS,3aR,4S,6R,7S,7aR)-6-((phenoxycarbonothioyl)oxy)octahydro-2H-4,7- methanoisoindole-l,2-dicarboxylate (280 mg, 58%) as a yellow solid. LC-MS (ESI, m / z) 348 [M-100+H]+.

[0217] To a mixture of 2-( / -butyl) 1-methyl (lS,3aR,4S,6R,7S,7aR)-6- ((phenoxycarbonothioyl)oxy)octahydro-2H-4,7-methanoisoindole- 1 ,2-dicarboxylate (280 mg, 0.626 mmol), sodium persulfate (298 mg, 1.25 mmol), 2,2'-bipyridine tris(trifhroromethyl) copper (267 mg, 0.626 mmol) in MeCN / tLO (8mL / lmL) was added 1,1, 1,3,3, 3-hexamethyl- 2-(trimethylsilyl)trisilane (312 mg, 1.25 mmol). The mixture was stirred overnight at rt under nitrogen with blue LEDs. The reaction was quenched with LiCl (30 mL, 5% in water). The mixture was extracted with EtOAc (3 x 30 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 crude product was chromatographed on a silica gel column withEtOAc:PE (3:7) to provide 2-(Lbutyl) 1-methyl (lS,3aR,4S,7S,7aS)-6- (trifluoromethyl)octahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (110 mg, 41%) as a light brown oil. 'H NMR (400 MHz, DMSO-de) 84.12-4.23 (m, 1H), 3.60-3.72 (m, 3H), 3.41 - 3.49 (m, 1H), 3.20-3.32 (m, 1H), 2.54-2.76 (m, 2H), 2.40-2.52 (m, 1H), 2.32-2.38 (m, 1H), 2.03-2.15 (m, 1H), 1.59-1.72 (m, 1H), 1.49-1.53 (m, 1H), 1.34-1.42 (m, 9H), 1.19-1.29 (m, 2H). LC-MS (ESI, m / z): 264 [M-100+H]+.

[0218] To a mixture of 2-( / -butyl) 1-methyl (lS,3aR,4S,7S,7aS)-6- (trifluoromethyl)octahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (110 mg, 0.303 mmol) in THF (3 mL) was added a solution of LiOH (22.0 mg, 0.909 mmol) in water (3 mL). The mixture was stirred for 3 h at rt and diluted with water (10 mL). The mixture was acidified to pH = 6 with HC1 (1 M) and then extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (lS,3aR,4S,7S,7aS)-2-(Lbutoxycarbonyl)-6-(trifluoromethyl)octahydro- lH-4,7-methanoisoindole-l -carboxylic acid (105 mg, crude) as a light yellow solid. LC-MS (ESI, m / z) 294 [M-56]+.(3R,5S)-6-(tert-butoxycarbonyl)-l,l-difluoro-6-azaspiro[2.5]octane-5-carboxylic acid

[0219] To a stirred solution of (S)-l-(tert-butoxycarbonyl)-4-oxopiperidine-2- carboxylic acid (10 g, 41.15 mmol, 1 eq.) and cesium carbonate (8 g, 24.69 mmol, 0.6 eq.) inDMF (25 mL) at 0 °C was added iodomethane (2.8 mL, 45.26 mmol, 1.1 eq.). The mixture was stirred for 2 h at rt. The mixture was diluted with ice-cold water and compound extracted with EA (3 x 30 mL). The separated organic layer was washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure to get 1 -( / -butyl) 2-methyl (S)- 4-oxopiperidine- 1 ,2-dicarboxylate (9.7 g, 92%, Chiral HPLC 95.5%) as a pale-yellow liquid. 'H NMR (400 MHz, DMSO-tfo) 8 4.91-4.75 (m, 1H), 3.89-3.87 (m, 1H), 3.65 (s, 1H), 3.58- 3.50 (m, 1H), 2.93-2.89 (m, 1H), 2.57 (d, 1H), 2.46-2.32 (m, 2H), 1.40 (d, 9H). LC-MS: Rt = 1.59 (99%); LC-MS (ESI, m / z) 202.0 [M+H-Boc]+

[0220] To a stirred solution of 1 -( / -butyl) 2-methyl (S)-4-methylenepiperidine- 1,2-dicarboxylate (1.8 g, 7.05 mmol, 1 eq.) in THF (14 mL) were added Nal (380 mg, 2.53 mmol, 0.36 eq.) and TMSCF3 (7.3 mL, 49.35 mmol, 7 eq.) at rt using sealed tube. The mixture was stirred at 65 °C for 16 h. Progress of the reaction was monitored by TLC and LC-MS. After completion of reaction, the mixture was concentrated under reduced pressure to get crude product, which upon purification by column chromatography over silica (230-400 mesh), eluting with 10-15% EA in PE to afford 6-(tert-butyl) 5-methyl (5S)-l,l-difluoro-6- azaspiro[2.5]octane-5,6-dicarboxylate as a pale yellow liquid (1.6 g, 74%, LC-MS 16%+83%).

[0221] Further separation of diastereomers by SFC-prep to get 6-(tert-butyl) 5- methyl (3S,5S)-l,l-difluoro-6-azaspiro[2.5]octane-5,6-dicarboxylate as a pale yellow liquid (1.1 g, Chiral HPLC 98%). ’H NMR (400 MHz, DMSO-de) 84.83 (d, 1H), 3.92-3.89 (m, 1H), 3.67 (s, 3H), 3.10-2.88 (m, 1H), 2.12-2.07 (m, 1H), 1.83-1.71 (m, 2H), 1.41-1.33 (m, 11H), 1.08-1.03 (m, 1H); LC-MS: Rt =2.12 (98.4%); 206.2 [M+H-Boc]+; and 6-( / -butyl) 5-methyl (3R,5S)-l,l-difluoro-6-azaspiro[2.5]octane-5,6-dicarboxylate (135 mg, Chiral HPLC 94.6%) as a pale yellow liquid. 'H NMR (400 MHz, DMSO-tfo) 8 4.70 (d, 1H), 3.89 (d, 1H), 3.63 (s, 3H), 3.16-3.00 (m, 1H), 2.24-2.20 (m, 1H), 1.88-1.73 (m, 2H), 1.46-1.30 (m, 12H); LC-MS: Rt =2.12 (98.3%); LC-MS (ESI, m / z): 206.2 [M+H-Boc]+

[0222] To a cold solution of 6-( / -butyl) 5-methyl (3R,5S)-l,l-difluoro-6- azaspiro[2.5]octane-5,6-dicarboxylate (130 mg, 0.42 mmol, 1.0 eq.) in THF-MeOH-H2O (1.5 mL, 1: 1: 1) was added LiOHHLO (27 mg, 0.63 mmol, 1.5 eq.) at 0 °C. The mixture was allowed to stir at rt for 3 h. The reaction progress was monitored by TLC. The mixture was concentrated and acidified with IN HC1 to pH ~2 and extracted with EtOAc (3 x 10 mL). The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure toafford (3R,5S)-6-(t-butoxycarbonyl)-l,l-difluoro-6-azaspiro[2.5]octane-5-carboxylic acid (115 mg, 94%, Chiral HPLC 91%+6%) as an off-white solid.!H NMR (400 MHz, DMSO-tfo) 8 12.72 (s, 1H), 4.74-4.54 (m, 1H), 3.88-3.85 (bs, 1H), 3.63-3.48 (m, 0.48H), 3.31-2.88 (m, 1H), 2.22-2.02 (m, 1H), 1.95-1.62 (m, 2H), 1.49-1.32 (m, 12H). LC-MS: Rt= 1.79 min (96%); LC-MS (ESI, m / z): 192.0 [M+H-Boc]+.(l'S,3a'R,4'S,7'R,7a'S)-2'-(Lbutoxycarbonyl)-2',3',3a',4',7',7a'-hexahydro-EH- spirofcyclopropane- 1 , 8'-[4,7]methanoisoindole] - l'-carboxylic acid

[0223] The tricyclo[5.2.1.0A{2,6}]deca-3,8-diene (110 g, 832 mmol) was stirred at 210 °C. The cyclopentadiene was distillation at 37°C-43°C. The fraction was collected to provide the product (46 g, 83%) as a colorless liquid.1H NMR (400 MHz, DMSO-sfe) 8 6.60- 6.69 (m, 2H), 4.43-6.56 (m, 2H), 3.04-3.05 (m, 2H).

[0224] To a stirred mixture of cyclopentadiene (42.0 g, 635 mmol) and ional (0.130 g, 0.572 mmol) in ethylene dichloride (62.8 g, 635 mmol). After stirred for 20 min, NaOH (139 g, 3462 mmol) and benzyltriethylazanium chloride (1.30 g, 5.72 mmol) were added. The mixture was stirred for 1 h at rt. The reaction was quenched with water (50 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was stirred at 130 °C. Spiro[2.4]hepta-4,6-diene was distillation at 60°C ~ 65°C under 0.7MPa. The desired fraction was collected to provide spiro[2.4]hepta-4,6-diene (10 g, 14%) as a colorless liquid. ’H NMR(400 MHz, DMSO-<76) 8 6.47-6.69 (m, 2H), 6.14- 6.24 (m, 2H), 1.71-1.72 (m, 4H).

[0225] To a stirred mixture of 1 - / -butyl 2-methyl (2R)-2,5-dihydropyrrole-l,2- dicarboxylate (6.00 g, 26.4 mmol) in xylene (6 mL) was added spiro[2.4]hepta-4,6-diene (4.87 g, 52.8 mmol). The mixture was stirred for 2 d at 140 °C and then concentrated under reduced pressure. The crude product was purified by Cl 8 column with CH3CN: Water (0.05% TFA). The desired fraction was concentrated under reduced pressure to provide 4'- / -butyl 3 '-methyl (TR,2'S,3'S,6'R,7'S)-4'-azaspiro[cyclopropane-l,10'-tricyclo[5.2.1.0A{2,6}]decan]-8'-ene- 3',4'-dicarboxylate (1.98 g, 23%) as a yellow oil.!H NMR (400 MHz, DMSO-de) 86.03-6.36 (m, 2H), 3.70-3.89 (m, 1H), 3.55-3.69 (m, 3H), 3.22-3.37 (m, 1H), 2.70-3.10 (m, 3H), 2.33- 2.42 (m, 1H), 2.22-2.29 (m, 1H), 1.08-1.53 (m, 9H), 0.22-0.48 (m, 4H). LC-MS (ESI, m / z): 220 [M+H-Boc]+.

[0226] To a stirred mixture of 4'- / -butyl 3'-methyl (TR,2'S,3'S,6'R,7'S)-4'- azaspiro[cyclopropane-l,10'-tricyclo[5.2.1.0A{2,6]]decan]-8'-ene-3',4'-dicarboxylate (1.00 g, 3.13 mmol) in THF (10 mL) was added LiOH (300 mg, 12.5 mmol in water 10 mL). The mixture was stirred for 2 h at rt. The pH was adjusted to 6 with HC1 (2 M). The mixture was extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to provide (TR,2'S,3'S,6'R,7'S)-4'-(L butoxycarbonyl)-4'-azaspiro[cyclopropane-l,10'-tricyclo[5.2.1.0A{2,6]]decan]-8'-ene-3'- carboxylic acid (917 mg, 89%) as a light yellow oil. LC-MS (ESI, m / z): 250 [M+H-56]+.(lS,3aR,4R,5S,6R,7S,7aS)-2-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)octahydro- 1 H-4,7-methanoisoindole- 1 -carboxy lie- 5 , 6-d2 acid

[0227] To a mixture of (lR,2S,3S,6R,7S)-4-[(2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl]-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3-carboxylic acid (200 mg, 0.515 mmol) in EA (5 mL) was added 10% palladium on activated carbon (80 mg). Themixture was stirred for 3 h at rt under deuterium. The mixture was filtered. The filtrate was concentrated under reduced pressure to provide (lS,3aR,4R,5S,6R,7S,7aS)-2-((S)-3,3- dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)octahydro-lH-4,7-methanoisoindole-l- carboxylic-5,6-d2 acid (190 mg, 91%) as an off-white solid. 'H NMR (400 MHz, DMSO-de) 8 12.73 (br, 1H), 9.14-9.61 (m, 1H), 4.69-4.84 (m, 1H), 4.41-4.59 (m, 1H), 3.76-3.88 (m, 1H), 3.43-3.67 (m, 1H), 2.53-2.82 (m, 2H), 2.26-2.41 (m, 1H), 2.13-2.24 (m, 1H), 1.35-1.54 (m, 2H), 1.15-1.31 (m, 2H), 0.93-1.06 (m, 9H). LC-MS (ESI, m / z): 393 [M+H]+.(3'S,3a'S,4'S,7'S,7a'R)-2'-((S)-2-amino-3,3-dimethylbutanoyl)octahydrospiro[cyclopropane- l,5'-[4,7]methanoisoindole]-3'-carboxylic acidBoc O Boc O

[0228] To a mixture of 4- / -butyl 3-methyl (lS,2S,3S,6R,7S)-9-methylidene-4- azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (400 mg, 1.30 mmol) and diazomethane (15 mL, excess in Et20) in Et20 (4 mL) was added palladium(II) acetate (88.0 mg, 0.390 mmol) at -30 °C. The mixture was stirred for 30 min at -30 °C, then allowed to reach rt. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the crude product (This process was repeated for 5 times until the starting materials was completely converted). The crude product was chromatographed on a silica gel column withEA:PE (1:9) to provide 4'-Lbutyl 5'-methyl (l'S,2'R,5'S,6'S,7'S)-4'-azaspiro[cyclopropane- l,8'-tricyclo[5.2.1.0A{2,6}]decane]-4',5'-dicarboxylate (350 mg, crude) as a yellow oil. LC- MS (ESI, m / z): 222 [M-100+H]+.

[0229] A solution of 4'-Lbutyl 5'-methyl (rS,2'R,5'S,6'S,7'S)-4'- azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6]]decane]-4',5'-dicarboxylate (350 mg, 1.09 mmol) in hydrogen chloride (10 mL, 2 M in Et2O) was stirred for 2 h at rt. The mixture was concentrated under reduced pressure to afford methyl (l'S,2'R,5'S,6'S,7'S)-4'- azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6}]decane]-5'-carboxylate hydrochloride (280 mg, crude) as a yellow solid. LC-MS (ESI, m / z) 222 [M+H]+.

[0230] To a mixture of (2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoic acid (251 mg, 1.09 mmol) and HATU(496 mg, 1.30 mmol.) in DMF (5 mL) was added DIPEA (842 mg, 6.52 mmol) at 0 °C. After stirred for 15 min at 0 °C, methyl (l'S,2'R,5'S,6'S,7'S)-4'- azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6]]decane]-5'-carboxylate hydrochloride (280 mg, 1.09 mmol) was added. The mixture was stirred for 1 h at rt. The reaction was quenched with water (30 mL). The mixture was extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (14:86) to provide methyl (l'S,2'R,5'S,6'S,7'S)-4'-[(2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4'- azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6]]decane]-5'-carboxylate (300 mg, 57%) as a yellow oil. LC-MS (ESI, m / z): 435 [M+H]+.

[0231] To a mixture of methyl (l'S,2'R,5'S,6'S,7'S)-4'-[(2S)-2-[(L butoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4'-azaspiro[cyclopropane-l,8'- tricyclo[5.2.1.0A{2,6]]decane]-5'-carboxylate (300 mg, 0.690 mmol) in THF (3 mL) / water (3 mL) was added LiOH (83.0 mg, 3.45 mmol). The mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure to remove THF and adjusted to pH=6 with HC1 (1 M). The mixture was extracted with EA (3 x 10 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (l'S,2'R,5'S,6'S,7'S)-4'-[(2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoyl]-4'- azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6]]decane]-5'-carboxylic acid (280 mg, crude)as a light yellow solid. LC-MS (ESI, m / z) 421 [M+H]+.

[0232] To a solution of (TS,2'R,5'S,6'S,7'S)-4'-[(2S)-2-[(Lbutoxycarbonyl)amino]- 3,3-dimethylbutanoyl]-4'-azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6}]decane]-5'- carboxylic acid (280 mg, 0.667 mmol) in DCM (6 mF) was added trifluoroacetic acid (TFA) (2 mL). The mixture was stirred for 1 h at rt and then concentrated under reduced pressure to afford (rS,2'R,5'S,6'S,7'S)-4'-[(2S)-2-amino-3,3-dimethylbutanoyl]-4'- azaspiro[cyclopropane-l,8'-tricyclo[5.2.1.0A{2,6]]decane]-5'-carboxylic acid (213 mg, crude) as a brown semi-solid. LC-MS (ESI, m / z): 321 [M+H]+.(lS,3aR,4S,7S,7aR)-2-(Lbutoxycarbonyl)-6,6-difluorooctahydro-lH-4,7-methanoisoindole- 1 -carboxylic acid

[0233] The 4-Lbutyl 3-methyl (lR,2S,3S,6R,7S)-4-azatricyclo[5.2.1.0A{2,6]]dec- 8-ene-3,4-dicarboxylate (4.00 g, 13.6 mmol) was dissolved in toluene (8 mL) under nitrogen and cooled to 0 C. (S)-MOP (S)-(-)-2-Diphenylphosphino-2'-methoxy-l,T-binaphthyl (15.9 mg, 0.034 mmol), [Pd(C3H5)Cl]2 allylpalladium chloride dimer (3.00 mg, 0.008 mmol) and trichlorosilane (5.87 g, 43.5 mmol) were added consecutively. The mixture was warmed to rt and then stirred for 3 d. The mixture was concentrated under reduced pressure. The residue was re-dissolved in THF (36 mL) and MeOH (36 mL). The mixture was poured into a suspension of KF (6.26 g, 108 mmol) and KHCO3 (13.6 g, 136 mmol) in THF (36 mL) and MeOH (36 mL) at 0 °C. Then H2O2 (20 mL) was added. The mixture was stirred for 1 d at rt. The mixture was extracted with EA (3 x 100 mF). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removedby filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (40:60) to provide 4-t-butyl 3-methyl (lS,2R,3S,6R,7S)-9-hydroxy-4-azatricyclo[5.2.1.0A{2,6]]decane-3,4-dicarboxylate (2.00 g, 47%) as a yellow oil. LC-MS (ESI, m / z): 256 [M-56+H]+.

[0234] To a stirred mixture of 4-t-butyl 3-methyl (lS,2R,3S,6R,7S)-9-hydroxy-4- azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (2.00 g, 6.43 mmol) in DMSO (20 mL) was added 2-iodoxybenzoic acid (5.29 g, 18.9 mmol). The mixture was stirred for overnight at rt. The reaction was quenched with sat. sodium bicarbonate (50 mL). The mixture was extracted with EA (3 x 80 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (50:50) to provide 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S)-9- oxo-4-azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (1.5 g, 78%) as a white oil. LC-MS (ESI, m / zy. 310 [M+H]+.

[0235] A mixture of 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S)-9-oxo-4- azatricyclo[5.2.1.0A{2,6]]decane-3,4-dicarboxylate (1.00 g, 3.23 mmol) in diethylaminosulfur trifluoride (20 mL) was stirred for 6 h at 70 °C. The mixture was diluted with dichloromethane (DCM) (50 mL). The reaction was quenched with sat. sodium bicarbonate (100 mL) at 0 °C. The mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x 60 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (7:3) to afford 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S)-9,9-difluoro-4-azatricyclo [5.2.1.0A{2,6]]decane-3,4-dicarboxylate (300 mg, 28%) as a yellow oil. LC-MS (ESI, m / z): 310 [M+H]+.

[0236] To a stirred mixture of 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S)-9,9-difluoro- 4-azatricyclo[5.2.1.0A{2,6]]decane-3,4-dicarboxylate (300 mg, 0.905 mmol) in THF (3 mL) and H2O (3 mL) was added LiOH (108 mg, 4.52 mmol) at rt. The mixture was stirred for 2 h and acidified to pH=3 with HC1 (IM in H2O). The aqueous layer was extracted with EA(3 x 30 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (lS,2R,3S,6R,7S)-4-(Lbutoxycarbonyl)-9,9-difluoro-4-azatricyclo[5.2.1.0A{2,6}]decane-3-carboxylic acid (270 mg, crude) as a light yellow solid. LC-MS (ESI, m / z) 318 [M+H]+.(lS,3aR,4R,6R,7R,7aS)-2-( / -butoxycarbonyl)-6-methyloctahydro-lH-4,7-methanoisoindole- 1 -carboxylic acid

[0237] To a mixture of 2-( / -butyl) 1-methyl (lS,3aR,4S,6R,7S,7aR)-6- hydroxyoctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (780 mg, 2.50 mmol, 1.0 eq.), CH3OH (120 mg, 3.76 mmol, 1.5 eq.) and 5,7-di- / -butyl-3-phenylbenzo[d]oxazol-3-ium tetrafluoroborate (2.97 g, 7.51 mmol, 3.0 eq.) in MTBE (10 mL) was added dropwise pyridine (535 mg, 6.76 mmol, 2.7 eq.). After stirring for 4 h at rt, a solution of (4,4'-Di-Lbutyl-2,2'- bipyridine)bis [3 , 5-difluoro-2- [5 -trifluoromethyl-2-pyridinyl-kN)phenyl-kC] iridium(III) hexafluorophosphate (85.0 mg, 0.075 mmol) and quinuclidine (1.39 g, 12.5 mmol) in DMSO (10 mL) was added. Benzoyl benzenecarboperoxoate (911 mg, 3.76 mmol, 1.5 eq.) and nickel(II) acetylacetonate (161 mg, 0.625 mmol, 0.25 eq.) were then added. The mixture was stirred for 1 h at rt with 450 nm blue LEDs and the reaction was quenched with 5% LiCl solution (30 mL). The mixture was extracted with EtOAc (3 x 30 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the crude product. The crude product was purified by C18 column with CHsCN / Water (0.05% TFA), and the fraction was concentrated under reduced pressure to provide 2-(Lbutyl) 1-methyl (lS,3aR,4R,6R,7R,7aS)-6- methyloctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (120 mg, 15%) as a colorless oil. 'H NMR (400 MHz, DMSO-de) 8 4.12-4.27 (m, 1H), 3.65 (d, J = 7.2Hz, 3H), 3.15-3.35 (m, 2H), 2.54-2.60 (m, 1H), 2.41-2.49 (m, 1H), 2.12-2.26 (m, 1H), 1.94-2.04 (m, 1H), 1.54-LOS (m, 2H), 1.30-1.47 (m, 10H), 1.15-1.28 (m, 2H), 0.79-0.92 (m, 3H). LC-MS (ESI, m / z): 210 [M-100+H]+.

[0238] To a mixture of 2-( / -butyl) 1-methyl (lS,3aR,4R,6R,7R,7aS)-6- methyloctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (115 mg, 0.372 mmol) in THF (1 mL) was added a solution of LiOH (45.0 mg, 1.86 mmol) in H2O (1 mL). The mixture was stirred for 2 h at rt. The reaction was quenched with water (3 mL) and extracted with EtOAc (5 mL). The aqueous layer was acidified to pH = 4 with HC1 (I M, aq.) and extracted with EtOAc (3 x 6 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford (lS,3aR,4R,6R,7R,7aS)-2-(t- butoxycarbonyl)-6-methyloctahydro-lH-4,7-methanoisoindole-l-carboxylic acid (110 mg, crude) as a yellow oil. LC-MS (ESI, m / z) 240 [M-56+H]+.(lS,3aR,4S,7S,7aS)-2-(Lbutoxycarbonyl)-6-methyleneoctahydro-lH-4,7-methanoisoindole- 1 -carboxylic acid

[0239] To a mixture of bromo(methyl)triphenyl-5-phosphane (2.96 g, 8.27 mmol) in toluene (48 mL) was added potassium Lbutoxide (928 mg, 8.27 mmol). After stirred for 2 h at 110 °C, 4-t-butyl 3-methyl (lS,2R,3S,6R,7S)-9-oxo-4- azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (1.60 g, 5.17 mmol) was added. The mixture was stirred overnight at 110 °C. The reaction was quenched with ice-water (50 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (15:85) to provide 4-Lbutyl 3-methyl (lS,2S,3S,6R,7S)-9-methylidene-4-azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (480 mg, 29%) as a light yellow oil. 'H NMR (400 MHz, Chloroform-d) 84.89-4.96 (m, 1H), 4.71- 4.80 (m, 1H), 4.17-4.33 (m, 1H), 3.72 (s, 3H), 3.52-3.66 (m, 1H), 3.35-3.44 (m, 1H), 2.56-2.85 (m, 3H), 2.33-2.42 (m, 1H), 1.98-2.22(m, 2H), 1.62-1.71 (m, 1H), 1.52-1.60 (m, 1H), 1. SO1.50 (m, 9H). LC-MS (ESI, m / z) 208 [M-100+H]+.

[0240] To a mixture of 4- / -butyl 3-methyl (lS,2S,3S,6R,7S)-9-methylidene-4- azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (220 mg, 0.716 mmol) in THF (2 mL) / water (2 mL) was added LiOH (86.0 mg, 3.58 mmol). The mixture was stirred for 3 h at rt. The reaction was quenched with water (5 mL) and extracted with EA (5 mL). The aqueous phase was adjusted to pH=6 with HC1 (IM). The mixture was extracted with EA (3 x 5 mL). The organic layers were combined, washed with brine (2 x 5 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (lS,2S,3S,6R,7S)-4-(Lbutoxycarbonyl)-9-methylidene-4- azatricyclo[5.2.1.0A{2,6}]decane-3-carboxylic acid (170 mg, 76%, crude) as a yellow oil. LC- MS (ESI, m / z): 194 [M-Boc+H]+.(lS,3aS,4S,7R,7aR)-2-((S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylic acidliquid NH3, Na CH3I, K2CO3, DMF HCI, dioxane EtOH / Et2O(1 / 1).-40 °C, 20min rt, 1h 80°C, overnight

[0241] A mixture of l,2,3,4-tetrachloro-5,5-dimethoxycyclopenta-l,3-diene (17.4 g, 66.0 mmol) and 1-Lbutyl 2-methyl (2S)-2,5-dihydropyrrole-l,2-dicarboxylate (10.0 g, 44.0 mmol) in toluene (10 mL) was stirred overnight at 110 °C under nitrogen and then concentrated under reduced pressure. The residue was chromatographed on a silica gel column with EA:PE (17: 100). The crude product was purified by C18 column with CILCN / Water (0.05% TFA). The desired fraction was concentrated under reduced pressure to provide 4-Lbutyl 3-methyl (lS,2S,3S,6R,7R)-l,7,8,9-tetrachloro-10,10-dimethoxy-4-azatricyclo[5.2.1.0A{2,6]]dec-8- ene-3,4-dicarboxylate (7.5 g, 31%) as a yellow solid. ’H NMR (400 MHz, DMSO-de) 84.02- 4.23 (m, 1H), 3.65-3.77 (m, 3H), 3.51-3.58 (m, 3H), 3.45-3.49 (m, 3H), 3.31-3.44 (m, 4H), 1.23-1.47 (m, 9H). LC-MS (ESI, m / z): 392 [M-Boc+H]+.

[0242] To a stirred solution of 4-Lbutyl 3-methyl (1S,2S,3S,6R,7R)-1,7,8,9- tetrachloro-10,10-dimethoxy-4-azatricyclo[5.2.E0A{2,6]]dec-8-ene-3,4-dicarboxylate (7.50 g, 15.2 mmol) in THF (40 mL) / water (40 mL) was added LiOH (L46 g, 61.0 mmol). The mixture was stirred for 2 h at 50 °C and then concentrated under reduced pressure to removed THF. The mixture was adjusted to pH=6 with HC1 (2M) and extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (lS,2S,3S,6R,7R)-4-(Lbutoxycarbonyl)-l,7,8,9-tetrachloro-10,10- dimethoxy-4-azatricyclo[5.2.1.0A{2,6]]dec-8-ene-3-carboxylic acid (6.3 g, 86%, crude) as anoff-white solid. 'H NMR (400 MHz, DMSO-de) 83.99-4.08 (m, 1H), 3.50-3.58 (m, 3H), 3.43- 3.47 (m, 3H), 3.22-3.42 (m, 4H), 1.25-1.48 (m, 9H). LC-MS (ESI, m / z): 378 [M-Boc+H]+.

[0243] To a stirred solution of sodium (6 x 1.68 g, 438 mmol) in liquid NH3 (6 x 34 mL) was added (lS,2S,3S,6R,7R)-4-(Lbutoxycarbonyl)-l,7,8,9-tetrachloro-10,10- dimethoxy-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3-carboxylic acid (6 x 1.00 g, 12.5 mmol) in ethanol (EtOH): ether (6 xl6 mL, 1:1 ratio) drop wise under nitrogen at -40 °C for 20 min. The mixture was stirred for 20 min at -40 °C and then NH4C1(S) (6 x 2g) was added. The mixture was warmed to rt in 2 h and then diluted with water (6 x 50 mL). The mixture was extracted with EA (300 mL). The aqueous phase was adjusted to pH=6 with HC1 (2M). The mixture was extracted with EA (3 x 300 mL). The organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (lR,2R,3S,6S,7S)-4-(L butoxycarbonyl)-10,10-dimethoxy-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3-carboxylic acid (3.4 g, crude) as a brown oil. LC-MS (ESI, m / z): 240 [M-Boc+H]+.

[0244] To a stirred mixture of (lR,2R,3S,6S,7S)-4-(Lbutoxycarbonyl)-10,10- dimethoxy-4-azatricyclo[5.2.1.0A{2,6]]dec-8-ene-3-carboxylic acid (3.40 g, 10.0 mmol) and potassium carbonate (2.22 g, 16.0 mmol) in DMF (30 mL) was added iodomethane (1.49 g, 10.5 mmol). The mixture was stirred for 1 h at rt. The reaction was quenched with water (100 mL). The mixture was extracted with EtOAc (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (31: 100) to provide 4-Lbutyl 3-methyl (lR,2R,3S,6S,7S)-10,10-dimethoxy-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3,4-dicarboxylate (1.62 g, 41%) as a yellow oil. 'H NMR (400 MHz, DMSO-de) 8 6.07-6.23 (m, 2H), 3.70-3.86 (m, 1H), 3.60-3.69 (m, 3H), 3.26-3.33 (m, 1H), 3.08-3.12 (m, 3H), 3.01-3.07 (m, 2H), 2.97- 3.00 (m, 3H), 2.78-2.96 (m, 3H), 1.23-1.44 (m, 9H). LC-MS (ESI, m / z): 254 [M-Boc+H]+.

[0245] To a stirred mixture of 4-Lbutyl 3-methyl (1R,2R,3S,6S,7S)-1O,1O- dimethoxy-4-azatricyclo[5.2.1.0A{2,6]]dec-8-ene-3,4-dicarboxylate (1.62 g, 4.58 mmol) in dioxane (3 mL) was added hydrogen chloride (20 mL, 4M in dioxane). The mixture was stirred for overnight at 80 °C and then concentrated under reduced pressure to afford methyl (lR,2R,3S,6S,7S)-10-oxo-4-azatricyclo[5.2.1.0A{2,6]]dec-8-ene-3-carboxylate (949 mg,crude) as an off-white solid. LC-MS (ESI, m / z): 208 [M+H]+.

[0246] To a stirred mixture of methyl (lR,2R,3S,6S,7S)-10-oxo-4- azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3-carboxylate (949 mg, 4.57 mmol) in DCM (10 mL) was added NEb (1.39 g, 13.7 mmol) and di-t-butyl dicarbonate (1.30 g, 5.95 mmol). The mixture was stirred for 1 h at rt. The reaction was quenched with water (50 mL). The mixture was extracted with DCM (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (29: 100) to provide 4-Lbutyl 3 -methyl (1R,2R,3S,6S,7S)-1O- oxo-4-azatricyclo[5.2.1.0A{2,6}]dec-8-ene-3,4-dicarboxylate (800 mg, 56%) as an off-white solid. 'H NMR (400 MHz, DMSO-de) 8 6.46-6.71 (m, 2H), 3.80-4.00 (m, 1H), 3.57-3.75 (m, 3H), 3.38-3.48 (m, 1H), 2.95-3.27 (m, 5H), 1.11-1.49 (m, 9H). LC-MS (ESI, m / z): 208 [M- Boc+H]+.

[0247] A mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR)-8-oxo-l,3,3a,4,7,7a- hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (500 mg, 1.63 mmol) in diethylaminosulfur trifluoride (10 mL) was stirred for overnight at 45 °C. The mixture was diluted with DCM (30 mL). The reaction was quenched with sat. sodium bicarbonate (50 mL) at 0 °C. The mixture was extracted with DCM (3 x 80 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (7:3) to afford 2-(Lbutyl) 1 -methyl (lS,3aS,4S,7R,7aR)-8,8-difluoro-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2- dicarboxylate (350 mg, 65%) as a yellow oil. LC-MS (ESI, m / z)'- 230 [M-Boc+H]+.

[0248] To a stirred mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR)-8,8- difluoro-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (350 mg, 1.06 mmol) in DCM (4 mL) was added TFA (1.3 mL) at rt. The mixture was stirred for 2 h at rt and then concentrated under reduced pressure to provide methyl (lS,3aS,4S,7R,7aR)-8,8- difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (243 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 230 [M+H]+.

[0249] To a mixture of (2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoic acid (246 mg, 1.06 mmol) in N,N-dimethylformamide (3mL) were added HATU(485 mg, 1.28mmol.) and DIPEA (825 mg, 6.38 mmol) at 0 °C. The mixture was stirred for 20 min at 0 °C, and then methyl (lS,3aS,4S,7R,7aR)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylate (243 mg, 1.06 mmol) was added at 0 °C. The mixture was stirred for 2 h at rt. The mixture was purified by C18 column with CHaCN / Water (0.05% TFA). The desired fraction was concentrated under reduced pressure to provide methyl (lS,3aS,4S,7R,7aR)-2-((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-8,8-difluoro- 2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (300 mg, 63%) as a yellow solid. 'H NMR (400 MHz, DMSO-de) 8 6.58-6.72 (m, 1H), 6.02-6.35 (m, 2H), 4.19-4.31 (m, 1H), 4.05-4.13 (m, 1H), 3.70-3.87 (m, 1H), 3.61-3.69 (m, 3H), 3.43-3.59 (m, 1H), 3.19-3.36 (m, 2H), 2.93-3.16 (m, 2H), 1.30-1.49 (m, 9H), 0.77-1.00 (m, 9H). LC-MS (ESI, m / z) 443 [M+H]+.

[0250] To a stirred methyl (lS,3aS,4S,7R,7aR)-2-((S)-2-((t- butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylate (300 mg, 0.680 mmol) in THF (3 mL) and water (3 mL) was added LiOH (81.2 mg, 3.39 mmol) at rt. The mixture was stirred for 2 h at rt. The mixture was acidified to pH=3 with HC1 (2M) and then extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford (lS,3aS,4S,7R,7aR)-2-((S)-2-((L butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (265 mg, crude) as an orange solid. ’ H NMR (400 MHz, DMSO-<76) 8 12.51-13.00 (m, 1H), 6.43-6.78 (m, 1H), 5.93-6.33 (m, 2H), 4.10-4.19 (m, 1H), 3.65-3.89 (m, 1H), 3.48-3.60 (m, 1H), 3.15-3.44 (m, 3H), 2.90-3.13 (m, 2H), 1.22-1.60 (m, 9H), 0.61-1.04 (m, 9H). LC-MS (ESI, m / z) 429 [M+H]+.

[0251] To a stirred mixture of (lS,3aS,4S,7R,7aR)-2-((S)-2-((L butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (265 mg, 0.618 mmol) in DCM (3 mL) was added TFA ( 1 mL) at rt. The mixture was stirred for 2 h at rt and then concentrated under reduced pressure to afford (lS,3aS,4S,7R,7aR)-2-((S)-2-amino-3,3-dimethylbutanoyl)-8,8-difluoro- 2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylic acid (203 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 329[M+H]+.

[0252] To a stirred mixture of (lS,3aS,4S,7R,7aR)-2-((S)-2-amino-3,3-dimethylbutanoyl)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l- carboxylic acid (203 mg, 0.618 mmol) and trimethylamine (750 mg, 7.41 mmol) in MeOH (2 mL) was added ethyl 2,2,2-trifluoroacetate (878 mg, 6.18 mmol). The mixture was stirred for 2 days at rt and then acidified to pH=4 with HC1 (2M). The mixture was extracted with EA (3 x 50mL). The organic layers were combined, washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The combined organic layers were concentrated under reduced pressure to afford (lS,3aS,4S,7R,7aR)-2-((S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl)-8,8-difluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7- methanoisoindole- 1 -carboxylic acid (250 mg, crude) as a light yellow oil. LC-MS (ESI, m / z) 425 [M+H]+.(lS,2R,3S,6R,7S,9R)-4-[(2S)-3,3-dimethyl-2-(2,2,2-trifluoroacetamido)butanoyl]-9-fluoro-4- azatricyclo [5.2.1.0A{ 2, 6 } ]decane-3-carboxylic acid

[0253] A mixture of 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S,9R)-9-hydroxy-4-azatricyclo[5.2.1.0A{2,6]]decane-3,4-dicarboxylate (500 mg, 1.60 mmol) in diethylaminosulfur trifluoride (10 mL) was stirred for 6 h at 45 °C. The mixture was diluted with DCM (80 mL), and the reaction quenched with sat. sodium bicarbonate (50 mL) at 0 °C. The mixture was extracted with DCM (3 x 80 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with PE:EA (7:3) to afford 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S,9R)-9-fluoro-4-azatricyclo[5.2.L0A{2,6}]decane-3,4-dicarboxylate (210 mg, 42%) as a yellow oil. LC-MS (ESI, m / z) 258 [M-56+H]+.

[0254] To a stirred mixture of 4-Lbutyl 3-methyl (lS,2R,3S,6R,7S,9R)-9-fluoro-4- azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (210 mg, 0.670 mmol) in DCM (3 mL) was added TFA ( 1 mL) at rt. The mixture was stirred for 2 h at rt and then concentrated under reduced pressure to provide product methyl (lS,2R,3S,6R,7S,9R)-9-fluoro-4- azatricyclo[5.2.1.0A{2,6}]decane-3-carboxylate (155 mg, crude) as a yellow oil. LC-MS (ESI, m / z) 213 [M+H]+.

[0255] To a mixture of (2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoic acid (155 mg, 0.671 mmol) in N,N-dimethylformamide (2 mL) was added HATU(305 mg, 0.805 mmol) and DIPEA (520 mg, 4.026 mmol) at 0 °C. The mixture was stirred for 20 min at 0 °C, and then methyl (lS,2R,3S,6R,7S,9R)-9-fluoro-4-azatricyclo[5.2.1.0A{2,6]]decane-3- carboxylate (143 mg, 0.671 mmol) was added at 0 °C. The mixture was stirred for 2 h at rt and then purified by a C18 column with CILCN / Water (0.05% TFA). The desired fraction was concentrated under reduced pressure to provide methyl (lS,2R,3S,6R,7S,9R)-4-[(2S)-2- [(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoyl]-9-fluoro-4- azatricyclo[5.2.1.0A{2,6]]decane-3-carboxylate (190 mg, 66%) as a yellow solid. LC-MS (ESI, m / z) 427 [M+H]+.

[0256] To a stirred methyl (lS,2R,3S,6R,7S,9R)-4-[(2S)-2-[(L butoxy carbonyl) amino] -3 , 3-dimethylbutanoyl] -9-fluoro-4-azatricyclo[5.2.1.0A{ 2, 6 } ]decane- 3-carboxylate (190 mg, 0.445 mmol) in THF (2 mL) and water (2 mL) was added LiOH (53.3 mg, 2.22 mmol) at rt. The mixture was stirred for 2 h and acidified to pH = 3 with HC1 (2M). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The mixture wasconcentrated under reduced pressure to afford (lS,2R,3S,6R,7S,9R)-4-[(2S)-2-[(L butoxy carbonyl) amino] -3 , 3-dimethylbutanoyl] -9-fluoro-4-azatricyclo[5.2.1.0A{ 2, 6 } ]decane- 3-carboxylic acid (180 mg, crude) as an orange solid. LC-MS (ESI, m / z): 413 [M+H]+.

[0257] To a stirred mixture of (lS,2R,3S,6R,7S,9S)-4-[(2S)-2-[(t- butoxy carbonyl) amino] -3 , 3-dimethylbutanoyl] -9-fluoro-4-azatricyclo[5.2.1.0A{ 2, 6 } ]decane- 3-carboxylic acid (160 mg, 0.388 mmol) in DCM (2 mL) was added TFA (0.6 mL) at rt. The mixture was stirred for 2 h at rt and then concentrated under reduced pressure to (lS,2R,3S,6R,7S,9S)-4-[(2S)-2-amino-3,3-dimethylbutanoyl]-9-fluoro-4- azatricyclo[5.2.1.0A{2,6]]decane-3-carboxylic acid (121 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 313 [M+H]+.

[0258] To a stirred mixture of (lS,2R,3S,6R,7S,9R)-4-[(2S)-2-amino-3,3- dimethylbutanoyl]-9-fluoro-4-azatricyclo[5.2.1.0A{2,6]]decane-3-carboxylic acid (121 mg, 0.387 mmol) and trimethylamine (470 mg, 4.64 mmol) in MeOH ( 1 mL) was added ethyl 2,2,2- trifluoroacetate (550 mg, 3.870 mmol). The mixture was stirred for 2 days at rt. The reaction was quenched with water (10 mL). The mixture was concentrated under reduced pressure to remove MeOH and then acidified to pH = 4 with HC1 (2M). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The combined organic layers were concentrated under reduced pressure to afford (lS,2R,3S,6R,7S,9R)-4-[(2S)-3,3-dimethyl-2-(2,2,2- trifluoroacetamido)butanoyl]-9-fluoro-4-azatricyclo[5.2.1.0A{2,6]]decane-3-carboxylic acid (160 mg, crude) as a light yellow oil. LC-MS (ESI, m / z): 409 [M+H]+.(lS,3aR,4R,4aR,5aS,6S,6aS)-2-((S)-2-((Lbutoxycarbonyl)amino)-3, 3-dimethylbutanoyl)- l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6-ethenocyclopropa[f]isoindole-l-carboxylic acid

[0259] To a solution of cyclohepta- 1,3, 5 -triene (3.13 g, 34.0 mmol) in xylene (15 mL, 81.0 mmol) was added lH-pyrrole-2, 5-dione (3.0 g, 30.9 mmol). The mixture was stirred for 24 h at 140 °C and then cooled to rt. The mixture was filtered, and the filter cake was washed with DCM (2 x 30 mL). The filter cake was combined to provide (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-4,6-ethenocyclopropa[f]isoindole- l,3(2H,3aH)-dione (5.0 g, 85%) as an off-white solid.1H NMR (400 MHz, DMSO-sfc) 8 10.94 (s, 1H), 5.72-5.76 (m, 2H), 3.14-3.18 (m, 2H), 2.96-2.97 (m, 2H), 1.07-1.11 (m, 2H), 0.21- 0.25 (m, 1H), 0.01-0.06 (m, 1H). LC-MS (ESI, m / z) 190 [M+H]+.

[0260] A solution of (3aR,4R,4aR,5aS,6S,6aS)-4,4a,5,5a,6,6a-hexahydro-4,6- ethenocyclopropa[f]isoindole-l,3(2H,3aH)-dione (5.00 g, 26.4 mmol) in toluene was stirred at 0 °C, and then sodium bis(2-methoxyethoxy) aluminum hydride (38.4 g, 133 mmol, 70% in toluene) was added dropwise. The mixture was stirred for 20 min at 0 °C. The solution was stirred for 2 days at 100 °C and then cooled to rt. A NaOH aqueous solution (100 mL, 30%) was added dropwise at 0 °C. The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (3aR,4R,4aR,5aS,6S,6aS)-l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6- ethenocyclopropa[f] isoindole (3.5g, crude) as a red oil. LC-MS (ESI, m / z) 162 [M+H]+.

[0261] To a solution of (3aR,4R,4aR,5aS,6S,6aS)-l,2,3,3a,4,4a,5,5a,6,6a- decahydro-4,6-ethenocyclopropa[f]isoindole (3.50 g, 21.7 mmol) in DCM (60 mL) was added 2-Iodoxybenzoic acid (6.69 g, 23.9 mmol). The mixture was stirred for 3 h at 60 °C. The reaction was quenched with aqueous sodium thiosulfate (30 mL). The mixture was extractedwith DCM (3 x 100 mL). The organic layers were combined, washed with saturated sodium bicarbonatebrine aqueous (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (60%-70%) to provide rac- (3aS,4S,4aS,5aR,6R,6aR)-l,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindole (1.7 g, crude) as an off-white solid. ’H NMR (400 MHz, CDCI3) 8 7.32-7.33 (m, 1H), 5.71- 5.73 (m, 2H), 3.83-3.91 (m, 1H), 3.31-3.38 (m, 1H), 3.13-3.17 (m, 1H), 3.00-3.04 (m, 1H), 2.85-2.89 (m, 1H), 2.52-2.59 (m, 1H), 0.92-1.03 (m, 2H), 0.16-0.29 (m, 2H). LC-MS (ESI, m / z) 160 [M+H]+.

[0262] To a solution of rac-(3aS,4S,4aS,5aR,6R,6aR)-l,3a,4,4a,5,5a,6,6a- octahydro-4,6-ethenocyclopropa[f]isoindole (1.7 g, 10.7 mmol) in toluene (40 mL) was added zinc iodide (409 mg, 1.28 mmol) and trimethylsilyl cyanide (4.77 g, 48.0 mmol). The mixture was stirred overnight at rt. The reaction was quenched with water (30 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (60%-80%) to provide rac-(3aR,4R,4aR,5aS,6S,6aS)- 1 ,2,3 ,3a,4,4a,5,5a,6,6a-decahydro-4,6-ethenocyclopropa[f]isoindole- 1 -carbonitrile (1.1 g, 49%) as a light yellow oil. LC-MS (ESI, m / z): 187 [M+H]+.

[0263] A mixture rac-(3aR,4R,4aR,5aS,6S,6aS)-l,2,3,3a,4,4a,5,5a,6,6a- decahydro-4,6-ethenocyclopropa[f]isoindole-l -carbonitrile (800 mg, 4.30 mmol) in hydrogen chloride (7.5 mL, 4 M in MeOH) was stirred for 2 h at 50 °C. The mixture was concentrated under reduced pressure to afford methyl rac-(3aR,4R,4aR,5aS,6S,6aS)- l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6-ethenocyclopropa[f]isoindole-l-carboxylate hydrochloride (800 mg, crude) as a yellow solid. LC-MS (ESI, m / z . 220 [M+H]+.

[0264] To a solution of methyl rac-(3aR,4R,4aR,5aS,6S,6aS)- l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6-ethenocyclopropa[f]isoindole-l-carboxylate hydrochloride (800 mg, 3.65 mmol) in DCM (10 mL) was added NEta (1.11 g, 10.9 mmol) and di-Lbutyl dicarbonate (1.04 g, 4.74 mmol). The mixture was stirred for 1 h at rt. The reaction was quenched with H2O (20 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodiumsulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (10%- 15%) to provide rac-2-(7-butyl) 1-methyl (3aR,4R,4aR,5aS,6S,6aS)-3,3a,4,4a,5,5a,6,6a- octahydro-4,6-ethenocyclopropa[f]isoindole-l,2(lH)-dicarboxylate (830 mg, 71%) as a colorless oil. 'H NMR (400 MHz, CD3OD-t / 4) 8 5.81-5.89 (m, 2H), 3.92-3.98 (m, 1H), 3.74- 3.75 (m, 3H), 3.52-3.58 (m, 1H), 3.20-3.29 (m, 1H), 3.02-3.06 (m, 1H), 2.88-2.92 (m, 1H), 2.55-2.66 (m, 2H), 1.38-1.46 (m, 9H), 0.94-0.99 (m, 2H), 0.13-0.21 (m, 2H). LC-MS (ESI, m / z) 320 [M+H]+.

[0265] To a mixture of rac-2-(Lbutyl) 1-methyl (3aR,4R,4aR,5aS,6S,6aS)- 3,3a,4,4a,5,5a,6,6a-octahydro-4,6-ethenocyclopropa[f]isoindole-l,2(lH)-dicarboxylate (400 mg, 1.25 mmol) inl,4-dioxane (4 mL) was added hydrogen chloride (4 mL, 4 M in 1,4- dioxane) stirred at rt. The mixture was stirred for 2 h at rt and then concentrated under reduced pressure to afford rac-methyl (lS,3aR,4R,4aR,5aS,6S,6aS)-l,2,3,3a,4,4a,5,5a,6,6a-decahydro- 4,6-ethenocyclopropa[f]isoindole-l -carboxylate hydrochloride (300 mg, crude) as a light yellow solid. LC-MS (ESI, m / z) 220 [M+H]+.

[0266] To a mixture of (S)-2-((Lbutoxycarbonyl)amino)-3,3-di methyl butanoic acid (271 mg, 1.17 mmol) and HATU (535 mg, 1.41 mmol.) in dimethylformamide (5 mL) was added DIPEA (910 mg, 7.04 mmol) at 0 °C. After stirring for 20 min, rac-methyl (lS,3aR,4R,4aR,5aS,6S,6aS)-l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6- ethenocyclopropa[f]isoindole-l -carboxylate hydrochloride (300 mg, 1.17 mmol) was added. The mixture was stirred for 1 h at rt. The reaction was quenched with water (20 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (11%-13%) to provide methyl (3aR,4R,4aR,5aS,6S,6aS)-2-((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)- l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6-ethenocyclopropa[f]isoindole-l-carboxylate (350 mg, 62 %, white solid) as a diastereomeric mixture. LC-MS (ESI, m / z): 433 [M+H]+.

[0267] To the diastereomeric mixture with methyl (3aR,4R,4aR,5aS,6S,6aS)-2- ((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-l,2,3,3a,4,4a,5,5a,6,6a-decahydro- 4,6-ethenocyclopropa[f]isoindole-l -carboxylate (350 mg, 0.809 mmol) in THF (4 mL) andH2O (2 mL) was added LiOH (96.9 mg, 4.05 mmol). The mixture was stirred for 1 h at rt and then concentrated under reduced pressure to remove THF. The mixture was acidified to pH = 5 with HC1 (1 M). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to provide (3aR,4R,4aR,5aS,6S,6aS)-2-((S)- 2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-l,2,3,3a,4,4a,5,5a,6,6a-decahydro-4,6- ethenocy clopropaff] isoindole- 1 -carboxylic acid (320 mg, 94%, white solid) as a diastereomeric mixture. LC-MS (ESI, m / z): 419 [M+H]+.Methyl (lS,3aS,4S,7R,7aR)-8-hydroxy-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l- carboxylate

[0268] To a solution of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR)-8-oxo- l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (950 mg, 3.09 mmol) in methanol (10 mL) was added sodium borohydride (114 mg, 3.09 mmol) at 0 °C. The mixture was stirred for 1 h at rt. The reaction was quenched with sat. ammonium chloride (aq.). The mixture was extracted with EA (3 x 80 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR,8R)-8-hydroxy-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2- dicarboxylate (700 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 210 [M-Boc+H]+.

[0269] To a stirred mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR)-8- hydroxy-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (450 mg, 1.45 mmol) in DCM (4.5mL) was added TFA (1.5 mL) at rt. The mixture was stirred for 1 h at rt and then concentrated under reduced pressure to afford methyl (lS,3aS,4S,7R,7aR,8R)-8- hydroxy-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (305 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 210 [M+H]+.Methyl (lS,3aS,4S,7R,7aR,8R)-8-fluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-1 -carboxylate

[0270] A mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR,8R)-8-hydroxy- l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (1.0 g, 3.23 mmol) in diethylaminosulfur trifluoride (20 mL) was stirred for 5 h at 45 °C. The mixture was diluted with DCM (100 mL). The reaction was quenched with sat. sodium bicarbonate (80 mL) at 0 °C. The mixture was extracted with DCM (3 x 80 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by prep-HPLC (Column: XSelect CSH Prep Cl 8 OBD, 19 x 150 mm, 5pm; Mobile Phase A: Water (0.05%TFA), Mobile Phase B: CH3CN; Flow rate: 25 mL / min; Gradient: 32 to 52% B in 10 min; Wave Length: 254 nm; RT (min): 8.78, 9.3) to provide 2-(Lbutyl) 1- methyl (lS,3aS,4S,7R,7aR,8S)-8-fluoro-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole- 1 ,2-dicarboxylate (350 mg, 35%) as a white oil. ’H NMR (400 MHz, DMSO-de) 8 6.05-6.24 (m, 2H), 4.25-4.57 (m, 1H), 3.81-4.03 (m, 1H), 3.56-3.76 (m, 3H), 3.34-3.48 (m, 1H), 3.10- 3.26 (m, 1H), 2.83-3.09 (m, 4H), 1.19-1.51 (m, 9H). LC-MS (ESI, m / z): 256 [M-56+H]+.

[0271] To a stirred mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR,8*S)-8- fluoro-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (350 mg, 1.12 mmol) in DCM (3 mL) was added TFA ( 1 mL) at rt. The mixture was stirred for 2 h at rt. The mixture was concentrated under reduced pressure to provide methyl (lS,3aS,4S,7R,7aR,8*S)- 8-fluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (240 mg, crude) as a yellow oil. LC-MS (ESI, m / z): 212 [M+H]+.2-(Lbutyl) 1 -methyl (lS,3aR,4S,7R,7aS)-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole- 1 ,2-dicarboxylate-6-d

[0272] To a stirred mixture of 4-t-butyl 3-methyl (lS,2R,3S,6R,7S)-9-oxo-4- azatricyclo[5.2.1.0A{2,6}]decane-3,4-dicarboxylate (600 mg, 1.93 mmol) in THF (6 mL) was added lithium diisopropylamide (1.94 mL, 3.87 mmol) dropwise at -78 °C under nitrogen. The mixture was stirred for 1 h at 0 °C and then 1,1,1-trifhioro-N-phenyl-N- ((trifluoromethyl)sulfonyl)methanesulfonamide (1.03 g, 2.90 mmol) was added slowly at -78 °C. The mixture was stirred for 2 h at 0 °C, then quenched with water (20 mL). The mixture was extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (3:7), then purified by Cis column with CHiCN / Water (0.05% FA). The desired fraction was concentrated under reduced pressure to provide 4-t-butyl 3- methyl (lS,2R,3S,6R,7R)-9-(trifluoromethanesulfonyloxy)-4-azatricyclo[5.2.1.0A{2,6]]dec- 8-ene-3,4-dicarboxylate (400 mg, 44%) as a light yellow oil. LC-MS (ESI, m / z) 342 [M- Boc+H]+.

[0273] To a mixture of 4-Lbutyl 3-methyl (lS,2R,3S,6R,7R)-9- (trifluoromethanesulfonyloxy)-4-azatricyclo[5.2.1.0A{2,6]]dec-8-ene-3,4-dicarboxylate (180 mg, 0.408 mmol), lithium chloride (138 mg, 3.26 mmol) and tetrakis(triphenylphosphine)platinum(0) (80.0 mg, 0.069 mmol) in THF (2 mL) was added tri butyl stannane-<7 (834 mg, 2.86 mmol) under nitrogen. The mixture was stirred for 2 h at 50 °C. 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 (2 x 10 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 column with CH CN / Water (0.05% NH4HCO3+NH3.H2O, pH~13). The desired fraction was concentrated under reduced pressure to provide 2-(Lbutyl) 1-methyl (!S,3aR,4S,7R,7aS)-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate-6-<7 (60.0 mg, 44%) as a light yellow semi-solid. 'H NMR (400 MHz, CDC13) 8 6.14-6.30 (m, 1H), 3.82-3.98 (m, 1H), 3.61-3.77 (m, 3H), 3.35-3.53 (m, 1H), 3.01-3.24 (m, 2H), 2.73-2.98 (m, 3H), 1.50-1.58 (m, 1H), 1.32- 1.49 (m, 10H). LC-MS (ESI, m / z): 195 [M-Boc+H]+.(+ / -)-Methyl (lS,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-lH-4,7-ethanoisoindole-l- carboxylate hydrochloride

[0274] To a solution of (3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-lH-4,7- ethanoisoindole (1.1 g, 7.37 mmol) in DCM (35 mL) was added IBX (2.06 g, 7.37 mmol). The mixture was stirred in sealed tube at 60 °C for 1 h. After cooling to rt, the mixture was washed with sat. sodium dithionate (40 mL). The phases were separated. The organic phase was washed with sat. sodium carbonate (70 mL) and brine (30 mL). The aqueous phases were extracted with DCM (3 x 100 mL). The organic phases were combined, dried over Na2SO4, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH ( 1 to 5%) in DCM to afford (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-lH-4,7-ethanoisoindole (780 mg, 71%) as a white oil.

[0275] To a solution of (3aS,4R,7S,7aR)-3a,4,7,7a-tetrahydro-lH-4,7- ethanoisoindole (780 mg, 5.31 mmol) in DCM (8 mL) and MeOH (0.6 mL) cooled at 0 °C was added TMSCN (1.8 mL, 13.3 mmol). The mixture was stirred at 0-10 °C for 4 h. The mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of MeOH (1 to 5%) in DCM to afford (+ / -)-(lS,3aR,4S,7R,7aS)- 2,3,3a,4,7,7a-hexahydro-lH-4,7-ethanoisoindole-l-carbonitrile (550 mg, 59%) as a brown oil.

[0276] A solution of (+ / -)-(lS,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-lH-4,7- ethanoisoindole- 1 -carbonitrile (550 mg, 3.16 mmol) in 4N HC1 in MeOH (5.5 mL) was stirred for 6 h at 60 °C. The mixture was concentrated under reduced pressure to afford (+ / -)-methyl (!S,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro-lH-4,7-ethanoisoindole-l-carboxylatehydrochloride (580 mg, 88%) as a yellow oil.(+)-enantiomerThe chiral centers noted with are tentatively assigned.

[0277] To a solution of (+ / -)-methyl (lS,3aR,4S,7R,7aS)-2,3,3a,4,7,7a-hexahydro- lH-4,7-ethanoisoindole-l -carboxylate hydrochloride (1 g, 4.10 mmol) in dioxane (15 mL) cooled at 0°C were added Na2COs (870 mg, 8.21 mmol) and BOC2O (1.8 g, 8.21 mmol). The mixture was stirred at rt for 24 h. After cooling to 0 °C, Na2COs (870 mg, 8.21 mmol) and BOC2O (1.8 g, 8.21 mmol) were added. The mixture was stirred at rt for 24 h. The mixture was diluted with EA (50 mL) and washed with water. The phases were separated. The aqueous phase was extracted twice with EA. The organic phases were combined, washed with brine, dried over Na2SO4, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel using a gradient of EA (0 to 30%) in PE to afford (+ / -)-2-(Lbutyl) 1-methyl (lS,3aR,4S,7R,7aS)- l,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindole-l,2-dicarboxylate (1.1 g, 74%) as a brown oil.

[0278] (+ / -)-2-(7-Butyl) 1-methyl (lS,3aR,4S,7R,7aS)-l,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindole-l,2-dicarboxylate (900 mg) was purified by prep-SFC using the following conditions: Column: Lux Cellulose-2, 30 x 250 mm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH; Flow rate: 60 g / min; Gradient: isocratic 10% B; Column Temperature: 30°C; Back Pressure: 100 bar. Purification resulted in 2-(Lbutyl) 1-methyl (lS*,3aR*,4S*,7R*,7aS*)-l,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindole-l,2- dicarboxylate (370 mg) and 2-(Lbutyl) 1-methyl (lR*,3aS*,4R*,7S*,7aR*)-l,3,3a,4,7,7a- hexahydro-2H-4,7-ethanoisoindole-l,2-dicarboxylate (370 mg).

[0279] 2-( / -Butyl) 1-methyl (lS*,3aR*,4S*,7R*,7aS*)-l,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindole-l,2-dicarboxylate:!H NMR (400 MHz, CDCI3) 8 6.22-6.33 (m, 2H), 3.87-4.02 (m, 1H), 3.71 (s, 3H), 3.52-3.70 (m, 1H), 3.14-3.28 (m, 1H), 2.78 (m, 1H), 2.59 (m, 1H), 2.40-2.52 (m, 2H), 1.32-1.50 (m, 11H), 1.18-1.30 (m, 2H). [a]25D: -29.1° (c 0.1, CHCh). SFC: Lux Cellulose-2, 4.6 x 150 mm, 3 pm, Mobile Phase A: CO2, Mobile Phase B: 0.5% DEA in MeOH; Flow rate: 3 g / min; Gradient: isocratic 15% B; Column Temperature: 30°C; Back Pressure: 100 bar, Rt: 0.98 min.

[0280] 2-( / -Butyl) 1-methyl (lR*,3aS*,4R*,7S*,7aR*)-l,3,3a,4,7,7a-hexahydro-2H-4,7-ethanoisoindole-l,2-dicarboxylate: 'H NMR (400 MHz, CDCI3) 8 6.22-6.33 (m, 2H), 3.87-4.02 (m, 1H), 3.71 (s, 3H), 3.52-3.70 (m, 1H), 3.14-3.28 (m, 1H), 2.78 (m, 1H), 2.59 (m, 1H), 2.40-2.52 (m, 2H), 1.32-1.50 (m, 11H), 1.18-1.30 (m, 2H). [a]25D: +21.6° (c 0.1, CHCI3). SFC: Eux Cellulose-2, 4.6 x 150 mm, 3 pm, Mobile Phase A: CO2, Mobile Phase B: 0.5% DEA in MeOH; Flow rate: 3 g / min; Gradient: isocratic 15% B; Column Temperature: 30°C; Back Pressure: 100 bar, Rt: 1.12 min.(lS,3aS,4R,5S,7R,7aS)-2-((S)-2-((Abutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5- fluorooctahydro-lH-4,7-methanoisoindole-l -carboxylic acid

[0281] A 40-mL vial was charged with 2-( / -butyl) 1-methyl (!S,3aR,4S,7R,7aS)- l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (3.0 g, 10.2 mmol), [(R)-2'-Methoxy[l,r-binaphthalen]-2-yl]diphenylphosphine (12.0 mg, 0.026 mmol) andallylpalladium(II) chloride dimer (2.4 mg, 0.006 mmol), toluene(6 mL) at 0 °C under nitrogen. Trichlorosilane (4.43 g, 30.6 mmol) was added at 0 °C. The mixture was warmed to rt and stirred for 4 days. After evaporation of the solvent, the residue was dissolved in THF (27 mL) and MeOH (27 mL) and then poured at 0 °C into a suspension of KF (4.75 g, 81.6 mmol) and potassium bicarbonate (10.2 g, 102 mmol) in THF ( 1 mL) and MeOH (27 mL). Hydrogen peroxide (20.0 mL) was then added at 0 °C and the mixture was stirred overnight at rt. The suspension was filtered and the filter cake was washed with MeOH (2 x 50 mL). The mixture was extracted with EA (3 x 200 mL). The organic layers were combined, washed with brine (2 x 80 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (40L60) to provide 2-(Lbutyl) 1-methyl (lS,3aS,4R,5S,7R,7aS)-5-hydroxyoctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (1.6 g, 50%) as a yellow oil. 'H NMR (400 MHz, CDC13) 8 8.09-8.31 (m, 1H), 4.08-4.34 (m, 1H), 3.89-4.04 (m, 1H), 3.71-3.76 (m, 3H), 3.57-3.70 (m, 1H), 3.33-3.45 (m, 1H), 2.39-2.66 (m, 3H), 2.21-2.31 (m, 1H), 1.90-2.04 (m, 1H), 1.79-1.89 (m, 1H), 1.35-1.51 (m, 10H), 1.24- 1.34 (m, 1H). LC-MS (ESI, m / z) 256 [M-56+H]+.

[0282] A mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4R,5S,7R,7aS)-5- hydroxyoctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (600 mg, 1.93 mmol) in diethylaminosulfur trifluoride (12 mL) was stirred for 6 h at 45 °C. The mixture was diluted with DCM (80 mL) and the reaction was quenched with sat. sodium bicarbonate (50 mL) at 0 °C. The mixture was extracted with DCM (3 x 80 mL). The organic layers were combined, washed with brine (2 x 30 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography with PE:EA (3:7) to afford 2-(t- butyl) 1-methyl (lS,3aS,4R,5S,7R,7aS)-5-fluorooctahydro-2H-4,7-methanoisoindole-l,2- dicarboxylate (300 mg, 50%) as a yellow oil.1H NMR (400 MHz, DMSO-ds) 84.45-4.77 (m, 1H), 3.97-4.15 (m, 1H), 3.60-3.71 (m, 3H), 3.46-3.56 (m, 1H), 3.05-3.28 (m, 1H), 2.52-2.70 (m, 2H), 2.33-2.45 (m, 1H), 1.76-1.96 (m, 1H), 1.58-1.72 (m, 1H), 1.46-1.56 (m, 1H), 1.28- 1.42 (m, 11H). LC-MS (ESI, m / z): 214 [M-Boc+H]+.

[0283] To a stirred mixture of 2-(Lbutyl) 1-methyl (lS,3aS,4R,5S,7R,7aS)-5- fluorooctahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (300 mg, 0.958 mmol) in DCM(5 mL) was added TFA (1.7 mL) at rt. The mixture was stirred for 2 h at rt and concentrated under reduced pressure to provide methyl (lS,3aS,4R,5S,7R,7aS)-5-fluorooctahydro-lH-4,7- methanoisoindole- 1 -carboxylate (204 mg, crude) as a yellow oil. LC-MS (ESI, m / z) 214 [M+H]+.

[0284] To a mixture of (S)-2-((Lbutoxycarbonyl)amino)-3,3-di methyl butanoic acid (221 mg, 0.957 mmol) in N,N-dimethylformamide (4mL) were added HATU (436 mg, 1.15 mmol) and DIPEA (742 mg, 5.74 mmol) at 0 °C. The mixture was stirred for 20 min at 0 °C, then methyl (lS,3aR,4S,6R,7S,7aR)-6-fhiorooctahydro-lH-4,7-methanoisoindole-l- carboxylate (204 mg, 0.957 mmol) was added at 0 °C. The mixture was stirred for 2 h at rt. The mixture was purified by Cl 8 column with CHsCN / Water (0.05% TFA), and the fraction was concentrated under reduced pressure to provide methyl (lS,3aS,4R,5S,7R,7aS)-2-((S)-2- ((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-fluorooctahydro-lH-4,7- methanoisoindole- 1 -carboxylate (300 mg, 74%) as a yellow oil. 'H NMR (400 MHz, DMSO- d6) 8 6.76-6.90 (m, 0.34H), 4.85-5.17 (m, 1H), 4.36-4.81 (m, 1H), 4.61-4.31 (m, 1H), 3.95- 4.11 (m, 1H), 3.58-3.71 (m, 3H), 3.44-3.52(m, 1H), 2.62-2.86 (m, 2H), 2.26-2.43 (m, 2H), 1.53-1.70 (m, 2H), 1.17-1.50 (m, 11H), 0.71-1.11 (m, 9H). LC-MS (ESI, m / z): 427 [M+H]+.

[0285] To a stirred of methyl (lS,3aS,4R,5S,7R,7aS)-2-((S)-2-((L butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-fluorooctahydro-lH-4,7-methanoisoindole- 1 -carboxylate (300 mg, 0.704 mmol) in THF (3 mL) and water (3 mL) was added LiOH (85.0 mg, 3.51 mmol) at rt. The mixture was stirred for 2 h and acidified to pH = 3 with HC1 (2M). The aqueous layer was extracted with EA (3 x 60 mL). The organic layers were combined, washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure to afford (lS,3aS,4R,5S,7R,7aS)-2-((S)-2-((L butoxycarbonyl)amino)-3,3-dimethylbutanoyl)-5-fluorooctahydro-lH-4,7-methanoisoindole- 1-carboxylic acid (270 mg, crude) as a yellow solid. LC-MS (ESI, m / z) 413 [M+H]+.Methyl (lS,3aS,4S,7R,7aR)-2-((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3a- fluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate

[0286] To a solution of l-t-butyl 2-methyl (2S)-4-oxopyrrolidine-l,2- dicarboxylate (15.0 g, 61.7 mmol) in THF (240 mL) was added lithium bis(trimethylsilyl)amide (74 mL, 74.0 mmol, IM in THF) at -78 °C under nitrogen. After stirring for 1 h at -78 °C, a solution of Comins' reagent (29.0 g, 74.0 mmol) in THF (60 mL) was added dropwise. The mixture was stirred for Ih at -78 °C under nitrogen. The reaction was quenched with water (600 mL). The mixture was extracted with EA (3 x 500 mL). The organic layers were combined, washed with brine (2 x 500 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gelcolumn with EA:PE (1:9) to provide I - / -butyl 2-methyl (2S)-4- (trifluoromethanesulfonyloxy)-2,5-dihydropyrrole-l,2-dicarboxylate (12.3 g, 48%) as a colorless oil. 'H NMR (400 MHz, CDC13) 8 5.70-5.80 (m, 1H), 5.00-5.12 (m, 1H), 4.24-4.47 (m, 2H), 3.79 (s, 3H), 1.42-1.53 (m, 9H). LC-MS (ESI, m / z): 320 [M-56+H]+.

[0287] To a mixture of 1 - / -butyl 2-methyl (2S)-4-(trifluoromethanesulfonyloxy)- 2,5-dihydropyrrole-l,2-dicarboxylate (10.0 g, 26.6 mmol), lithium chloride (3.95 g, 93.2 mmol) and tetrakis(triphenylphosphine)platinum(0) (4.62 g, 4.00 mmol) inTHF (120 mL) was added hexamethyldistannane (13.1 g, 40.0 mmol). The mixture was stirred overnight at 60 °C under nitrogen. The reaction was quenched with water (300 mL). The mixture was extracted with EA (3 x 300 mL). The organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (6:94) to provide I - / -butyl 2-methyl (2S)-4-(trimethylstannyl)-2,5- dihydropyrrole- 1 ,2-dicarboxylate (5.45 g, 49 %) as a colorless oil. ’ H NMR (400 MHz, CDCI3) 8 5.70-5.82 (m, 1H), 4.93-5.09 (m, 1H), 4.19-4.41 (m, 2H), 3.74-3.79 (m, 3H), 1.42- 1.53 (m, 9H), 0.14-0.31 (m, 9H). LC-MS (ESI, m / z): 336 [M-56+H]+.

[0288] To a mixture of silver trifluoromethanesulfonate (4.67 g, 18.2 mmol) and 1- chloromethyl-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (9.90 g, 27.9 mmol) in dry acetone (165 mL) was added dropwise a solution of 1 - / -butyl 2-methyl (2S)-4- (trimethylstannyl)-2,5-dihydropyrrole-l,2-dicarboxylate (5.45 g, 14.0 mmol) in dry acetone (55 mL) under nitrogen. The mixture was stirred for 1 h at rt. The reaction was quenched with saturated aqueous ammonium chloride (300 mL). The mixture was extracted with MTBE (3 x 300 mL). The organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA / PE (5:95) to provide l- / -butyl 2-methyl (2S)-4-fluoro-2,5-dihydropyrrole- 1 ,2-dicarboxylate (780 mg, 20%) as a light yellow oil. ’H NMR (400 MHz, CDCI3) 8 5.11- 5.22 (m, 1H), 4.87-4.99 (m, 1H), 4.24-4.36 (m, 1H), 4.12-4.23 (m, 1H), 3.75-3.80 (m, 3H), 1.42-1.53 (m, 9H). LC-MS (ESI, m / z): 190 [M-56+H]+.

[0289] A mixture of 1 - / -butyl 2-methyl (2S)-4-fluoro-2,5-dihydropyrrole-l,2- dicarboxylate (400 mg, 1.63 mmol) in dicyclopentadiene (10 mL) was stirred overnight at 170°C. The mixture was chromatographed on a silica gel column with EA:PE (3:7). The crude product was purified by C18 column with CtLCN / Water (0.05% TFA). The desired fraction was concentrated under reduced pressure to provide 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR)- 3a-fluoro-l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (140 mg, crude) as a brown oil. LC-MS (ESI, m / z) 212 [M-Boc+H]+.

[0290] To a solution of 2-(Lbutyl) 1-methyl (lS,3aS,4S,7R,7aR)-3a-fluoro- l,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindole-l,2-dicarboxylate (140 mg, 0.450 mmol) in DCM (1.5 mL) was added TFA (0.5 mL). The mixture was stirred for 1 h at rt and then concentrated under reduced pressure to afford the methyl (lS,3aS,4S,7R,7aR)-3a-fluoro- 2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (95 mg, crude) as a brown oil. LC-MS (ESI, m / z): 212 [M+H]+.

[0291] To a mixture of (2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylbutanoic acid (104 mg, 0.450 mmol) and HATU (205 mg, 0.540 mmol) in DMF (3 mL) was added DIPEA (349 mg, 2.70 mmol) at 0 °C. After stirring for 15 min, methyl (lS,3aS,4S,7R,7aR)- 3a-fluoro-2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (95.0 mg, 0.450 mmol) was added. The mixture was stirred for 1 h at rt. The reaction was quenched with water (10 mL). The mixture was extracted with EA (3 x 10 mL). The organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (15:85) to provide methyl (lS,3aS,4S,7R,7aR)-2-((S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylbutanoyl)-3a- fluoro- 2,3,3a,4,7,7a-hexahydro-lH-4,7-methanoisoindole-l-carboxylate (65.0 mg, 24%) as a light yellow semi-solid. LC-MS (ESI, m / z): 425 [M+H]+. / -butyl (2R,5'S)-5'-carbamoyl-5,7-difluoro-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3' -pyrrolidine] - 1 ' -carboxylate

[0292] To a mixture of 1 - / -butyl 2-methyl (2S,4S)-4-hydroxy-4- (trichloromethyl)pyrrolidine- 1 ,2-dicarboxylate (12.0 g, 33.1 mmol) and 2-bromo-3,5- difluorophenol (13.8 g, 66.2 mmol) in acetone (150 mL) was added sodium hydroxide (8.00 g, 199 mmol) at 0 °C. The mixture was stirred overnight at rt and the reaction was quenched with water (150 mL). The mixture was adjusted to pH = 5 with HC1 (1 M) and extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to remove the solvent. The crude product was purified by C18 column with CtLCN / Water (0.05% TFA), and the fraction was concentrated under reduced pressure to afford (2S,4R)-4-(2-bromo-3,5-difluorophenoxy)-l-( / - butoxycarbonyl)pyrrolidine-2,4-dicarboxylic acid (7.0 g, crude) as a brown oil. LC-MS (ESI, m / z): 410 [M-56+H]+.

[0293] To a mixture of (2S,4R)-4-(2-bromo-3,5-difluorophenoxy)-l-( / - butoxycarbonyl)pyrrolidine-2,4-dicarboxylic acid (7.00 g, 15.0 mmol) in THF (80 mL) were added 1 -hydroxybenzotriazole (10.0 g, 75.1 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (11.5 g, 60.0 mmol) at 0 °C. After stirred for 30 mins at rt, ammonium hydroxide (80 mL, 30 % in water) was added at 0 °C. The mixture was stirred for 2 h at rt and then diluted with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL) and dried overanhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with MeOH:DCM (8:92) to provide / -butyl (2S,4R)-4-(2-bromo-3,5- difhrorophenoxy)-2,4-dicarbamoylpyrrolidine-l -carboxylate (1.2 g, 16%) as a light yellow solid. 'H NMR (400 MHz, DMSO-de) 8 8.00-8.10 (m, 1H), 7.76 (s, 1H), 7.40-7.52 (m, 1H), 7.19-7.31 (m, 1H), 6.98-7.09 (m, 1H), 6.40-6.60 (m, 1H), 4.08-4.25 (m, 1H), 3.95-4.06 (m, 1H), 3.64-3.72 (m, 1H), 2.60-2.72 (m, 1H), 2.24-2.36 (m, 1H), 1.31-1.38 (m, 9H). LC-MS (ESI, m / z) 408 [M-56+H]+.

[0294] To a mixture of / -butyl (2S,4R)-4-(2-bromo-3,5-difluorophenoxy)-2,4- dicarbamoylpyrrolidine- 1 -carboxylate (1.2 g, 2.58 mmol), methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-amino- 1 , l'-biphenyl-2- yl)palladium(II) (219 mg, 0.259 mmol) and 2-(dicyclohexylphosphino)-2',4',6'- triisopropylbiphenyl (123mg, 0.259 mmol) in dioxane (15 mL) was added cesium carbonate (1.80 g, 5.62 mmol). The mixture was stirred overnight at 90 °C under nitrogen and the reaction was quenched with water (50 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with MeOH:DCM (1:25) to provide / -butyl (2R,5'S)-5'-carbamoyl-5,7-difluoro-3-oxo-4H- spiro[l,4-benzoxazine-2,3'-pyrrolidine]-l'-carboxylate (670 mg, 64%) as a light yellow solid. 'H NMR (400 MHz, DMSO-de) 8 11.20 (s, 1H), 7.49-7.60 (m, 1H), 6.99-7.18 (m, 2H), 6.80- 6.94 (m, 1H), 4.17-4.32 (m, 1H), 3.64-3.81 (m, 2H), 2.50-2.55 (m, 1H), 2.22-2.36 (m, 1H), 1.37 (s, 9H). LC-MS (ESI, m / z) 328 [M-56+H]+.(2R,5'S)-5,7-difluoro-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-5'-

[0295] To a solution of / -butyl (2R,5'S)-5'-carbamoyl-5,7-difluoro-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-T-carboxylate (100 mg, 0.261 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 1 h at rt and concentrated under reduced pressure to afford (2R,5'S)-5,7-difluoro-3-oxo-3,4- dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-5'-carboxamide (75 mg, crude) as a yellow solid. LC-MS (ESI, m / z) 306 [M+Na]+. / -butyl (2R,5'S)-5'-carbamoyl-3-oxo-3,4-dihydrospiro[pyrido[3,2-b][l,4]oxazine-2,3'- pyrrolidine]- 1 '-carboxylate

[0296] To a mixture of l-(Lbutyl) 2-methyl (2S,4S)-4-hydroxy-4- (trichloromethyl)pyrrolidine- 1 ,2-dicarboxylate (5.00 g, 13.7 mmol), 2-bromopyridin-3-ol (4.80 g, 27.5 mmol) in acetone (60 mL) was added sodium hydroxide (3.31 g, 82.7 mmol) at 0 °C. The mixture was stirred overnight at rt and adjusted to pH = 6 with HC1 (4 M in dioxane) at 0 °C. The mixture was concentrated under reduced pressure to remove the solvent. The crude product was purified by Cl 8 column with CtLCN / Water (0.05% TFA), and the fraction was concentrated under reduced pressure to afford (2S,4R)-4-((2-bromopyridin-3-yl)oxy)-l-(L butoxycarbonyl)pyrrolidine-2,4-dicarboxylic acid (4.40 g, crude) as a red oil. LC-MS (ESI, m / z): 375 [M-56+H]+.

[0297] To a mixture of (2S,4R)-4-((2-bromopyridin-3-yl)oxy)-l-(L butoxycarbonyl)pyrrolidine-2,4-dicarboxylic acid (4.40 g, 10.2 mmol) in THF (50 mL) were added hydroxybenzotriazole (8.27 g, 61.2 mmol) and l-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (9.78 g, 51.0 mmol) at 0 °C. After stirred for 30 min at rt,ammonium hydroxide (60 mL, 30% in water) was added at 0 °C. The resulting mixture was stirred for 2 h at rt and diluted with water (100 mL). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (150 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by Cl 8 column with CtLCN / Water (0.05% NH4HCO3), and the fraction was concentrated under reduced pressure to provide Lbutyl (2S,4R)-4-((2-bromopyridin-3-yl)oxy)-2,4-dicarbamoylpyrrolidine-l- carboxylate (1.00 g, 22%) as a red solid.!H NMR (400 MHz, DMSO-de) 8 8.00-8.10 (m, 2H), 7.70-7.78 (m, 1H), 7.39-7.55 (m, 2H), 7.15-7.23 (m, 1H), 6.99-7.07 (m, 1H), 4.08-4.29 (m, 1H), 3.92-4.04 (m, 1H), 3.65-3.78 (m, 1H), 2.59-2.67 (m, 1H), 2.25-2.43 (m, 1H), 1.29-1.50 (m, 6H), 1.24-1.27 (m, 3H). LC-MS (ESI, m / z): 373 [M-56+H]+.

[0298] To a mixture of Lbutyl (2S,4R)-4-((2-bromopyridin-3-yl)oxy)-2,4- dicarbamoylpyrrolidine- 1 -carboxylate (1.13 g, 2.63 mmol), copper(I) iodide (300 mg, 1.57 mmol) and cesium carbonate (1.72 g, 5.26 mmol) in THF (15 mL) was added N,N'-Dimethyl- 1 ,2-ethanediamine (394 mg, 4.47 mmol). The mixture was stirred for 1 h at 70 °C under nitrogen and the reaction was quenched with water (50 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by Cl 8 column with CtLCN / Water (0.05% TFA), and the fraction was concentrated under reduced pressure to provide Lbutyl (2R,5'S)-5'-carbamoyl-3-oxo-3,4-dihydrospiro[pyrido[3,2-b][l,4]oxazine- 2,3'-pyrrolidine]-T-carboxylate (590 mg, 64%) as a light yellow solid. ’H NMR (400 MHz, DMSO-<76) 8 11.53 (s, 1H), 7.93-8.06 (m, 1H), 7.34-7.58 (m, 2H), 6.94-7.20 (m, 2H), 4.17- 4.41 (m, 1H), 3.62-3.80 (m, 2H), 2.43-2.48 (m, 1H), 2.25-2.37 (m, 1H), 1.31-1.49 (m, 9H). LC-MS (ESI, m / z):293 [M-56+H]+.(2R,5'S)-3-oxo-3,4-dihydrospiro[pyrido[3,2-b][l,4]oxazine-2,3'-pyrrolidine]-5'-carboxamide

[0299] To a mixture of t-butyl (2R,5'S)-5'-carbamoyl-3-oxo-3,4-dihydrospiro[pyrido[3,2-b][l,4]oxazine-2,3'-pyrrolidine]-l'-carboxylate (300 mg, 0.861 mmol) in DCM (12 mL) was added TFA (4 mL). The mixture was stirred for 1 h at rt and concentrated under reduced pressure to afford (2R,5'S)-3-oxo-3,4-dihydrospiro[pyrido[3,2- b][l,4]oxazine-2,3'-pyrrolidine]-5'-carboxamide (210 mg, crude) as a yellow solid. LC-MS (ESI, m / z): 249 [M+H]+. / -butyl (5'S)-5'-carbamoyl-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-T- carboxylate O t

[0300] To a mixture of 1 -( / -butyl) 2,4-dimethyl (2S)-4-hydroxypyrrolidine- 1,2,4- tricarboxylate (800 mg, 2.64 mmol), o-nitrophenol (367 mg, 2.64 mmol) in toluene (8 mL) was added triphenylphosphane (997 mg, 3.17 mmol) at 0 °C under nitrogen. The mixture was stirred for 20 min at 0 °C. Diisopropyl azodicarboxylate (768 mg, 3.17 mmol) was then added at 0 °C for 20 min. The mixture was stirred for overnight at rt. The reaction was quenched with water (30 mL). The mixture was extracted with EA (3 x 80 mL). The organic layers were combined, washed with brine (2 x 40 mL) and dried over anhydrous Na2SO4. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the crude product that was chromatographed on a silica gel column with EA:PE (1: 1) to provide 1 -( / -butyl) 2,4-dimethyl (2S)-4-(2-nitrophenoxy)pyrrolidine-l,2,4-tricarboxylate (2.00 g, crude) as a red oil. LC-MS (ESI, m / z): 425 [M+H]+.

[0301] To a mixture of 1 -( / -butyl) 2,4-dimethyl (2S)-4-(2-nitrophenoxy )pyrrolidine- 1 , 2, 4-tricarboxylate (1.12 g, 2.64 mmol) and NH4CI (340 mg, 6.34 mmol) in MeOH (12 mL) and water (3 mL) was added iron (738 mg, 5.47 mmol) at rt. The mixture was stirred overnight, and then filtered through a celite pad and washed with DCM (3 x 50 mL). The organic layers were concentrated under reduced pressure to afford l'-(Lbutyl) 5'-methyl (5'S)-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-l',5'- dicarboxylate (2.81 g, crude) as a red oil. LC-MS (ESI, m / z): 363 [M+H]+.

[0302] To a stirred of l'-(Lbutyl) 5'-methyl (5'S)-3-oxo-3,4- dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-T,5'-dicarboxylate (956 mg, 2.64 mmol) in THF (9 mL) and water (9 mL) was added LiOH (317 mg, 13.2 mmol) at rt. The mixture was stirred for 2 h and acidified to pH = 3 with HC1 (2M). The aqueous layer was extracted with EA (3 x 100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford (5'S)-l'-(Lbutoxycarbonyl)-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'- pyrrolidine]-5'-carboxylic acid (730 mg, 76%) as a yellow oil. LC-MS (ESI, m / z): 349 [M+H]+.

[0303] To a mixture of (5'S)-l'-(t-butoxycarbonyl)-3-oxo-3,4- dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-5'-carboxylic acid (730 mg, 2.09 mmol) in THF (7 mL) were added 1 -hydroxybenzotriazole (847 mg, 6.27 mmol) and l-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (878 mg, 4.60 mmol). The mixture was stirred for 30 min at 0 °C. Ammonia (14.6 mL) was added at 0 °C and the mixture was stirred for 2 h at rt. The mixture was purified by C18 column with CILCN / water (0.05% NH4HCO3). The fraction was concentrated under reduced pressure to provide / -butyl (5'S)-5'- carbamoyl-3 -oxo-3 ,4-dihydrospiro [benzo [b] [1,4] oxazine-2,3 '-pyrrolidine] - 1 '-carboxylate (730 mg, crude) as a yellow solid. LC-MS (ESI, m / z) 348 [M+H]+.(2R,5'S)-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-5'-carboxamide

[0304] To a mixture of Lbutyl (2R,5'S)-5'-carbamoyl-3-oxo-3,4- dihydrospiro[benzo[b][l,4]oxazine-2,3'-pyrrolidine]-l'-carboxylate (100 mg, 0.288 mmol) inDCM (3 mL) was added TFA (1 mL). The mixture was stirred for 1 h at rt and concentrated under reduced pressure to afford (2R,5'S)-3-oxo-3,4-dihydrospiro[benzo[b][l,4]oxazine-2,3'- pyrrolidine]-5'-carboxamide (68.0 mg, crude) as a yellow oil. LC-MS (ESI, m / z) 270 [M+Na]+. / -butyl (3R,5'S)-5'-carbamoyl-2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'- pyrrolidine]- 1 '-carboxylate

[0305] To a mixture of 1 -( / -butyl) 2-methyl (S)-4-oxopyrrolidine- 1 ,2- dicarboxylate (10.0 g, 41.1 mmol) in DCM (100 mL) were added trimethylsilyl cyanide (8.20 g, 82.2 mmol) and tetrabutylammonium cyanide (1.20 g, 4.11 mmol). The mixture was stirred overnight on the magnetic stirrer at rt under nitrogen and the reaction was quenched with water (150 mL). The mixture was extracted with DCM (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 1 -( / -butyl) 2-methyl (2S)-4-cyano-4-((trimethylsilyl)oxy)pyrrolidine-l,2-dicarboxylate (14.0 g, crude) as a brown oil. LC-MS (ESI, m / z 287 [M-56+H]+.

[0306] A mixture of 1 -( / -butyl) 2-methyl (2S)-4-cyano-4- ((trimethylsilyl)oxy)pyrrolidine- 1 ,2-dicarboxylate (14.0 g, 41.1 mmol) in hydrogen chloride (140 mL, 4 M in MeOH) was stirred overnight at 50 °C. The mixture was concentrated under reduced pressure to afford dimethyl (2S)-4-hydroxypyrrolidine-2,4-dicarboxylate (8.40 g, crude) as a black oil. LC-MS (ESI, m / z) 204 [M+H]+.

[0307] To a mixture of dimethyl (2S)-4-hydroxypyrrolidine-2,4-dicarboxylate (8.4.0 g, 41.3 mmol) in DCM (85 mL) / THF (35 mL) were added trimethylamine (17.0 g, 165 mmol) and di-Lbutyl dicarbonate (18.0 g, 82.6 mmol). The mixture was stirred overnight at rt and the reaction was quenched with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE ( 1 :4) to provide 1 -( / -butyl) 2,4-dimethyl (2S)-4-hydroxypyrrolidine- 1 ,2,4- tricarboxylate (6.90 g, 49% over 3 steps, R:S=4:6) as a yellow oil. 'H NMR (400 MHz, DMSO- d6) 85.73-6.13 (m, 1H), 4.20-4.46 (m, 1H), 3.35-3.75 (m, 8H), 2.55-2.68 (m, 0.6H), 2.07-2.38 (m, 1.4H), 1.28-1.46 (m, 9H). LC-MS (ESI, m / z): 204 [M-boc+H]+.

[0308] To a mixture of 1 -( / -butyl) 2,4-dimethyl (2S)-4-hydroxypyrrolidine- 1,2,4- tricarboxylate (5.00 g, 16.5 mmol) in THF (150 mL) was added dropwise sodium bis(trimethylsilyl)amide (12.4 mL, 24.8 mmol, 2 M in THF) at -78 °C under nitrogen. After stirred for 5 min at the same temperature, a solution of 2-fluoro-3-nitropyridine (3.51 g, 24.8 mmol) in THF (10 mF) was added dropwise at -78 °C. The mixture was stirred for 2 h from - 78 °C to rt under nitrogen and the reaction was quenched with sat. aqueous ammonium chloride (300 mF). The mixture was extracted with EA (3 x 300 mF). The organic layers were combined, washed with brine (2 x 300 mF) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (21 :79) to provide 1- (t-butyl) 2,4-dimethyl (2S)-4-((3-nitropyridin-2-yl)oxy)pyrrolidine-l,2,4-tricarboxylate (5.50 g, 58%) as a light yellow solid. 'H NMR (400 MHz, DMSO-tfo) 8 8.40-8.56 (m, 2H), 7.30- 7.38 (m, 1H), 4.16-4.65 (m, 2H), 3.86-4.09 (m, 1H), 3.62-3.72 (m, 6H), 2.81-3.02 (m, 1H), 2.53-2.72 (m, 1H), 1.32-1.41 (m, 9H). EC-MS (ESI, m / z): 448 [M+Na]+.

[0309] A mixture of 1 -( / -butyl) 2,4-dimethyl (2S)-4-((3-nitropyridin-2-yl)oxy)pyrrolidine- 1 ,2,4-tricarboxylate (5.50 g, 12.9 mmol), iron (3.61 g, 64.6 mmol) and ammonium chloride (1.66 g, 31.0 mmol) in MeOH (60 mL) / H2O (15 mL) was stirred overnight at 60 °C. The mixture was filtered through a celite pad and washed with EA (3 x 50 mL). The filtrate was diluted with water (150 mL). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (2 x 150 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (3:7) to provide l'-(Lbutyl) 5'-methyl (5'S)-2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine- 3,3'-pyrrolidine]-T,5'-dicarboxylate (4.40 g, 84%) as a light yellow solid. ’H NMR (400 MHz, DMSO-tfc) 8 11.01-11.25 (m, 1H), 7.80-7.95 (m, 1H), 7.23-7.35 (m, 1H), 7.03-7.17 (m, 1H), 4.33-4.62 (m, 1H), 3.91-4.10 (m, 1H), 3.67-3.72 (m, 3H), 3.58-3.65 (m, 1H), 2.63-2.84 (m, 1H), 2.20-2.37 (m, 1H), 1.33-1.42 (m, 9H). LC-MS (ESI, m / z): 386 [M+Na]+.

[0310] A mixture of l'-(Lbutyl) 5'-methyl (5'S)-2-oxo-l,2- dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidine]-T,5'-dicarboxylate (4.40 g, 12.1 mmol) in ammonia (100 mL, 7.0 M in MeOH) was stirred for 3 days at 60 °C. The mixture was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with MeOH:DCM (5:95) to provide Lbutyl (5'S)-5'-carbamoyl-2-oxo-l,2- dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidine]-l'-carboxylate (3.50 g, 66%) as a yellow solid.!H NMR (400 MHz, DMSO-tfo) 8 11.03 (br, 1H), 7.81-7.94 (m, 1H), 7.23-7.36 (m, 2H), 7.01-7.15 (m, 2H), 4.19-4.37 (m, 1H), 3.67-3.79 (m, 1H), 3.50-3.65 (m, 1H), 2.65- 2.83 (m, 1H), 2.10-2.28 (m, 1H), 1.33-1.40 (m, 9H). LC-MS (ESI, m / z): 349 [M+H]+.

[0311] The crude product Lbutyl (5'S)-5'-carbamoyl-2-oxo-l,2- dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidine]-l '-carboxylate (3.50 g, 10.0 mmol) was separated by prep-ACIRAL-SFC-HPLC column (Column: GreenSep Basic 3 x 15 cm, 5 pm; Mobile Phase A: CO2, Mobile Phase B: MeOH(l% 2M NH3 in MeOH); Flow rate: 75 mL / min; Gradient: isocratic 20% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 5.13; RT2(min): 6.82; Sample Solvent: MeOH; Injection Volume: 4 mL). Purification resulted in isomer 1: Lbutyl (3S,5'S)-5'-carbamoyl-2-oxo-l,2- dihydrospiro[pyrido[2,3-b][l,4]oxazine-3,3'-pyrrolidine]-l'-carboxylate (950 mg, 25%) as a light yellow solid.!H NMR (400 MHz, DMSO-tfo) 8 11.06 (s, 1H), 7.79-7.88 (m, 1H), 7.24- 7.45 (m, 2H), 7.00-7.19 (m, 2H), 4.20-4.32 (m, 1H), 3.95-4.02 (m, 1H), 3.49-3.65 (m, 1H),2.63-2.81 (m, 1H), 2.10-2.26 (m, 1H), 1.23-1.51 (m, 9H). LC-MS (ESI, m / z): 349 [M+H]+; and isomer 2: / -butyl (3R,5'S)-5'-carbamoyl-2-oxo-l,2-dihydrospiro[pyrido[2,3-b][l,4]oxazine- 3,3'-pyrrolidine]-l'-carboxylate (980 mg, 26%) as a light yellow solid. ’H NMR (400 MHz, DMSO-tfo) 8 11.12 (s, 1H), 7.79-7.95 (m, 1H), 7.45-7.61 (m, 1H), 7.23-7.39 (m, 1H), 6.93- 7.20 (m, 2H), 4.18-4.39 (m, 1H), 3.61-3.80 (m, 2H), 2.43-2.49 (m, 1H), 2.24-2.41 (m, 1H), 1.17-1.51 (m, 9H). LC-MS (ESI, m / z): 349 [M+H]+.(3R,5'S)-2-oxo-l,2-dihydrospiro[pyrido[2,3-Z?][l,4]oxazine-3,3'-pyrrolidine]-5'-carboxamide

[0312] To a mixture of / -butyl (3R,5'S)-5'-carbamoyl-2-oxo-l,2- dihydrospiro[pyrido[2,3-Z?][l,4]oxazine-3,3'-pyrrolidine]-l'-carboxylate (100 mg, 0.287 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 1 h at rt and concentrated under reduced pressure to afford (3R,5'S)-2-oxo-l,2-dihydrospiro[pyrido[2,3- &][l,4]oxazine-3,3'-pyrrolidine]-5'-carboxamide (70.0 mg crude) as a yellow semi-solid. LC- MS (ESI, m / z): 249 [M+H]+. / -butyl (3S,5S)-5-carbamoyl-2'-oxo-T,4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]-l- carboxylate

[0313] To a stirred suspension of zinc dust (523 mg, 8.00 mmol) in THF (8 mL) was added 1 ,2-dibromoethane (37.6 mg, 0.20 mmol) dropwise at rt. The mixture was placed in an oil bath, heated to reflux and stirred for 10 min. Chlorotrimethylsilane (8.69mg, 0.08 mmol) was added dropwise. The mixture was stirred at 60 °C for 15 mins, l-bromo-2- (bromomethyl)benzene (1.00 g, 4.00 mmol) in THF (2.0 mL) was added slowly at 0 °C. The mixture was stirred at rt for 4 h (monitored by TLC). The stirring was discontinued, and the unreacted zinc was allowed to settle. The mixture was cooled to rt to afford a solution of (2- bromobenzyl)zinc(II) bromide (0.4 mmol / mL in THF).

[0314] To a solution of 1 -( / -butyl) 2-methyl (S)-4-oxopyrrolidine-l,2- dicarboxylate (1.00 g, 4.11 mmol) and tribromomethane (2.08 g, 8.22 mmol) in THF (10 mL) was added dropwise lithium bis(trimethylsilyl)amide (8.2 mL, 8.22 mmol, 1 M in THF) at - 78 °C under nitrogen. The mixture was stirred for 1 h at -78 °C and the reaction was quenched with NH4CI (sat., aq., 100 mL). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (2 x 80 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (35-45%) to provide 1-Lbutyl 2-methyl (2S,4S)-4-hydroxy-4-(tribromomethyl)pyrrolidine-l,2- dicarboxylate (1.14 g, crude) as a light yellow solid. ’H NMR (400 MHz, DMSO-de) 8 6.77- 6.83 (m, 1H), 4.54-4.70 (m, 1H), 3.78-3.95 (m, 1H), 3.61-3.74 (m, 4H), 2.89-3.15 (m, 1H), 2.20-2.33 (m, 1H), 1.29-1.47 (m, 9H). LC-MS (ESI, m / z): 394 [M-100+H]+.

[0315] To a mixture of l-(Lbutyl) 2-methyl (2S,4S)-4-hydroxy-4- (tribromomethyl)pyrrolidine-l,2-dicarboxylate (500 mg, 1.01 mmol) and CH3OH (113 mg, 3.55 mmol) in dioxane (5 mL) was added l,8-diazabicyclo[5.4.0]undec-7-ene (339 mg, 2.23 mmol) at 0 °C. The mixture was stirred for 1 h at 0 °C and the reaction was quenched with saturated ammonium chloride aqueous solution (20 mL). The mixture was extracted with EA (3 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate wasconcentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (1:4) to provide 1 -( / -butyl) 2,4-dimethyl (2S,4R)-4-bromopyrrolidine-1.2.4-tricarboxylate (170 mg, >90%pure, -45% yield) as a light yellow oil. 'H NMR (400 MHz, DMSO-sfe) 8 4.38-4.68 (m, 1H), 3.98-4.30 (m, 1H), 3.78-3.92 (m, 1H), 3.63-3.77 (m, 6H), 3.04-3.16 (m, 0.4H), 2.56-2.83 (m, 1.6H), 1.35-1.43 (m, 9H). LC-MS (ESI, m / z): 266 [M-Boc+H]+.

[0316] A solution of CoBr2 (180 mg, 0.819 mmol) and 1,2- bis(diphenylphosphino)ethane (653 mg, E64 mmol) in DMF (30 mL) and THF (30 mL) was stirred for 15 mins at rt. I -( / -butyl) 2,4-dimethyl (2S,4R)-4-bromopyrrolidine- 1,2,4- tricarboxylate (3.00 g, 8.19 mmol) and the solution of (2-bromobenzyl)zinc(II) bromide (60.0 mL, 32.8 mmol) were added. The mixture was stirred for 1 h at 40 °C and the reaction was quenched with ammonium chloride solution (50 mL). The mixture was extracted with EA (3 x 200 mL). The organic layers were combined and dried over magnesium sulfate anhydrous. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by C 18 column with CH3CN / W ater (0.05% TFA), (68%). The fraction was concentrated under reduced pressure to provide 1 -( / -butyl) 2,4-dimethyl (S)-4-(2- bromobenzyl)pyrrolidine- 1 ,2,4-tricarboxylate (1.32 g, 35%) as a yellow oil. ’ H NMR (400 MHz, DMSO-de) 8 7.52-7.90 (m, 1H), 7.25-7.50 (m, 1H), 7.05-7.23 (m, 2H), 4.20-4.35 (m, 1H), 3.85-4.15 (m, 1H), 3.70-3.80 (m, 1H), 3.10-3.65 (m, 6H), 2.65-3.20 (m, 2H), 1.85-2.45 (m, 2H), 1.20-1.45 (m, 9H). LC-MS (ESI, m / z): 456 [M+H]+.

[0317] To a stirred mixture of 1 -( / -butyl) 2,4-dimethyl (S)-4-(2- bromobenzyl)pyrrolidine- 1 ,2,4-tricarboxylate (1.00 g, 1.97 mmol) in THF (10 mL) and water (10 mL) was added LiOH (262 mg, 9.86 mmol) at rt. The mixture was stirred for 3 h and acidified to pH = 3 with HC1 (2M). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The organic layers was concentrated under reduced pressure to afford (S)-4-(2-bromobenzyl)-l-( / - butoxycarbonyl)pyrrolidine-2,4-dicarboxylic acid (1.00 g, crude) as a yellow oil. LC-MS (ESI, m / z): 428 [M+H]+.

[0318] To a mixture of (S)-4-(2-bromobenzyl)-l -( / -butoxycarbonyl )pyrrolidine-2.4-dicarboxylic acid (900 mg, 2.10 mmol) in THF (9 mL) were added 1 -hydroxybenzotriazole (1.71 g, 12.6 mmol) and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide HC1 (2.00 g, 10.5mmol). The mixture was stirred for 30 mins at 0 °C and then ammonia (15 mL) was added at 0 °C. The mixture was stirred for 2 h at rt and the reaction was quenched with water (30 mL). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (2 x 30 mL) and dried over magnesium sulfate anhydrous. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford / -butyl (S)-4- (2-bromobenzyl)-2,4-dicarbamoylpyrrolidine-l -carboxylate (870 mg, crude) as a yellow solid. LC-MS (ESI, m / z): 426 [M+H]+.

[0319] To a mixture of / -butyl (S)-4-(2-bromobenzyl)-2,4-dicarbamoylpyrrolidine- 1-carboxylate (770 mg, 1.81 mmol) in THF (8 mL) were added cuprous iodide (206 mg, 1.08 mmol), cesium carbonate (1.18 g, 3.61 mmol) and dimethylethylenediamine (303 mg, 3.43 mmol). The mixture was stirred for 3 h at 70 °C under nitrogen and the reaction was quenched with water (25 mL). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (2 x 30 mL) and dried over magnesium sulfate anhydrous. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with CtLOITDCM (7:93) to provide / -butyl (3S,5S)-5-carbamoyl-2'-oxo-l',4'-dihydro-2'H-spiro[pyrrolidine-3,3'- quinoline]-l -carboxylate (260 mg, 41 %, isomer ratio: 1:2.3) as a yellow solid. The two isomers were separated by prep- HPLC (Column: XSelect CSH Prep Cl 8 OBD, 30 x 150 mm, 5 pm; Mobile Phase A: Water (0.1% FA), Mobile Phase B: CH3CN; Flow rate: 60 mL / min; Gradient: 26 to 65% B; Wave Length: 220 nm) to provide / -butyl (3R,5S)-5-carbamoyl-2'-oxo- l',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]-l-carboxylate (48.0 mg) and / -butyl (3S,5S)-5-carbamoyl-2'-oxo-l',4'-dihydro-2'H-spiro[pyrrolidine-3,3'-quinoline]-l- carboxylate (116.0 mg) as white solids. / -butyl (2R,5'S)-5'-carbamoyl-3-oxo-4,5-dihydro-3H-spiro[benzo[f][l,4]oxazepine-2,3'- pyrrolidine]- 1 '-carboxylate

[0320] To a mixture of l-(Lbutyl) 2-methyl (2S,4S)-4-hydroxy-4- (trichloromethyl)pyrrolidine- 1 ,2-dicarboxylate (2.00 g, 5.51 mmol) and / -butyl (2- hydroxybenzyl)carbamate (1.85 g, 8.27 mmol) in acetone (50 mL) was added NaOH (1.10 g, 27.6 mmol) at 0 °C. The mixture was stirred overnight at rt and the reaction was quenched with water (100 mL). The mixture was adjusted to pH = 5 with HC1 (1 M) and extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The solvents were removed by filtration and the solvate was concentrated under reduced pressure to afford (2S,4R)-l-(Lbutoxycarbonyl)-4-(2-(((L butoxycarbonyl)amino)methyl)phenoxy)pyrrolidine-2,4-dicarboxylic acid (2.66 g, crude) as a brown oil. LC-MS (ESI, m / z): 503 [M+Na]+.

[0321] To a mixture of (2S,4R)-l-( / -butoxycarbonyl)-4-(2-(((t- butoxycarbonyl)amino)methyl)phenoxy)pyrrolidine-2,4-dicarboxylic acid (2.66 g, 5.54 mmol) and potassium carbonate (3.08 g, 22.1 mmol) in DMF (30 mL) was added iodomethane (1.57 g, 11.1 mmol) at 0 °C. The mixture was stirred for 1 h at rt and the reaction was quenched with water (80 mL). The mixture was extracted with EA (3 x 80 mL). The organic layers were combined, washed with brine (2 x 80 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by C18 column with CH3CN: Water (0.05% TFA). The fraction was concentrated under reduced pressure to provide I -( / -butyl) 2,4-dimethyl (2S,4R)-4-(2-(((t- butoxycarbonyl)amino)methyl)phenoxy)pyrrolidine-l,2,4-tricarboxylate (1.00 g, 33%). ’ H NMR (400 MHz, DMSO-tfo) 87.10-7.28 (m, 3H), 6.96-7.06 (m, 1H), 6.50-6.58 (m, 1H), 4.34- 4.46 (m, 1H), 4.05-4.16 (m, 2H), 3.95-4.01 (m, 1H), 3.78-3.88 (m, 1H), 3.61-3.77 (m, 6H), 2.78-2.89 (m, 1H), 2.51-2.56 (m, 1H), 1.26-1.45 (m, 18H). LC-MS (ESI, m / z): 531 [M+Na]+.

[0322] To a solution of l-(Lbutyl) 2,4-dimethyl (2S,4R)-4-(2-(((t-butoxycarbonyl)amino)methyl)phenoxy)pyrrolidine-l,2,4-tricarboxylate (500 mg, 0.983 mmol) in DCM (10 mL) was added TFA (3 mL). The mixture was stirred for 1 h at rt and concentrated under reduced pressure to afford dimethyl (2S,4R)-4-(2- (aminomethyl)phenoxy)pyrrolidine-2,4-dicarboxylate (303 mg, crude). LC-MS (ESI, m / z) 309 [M+H]+.

[0323] To a mixture of dimethyl (2S,4R)-4-(2-(aminomethyl)phenoxy)pyrrolidine- 2,4-dicarboxylate (303 mg, 0.983 mmol) in MeOH (5 mL) was added N-ethyl-N- isopropylpropan-2- amine (381 mg, 2.95 mmol). The mixture was stirred for 2 h at rt and concentrated under reduced pressure to afford methyl (2R,5'S)-3-oxo-4,5-dihydro-3H- spiro[benzo[f][l,4]oxazepine-2,3'-pyrrolidine]-5'-carboxylate (272 mg, crude). LC-MS (ESI, m / z): 277 [M+H]+.

[0324] A mixture of methyl (2R,5'S)-3-oxo-4,5-dihydro-3H- spiro[benzo[f][l,4]oxazepine-2,3'-pyrrolidine]-5'-carboxylate (272 mg, 0.984 mmol) in ammonia (5 mL, 7 M in MeOH) was stirred overnight at 50 °C in a sealed vial. The mixture was concentrated under reduced pressure to afford (2R,5'S)-3-oxo-4,5-dihydro-3H- spiro[benzo[f][l,4]oxazepine-2,3'-pyrrolidine]-5'-carboxamide (257 mg, crude). LC-MS (ESI, m / z): 262 [M+H]+.

[0325] To a mixture of (2R,5'S)-3-oxo-4,5-dihydro-3H- spiro[benzo[f][l,4]oxazepine-2,3'-pyrrolidine]-5'-carboxamide (257 mg, 0.984 mmol) and di- Lbutyl dicarbonate (258 mg, 1.18 mmol) in DCM (5 mL) was added NEta (199 mg, 1.97 mmol). The mixture was stirred for 2 h at rt and concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with MeOH:DCM (6:94) to provide t- butyl (2R,5'S)-5'-carbamoyl-3-oxo-4,5-dihydro-3H-spiro[benzo[ / ][l,4]oxazepine-2,3'- pyrrolidine]- 1 '-carboxylate (105 mg, 28%) as an off-white solid.!H NMR (400 MHz, DMSO- d68 8.48-8.56 (m, 1H), 7.48-7.57 (m, 1H), 7.33-7.41 (m, 2H), 7.14-7.23 (m, 1H), 6.99-7.09 (m, 1H), 6.90-6.97 (m, 1H), 4.11-4.38 (m, 3H), 3.74-3.87 (m, 1H), 3.54-3.62 (m, 1H), 2.51- 2.57 (m, 1H), 2.29-2.40 (m, 1H), 1.41 (s, 9H). LC-MS (ESI, m / z): 362 [M+H]+.tert-butyl (3S,5R)-3-carbamoyl-6-oxo-8-phenyl-2,7-diazaspiro[4.4]non-8-ene-2-carboxylate

[0326] To a mixture of 1 -( / -butyl) 2,4-dimethyl (2S,4R)-4-bromopyrrolidine- 1,2,4- tricarboxylate (3.00 g, 8.19 mmol) in THF (60 mL) were added ethynylbenzene (2.51 g, 24.6 mmol), copper(I) bromide (118 mg, 0.819 mmol), pentamethyldiethylenetriamine (142 mg, 0.819 mmol) and NEu (1.25 g, 12.3mmol). The mixture was stirred overnight at 60 °C under nitrogen and the reaction was quenched with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 100 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (1:3) to provide isomer 1: l-(Z-butyl) 2,4-dimethyl (2S,4S)-4-((E)-2- bromo-2-phenylvinyl)pyrrolidine-l,2,4-tricarboxylate (740 mg, 13%) as a light yellow oil. ’ H NMR (400 MHz, DMSO-tfo) 87.38-7.42 (m, 3H), 7.21-7.28 (m, 2H), 6.40-6.53 (m, 1H), 4.17- 4.33 (m, 1H), 3.97-4.11 (m, 1H), 3.77-3.93 (m, 1H), 3.30-3.46 (m, 6H), 2.56-2.67 (m, 1H), 2.22-2.45 (m, 1H), 1.27-1.33 (m, 9H). LC-MS (ESI, m / z): 368 [M-100+H]+; and isomer 2: 1- ( -butyl) 2,4-dimethyl (2S,4R)-4-((E)-2-bromo-2-phenylvinyl)pyrrolidine- 1 ,2,4-tricarboxylate (1.00 g, 20%) as a light yellow oil. 'H NMR (400 MHz, DMSO-tfo) 87.39-7.43 (m, 3H), 7.22- 7.27 (m, 2H), 6.39-6.52 (m, 1H), 4.54-4.76 (m, 1H), 4.20-4.27 (m, 1H), 3.79-3.89 (m, 1H), 3.30-3.41 (m, 6H), 2.57-2.66 (m, 1H), 2.27-2.38 (m, 1H), 1.28-1.35 (m, 9H). LC-MS (ESI, m / z): 368 [M-100+H]+.

[0327] A mixture of 1 -( / -butyl) 2,4-dimethyl (2S,4R)-4-((E)-2-bromo-2-phenylvinyl)pyrrolidine- 1 ,2,4-tricarboxylate (1.00 g, 2.14 mmol) in ammonia (60 mL, 7 M in MeOH) was stirred for 3 days at 55 °C. The mixture was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with MeOH:DCM (1:24) to provide / -butyl (2S,4R)-4-((E)-2-bromo-2-phenylvinyl)-2,4-dicarbamoylpyrrolidine- 1 - carboxylate (500 mg, 41%) as a light yellow solid. 'H NMR (400 MHz, DMSO-rfc) 8 7.34- 7.67 (m, 4H), 7.12-7.33 (m, 4H), 6.84-7.04 (m, 1H), 6.32-6.47 (m, 1H), 3.87-3.99 (m, 1H), 3.40-3.65 (m, 1H), 3.13-3.29 (m, 1H), 2.04-2.24 (m, 1H), 1.89-2.03 (m, 1H), 1.28-1.44 (m, 9H). LC-MS (ESI, m / z): 438 [M+H]+.

[0328] To a mixture of / -butyl (2S,4R)-4-((E)-2-bromo-2-phenylvinyl)-2,4- dicarbamoylpyrrolidine- 1 -carboxylate (500 mg, 1.14 mmol), 2-(dicyclohexylphosphino)- 2',4',6'-triisopropylbiphenyl (164 mg, 0.343 mmol) and methanesulfonato(2- dicyclohexylphosphino-2',4',6'-tri-i-propyl- 1 , 1 '-biphenyl)(2'-amino- 1 , l'-biphenyl-2- yl)palladium(II) (386 mg, 0.456 mmol) in dioxane (15 mL) was added cesium carbonate (1.49 g, 4.56 mmol). The mixture was stirred overnight at 90 °C under nitrogen and the reaction was quenched with water (30 mL). The mixture was extracted with EA (3 x 30 mL). The organic layers were combined, washed with brine (2 x 30 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was purified by TLC (Mobile phase: MeOH:DCM =1:10; Rf = 0.4; detection: UV) to provide / -butyl (3S,5R)-3-carbamoyl-6-oxo-8-phenyl-2,7- diazaspiro[4.4]non-8-ene-2-carboxylate (120 mg, 23%) as a light yellow solid. 'H NMR (400 MHz, DMSO-tfc) 8 7.61-7.70 (m, 1H), 7.37-7.54 (m, 4H), 7.12-7.29 (m, 1H), 6.85-7.09 (m, 2H), 6.36-6.71 (m, 1H), 4.18-4.35 (m, 1H), 3.84-3.95 (m, 1H), 3.48-3.61 (m, 1H), 2.18-2.31 (m, 1H), 1.88-2.07 (m, 1H), 1.15-1.48 (m, 9H). LC-MS (ESI, m / z): 358 [M+H]+. / -butyl (5'S)-5'-carbamoyl-2-oxohexahydro-2H-spiro[cyclopenta[b]pyrrole-3,3'-pyrrolidine]- l'-carboxylate

[0329] To a mixture of 1 -( / -butyl) 2,4-dimethyl (2S,4R)-4-bromopyrrolidine- 1,2,4- tricarboxylate (3.00 g, 8.19 mmol) in THF (45 mL) WERE added (cyclopent- 1-en-l- yloxy)trimethylsilane (3.84 g, 24.5 mmol), A;-(2-(dimethylamino)ethyl)-A;,A2,A2- trimethylethane- 1 ,2-diamine (141 mg, 0.819 mmol), NEta (1.24 g, 12.2 mmol) and cuprous bromide (117 mg, 0.819 mmol). The mixture was stirred overnight at 60 °C under nitrogen and the reaction was quenched with water (100 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (l x 100 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was chromatographed on a silica gel column with EA:PE (35:65) to afford the crude product l-(t-butyl) 2,4-dimethyl (2S)-4-(2-oxocyclopentyl)pyrrolidine-l,2,4-tricarboxylate (1.1 g, crude) as a light yellow oil. LC-MS (ESI, m / z) 392 [M+Na]+.

[0330] To a mixture of 1 -( / -butyl) 2,4-dimethyl (2S)-4-(2- oxocyclopentyl)pyrrolidine- 1 ,2,4-tricarboxylate (1.10 g, 2.97 mmol) in EtOH (30 mL) were added hydroxylamine hydrochloride (1.03 g, 14.8 mmol) and sodium acetate (1.22 g, 14.8 mmol). The mixture was reflux for 3 h and the reaction was quenched with water (60 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 30 mL) and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford 1 -( / -butyl) 2,4- dimethyl (2S)-4-(-2-(hydroxyimino)cyclopentyl)pyrrolidine-l,2,4-tricarboxylate (800 mg, crude) as a yellow oil. LC-MS (ESI, m / z . 407 [M+Na]+.

[0331] To a mixture of l-(Z-butyl) 2,4-dimethyl (2S)-4-((E)-2-(hydroxyimino)cyclopentyl)pyrrolidine- 1 ,2,4-tricarboxylate (800 mg, 2.08 mmol) in EtOH (20 mL) was added platinum dioxide (470 mg, 2.08 mmol). The mixture was stirred for 2 days at rt under hydrogen atmosphere. The mixture was filtered through a celite pad and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (85:15) to provide l'-(t-butyl) 5'-methyl (5'S)-2-oxohexahydro-2H- spiro[cyclopenta[b]pyrrole-3,3'-pyrrolidine]-r,5'-dicarboxylate (150 mg, 5% for 3 steps) as a yellow oil. ’H NMR (400 MHz, DMSO-de) 8 7.86 (s, 1H), 4.15-4.26 (m, 1H), 3.91-4.01 (m, 1H), 3.62-3.72 (m, 3H), 3.45-3.54 (m, 1H), 3.33-3.40 (m, 1H), 2.25-2.48 (m, 2H), 1.42-1.82 (m, 7H), 1.29-1.38 (m, 9H). LC-MS (ESI, m / z): 339 [M+H]+.

[0332] To a mixture of 1 '-( / -butyl) 5'-methyl (5'S)-2-oxohexahydro-2H- spiro[cyclopenta[b]pyrrole-3,3'-pyrrolidine]-l',5'-dicarboxylate (150 mg, 0.443 mmol) in THF (2 mL) was added a solution of LiOH (31.0 mg, 1.32 mmol) in H2O (2 mL). The mixture was stirred for 2 h at rt and the reaction was quenched with water (5 mL). The mixture was acidified to pH = 3 with HC1 (1 M). The mixture was extracted with EA (3 x 10 mL). The organic layers were combined and dried over anhydrous sodium sulfate. The solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (5'S)-l'-( / - butoxycarbonyl)-2-oxohexahydro-2H-spiro[cyclopenta[b]pyrrole-3,3'-pyrrolidine]-5'- carboxylic acid (80.0 mg, crude) as a light yellow solid.!H NMR (400 MHz, DMSO-de) 8 12.58 (br, 1H), 7.81-7.89 (m, 1H), 3.95-4.12 (m, 2H), 3.43-3.52 (m, 1H), 3.33-3.38 (m, 1H), 2.28-2.48 (m, 2H), 1.44-1.85 (m, 7H), 1.30-1.38 (m, 9H). LC-MS (ESI, m / z): 325 [M+H]+.

[0333] To a mixture of (5'S)-l'-( / -butoxycarbonyl)-2-oxohexahydro-2H- spiro[cyclopenta[b]pyrrole-3,3'-pyrrolidine]-5'-carboxylic acid (80.0 mg, 0.247 mmol), ammonium chloride (92.0 mg, 1.72 mmol) and HATU (112 mg, 0.296 mmol) in DMF (3 mL) was added DIPEA (191 mg, 1.48 mmol) at 0 °C. The mixture was stirred for 2 h at rt. The mixture was purified by C18 column with CHaCN / Water (0.05% TFA), and the fraction was concentrated under reduced pressure to provide / -butyl (5'S)-5'-carbamoyl-2-oxohexahydro- 2H-spiro[cyclopenta[b]pyrrole-3,3'-pyrrolidine]-l '-carboxylate (50.0 mg, 56%) as a light yellow solid. ’H NMR (400 MHz, DMSO-de) 87.82 (s, 1H), 7.34-7.43 (m, 1H), 6.91-6.99 (m, 1H), 3.96-4.05 (m, 2H), 3.58-3.67 (m, 1H), 3.12-3.20 (m, 1H), 2.30-2.44 (m, 2H), 1.50-1.72 (m, 7H), 1.31-1.38 (m, 9H). LC-MS (ESI, m / z): 324 [M+H]+.(S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylpent-4-ynoic acid

[0334] To a mixture of 4-methoxyaniline (5.0 g, 36.4 mmol) and magnesium sulfate (24.4 g, 202 mmol) in DCM (100 mL) was added methyl 2-hydroxy-2-methoxyacetate (4.88 g, 40.5 mmol). The mixture was stirred for 3 h at rt and filtered. The filter cake was washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure to afford methyl (2Z)-2-[(4-methoxyphenyl)imino] acetate (8 g, crude) as a brown yellow oil.1H NMR (400 MHz, CDC13) 8 7.95 (s, 1H), 7.33-7.43 (m, 2H), 6.85-6.99 (m, 2H), 3.94 (s, 3H), 3.83 (s, 3H). LC-MS (ESI, m / z) 194 [M+H]+.

[0335] To a stirred mixture of powdered molecular sieves (5 A, 4g), sulfamide (0.20 g, 2.07 mmol) and N,N-dimethylpyridin-4-amine (0.25 g, 2.07 mmol) in DCM (40 mL) was added methyl (2Z)-2-[(4-methoxyphenyl)imino] acetate (8.00 g, 41.4 mmol) and isobutyraldehyde (3.58 g, 49.6 mmol) at rt. The mixture was stirred for overnight at rt. The reaction was quenched with water (150 mL). The mixture was extracted with EA (3 x 150 mL). The organic layers were combined, washed with brine (2 x 150 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the crude product that was chromatographed on a silica gel column with EA:PE (1:4) to provide methyl (2S)-2-[(4-methoxyphenyl)amino]- 3,3-dimethyl-4-oxobutanoate (4.5 g, 36 %) as a light yellow oil. 'H NMR (400 MHz, DMSO- d&) 8 9.58 (s, 1H), 6.73 (m, 4H), 5.42 (d, J = 8.0 Hz, 1H), 4.44 (d, J = 8.0 Hz, 1H), 3.65 (s, 3H), 3.61 (s, 3H), 0.85-1.34 (m, 6H). LC-MS (ESI, m / z) 266 [M+H]+.

[0336] To a stirred mixture of methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3- dimethyl-4-oxobutanoate (4.5 g, 16.9 mmol) and potassium carbonate (4.69 g, 33.9 mmol) in MeOH (50 mL) was added dimethyl (l-diazo-2-oxopropyl)phosphonate (4.24 g, 22.0 mmol) dropwise at rt under N2. The mixture was stirred for 2 h at rt. The reaction was quenched with water (200 mL). The mixture was extracted with EA (3 x 200 mL). The organic layers were combined, washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (1:9) to provide methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethylpent-4-ynoate (1.70 g, 36 %) as a yellow oil. ’H NMR (400 MHz, DMSO-de) 8 6.65-6.76 (m, 4H), 5.05 (d, J = 12.0 Hz, 1H), 3.92 (d, J = 12.0 Hz, 1H), 3.61-3.64 (m, 6H), 3.09 (s, 1H), 1.34 (s, 3H), 1.29 (s, 3H). LC-MS (ESI, m / z): 262 [M+H]+.

[0337] To a stirred mixture of methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3- dimethylpent-4-ynoate (1.14 g, 4.36 mmol) in CH3CN (9 mL) and H2O (3 mL) were added ceric ammonium nitrate (12.0 g, 21.8 mmol) at rt. The mixture was stirred for 2 h at rt. THF (10 mL) was added, followed by trimethylamine and di-tert-butyl dicarbonate (5.48 g, 25.1 mmol). The mixture was stirred for 4 h at rt and then diluted with water (50 mL). The mixture was extracted with EA (3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford the crude product that was chromatographed on a silica gel column with EA:PE (1:9) to afford methyl (2S)-2-[(L butoxycarbonyl)amino]-3,3-dimethylpent-4-ynoate (800 mg, 63 %) as a yellow oil.1H NMR (400 MHz, DMSO-<76) 87.01 (d, J= 12.0 Hz, 1H), 4.11 (d, J= 12.0 Hz, 1H), 3.65 (s, 3H), 3.06 (s, 1H), 1.39 (s, 9H), 1.21-1.23 (m, 6H). LC-MS (ESI, m / z): 156 [M+H-Boc]+.

[0338] To a stirred mixture of methyl (2S)-2-[(Lbutoxycarbonyl)amino]-3,3- dimethylpent-4-ynoate (800 mg, 3.13 mmol) in THF (6 mL) and H2O (2 mL) was added LiOH (375 mg, 15.6 mmol) at rt . The mixture was stirred for 1 h at 60 °C. The mixture was acidified to pH 3 with HC1 (IM). The aqueous layer was extracted with EA (3 x 20 mL). The mixture was concentrated under reduced pressure to afford (2S)-2-[(Lbutoxycarbonyl)amino]-3,3- dimethylpent-4-ynoic acid (700 mg, 92%) as an orange solid.1H NMR (400 MHz, DMSO- d6) 8 12.76 (s, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.00 (d, J = 8.0 Hz, 1H), 3.03 (s, 1H), 1.40 (s, 9H), 1.17-1.24 (m, 6H). LC-MS (ESI, m / z): 142 [M-100+H]+.(S)-2-((Lbutoxycarbonyl)amino)-3,3-dimethylpent-4-enoic acid

[0339] To a solution of methyl (S)-2-((4-methoxyphenyl)amino)-3,3-dimethyl-4- oxobutanoate (5.17 g, 18.6 mmol) in toluene was added sodium bis(trimethylsilyl)amide (3.42 g, 18.6 mmol) at 0°C. The mixture was stirred for 30 min at rt. After cooling to 0°C, a solution of methyl (2S)-2-[(4-methoxyphenyl)amino]-3,3-dimethyl-4-oxobutanoate (4.50 g, 16.9 mmol) in toluene (50 mL) was added. The mixture was stirred for 30 min at 0°C and then poured into ice-cold water (50 mL). The mixture was extracted with EA(3 x 80 mL). The organic phases were combined, washed with brine (50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (6:94) and then was purified by Cl 8 column with CH3CN: Water (0.05% FA). The desired fraction was concentrated under reduced pressure to provide methyl (S)-2-((4-methoxyphenyl)amino)- 3,3-dimethylpent-4-enoate (600 mg, crude) as a brown oil.1H NMR (400 MHz, DMSO- e) 8 6.26 -7.33 (m, 4H), 5.64-6.16 (m, 1H), 4.76-5.27 (m, 2H), 3.72-3.87 (m, 1H), 3.37 -3.71 (m, 6H), 0.47-1.43 (m, 6H). LC-MS (ESI, m / z): 264 [M+H]+.

[0340] To a stirred mixture of methyl (S)-2-((4-methoxyphenyl)amino)-3,3- dimethylpent-4-enoate (0.460 g, 1.75 mmol) in CH3CN (2.4 mL) and H2O (0.8 mL) were added ceric ammonium nitrate (4.80 g, 8.73 mmol) at rt. The mixture was stirred for 2 h at rt and THF (2.5 mL), trimethylamine (basified to pH=8), di-Lbutyl dicarbonate (2.28 g, 10.4 mmol) were added. The mixture was stirred for 2 h at rt. The reaction was quenched with water (30 mL). The mixture was extracted with EA(3 x 50 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product waschromatographed on a silica gel column with EA:PE (10:90) to provide methyl (S)-2-((t- butoxycarbonyl)amino)-3,3-dimethylpent-4-enoate (195 mg, 43%) as a yellow oil. ’H NMR (400 MHz, DMSO-r / e) 8 6.75-7.25 (m, 1H), 5.52-6.16 (m, 1H), 4.68-5.20 (m, 2H), 3.80-4.10 (m, 1H), 3.43-3.70 (m, 3H), 1.13-1.73 (m, 9H), 0.64-1.10 (m, 6H). LC-MS (ESI, m / z): 202 [M-56+H]+.

[0341] To a stirred mixture of methyl (S)-2-((Lbutoxycarbonyl)amino)-3,3- dimethylpent-4-enoate (195 mg, 0.758 mmol) in THF (3 mL) andH2O (1 mL) was added LiOH (90.7 mg, 3.79 mmol) at rt. The mixture was stirred for 2 h at 60 °C and then acidified to pH=3 with HC1 (IM). The mixture was extracted with EA(3 x 20 mL). The organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (2S)-2-[(Lbutoxycarbonyl)amino]-3,3-dimethylpent-4-enoic acid (160 mg, 86%, crude) as a light orange solid. LC-MS (ESI, m / z): 188 [M-56+H]+.(S)-2-((Lbutoxycarbonyl)amino)-2-( 1 -vinylcyclobutyl) acetic acid

[0342] To a solution of 4-methoxyaniline (7.00 g, 56.8 mmol) in DCM (100 mL) was added methyl 2-hydroxy-2-methoxyacetate (6.83 g, 56.8 mmol) and magnesium sulfate (34.2 g, 284 mmol). The mixture was stirred for 3 h at rt. The mixture was filtered through acelite pad and washed with DCM (3 x 100 mL). The filtrate was concentrated under reduced pressure to afford methyl (Z)-2-((4-methoxyphenyl)imino)acetate (11.0 g, crude) as a yellow oil. LC-MS (ESI, m / z): 194 [M+H]+.

[0343] To a mixture of powdered molecular sieves (5A, 5.5 g), 2-amino-3-(L butoxy)butanoic acid (499 mg, 2.85 mmol), sulfamide (274 mg, 2.85 mmol) and N,N- dimethylpyridin-4- amine (348 mg, 2.85 mmol) in DCM (60 mL) were added methyl (Z)-2-((4- methoxyphenyl)imino)acetate (11.0 g, 56.9 mmol) and cyclobutyral (7.66 g, 91.1 mmol) at rt. The mixture was stirred overnight at rt. The reaction was quenched with water (50 mL). The mixture was extracted with DCM (3 x 150 mL). The organic layers were combined, washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (16:100) to provide methyl (S)-2-(l- formylcyclobutyl)-2-((4-methoxyphenyl)amino)acetate (2.6 g, crude) as a red oil. LC-MS (ESI, m / z) 278 [M+H]+.

[0344] To a stirred mixture of methyltriphenylphosphanium bromide (4.69 g, 13.1 mmol) in toluene (30 mL) was added sodium bis(trimethylsilyl)amide (6.55 mL, 13.1 mmol, 2 M in THF) at 0 °C under nitrogen. The mixture was stirred for 1 h at 0 °C, and then methyl (S)-2-(l-formylcyclobutyl)-2-((4-methoxyphenyl)amino)acetate (2.6 g, 9.38 mmol) was added. The mixture was stirred for 1 h at 0 °C. The reaction was quenched with water (20 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (11: 100) to provide methyl (S)-2-((4- methoxyphenyl)amino)-2-(l-vinylcyclobutyl)acetate (820 mg, 31%) as a yellow oil. LC-MS (ESI, m / z) 276 [M+H]+.

[0345] To a stirred mixture of methyl (S)-2-((4-methoxyphenyl)amino)-2-(l- vinylcyclobutyl) acetate (820 mg, 2.98 mmol) in CH3CN (20 mL) and H2O (5 mL) were added ceric ammonium nitrate (8.19 g, 14.9 mmol). The mixture was stirred for 2 h at rt. THF (5 mL) was added, and the mixture was basified to pH=8 with NEts. Di-Lbutyl dicarbonate (3.90 g, 17.9 mmol) was added. The mixture was stirred for 2 h at rt. The reaction was quenched with H2O (30 mL). The mixture was extracted with EA (3 x 100 mL). The organic layers werecombined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (6: 100) to provide methyl (S)-2-((Lbutoxycarbonyl)amino)-2-(l-vinylcyclobutyl)acetate (470 mg, crude) as a yellow oil. 'H NMR (400 MHz, CDC13) 8 5.72-5.80 (m, 1H), 5.35-5.52 (m, 2H), 4.45-4.50 (m, 1H), 3.72 (s, 3H), 2.25-2.45 (m, 1H), 2.10-2.21 (m, 2H), 1.75-2.00 (m, 3H), 1.47 (s, 9H). LC-MS (ESI, m / z) 270 [M+H]+.

[0346] To a mixture of methyl (S)-2-((Lbutoxycarbonyl)amino)-2-(l- vinylcyclobutyl)acetate (470 mg, 1.75 mmol) in THF (3 mL), H2O (2 mL) and MeOH (ImL) was added LiOH (209 mg, 8.73 mmol). The mixture was stirred for 1 h at 50 °C and then concentrated under reduced pressure to remove MeOH. The mixture was adjusted to pH=5 with HC1 (1 M). The mixture was extracted with EA (3 x 80 mL). The organic layers were combined, dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to provide (S)-2-((Lbutoxycarbonyl)amino)- 2-(l-vinylcyclobutyl)acetic acid (420 mg, crude) as an off-white solid. LC-MS (ESI, m / z) 256 [M+H]+.(S)-2-((Lbutoxycarbonyl)amino)-3-cyclopropyl-3-methylbutanoic acid

[0347] To a solution of methyl (2S)-2-[(Lbutoxycarbonyl)amino]-3,3- dimethylpent-4-i(1.80 g, 7.00 mmol) in Et2O (20 mL) at -30 °C was added diazomethane (54.0 g, 210 mmol) and palladium(II) acetate (0.235 g, 1.05 mmol). The mixture was stirred for 1 h at rt and then filtered. The filter cake was washed with diethyl ether (3 x 80 mL). The filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (13:87) to provide methyl (2S)-2-[(t- butoxycarbonyl)amino]-3-cyclopropyl-3-methylbutanoate (0.800 g, 42%) as a light yellow oil. LC-MS (ESI, m / z): 272 [M+H]+.

[0348] To a stirred mixture of methyl (2S)-2-[(Lbutoxycarbonyl)amino]-3- cyclopropyl-3-methylbutanoate (800 mg, 2.95 mmol) in THF (18 mL) and H2O (18 mL) wasadded LiOH (338 mg, 14.7 mmol) at rt. The mixture was stirred for 3 h at 60 °C. The mixture was acidified to pH = 3 with HCI (2M). The aqueous layer was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 80 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure to afford (2S)-2-[(Lbutoxycarbonyl)amino]-3-cyclopropyl-3-methylbutanoic acid (500 mg, crude) as a light yellow solid. LC-MS (ESI, m / z) 258 [M+H]+. (Lbutoxycarbonyl)amino)-3,3,4-trimethylpent-4-enoic acidTMSCH2N2, MgBr2PPh3CH3BrEt2O, HCI, MeOH t-BuOK, THF 0 °C to r 0 °C to rt, 3ht, overnight

[0349] To a solution of methyl (S)-2-((4-methoxyphenyl)amino)-3,3-dimethyl-4- oxobutanoate (12.0 g, 45.2 mmol) and magnesium bromide (29.2 g, 113 mmol) in Et2O (200 mL) was added (trimethylsilyl)diazomethane (11.4 g, 99.5 mmol) at 0 °C. The mixture was stirred for 0.5 h at 0 °C and then stirred overnight at rt. MeOH (60 mL) and HCI (40 mL, 2 M) were added at 0 °C. The mixture was stirred for 1 h at rt. The mixture was extracted with EA (3 x 100 mL). The organic layers were combined, washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, the solids were removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was chromatographed on a silica gel column with EA:PE (17%) to provide methyl (S)-2-((4-methoxyphenyl)amino)-3,3-dimethyl- 4-oxopentanoate (3...

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:wherein:Ring A1is a monocyclic moiety selected from the group consisting, wherein each is optionally substituted with one or more moieties independently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl, an unsubstituted or a substituted C3-6 monocyclic cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted -O-aryl and an unsubstituted or a substituted -O-benzyl; orRing A1is a multicyclic moiety selected from the group consistingeach is optionally substituted with one or more moieties independently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl;R1is selected from the group consisting, wherein each is optionally substituted with one or more moieties independently selected from the group consisting of halogen, cyano, hydroxy, an unsubstituted Ci-6 alkyl, an unsubstituted -O(Ci-6 alkyl), an unsubstituted C1-4 haloalkyl, an unsubstituted C1-4 haloalkoxy, an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted C3-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted benzyl, an unsubstituted or a substituted 5- or 6-membered heteroaryl, -S(=O)2(an unsubstituted C1-4 alkyl), -NRN1RN2and -C(=O)-NRN1RN2, wherein RN1and RN2are independently hydrogen or an unsubstituted C1-4 alkyl, or RN1and RN2are taken together to form a monocyclic heterocyclyl;R2is hydrogen, deuterium or halogen;R4is 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, -C(=O)NH2, -CH(OH)-(S(=O)2-OH), -CH(OH)-(S(=O)2-O ), -CH(OH)((P=O)(OR6)2) and -C(=O)CH2-O-((P=O)(OR7)2);R5ais selected from the group consisting of hydrogen, an unsubstituted or a substituted Ci-4 alkyl, an unsubstituted or a substituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 cycloalkyl;Z1is -C(=O)- or -S(=O)2-; each R6and each R7are independently hydrogen, an unsubstituted Ci-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(Ci-4 alkyl);R8and R10are independently selected from the group consisting of an unsubstituted or a substituted Ci-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 or a substituted bicyclic 5- to 8-membered heterocyclyl, wherein when the Ci-6 alkyl is substituted, the Ci-6 alkyl is substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, cyano, -NH2, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-6 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic 5- or 6-membered heteroaryl, an unsubstituted or a substituted monocyclic 4-6 membered heterocyclyl, an unsubstituted C1-4 alkoxy, an unsubstituted or a substituted phenoxy, an unsubstituted or a substituted -O-(CH2)-phenyl and an unsubstituted C1-4 haloalkoxy, or the Ci- 6 alkyl is substituted 1 to 13 times with deuterium; wherein when the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6cycloalkyl, the bicyclic C5-8 cycloalkyl, the monocyclic 4- to 6-membered heterocyclyl and the bicyclic 5- to 8-membered heterocyclyl are substituted, the C2-6 alkenyl, the C2-6 alkynyl, the monocyclic C3-6 cycloalkyl, the bicyclic C5-8 cycloalkyl, the monocyclic 4- to 6-membered heterocyclyl and the bicyclic 5- to 8-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;R8ais hydrogen or an unsubstituted C1-4 alkyl; orR8and R8aare taken together to form an unsubstituted monocyclic C3-6 cycloalkyl or a halogen-substituted monocyclic C3-6 cycloalkyl;R9is selected from the group consisting of an unsubstituted or a substituted Ci-6 alkyl, an unsubstituted or a substituted Ci-6 haloalkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C5-12 cycloalkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted monocyclic heteroaryl, an unsubstituted or a substituted monocyclic heterocyclyl, an unsubstituted or a substituted alkoxy and -NR17R18, wherein the substituted Ci-6 alkyl is substituted 1 or 2 times with a substituent selected from hydroxy and an unsubstituted C1-4 alkoxy, or the Ci-6 alkyl is substituted 1 to 13 times with deuterium, 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 Ci- 4 alkyl, an unsubstituted C1-4 alkoxy, an unsubstituted C1-4 haloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl and an unsubstituted or a substituted phenyl, wherein when the phenyl is substituted it is substituted with one or more substituents selected from -F, -Cl, -CH3 and -CF3, and wherein the substituted Ci-6 haloalkyl is substituted 1 or 2 times with a substituent independently selected from the group consisting of an unsubstituted C1-4 alkoxy and an unsubstituted or a substituted monocyclic C3-6 cycloalkyl;R11is an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl,-(NH)-(an unsubstituted or a substituted 5- to 10-membered heteroaryl), -O-(an unsubstituted or a substituted Ci-6 alkyl), -O-(an unsubstituted or a substituted C3-8 cycloalkyl) or -O-(Ci-4 alkyl)-(an unsubstituted or a substituted C3-8 cycloalkyl);R12is an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2- 8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 12-membered monocyclic heterocyclyl, an unsubstituted or a substituted 5- to 12-membered bicyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl), an unsubstituted or a substituted heteroaryl(alkyl), an unsubstituted or a substituted heterocyclyl(alkyl), an unsubstituted or a substituted C- carboxy, -OR13, -NR14R15or -C(=O)-NR16AR16B;R13is an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2- 8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl) or an unsubstituted or a substituted heteroaryl( alkyl) ;R14are R15are independently selected from the group consisting of hydrogen, an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted monocyclic C3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted 3- to 8 -membered monocyclic heterocyclyl, an unsubstituted or a substituted aryl(alkyl) and an unsubstituted or a substituted heteroaryl(alkyl);R16Ais hydrogen or an unsubstituted C1-3 alkyl;R16Bis an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl; and R17and R18are independently selected from the group consisting of hydrogen, an unsubstituted or a substituted Ci-8 alkyl, an unsubstituted or a substituted C2-8 alkenyl, an unsubstituted or a substituted C2-8 alkynyl, an unsubstituted or a substituted C3-8 cycloalkyl, an unsubstituted or a substituted 3-8 membered heterocyclyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted aryl(alkyl)and an unsubstituted or a substituted heteroaryl(alkyl); orR17and R18are taken together along with the nitrogen to which they are connected to form an unsubstituted or a substituted 3-8 membered heterocyclyl.

2. The compound of Claim 1, wherein Ring A1is a monocyclic moiety selectedis optionally substituted with one or more moieties independently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted Ci-4 alkyl, an unsubstituted Ci-4 haloalkyl, -O-(unsubstituted Ci-4 alkyl), an unsubstituted C2-4 alkenyl, an unsubstituted or a substituted C3-6 monocyclic cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted -O-aryl and an unsubstituted or a substituted -O-benzyl.

3. The compound of Claim 1, wherein Ring A1is a multicyclic moiety selectedwherein each is optionally substituted with one or more moieties independently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted CM haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl.

4. The compound of Claim 3, wherein Ring A1is a multicyclic moiety selectedindependently selected from the group consisting of =0, =CH2, deuterium, halogen, hydroxy, an unsubstituted C1-4 alkyl, an unsubstituted CM haloalkyl, -O-(unsubstituted C1-4 alkyl), an unsubstituted C2-4 alkenyl and an unsubstituted or a substituted C3-6 monocyclic cycloalkyl.

5. The compound of Claim 1, wherein Ring A1is selected from the group consisting of:The compound of Claim 1, wherein Ring A1is selected from the group consisting of:

7. The compound of Claim 1, wherein Ring8. The compound of any one of Claims 1-7, wherein R4is an unsubstituted or a substituted ketoamide or -C(=0)NH2.

9. The compound of any one of Claims 1-7, wherein R4is an unsubstituted or a substituted acyl.

10. The compound of any one of Claims 1-7, wherein R4is -CH(OH)-(S(=O)2-OH) or-CH(OH)-(S(=O)2-O ).

11. The compound of any one of Claims 1-7, wherein R4is -CH(OH)((P=O)(OR6)2), wherein each R6are independently hydrogen, an unsubstituted Ci-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(Ci-4 alkyl).

12. The compound of any one of Claims 1-7, wherein R4is -C(=O)CH2-O- ((P=O)(OR7)2), wherein each R7are independently hydrogen, an unsubstituted Ci-6 alkyl, an unsubstituted C2-6 alkenyl, an unsubstituted Ci-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(Ci-4 alkyl).

13. The compound of any one of Claims 1-7, wherein R4is cyano.

14. The compound of any one of Claims 1-7, wherein R4is an unsubstituted or a substituted C2-5 alkynyl.

15. The compound of any one of Claims 1-14, wherein R5ais hydrogen.

16. The compound of any one of Claims 1-14, wherein R5ais an unsubstituted or a substituted C1-4 alkyl.

17. The compound of any one of Claims 1-14, wherein R5ais an unsubstituted or a substituted C2-4 alkenyl.

18. The compound of any one of Claims 1-14, wherein R5ais an unsubstituted or a substituted C3-6 cycloalkyl.

19. The compound of any one of Claims 1-18, wherein R1is selected from the group consisting of:

20. The compound of any one of Claims 1-18, wherein R1is selected from the group consisting of:

21. The compound of any one of Claims 1-18, wherein22. The compound of any one of Claims 1-18, wherein R1is selected from the group consisting of:

23. The compound of any one of Claims 1-18, wherein R1is selected from the group consisting of:

24. The compound of any one of Claims 1-23, wherein R3is25. The compound of Claim 24, wherein R8is an unsubstituted Ci-6 alkyl.

26. The compound of Claim 24, wherein R8is a substituted Ci-6 alkyl.

27. The compound of Claim 24, wherein R8is an unsubstituted C2-6 alkenyl.

28. The compound of Claim 24, wherein R8is a substituted C2-6 alkenyl.

29. The compound of Claim 24, wherein R8is an unsubstituted C2-6 alkynyl.

30. The compound of Claim 24, wherein R8is a substituted C2-6 alkynyl.

31. The compound of Claim 24, wherein R8is an unsubstituted monocyclic C3-6 cycloalkyl.

32. The compound of Claim 24, wherein R8is a substituted monocyclic C3-6 cycloalkyl.

33. The compound of Claim 24, wherein R8is an unsubstituted bicyclic C5-8 cycloalkyl.

34. The compound of Claim 24, wherein R8is a substituted bicyclic C5-8 cycloalkyl.

35. The compound of Claim 24, wherein R8is an unsubstituted monocyclic 4- to 6- membered heterocyclyl.

36. The compound of Claim 24, wherein R8is a substituted monocyclic 4- to 6- membered heterocyclyl.

37. The compound of Claim 24, wherein R8is an unsubstituted monocyclic C3-6 cycloalkyl(CH2)-.

38. The compound of any one of Claims 24-37, wherein R9is an unsubstituted Ci- 6 alkyl.

39. The compound of any one of Claims 24-37, wherein R9is a substituted Ci-6 alkyl.

40. The compound of any one of Claims 24-37, wherein R9is an unsubstituted Ci- 6 haloalkyl.

41. The compound of any one of Claims 24-37, wherein R9is a substituted Ci-6 haloalkyl.

42. The compound of any one of Claims 24-37, wherein R9is an unsubstituted or substituted monocyclic C3-6 cycloalkyl.

43. The compound of any one of Claims 24-37, wherein R9is an unsubstituted or a substituted bicyclic C5-6 cycloalkyl.

44. The compound of any one of Claims 24-37, wherein R9is an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted monocyclic heterocyclyl.

45. The compound of any one of Claims 24-37, wherein R9is an unsubstituted or a substituted alkoxy.

46. The compound of Claim 45, wherein R9is -O-(an unsubstituted Ci-6 alkyl).

47. The compound of any one of Claims 24-37, wherein R9is -NR17R18.

48. The compound of any one of Claims 24-47, wherein Z1is -C(=O)-.

49. The compound of any one of Claims 24-47, wherein Z1is -S(=O)2-.JVX / VV50. The compound of any one of Claims 1-23, wherein R3is.

51. The compound of Claim 50, wherein R10is an unsubstituted Ci-6 alkyl.

52. The compound of Claim 50, wherein R10is a substituted Ci-6 alkyl.

53. The compound of Claim 50, wherein R10is an unsubstituted C2-6 alkenyl.

54. The compound of Claim 50, wherein R10is a substituted C2-6 alkenyl.

55. The compound of Claim 50, wherein R10is an unsubstituted C2-6 alkynyl.

56. The compound of Claim 50, wherein R10is a substituted C2-6 alkynyl.

57. The compound of Claim 50, wherein R10is an unsubstituted monocyclic C3-6 cycloalkyl.

58. The compound of Claim 50, wherein R10is a substituted monocyclic C3-6 cycloalkyl.

59. The compound of Claim 50, wherein R10is an unsubstituted bicyclic C5-8 cycloalkyl.

60. The compound of Claim 50, wherein R10is a substituted bicyclic C5-8 cycloalkyl.

61. The compound of Claim 50, wherein R10is an unsubstituted monocyclic 4- to 6-membered heterocyclyl.

62. The compound of Claim 50, wherein R10is a substituted monocyclic 4- to 6- membered heterocyclyl.

63. The compound of Claim 50, wherein R10is an unsubstituted monocyclic C3-6 cycloalkyl(CH2)-.

64. The compound of any one of Claims 50-63, wherein R11is an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl.

65. The compound of any one of Claims 50-63, wherein R11is -(NH)- (an unsubstituted or a substituted 5- to 6-membered monocyclic heteroaryl).

66. The compound of any one of Claims 50-63, wherein R11is -O-(an unsubstituted or a substituted Ci-6 alkyl).

67. The compound of any one of Claims 50-63, wherein R11is -O-(an unsubstituted or a substituted C3-8 cycloalkyl).

68. The compound of any one of Claims 50-63, wherein R11is -O-(Ci-4alkyl)-(an unsubstituted or a substituted C3-8 cycloalkyl).

69. The compound of any one of Claims 1-23, wherein R3is R12.

70. The compound of Claim 69, wherein R12is a substituted Ci-8 alkyl.

71. The compound of Claim 69, wherein R12is an unsubstituted or a substituted C2- 8 alkenyl.

72. The compound of Claim 69, wherein R12is an unsubstituted or a substituted C2- 8 alkynyl.

73. The compound of Claim 69, wherein R12is an unsubstituted or a substituted C3- 8 cycloalkyl.

74. The compound of Claim 69, wherein R12is an unsubstituted or a substituted aryl.

75. The compound of Claim 69, wherein R12is an unsubstituted or a substituted heteroaryl.

76. The compound of Claim 75, wherein R12is, wherein each is unsubstituted or substituted.

77. The compound of Claim 69, wherein R12is an unsubstituted or a substituted 3- to 8-membered monocyclic heterocyclyl.

78. The compound of Claim 69, wherein R12is an unsubstituted or a substituted aryl(alkyl).

79. The compound of Claim 69, wherein R12is an unsubstituted or a substituted heteroaryl( alkyl) .

80. The compound of Claim 69, wherein R12is an unsubstituted or a substituted heterocyclyl(alkyl).

81. The compound of Claim 69, wherein R12is an unsubstituted or a substituted C- carboxy.

82. The compound of Claim 69, wherein R12is -OR13.

83. The compound of Claim 69, wherein R12is -NR14R15.

84. The compound of Claim 69, wherein R12is -C(=O)-NR16AR16B.

85. The compound of any one of Claims 1-23, wherein R3is selected from the group consisting of:86. The compound of any one of Claims 1-23, wherein R3is selected from the group consisting of:

87. The compound of any one of Claims 1-23, wherein R3is88. The compound of any one of Claims 1-23, wherein R3is selected from the group consisting of:

89. The compound of any one of Claims 1-23, wherein R3is selected from the group consisting of:

90. The compound of any one of Claims 1-23, wherein R3is selected from the group consisting of:moiety is unsubstituted or substituted.

91. The compound of any one of Claims 1-90, wherein R2is hydrogen.

92. The compound of any one of Claims 1-90, wherein R2is deuterium.

93. The compound of any one of Claims 1-90, wherein R2is halogen.

94. The compound of Claim 1, wherein the compound is selected from the group consisting of:foregoing.

95. The compound of Claim 1, wherein the compound is selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing.

96. The compound of Claim 1, wherein the compound is selected from the group consisting of:acceptable salt of any of the foregoing.

97. The compound of Claim 1, wherein the compound is selected from the group consisting of:pharmaceutically acceptable salt of any of the foregoing.

98. The compound of Claim 1, wherein the compound is selected from the groupconsisting of:pharmaceutically acceptable salt of any of the foregoing.

99. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, and excipient.

100. Use of the compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a coronavirus infection.

101. The use of Claim 100, wherein the use further comprises the use of 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 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.

102. The use of Claim 101, 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, GS-5245 (Obeldesivir) and AT-527.

103. The use of any one of Claims 100-102, wherein the coronavirus is P- corona virus.

104. The use of any one of Claims 100-102, 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.

105. Use of the compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a picornavirus infection.

106. The use of Claim 105, wherein the picornavirus infection is a rhino virus infection.

107. Use of the compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment of a norovirus infection.

108. A compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, for use in treating a coronavirus infection.

109. The compound of Claim 108, 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 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.

110. The compound of Claim 109, 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 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, GS-5245 (Obeldesivir) and AT-527.

111. The compound of any one of Claims 108-110, wherein the coronavirus is P-coronavirus.

112. The compound of any one of Claims 108-110, 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.

113. A compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, for use in treating a picornavirus infection.

114. The compound of Claim 113, wherein the picornavirus infection is a rhino virus infection.

115. A compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, for use in treating a norovirus infection.

116. 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 1-98, or a pharmaceutically acceptable salt thereof.

117. The method of Claim 116, 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 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.

118. The method of Claim 117, 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, GS-5245 (Obeldesivir) and AT-527.

119. The method of any one of Claims 116-118, wherein the coronavirus is P-coronavirus.

120. The method of any one of Claims 116-118, 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.

121. A method for treating a picorna virus infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof.

122. The method of Claim 121, wherein the picornavirus infection is a rhino virus infection.

123. 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 1-98, or a pharmaceutically acceptable salt thereof.

124. The use of any one of Claims 100-107, the compound of any one of Claims 108-115, or the method of any one of Claims 116-123, wherein the subject is a human.

125. The use, compound or method of Claim 124, wherein the subject is 60 years old or older.

126. The use, compound or method of Claim 124, wherein the subject is a nonhuman primate.

127. The use, compound or method of Claim 124, wherein the subject is a cat.

128. The use, compound or method of Claim 124, wherein the subject is a camel.

129. The use of any one of Claims 100-107, the compound of any one of Claims 108-115, or the method of any one of Claims 116-123, 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.

130. The use of any one of Claims 100-107, the compound of any one of Claims 108-115, or the method of any one of Claims 116-123, wherein the coronavirus causes a complication selected from the group consisting of sinusitis, otitis media, pneumonia, acuterespiratory distress syndrome, disseminated intravascular coagulation, pericarditis and kidney failure.

131. The use of any one of Claims 100-107, the compound of any one of Claims 108-115, or the method of any one of Claims 116-123, wherein the compound is administered intravenously, subcutaneously, orally or via inhalation.

132. The use of Claim 102, the compound of Claim 110, or the method of Claim 118, wherein the interferon is selected from the group consisting of recombinant interferon alpha 2b, IFN-Ol and PEG-IFN-0l-2a.

133. 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 - 98, or a pharmaceutically acceptable salt thereof, wherein the compound of any one of Claims 1-98, or a pharmaceutically acceptable salt thereof, selectively inhibits the coronavirus protease compared to a host protease.

134. The method of Claim 133, 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.

135. The method of Claim 133 or 134, wherein the host protease is selected from Cathepsin L and Cathepsin B.

136. The method of any one of Claims 133-135, wherein the selectively is > 2-fold.

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