SARS-COV-2 inhibitors for treating coronavirus infections

Abstract

Provided herein are compounds, pharmaceutical compositions, and methods for treating SARS-CoV-2 infection.

Description

[Technical field]

[0001] cross reference This patent application claims the benefit of international application PCT / CN2021 / 128243, filed November 2, 2021, and international application PCT / CN2022 / 117034, filed September 5, 2022, which are incorporated by reference in their entireties. [Background technology]

[0002] SARS-CoV-2 (also known as 2019-nCoV or COVID-19) first emerged in 2019. Symptoms associated with the disease include fever, muscle pain, cough, dyspnea, and fatigue (Huang et al., 2020). Currently, there is no treatment available for SARS-CoV-2. Nevertheless, treatment with well-known drugs such as chloroquine or investigational drugs such as remdesivir has been proposed for the disease (Colson et al., 2020; Wang et al., 2020). The human immunodeficiency virus (HIV) drug, lopinavir / ritonavir cocktail, has also been investigated as a treatment for SARS-CoV-2 as they have shown anticoronavirus effects in vitro (Que et al., 2003; Chu et al., 2004; Chan et al., 2015; Li and De Clercq, 2020).

[0003] SARS-CoV-2 is a beta-coronavirus, a member of the Coronaviridae family, which contains the largest positive-sense single-stranded RNA viruses (Cui et al., 2019). The virus contains four nonstructural proteins: papain-like protease (PL pro ) and 3-chymotrypsin-like protease (3CL pro ), RNA polymerase and helicase (Zumla et al., 2016). Both proteases (PL pro and 3CL pro ) are involved in viral transcription and replication. prois thought to be mainly involved in viral replication (de Wit et al., 2016). pro The SARS-CoV-2 cysteine ​​protease 3CL hydrolyzes the viral polyproteins pp1a and pp1ab to produce functional proteins during coronavirus replication. pro reported that 3CL shows 96% sequence similarity to that of SARS-CoV ( Xu et al., 2020 ). Due to its highly conserved sequence and essential functional properties, pro are being validated as potential targets for the development of drugs to treat SARS-CoV-2.

[0004] As a viable treatment remains elusive, there is a need for compounds and / or methods for inhibiting SARS-CoV-2 and for treating subjects infected with SARS-CoV-2. Summary of the Invention

[0005] As used herein, the formula (I)

[0006] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 is a halogen, R 2 is a halogen, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 3 are each independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SRa, -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR cR d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a or Or two R on the same atom 3 come together to form oxo, R 3a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2Ra , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 3a come together to form oxo, n is 0 to 4; L is -(CR 4 R 4 ) p - and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same carbon 4 Each of them is one or more R 4a optionally substituted with, taken together to form a cycloalkyl or heterocycloalkyl; R 4a are each independently halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; p is 0 to 4; R 5 is deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 6a is replaced by Or two R on the same atom 6 come together to form oxo, R 6a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d, -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 6a come together to form oxo, m is 0 to 4; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R8a is replaced by R 8a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 8a come together to form oxo, Or R 7 and R 8 together and optionally independently one or more R 7a forming a heterocycloalkyl substituted with R 7a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 7a come together to form oxo, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R bare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R c and R d are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1- C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0007] Also disclosed herein are pharmaceutical compositions comprising a therapeutically effective amount of a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, and a pharma- ceutically acceptable excipient.

[0008] Also disclosed herein is a method of treating or preventing a coronavirus infection in a patient in need thereof, comprising administering to the patient a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0009] Also disclosed herein is a method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof, comprising administering to the patient a compound disclosed herein or a pharma-ceutically acceptable salt, solvate, or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0010] In some embodiments, the compound or pharmaceutical composition is administered to the patient until the infection is reduced or eliminated. In some embodiments, the method includes treating one or more symptoms of SARS-CoV-2 in the patient.

[0011] Also disclosed herein is an in vivo method of inhibiting a SARS-CoV-2 protease, comprising contacting the protease with a compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof.

[0012] In some embodiments, the compound binds to a cysteine ​​residue of a protease. In some embodiments, the compound binds reversibly or irreversibly to the cysteine ​​residue. In some embodiments, the compound binds irreversibly to the cysteine ​​residue. In some embodiments, the compound covalently binds to the cysteine ​​residue. In some embodiments, the protease is a 3CL-protease. In some embodiments, the cysteine ​​is cysteine ​​145 of the 3CL-protease. In some embodiments, the protease is SARS-CoV-2 MPRO.

[0013] Also disclosed herein are modified SARS-CoV-2 MPRO proteins, including the SARS-CoV-2 MPRO protein and the compounds disclosed herein covalently bound to the SARS-CoV-2 MPRO protein.

[0014] INCORPORATION BY REFERENCE All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] definition In the following description, certain specific details are described to provide a thorough understanding of various embodiments. However, those skilled in the art will understand that the present disclosure can be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring the description of the embodiments. Unless otherwise required by context, throughout this specification and the following claims, the word "comprise" and variations thereof, such as "comprises" and "comprising," should be interpreted in an inclusive sense, i.e., "including but not limited to." Furthermore, the headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed disclosure.

[0016] Throughout this specification, reference to "some embodiments" or "an embodiment" means that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Thus, the appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. It should also be noted that the term "or" is generally used in the sense of including "and / or" unless the content clearly dictates otherwise.

[0017] As used herein, the following terms have the following meanings, unless otherwise indicated:

[0018] "Oxo" refers to =O.

[0019] "Carboxyl" refers to --COOH.

[0020] "Cyano" refers to -CN.

[0021] "Alkyl" refers to a straight or branched chain saturated hydrocarbon monoradical having from 1 to about 10 carbon atoms, more preferably from 1 to 6 carbon atoms. Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl, and hexyl, as well as longer alkyl groups such as heptyl, octyl, etc. Whenever appearing herein, "C1-C6 alkyl" or "C 1-6 Numeric ranges such as "alkyl" mean that the alkyl group can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, although this definition also encompasses occurrences of the term "alkyl" where no numerical range is specified. In some embodiments, alkyl is C 1-10 In some embodiments, alkyl is C 1-6 In some embodiments, alkyl is C 1-5 In some embodiments, alkyl is C 1-4 In some embodiments, alkyl is C 1-3Alkyl. Unless otherwise stated herein, alkyl groups may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, alkyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkyl is optionally substituted with halogen.

[0022] "Alkenyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. The group may be in either the cis or trans conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1-propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl, and the like. "C2-C6 alkenyl" or "C 2-6Numerical ranges such as "alkenyl" whenever they appear herein mean that the alkenyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkenyl" where no numerical range is specified. Unless otherwise stated herein, an alkenyl group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, an alkenyl is optionally substituted with oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkenyl is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkenyl is optionally substituted with halogen.

[0023] "Alkynyl" refers to a straight or branched chain hydrocarbon monoradical having one or more carbon-carbon triple bonds and having from 2 to about 10 carbon atoms, more preferably from 2 to about 6 carbon atoms. Examples include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl, and the like. "C2-C6 alkynyl" or "C 2-6Numerical ranges such as "alkynyl" whenever they appear herein mean that the alkynyl group can consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, or 6 carbon atoms, but this definition also encompasses occurrences of the term "alkynyl" where no numerical range is specified. Unless otherwise stated herein, alkynyl groups can be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, alkynyl is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, alkynyl is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, alkynyl is optionally substituted with halogen.

[0024] "Alkylene" refers to a straight or branched divalent hydrocarbon chain. Unless otherwise stated in the specification, an alkylene group may be optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkylene is optionally substituted with oxo, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkylene is optionally substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkylene is optionally substituted with halogen.

[0025] "Alkoxy" is a group of formula -OR a where R ais an alkyl radical as defined. Unless otherwise stated in the specification, an alkoxy group may be optionally substituted, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an alkoxy is substituted with, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy is substituted with halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy is optionally substituted with halogen.

[0026] "Aryl" refers to a radical derived from a hydrocarbon ring system containing 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is attached through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to, aryl radicals derived from anthrylene, naphthylene, phenanthrylene, anthracene, azulene, benzene, chrysene, fluoranthene, fluorene, as-indacene, s-indacene, indane, indene, naphthalene, phenalene, phenanthrene, pleiadene, pyrene, and triphenylene hydrocarbon ring systems. Unless otherwise stated herein, an aryl may be optionally substituted, for example, with halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, an aryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, an aryl is optionally substituted with halogen.

[0027] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbocyclic ring that may include fused ring systems (when fused to an aryl or heteroaryl ring, the cycloalkyl is attached through a non-aromatic ring atom), spiro ring systems, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having 3 to 15 carbon atoms (C3-C4, C5-C6, C7-C8, C9-C10, C11-C12, C13-C14, C15-C16, C17-C18, C19-C20, C21-C22, C23-C34, C24-C36, C25-C38, C26-C38, C27-C48, C28-C49, C29-C39, C31-C31-C41, C25-C31-C42, C27-C31-C43, C28-C32-C44, C29-C33-C45, C29-C34-C46, C29-C35-C47, C29-C36-C48, C29-C37-C49, C31-C38-C49, C29-C39-C41-C42, C29-C38-C43-C44, C29-C39-C45, C31-C31-C43-C44, C29-C31-C45, C29-C32-C45-C46, C29-C33-C47-C48, C29-C34-C49 15Fully saturated cycloalkyl or C3-C 15 Cycloalkenyl), cycloalkyl having 3 to 10 carbon atoms (C3-C 10 Fully saturated cycloalkyl or C3-C 10cycloalkenyl), cycloalkyl having 3 to 8 carbon atoms (C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), cycloalkyl having 3 to 6 carbon atoms (C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), cycloalkyl having 3 to 5 carbon atoms (C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or cycloalkyl having 3 to 4 carbon atoms (C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 to 10 membered fully saturated cycloalkyl or a 3 to 10 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 to 6 membered fully saturated cycloalkyl or a 3 to 6 membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5 to 6 membered fully saturated cycloalkyl or a 5 to 6 membered cycloalkenyl. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Examples of polycyclic cycloalkyl include adamantyl, norbornyl, decalinyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decalin, trans-decalin, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, and bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptanyl. Examples of partially saturated cycloalkyl include cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise in the specification, cycloalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like.In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl is optionally substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl is optionally substituted with halogen.

[0028] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodo. In some embodiments, the halogen is fluoro or chloro. In some embodiments, the halogen is fluoro.

[0029] "Haloalkyl" refers to an alkyl radical, as defined above, substituted by one or more halo radicals, as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0030] "Hydroxyalkyl" refers to an alkyl radical as defined above substituted with one or more hydroxyls. In some embodiments, the alkyl is optionally substituted with one hydroxyl. In some embodiments, the alkyl is one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0031] "Aminoalkyl" refers to an alkyl radical, as defined above, substituted with one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.

[0032] "Heteroalkyl" refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. In one aspect, the heteroalkyl is a C1-C6 heteroalkyl, where the heteroalkyl is composed of 1-6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, and the heteroalkyl is attached to the remainder of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyls include, for example, -CHOCH, -CHCHOCH, -CHCHOCHCHOCH, -CH(CH)OCH, -CHNHCH, -CHN(CH), -CHCHNHCH, or -CHCHN(CH). Unless otherwise stated herein, heteroalkyl is optionally substituted with, for example, oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heteroalkyl can be substituted with oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heteroalkyl is optionally substituted with halogen.

[0033] "Heterocycloalkyl" refers to a 3-24 membered partially or fully saturated ring radical containing 2-23 carbon atoms and 1-8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, a heterocycloalkyl is fully saturated. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heterocycloalkyl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heterocycloalkyl contains 1-3 nitrogens. In some embodiments, a heterocycloalkyl contains 1 or 2 nitrogens. In some embodiments, a heterocycloalkyl contains 1 nitrogen. In some embodiments, a heterocycloalkyl contains 1 nitrogen and 1 oxygen. Unless otherwise stated in the specification, a heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or heteroaryl ring, the heterocycloalkyl is attached through a non-aromatic ring atom), spiro, or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. Representative heterocycloalkyls include those having 2 to 15 carbon atoms (C2-C3). 15 Fully saturated heterocycloalkyl or C2-C 15 Heterocycloalkenyl, 2 to 10 carbon atoms (C2-C 10 Fully saturated heterocycloalkyl or C2-C 10heterocycloalkenyl), heterocycloalkyl having 2 to 8 carbon atoms (C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), 2 to 7 carbon atoms (C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), 2 to 6 carbon atoms (C2-C6 fully saturated heterocycloalkyl, or C2-C6 heterocycloalkenyl), 2 to 5 carbon atoms (C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or 2 to 4 carbon atoms (C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidinyl, 4-piperazin ... Examples of heterocycloalkyl include aryl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-1-yl, 3-oxo-1,3-dihydroisobenzofuran-1-yl, methyl-2-oxo-1,3-dioxol-4-yl, and 2-oxo-1,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides. In some embodiments, heterocycloalkyls have 2 to 10 carbons in the ring. It is noted that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including heteroatoms) that make up the heterocycloalkyl (i.e., the skeletal atoms of the heterocycloalkyl ring).In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3-8 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-7 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4-6 membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5-6 membered heterocycloalkenyl. Unless otherwise stated herein, heterocycloalkyls may be optionally substituted as described below, for example, with oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, heterocycloalkyls may be substituted with oxo, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, heterocycloalkyls are optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, heterocycloalkyls are optionally substituted with halogen.

[0034] "Heteroaryl" refers to a 5-14 membered ring system radical containing 1-13 carbon atoms, 1-6 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl contains 1-3 heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl contains 1-3 nitrogens. In some embodiments, the heteroaryl contains 1 or 2 nitrogens. In some embodiments, the heteroaryl contains 1 nitrogen. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused ring systems (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is attached by an aromatic ring atom) or bridged ring systems, and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized and the nitrogen atom may be optionally quaternized. In some embodiments, the heteroaryl is a 5-10 membered heteroaryl. In some embodiments, the heteroaryl is a 5-6 membered heteroaryl. In some embodiments, the heteroaryl is a 6 membered heteroaryl. In some embodiments, the heteroaryl is a 5 membered heteroaryl.Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzoindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indolyl. , indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-1H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetraazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise in the specification, a heteroaryl may be optionally substituted with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, etc. In some embodiments, a heteroaryl may be optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2.In some embodiments, the heteroaryl is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0035] The term "optional" or "optionally" means that the event or circumstance described below may or may not occur, and the description includes the cases where said event or circumstance occurs and does not occur. For example, "optionally substituted alkyl" means either "alkyl" or "substituted alkyl" as defined above. Furthermore, an optionally substituted group may be unsubstituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), monosubstituted (e.g., -CH2CH2F), or substituted at any level between fully and monosubstituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc.). Those skilled in the art will understand that with respect to any group containing one or more substituents, such groups are not intended to introduce any substitution or substitution pattern that is sterically impractical and / or synthetically infeasible. Thus, any substituent described should generally be understood as having a maximum molecular weight of about 1,000 daltons, more typically up to about 500 daltons.

[0036] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound administered to a mammalian subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0037] "Treatment" of an individual (e.g., a mammal such as a human) or cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition following the onset of a pathological event or contact with a pathogenic agent, and includes stabilization of the condition (e.g., the condition does not worsen) or alleviation of the condition.

[0038] compound The present disclosure includes compounds and / or materials for use as SARS-CoV-2 inhibitors and for treating subjects infected with SARS-CoV-2.

[0039] As used herein, the formula (I)

[0040] [ka] or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, During the ceremony, R 1 is a halogen, R 2 is a halogen, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 3 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -SF5, -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a is replaced by Or two R on the same atom 3 come together to form oxo, R 3a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 3a come together to form oxo, n is 0 to 4; L is -(CR 4 R 4 ) p - and R 4 are each independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Or two R on the same carbon 4 are taken together and each represents one or more R 4 forming a cycloalkyl or heterocycloalkyl optionally substituted by a; R 4a are each independently halogen, -CN, -NO2, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; p is 0 to 4; R 5 is deuterium, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R 6 are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NRc R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 6a is replaced by Or two R on the same atom 6 come together to form oxo, R 6a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a, -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 6a come together to form oxo, m is 0 to 4; R 7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R 8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 8a is replaced by R 8a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c Rd , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 8a come together to form oxo, Or R 7 and R 8 together and optionally independently one or more R 7a forming a heterocycloalkyl substituted with R 7a are each independently halogen, -CN, -NO2, -OH, -OR a , -OC(=O)R a , -OC(=O)OR b , -OC(=O)NR c R d , -SH, -SR a , -S(=O)R a , -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -NR b C(=O)NR c R d , -NR b C(=O)R a , -NR b C(=O)OR b , -NR b S(=O)2R a , -C(=O)Ra , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom 7a come together to form oxo, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; R b are each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; R c and R dare each independently hydrogen, C-C alkyl, C-C haloalkyl, C-C hydroxyalkyl, C-C aminoalkyl, C-C heteroalkyl, C-C alkenyl, C-C alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C-C alkylene(cycloalkyl), C-C alkylene(heterocycloalkyl), C-C alkylene(aryl), or C-C alkylene(heteroaryl), where alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are independently and optionally substituted with one or more R; Or R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -S(=O)C1-C6 alkyl, -S(=O)2C1-C6 alkyl, -S(=O)2NH2, -S(=O)2NHC1-C6 alkyl, -S(=O)2N(C1-C6 alkyl)2, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1- C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, or C1-C6 heteroalkyl; Alternatively, two R on the same atom combine to form an oxo.

[0041] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is

[0042] [ka] It is.

[0043] In some embodiments, the compound of formula (I), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is

[0044] [ka] It is.

[0045] In some embodiments of the compounds of Formula (I), R 8 is C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 8a In some embodiments of the compounds of Formula (I), R 8 is C1-C6 alkylene(aryl); where alkyl and aryl are optionally independently selected from one or more R 8a In some embodiments of the compounds of Formula (I), R 8 is cycloalkyl or heterocycloalkyl, where cycloalkyl and heterocycloalkyl are optionally independently selected from one or more R 8a In some embodiments of the compounds of Formula (I), R 8 optionally independently one or more R 8a In some embodiments of the compounds of Formula (I), R 8 optionally independently one or more R 8a In some embodiments of the compounds of Formula (I), R 8 is heterocycloalkyl containing 1 to 2 heteroatoms selected from O and N. In some embodiments of the compounds of Formula (I), R 8is a bridged bicyclic ring. In some embodiments of the compounds of Formula (I), R 8 is a fused bicyclic ring. In some embodiments of the compounds of Formula (I), R 8 is a monocyclic 6-membered cycloalkyl or heterocycloalkyl, each of which is one or more R 8a is optionally replaced by

[0046] In some embodiments of the compounds of Formula (I), R 8 teeth,

[0047] [ka] wherein Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and q is 0 to 4.

[0048] In some embodiments of the compounds of Formula (I), R 8 teeth,

[0049] [ka] It is.

[0050] In some embodiments of the compounds of Formula (I), R 8 teeth,

[0051] [ka] In some embodiments of the compounds of formula (I), R 8 teeth,

[0052] [ka] In some embodiments of the compounds of formula (I), R 8 teeth,

[0053] [ka] It is.

[0054] In some embodiments of the compounds of Formula (I), R 7 and R 8 together, one or more R 7a Form a heterocycloalkyl optionally substituted independently with

[0055] In some embodiments of the compounds of Formula (I), R 7a are each independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (I), R 7a are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl.

[0056] In some embodiments of the compound of Formula (I), the compound has the formula (Ia):

[0057] [ka] wherein: Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; q is 0 to 4.

[0058] In some embodiments, the compound of formula (Ia), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is

[0059] [ka] It is.

[0060] In some embodiments, the compound of formula (Ia), or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is

[0061] [ka] It is.

[0062] In some embodiments of the compound of formula (I) or (Ia), ring C is cycloalkyl or heterocycloalkyl. In some embodiments of the compound of formula (I) or (Ia), ring C is cycloalkyl. In some embodiments of the compound of formula (I) or (Ia), ring C is heterocycloalkyl. In some embodiments of the compound of formula (I) or (Ia), ring C is a 6-membered ring.

[0063] In some embodiments of the compound of formula (I) or (Ia), q is 0 to 2. In some embodiments of the compound of formula (I) or (Ia), q is 1 to 3. In some embodiments of the compound of formula (I) or (Ia), q is 1 or 2. In some embodiments of the compound of formula (I) or (Ia), q is 0 or 1. In some embodiments of the compound of formula (I) or (Ia), q is 0. In some embodiments of the compound of formula (I) or (Ia), q is 1. In some embodiments of the compound of formula (I) or (Ia), q is 2. In some embodiments of the compound of formula (I) or (Ia), q is 3. In some embodiments of the compound of formula (I) or (Ia), q is 4.

[0064] In some embodiments of the compounds of Formula (I) or (Ia), R 1 is fluoro or chloro. In some embodiments of the compounds of Formula (I) or (Ia), R 2is fluoro or chloro. In some embodiments of the compounds of Formula (I) or (Ia), R 1 is fluoro and R 2 In some embodiments of the compounds of Formula (I) or (Ia), R 1 is chloro and R 2 is fluoro.

[0065] In some embodiments of the compound of formula (I) or (Ia), ring A is aryl or heteroaryl. In some embodiments of the compound of formula (I) or (Ia), ring A is phenyl. In some embodiments of the compound of formula (I) or (Ia), ring A is 6-membered heteroaryl. In some embodiments of the compound of formula (I) or (Ia), ring A is a monocyclic ring. In some embodiments of the compound of formula (I) or (Ia), ring A is a bicyclic ring. In some embodiments of the compound of formula (I) or (Ia), ring A is a tricyclic ring.

[0066] In some embodiments of the compounds of Formula (I) or (Ia), R 3 are each independently halogen, -CN, -OH, -OR a , -SR a , -SF5, -S(=O)2R a , -S(=O)2NR c R d , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a In some embodiments of the compounds of Formula (I) or (Ia), R 3are each independently halogen, -CN, -OR a , -SR a , -SF5, -S(=O)2R a , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, where alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R 3a In some embodiments of the compounds of Formula (I) or (Ia), R 3 are each independently halogen, -CN, or -OR a , -SR a , -SF5, -S(=O)2R a , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heteroaryl, where alkyl, cycloalkyl, and heteroaryl are optionally independently selected from one or more R 3a In some embodiments of the compounds of Formula (I) or (Ia), R 3 are each independently halogen, -OR a , -SR a , -SF5, -S(=O)2R a , C1-C6 haloalkyl, cycloalkyl, or heteroaryl. In some embodiments of the compounds of formula (I) or (Ia), R 3 are independently -OR a or -SR a In some embodiments of the compounds of Formula (I) or (Ia), R 3 are each independently -OR a In some embodiments of the compounds of Formula (I) or (Ia), R 3 are each independently -SR a In some embodiments of the compounds of Formula (I) or (Ia), R 3 are each independently heteroaryl.

[0067] In some embodiments of the compounds of Formula (I) or (Ia), R 3aare each independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (I) or (Ia), R 3a are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 3a are each independently halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0068] In some embodiments of the compound of Formula (I) or (Ia), n is 1 or 2. In some embodiments of the compound of Formula (I) or (Ia), n is 1 to 3. In some embodiments of the compound of Formula (I) or (Ia), n is 0 to 2. In some embodiments of the compound of Formula (I) or (Ia), n is 1. In some embodiments of the compound of Formula (I) or (Ia), n is 2. In some embodiments of the compound of Formula (I) or (Ia), n is 3. In some embodiments of the compound of Formula (I) or (Ia), n is 4. In some embodiments of the compound of Formula (I) or (Ia), p is 0. In some embodiments of the compound of Formula (I) or (Ia), p is 1. In some embodiments of the compound of Formula (I) or (Ia), p is 2. In some embodiments of the compound of Formula (I) or (Ia), p is 3. In some embodiments of the compound of Formula (I) or (Ia), p is 1 to 3. In some embodiments of the compound of Formula (I) or (Ia), p is 0 to 2. In some embodiments of the compound of Formula (I) or (Ia), p is 0 or 1. In some embodiments of the compound of Formula (I) or (Ia), p is 1 or 2. In some embodiments of the compound of Formula (I) or (Ia), p is 0 (i.e., L is a bond).

[0069] In some embodiments of the compounds of Formula (I) or (Ia),

[0070] [ka] teeth,

[0071] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0072] [ka] teeth,

[0073] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0074] [ka] teeth,

[0075] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0076] [ka] teeth,

[0077] [ka] It is.

[0078] In some embodiments of the compounds of Formula (I) or (Ia),

[0079] [ka] teeth,

[0080] [ka] It is.

[0081] In some embodiments of the compounds of Formula (I) or (Ia),

[0082] [ka] teeth,

[0083] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0084] [ka] teeth,

[0085] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0086] [ka] teeth,

[0087] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0088] [ka] teeth,

[0089] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0090] [ka] teeth,

[0091] [ka] It is.

[0092] In some embodiments of the compounds of Formula (I) or (Ia), R 4 are each independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 4 are each independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 4 are each independently hydrogen or halogen. In some embodiments of the compounds of Formula (I) or (Ia), R 4 is hydrogen.

[0093] In some embodiments of the compounds of Formula (I) or (Ia), two R 4 taken together form a cycloalkyl or heterocycloalkyl, each of which may be one or more R 4a is optionally replaced by

[0094] In some embodiments of the compounds of Formula (I) or (Ia), R 4a are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 4a are each independently halogen, —OH, C1-C6 alkyl, or C1-C6 haloalkyl.

[0095] In some embodiments of the compounds of Formula (I) or (Ia), R 5 Each is deuterium or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 5 is independently deuterium, C1-C6 alkyl, or C1-C6 deuteroalkyl. In some embodiments of the compound of Formula (I) or (Ia), R 5 is each C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 5is each C1-C3 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 5 and each is methyl. In some embodiments of the compounds of Formula (I) or (Ia), R 5 In some embodiments of the compounds of formula (I) or (Ia), R 5 are deuterium.

[0096] In some embodiments of the compounds of formula (I) or (Ia), ring B is heterocycloalkyl or heteroaryl. In some embodiments of the compounds of formula (I) or (Ia), ring B is heteroaryl. In some embodiments of the compounds of formula (I) or (Ia), ring B is 5- or 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (Ia), ring B is 6-membered heteroaryl. In some embodiments of the compounds of formula (I) or (Ia), ring B is pyridinyl, pyrimidinyl, or pyrazinyl. In some embodiments of the compounds of formula (I) or (Ia), ring B is pyridinyl or pyrimidinyl. In some embodiments of the compounds of formula (I) or (Ia), ring B is pyridinyl. In some embodiments of the compounds of formula (I) or (Ia), ring B is pyrimidinyl.

[0097] In some embodiments of the compounds of Formula (I) or (Ia), R 6 are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 6 are each independently halogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 6 are each independently a halogen.

[0098] In some embodiments of the compounds of Formula (I) or (Ia), R 6aare each independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (I) or (Ia), R 6a are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, or C1-C6 haloalkyl.

[0099] In some embodiments of the compound of formula (I) or (Ia), m is 0 to 3. In some embodiments of the compound of formula (I) or (Ia), m is 1 to 3. In some embodiments of the compound of formula (I) or (Ia), m is 0 to 2. In some embodiments of the compound of formula (I) or (Ia), m is 0 or 1. In some embodiments of the compound of formula (I) or (Ia), m is 1 or 2. In some embodiments of the compound of formula (I) or (Ia), m is 0. In some embodiments of the compound of formula (I) or (Ia), m is 1. In some embodiments of the compound of formula (I) or (Ia), m is 2. In some embodiments of the compound of formula (I) or (Ia), m is 3.

[0100] In some embodiments of the compounds of Formula (I) or (Ia),

[0101] [ka] teeth,

[0102] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0103] [ka] teeth,

[0104] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0105] [ka] teeth,

[0106] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0107] [ka] teeth,

[0108] [ka] In some embodiments of the compound of formula (I) or (Ia),

[0109] [ka] teeth,

[0110] [ka] It is.

[0111] In some embodiments of the compounds of Formula (I) or (Ia), R 7is hydrogen or C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 7 is C1-C6 alkyl. In some embodiments of the compounds of Formula (I) or (Ia), R 7 is hydrogen.

[0112] In some embodiments of the compounds of Formula (I) or (Ia), R 8a are each independently halogen, -CN, -OH, -OR a , -NR c R d , -C(=O)R a , -C(=O)OR b , -C(=O)NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (I) or (Ia), R 8a are each independently halogen, -CN, -OH, -OR a , -NR c R d , C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compound of formula (I) or (Ia), R 8a are each independently halogen, -OH, or -OR a , C1-C6 alkyl, or C1-C6 haloalkyl.

[0113] In some embodiments of the compound of Formula (Ia),

[0114] [ka] teeth,

[0115] [ka] It is.

[0116] In some embodiments of the compound of Formula (Ia),

[0117] [ka] teeth,

[0118] [ka] In some embodiments of the compound of formula (Ia),

[0119] [ka] teeth,

[0120] [ka] In some embodiments of the compound of formula (Ia),

[0121] [ka] teeth,

[0122] [ka] It is.

[0123] In some embodiments of the compounds of Formula (Ia), R 1 is fluoro or chloro, R 2 is fluoro or chloro, R 5 is C1-C3 alkyl (e.g., methyl),

[0124] [ka] teeth,

[0125] [ka] and R 3 is halogen, -CN, -OH, -OR a , -SR a , -SF5, -S(=O)2R a , C1-C6 alkyl, or C1-C6 haloalkyl, where R a is C1-C6 alkyl or C1-C6 haloalkyl, and L is -(CR 4 R 4 ) p -, p is 0 (i.e., L is a bond), Ring B is a 6-membered heteroaryl, and R 6 are each independently halogen or C-C alkyl, m is 0, 1, or 2, Ring C is a 6-membered cycloalkyl or heterocycloalkyl, and R 8a are each independently halogen, -OH, or -OR a , C1-C6 alkyl, or C1-C6 haloalkyl.

[0126] In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R a is each independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, Ra are each independently C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, R a Each is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, R a Each independently is C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R a Each independently is C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R a are each independently C1-C6 haloalkyl.

[0127] In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R bare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, R b are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R b Each independently is hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R b is hydrogen. In some embodiments of the compounds disclosed herein, R b are each independently C1-C6 alkyl.

[0128] In some embodiments of the compounds disclosed herein, R c and R dare each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl), where alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl, where alkyl, cycloalkyl, and heterocycloalkyl are each independently optionally substituted with one or more R. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl). In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, R c and R d are each independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, R c and R dEach independently is hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, R c and R d is hydrogen. In some embodiments of the compounds disclosed herein, R c and R d are each independently C1-C6 alkyl.

[0129] In some embodiments of the compounds disclosed herein, R c and R d together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R.

[0130] In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -NHC(=O)OC1-C6 alkyl, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, -C(=O)N(C1-C6 alkyl)2, -C(=O)NHC1-C6 alkyl, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, -C(=O)C1-C6 alkyl, -C(=O)OH, -C(=O)OC1-C6 alkyl, -C(=O)NH2, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each R is independently halogen, -CN, -OH, -OC1-C6 alkyl, -NH2, C1-C6 alkyl, or C1-C6 haloalkyl.

[0131] In some embodiments of the compounds disclosed herein, R 3 , R 6 , R 8 , R a , R b , R c , Rd , two R 4 The ring formed by combining 7 and R 8 The ring formed by combining c and R d The rings formed by joining together are each optionally independently substituted with 1, 2, 3, or 4 substituents as defined herein. In some embodiments of the compounds disclosed herein, R 3 , R 6 , R 8 , R a , R b , R c , R d , two R 4 The ring formed by combining 7 and R 8 The ring formed by combining c and R d The rings formed by joining together are each optionally independently substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, R 3 , R 6 , R 8 , R a , R b , R c , R d , is two R 4 The ring formed by combining 7 and R 8 The ring formed by combining c and R d The rings which are formed together are each optionally independently substituted with one or two substituents as defined herein.

[0132] In some embodiments of the compounds disclosed herein, one or more hydrogens on ring A, ring B, or ring C are replaced with one or more deuteriums.

[0133] In some embodiments of the compounds disclosed herein, R, R 3 , R 3a , R 4 , R4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R a , R b , R c , and / or R d One or more of the groups contains a percentage of deuterium that is higher than the natural abundance of deuterium.

[0134] In some embodiments of the compounds disclosed herein, one or more hydrogens are selected from the groups R, R 3 , R 3a , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R a , R b , R c , and / or R d is replaced with one or more deuterium atoms.

[0135] In some embodiments of the compounds disclosed herein, R, R 3 , R 3a , R 4 , R 4a , R 5 , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , R 9 , R 9a , R 10 , R a , R b , R c , and / or Rd The abundance of deuterium in each of is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogens and deuteriums.

[0136] All combinations of the groups described above for the various variations are contemplated herein. Throughout the specification, groups and substituents thereof will be chosen by one of skill in the art to provide stable moieties and compounds.

[0137] In some embodiments, the compound disclosed herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, is one of the compounds in Table 1.

[0138] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

[0139] Further forms of the compounds disclosed herein Isomers / stereoisomers In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein have one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers, and their corresponding mixtures. In some circumstances, the compounds described herein have one or more chiral centers, and each center exists in the R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms, and their corresponding mixtures. In further embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomers resulting from a single preparation step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers, and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that does not result in racemization.

[0140] labeled compound In some embodiments, the compounds described herein are present in isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating disease by administering such isotopically labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds, which are identical to those listed herein except for the fact that one or more atoms are replaced by atoms having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. Examples of isotopes that can be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chloride, e.g., 2 H(D), 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 31 P, 32 P, 35 S, 18 F, and 36 Compounds described herein that contain the aforementioned isotopes and / or other isotopes of other atoms, and pharma- ceutically acceptable salts, solvates, or stereoisomers thereof, are within the scope of the present disclosure. Certain isotopically labeled compounds, e.g., 3 H and 14 Compounds incorporating a radioactive isotope, such as C, are useful in drug and / or substrate tissue distribution assays. 3 H and carbon-14, i.e. 14 C isotopes are particularly preferred for their ease of preparation and detectability.

[0141] In some embodiments, the abundance of deuterium in each of the substituents disclosed herein is independently at least 1%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or 100% of the total number of hydrogen and deuterium. In some embodiments, one or more of the substituents disclosed herein contain deuterium at a percentage higher than the natural abundance of deuterium. In some embodiments, one or more hydrogens are replaced with one or more deuteriums in one or more of the substituents disclosed herein.

[0142] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0143] Pharmaceutically acceptable salts In some embodiments, the compounds described herein are present as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0144] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with any of a number of inorganic or organic bases, as well as inorganic and organic acids, to form pharma- ceutically acceptable salts. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or their solvates or stereoisomers, or by separately reacting the purified compounds in free form with the appropriate acid or base and isolating the salt thus formed.

[0145] Examples of pharma- ceutically acceptable salts include salts prepared by reaction of the compounds described herein with a mineral acid, an organic acid, or an inorganic base, such as acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyne-1,4-dioate, camphorate, camphorsulfonate, and the like. e), caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogen phosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6-dioate, hydroxybenzoate, gamma-hydroxybutyrate, hydrochloride, hydrobromide. acid salt, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, mandelate, metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3-phenyl These include propionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylateundeconate and xylenesulfonate.

[0146] Additionally, the compounds described herein can be prepared as pharma- ceutically acceptable salts formed by reacting the free base form of the compound with a pharma- ceutically acceptable inorganic or organic acid, examples of which include, but are not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid, and the like; as well as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)acid, and the like. Organic acids such as aryl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and muconic acid. In some embodiments, other acids that are not themselves pharma-ceutically acceptable, such as oxalic acid, are used in the preparation of salts useful as intermediates in obtaining the compounds of the present disclosure, solvates, or stereoisomers thereof, as well as pharma-ceutically acceptable acid addition salts thereof.

[0147] In some embodiments, compounds described herein that contain free acid groups are reacted with a suitable base, such as hydroxides, carbonates, bicarbonates, sulfates of pharmaceutically acceptable metal cations, with ammonia, or with pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amines. Representative salts include alkali or alkaline earth salts, such as lithium, sodium, potassium, calcium, and magnesium, and aluminum salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N + (C 1-4 alkyl)4, etc.

[0148] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like. It should be understood that the compounds described herein also include the quaternization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quaternization.

[0149] solvate In some embodiments, the compounds described herein exist as solvates.The present disclosure provides a method for treating disease by administering such solvates.The present disclosure further provides a method for treating disease by administering such solvates as pharmaceutical compositions.

[0150] Solvates include stoichiometric or non-stoichiometric amounts of solvent, and in some embodiments, are formed during the crystallization process using pharma- ceutically acceptable solvents, such as water, ethanol, etc. Hydrates are formed when the solvent is water, and alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein are conveniently prepared or formed during the process described herein. By way of example only, hydrates of the compounds described herein are conveniently prepared by recrystallization from aqueous / organic solvent mixtures, using organic solvents, including, but not limited to, dioxane, tetrahydrofuran, or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, solvated forms are considered equivalent to unsolvated forms for the purposes of the compounds and methods provided herein.

[0151] Tautomers In some situations, compounds exist as tautomers. The compounds described herein include all possible tautomers in the formulas described herein. Tautomers are compounds that can be interconverted by migration of a hydrogen atom with a single bond and a switch of an adjacent double bond. In bond structures that allow tautomerization, chemical equilibrium of tautomers exists. All tautomeric forms of the compounds disclosed herein are contemplated. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH.

[0152] Treatment Method Disclosed herein are methods of treating or preventing a coronavirus infection in a patient in need thereof, comprising administering to the patient a compound described herein, e.g., a compound of formula (I), or a pharmaceutical composition comprising the compound. In some embodiments, the coronavirus infection is caused by the SARS-CoV-2 virus. In some embodiments, the coronavirus infection is caused by the MERS-CoV virus. In some embodiments, the coronavirus infection is caused by the SARS-CoV virus. In some embodiments, the coronavirus infection is caused by the HCoV-229E virus. In some embodiments, the coronavirus infection is caused by the HCoV-OC43 virus. In some embodiments, the coronavirus infection is caused by the HCoV-NL63 virus. In some embodiments, the coronavirus infection is caused by the HCoV-HKU1 virus.

[0153] In another aspect, a method of treating or preventing a SARS-CoV-2 infection in a patient in need thereof is provided, the method comprising administering to the patient a compound described herein, e.g., a compound of formula (I), or a pharmaceutical composition comprising a compound.

[0154] In some embodiments, the compounds disclosed herein are administered prophylactically to a subject, in some embodiments, the subject is suspected of having a SARS-CoV-2 infection before the SARS-CoV-2 infection is diagnosed.

[0155] In some embodiments, the compounds of the present disclosure are administered to a subject until the infection is treated, inhibited, or reduced. In some embodiments, the compounds are administered to a subject until one or more symptoms of SARS-CoV-2 infection are alleviated.

[0156] In another aspect, provided herein is a method of inhibiting a viral infection, the method comprising providing a compound disclosed herein to the infectious disease to inhibit viral infection. In some embodiments, the viral infection is caused by SARS-CoV-2. In some embodiments, the viral infection is caused by MERS-CoV. In some embodiments, the viral infection is caused by SARS-CoV. In some embodiments, the viral infection is caused by HCoV-229E. In some embodiments, the viral infection is caused by HCoV-OC43. In some embodiments, the viral infection is caused by HCoV-NL63. In some embodiments, the viral infection is caused by HCoV-HKU1.

[0157] In another aspect, provided herein is a method of inhibiting SARS-CoV-2 by binding to its protein, comprising providing a compound disclosed herein to SARS-CoV-2 to inhibit SARS-CoV-2. In some embodiments, SARS-CoV-2 binds to a protease on SARS-CoV-2. In some embodiments, a compound disclosed herein binds to a cysteine ​​residue of the major protease, thereby inhibiting SARS-CoV-2. In some embodiments, the cysteine ​​residue is at position 145 of the major protease. In some embodiments, the protease is 3CL.

[0158] dosage In some embodiments, compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatment. In certain therapeutic applications, the compositions are administered to patients already suffering from a disease or condition in an amount sufficient to cure or at least partially halt at least one of the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous treatments, the patient's health status, weight, and response to the drug, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, dose escalation and / or dose ranging clinical trials.

[0159] In prophylactic applications, compositions containing the compounds described herein are administered to patients susceptible to or otherwise at risk of a particular disease, disorder, or condition. Such amounts are defined as "prophylactically effective amounts or dosages." In this application, the exact amount varies depending on the patient's condition, weight, and the like. When used in patients, the effective amount for this use will depend on the severity and course of the disease, disorder, or condition, previous treatments, the patient's health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatment involves administering a pharmaceutical composition containing a compound described herein or a pharma- ceutically acceptable salt thereof to a mammal that has previously experienced at least one symptom or risk factor of the disease being treated and is now in remission, to prevent the recurrence of symptoms of the disease or condition.

[0160] In certain embodiments where the patient's condition does not improve, at the physician's discretion, administration of the compound is administered chronically, i.e., for an extended period of time, including for the lifetime of the patient, to ameliorate or otherwise control or limit the symptoms of the patient's disease or condition.

[0161] In certain embodiments where the patient's condition improves, the dosage of the administered drug may be temporarily reduced or temporarily stopped for a period of time (i.e., during a drug holiday). In certain embodiments, the length of the drug holiday is between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or 28 days or more. Dose reductions during drug holidays may be, by way of example only, 10% to 100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0162] Once the patient's condition has improved, a maintenance dose is administered if necessary. Thereafter, in specific embodiments, the dosage or frequency of administration, or both, is reduced, depending on the symptoms, to a level at which the improved disease, disorder, or condition is maintained. In certain embodiments, however, patients require intermittent or daily treatment for an extended period of time with recurrence of symptoms.

[0163] The amount of a given drug that corresponds to such an amount will vary depending on factors such as the particular compound, the disease state and its severity, the identity (e.g., weight, sex) of the subject or host requiring treatment, but will nevertheless be determined according to the particular circumstances surrounding the case, including, for example, the particular drug being administered, the route of administration, the disease being treated, and the subject or host being treated.

[0164] In general, however, dosages utilized for adult human treatment are typically in the range of 0.01 mg-5000 mg per day. In one aspect, dosages utilized for adult human treatment are from about 1 mg to about 1000 mg per day. In one embodiment, the desired dosage is suitably provided in a single dose or in divided doses administered simultaneously or at appropriate intervals, e.g., as two, three, four or more subdoses per day.

[0165] In one embodiment, a suitable daily dose for the compounds described herein, or pharma- ceutically acceptable salts thereof, is about 0.01 mg / kg to about 50 mg / kg of body weight. In some embodiments, the daily dosage of the active ingredient in the dosage form will be lower or higher than the ranges set forth herein, based on many variables related to the individual treatment regimen. In various embodiments, the daily dosage and unit dose will vary depending on many variables, including, but not limited to, the activity of the compound used, the disease or condition being treated, the mode of administration, the requirements of the individual subject, the severity of the disease or condition being treated, and the judgment of the practitioner.

[0166] The toxicity and therapeutic efficacy of such treatment regimens include, but are not limited to, LD 10 and ED 90 The therapeutic index is determined by standard pharmaceutical procedures in cell cultures or experimental animals, including determination of the LD. The dose ratio between toxic and therapeutic effects is the therapeutic index, which is the LD. 50 and ED 50 In certain embodiments, the data obtained from cell culture assays and animal studies are used to formulate a therapeutically effective daily dosage range and / or therapeutically effective unit dose for use in mammals, including humans. In some embodiments, the daily dosage of the compounds described herein is within the range of ED with minimal toxicity. 50 In certain embodiments, the daily dosage range and / or unit dose varies within this range depending on the dosage form employed and the route of administration utilized.

[0167] In any of the foregoing aspects, in further embodiments, an effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, is (a) administered systemically to a mammal, and / or (b) administered orally to a mammal, and / or (c) administered intravenously to a mammal, and / or (d) administered by injection to a mammal, and / or (e) administered locally to a mammal, and / or (f) administered non-systemically or locally to a mammal.

[0168] In any of the above aspects, further embodiments are provided that include a single administration of an effective amount of the compound, including further embodiments in which (i) the compound is administered to the mammal once daily, or (ii) the compound is administered to the mammal multiple times throughout the day.

[0169] In any of the above aspects, further embodiments are provided that include multiple administrations of an effective amount of the compound, including further embodiments in which (i) the compound is administered as a single dose, continuously or intermittently, (ii) the interval between multiple doses is every 6 hours, (iii) the compound is administered to the mammal every 8 hours, (iv) the compound is administered to the subject every 12 hours, or (v) the compound is administered to the subject every 24 hours. In further or alternative embodiments, the method includes a drug holiday, in which the administration of the compound is temporarily suspended or the amount of the compound being administered is temporarily reduced, and at the end of the drug holiday, the administration of the compound is resumed. In one embodiment, the length of the drug holiday varies from 2 days to 1 year.

[0170] Route of administration Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ocular, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration.Further, by way of example only, parenteral delivery includes intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections, as well as intramuscular, subcutaneous, intravenous, and intramedullary injections.

[0171] In certain embodiments, the compounds described herein are administered locally rather than systemically, for example, via injection of the compound directly into an organ, often as a depot or sustained release formulation. In specific embodiments, the long-acting formulation is administered by implantation (e.g., subcutaneously or intramuscularly) or intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, for example, in a liposome coated with an organ-specific antibody. In such embodiments, the liposome targets and is selectively taken up by the organ. In still other embodiments, the compounds described herein are provided in the form of a rapid release formulation, an extended release formulation, or an intermediate release formulation. In still other embodiments, the compounds described herein are administered locally. In still other embodiments, the compounds described herein are administered via inhalation. In some embodiments, the compounds of the present disclosure are formulated for intranasal administration. Such formulations include nasal sprays, nasal mists, and the like.

[0172] Pharmaceutical Compositions / Formulations The compounds described herein can be administered to a subject in need according to standard pharmaceutical practice, either alone or in combination with pharma- ceutically acceptable carriers, excipients, or diluents in pharmaceutical compositions.In one embodiment, the compounds of the present disclosure can be administered to animals.The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0173] In another aspect, the present specification describes pharmaceutical compositions comprising the compound provided herein or its pharmaceutically acceptable salt, solvate or solvate and at least one pharmaceutically acceptable excipient.The pharmaceutical composition is formulated in a conventional manner with one or more pharmaceutically acceptable excipients that facilitate the processing of active compound into pharmaceutically usable preparations.The suitable preparation depends on the route of administration selected. Summaries of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999) (Lippincott Williams & Wilkins 1999), which are incorporated herein by reference for their disclosure.

[0174] In some embodiments, the pharma- ceutically acceptable excipient is selected from a carrier, a binder, a filler, a suspending agent, a flavoring agent, a sweetening agent, a disintegrating agent, a dispersing agent, a surfactant, a lubricant, a coloring agent, a diluent, a solubilizing agent, a wetting agent, a plasticizer, a stabilizer, a permeation enhancer, a humectant, an antifoaming agent, an antioxidant, a preservative, and any combination thereof.

[0175] The pharmaceutical compositions described herein are administered to a subject by a suitable route of administration, including, but not limited to, oral, parenteral (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or transdermal routes of administration. Pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposomal dispersions, aerosols, solid oral dosage forms, powders, immediate release formulations, controlled release formulations, fast dissolving formulations, tablets, capsules, pills, powders, dragees, effervescent formulations, lyophilized formulations, delayed release formulations, sustained release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed immediate and controlled release formulations.

[0176] Pharmaceutical compositions containing a compound described herein, or a pharma- ceutically acceptable salt, solvate, or stereoisomer thereof, may be manufactured by conventional means such as, by way of example only, conventional mixing, dissolving, granulating, dragee-making, gelling, emulsifying, encapsulating, entrapping, or compressing processes.

[0177] Pharmaceutical compositions for oral use can be obtained by mixing one or more solid excipients with one or more of the compounds described herein, optionally grinding the resulting mixture, adding suitable auxiliaries as necessary, and then processing the mixture of granules to obtain tablets or dragee cores.Suitable excipients include, for example, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, microcrystalline cellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose; or others, such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate.If necessary, disintegrants are added, such as cross-linked carmellose sodium, polyvinylpyrrolidone, agar, or alginic acid or a salt of alginic acid, such as sodium alginate.In some embodiments, dyes or pigments are added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0178] Orally administered pharmaceutical compositions include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules contain active ingredients in a mixture with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds are dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In some embodiments, stabilizers are added.

[0179] Pharmaceutical compositions for parenteral use are formulated as drops or injections. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions or sterile powders containing the compounds described herein, or their pharma- ceutically acceptable salts, solvates, or stereoisomers. In some embodiments, pharmaceutical compositions include liquid carriers. In some embodiments, liquid carriers are solvents or liquid dispersion media, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), vegetable oils, non-toxic glyceryl esters, and any combination thereof. In some embodiments, pharmaceutical compositions further include a preservative to prevent the growth of microorganisms.

[0180] combination Disclosed herein are methods of treating diseases or disorders associated with SARS-COV-2 using the compounds disclosed herein, or a pharma-ceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0181] In some embodiments, the additional therapeutic agent is administered simultaneously with the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior to administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after administration of the compound disclosed herein.

[0182] In some embodiments, the additional therapeutic agent is an interferon, such as interferon alpha, or a pegylated interferon, such as PEG-Intron or Pegasus. In some embodiments, this combination provides greater clinical benefit than administering interferon, pegylated interferon, or any of the compounds disclosed herein alone. Examples of greater clinical benefit include greater reduction in symptoms, faster time to alleviation of symptoms, reduced lung pathology, greater reduction in the amount of SARS coronavirus in patients (viral load), and reduced mortality.

[0183] SARS coronavirus infects cells that express p-glycoprotein. In some embodiments, the compounds disclosed herein are p-glycoprotein substrates. In some embodiments, compounds that inhibit SARS coronavirus (which is also a p-glycoprotein substrate) are administered with a p-glycoprotein inhibitor. Examples of p-glycoprotein inhibitors include verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir, and cyclosporine. The p-glycoprotein inhibitor acts by inhibiting the efflux of the compounds disclosed herein from cells. Inhibition of p-glycoprotein-based efflux prevents the intracellular concentration of the compounds disclosed herein from decreasing due to p-glycoprotein efflux. Inhibition of p-glycoprotein efflux results in a greater intracellular concentration of the compounds disclosed herein. In some embodiments, administering a compound disclosed herein and a p-glycoprotein inhibitor to a patient infected with SARS coronavirus reduces the amount of the compounds disclosed herein required to achieve an effective dose by increasing the intracellular concentration of the compounds disclosed herein.

[0184] Among the agents that can be used to increase mammalian exposure to the compounds disclosed herein are those that can inhibit at least one isoform of cytochrome P450 (CYP450) enzymes. CYP450 isoforms that can be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. In some embodiments, the compounds disclosed herein include compounds that are CYP3A4 substrates and metabolized by CYP3A4. In some embodiments, administering a compound such as ritonavir, nelfinavir, or delavirdine, which is a CYP3A4 substrate and CYP3A4 inhibitor, to a SARS coronavirus-infected patient reduces the metabolism of the compound by CYP3A4. This results in a reduced clearance and increased plasma concentration of the compound. In some embodiments, the reduced clearance and higher plasma concentration results in a lower effective dose of the compounds disclosed herein. EXAMPLES

[0185] Examples 1a and 1b

[0186] [ka] A mixture of compound 1-1 (1 g, 5.67 mmol), 1-(pyrimidin-5-yl)ethanone (compound 1-2, 831 mg, 6.80 mmol) and AcOH (2.10 g, 34.97 mmol, 2 mL) in toluene (20 mL) was degassed and purged with N2 three times, then the mixture was heated to reflux for 16 h under N2 atmosphere with water removed by Dean-Stark trap. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-80% ethyl acetate / petroleum ether gradient) to give compound 1-3 (944 mg, 56.38% yield). 1H NMR (400MHz, DMSO-d6): δ9.38-9.29(m,3H),9.06(s,1H),8.31(s,1H),7.72(d,J=8.4Hz,2H),6.95(d,J=8.4Hz,2H),2.31(s,3H).

[0187] To a solution of compound 1-3 (944 mg, 3.37 mmol) in CF3CH2OH (10 mL), (2R)-2-chloro-2-fluoro-acetic acid (909 mg, 4.04 mmol, 50% purity) and 4,4-difluorocyclohexanecarbonitrile (489 mg, 3.37 mmol) were added. The mixture was stirred at 25°C for 18 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient) and further purified by prep-HPLC (Welch Xtimate C18 150*30 mm*5 μm; mobile phase: A: water (FA) B: ACN; gradient condition: 35% B to 65% B; flow rate: 60 mL / min) to give compound 1-4 (204 mg, 11.26% yield). LCMS: (M+H) = 538.1. SFC: Retention times: 1.420 min and 2.366 min, AD-3_EtOH(DEA)_40_25ML_5MI. 1 H NMR(400MHz,DMSO-d6):δ9.16-9.11(m,1H),9.09-9.01(m,1H),8.90-8.82(m,2H),8.44-8.38 (m,1H),7.88-7.69(m,3H),7.68-7.59(m,1H),7.42-7.15(m,1H),6.47-6.21(m,1H),3.88(br s,1H),2.12-1.72(m,8H),1.70-1.51(m,3H). 19 F NMR(376MHz,DMSO-d6):δ-91.95(br dd,J=90.2,232.3Hz,1F),-98.51 ~-100.31(m,1F),-141.93(br d,J=173.4Hz,1F).

[0188] Compounds 1-4 (200 mg) were separated by SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B = 60:40; flow rate: 80 mL / min) to obtain two fractions.

[0189] Example 1a: (64 mg, yield 32.00%) was obtained. LCMS: (M + H) = 538.2. SFC: retention time: 1.424 min, AD-3_EtOH(DEA)_40_25ML_5MI. 1 H NMR (400 MHz, DMSO-d6): δ 9.14 (s, 1H), 9.07 (s, 1H), 8.87 (s, 2H), 8.41 (s, 1H), 7.91 - 7.67 (m, 4H), 7.24 (d, J = 8.4 Hz, 1H), 6.49 - 6.26 (m, 1H), 3.88 (d, J = 8.4 Hz, 1H), 2.06 - 1.72 (m, 6H), 1.70 - 1.48 (m, 5H). 19 F NMR (376 MHz, DMSO-d6): δ -91.81 (br d, J = 234.6 Hz, 1F), -99.36 (br d, J = 234.6 Hz, 1F), -142.20 (s, 1F).

[0190] Example 1b: (79 mg, yield 38.25%) was obtained. LCMS: (M + H) = 538.2. SFC: retention time: 2.446 min, AD-3_EtOH(DEA)_40_25ML_5MI. 1 H NMR (400 MHz, DMSO-d6): δ 9.13 (s, 1H), 9.03 (s, 1H), 8.85 (s, 2H), 8.40 (s, 1H), 7.81 - 7.69 (m, 2H), 7.68 - 7.60 (m, 2H), 7.44 - 7.30 (m, 1H), 6.43 - 6.21 (m, 1H), 3.88 (br s, 1H), 2.06 - 1.69 (m, 9H), 1.67 - 1.47 (m, 2H). 19 F NMR (376 MHz, DMSO-d6): δ -92.04 (br d, J = 237.5 Hz, 1F), -99.15 (br d, J = 240.3 Hz, 1F), -141.73 (br s, 1F).

[0191] Examples 2a and 2b

[0192] [ka] The following compounds were prepared following procedures similar to those described for compound examples 1a and 1b.

[0193] Example 2a: (12 mg) was obtained. LCMS: (M+H)=522.2. SFC: Retention time: 3.651 min, AD-3_EtOH(DEA)_5_40_25ML. 1 H NMR(400MHz,DMSO-d6):δ9.07(s,1H),8.87(s,2H),8.71(d,J=2.00Hz,1H) ,8.01(d,J=8.00Hz,1H),7.83-7.94(m,2H),7.75(d,J=8.00Hz,1H),7.35(d ,J=9.20Hz,1H),7.15(d,J=1.80Hz,1H),6.26-6.50(m,1H),3.81-4.02(m, 1H),1.95-2.06(m,2H),1.74-1.93(m,4H),1.68(s,3H),1.49-1.65(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-142.25(s,1F),-99.36(br d,J=234.61Hz,1F),-91.83(br d,J=234.61Hz,1F).

[0194] Example 2b: (27.01 mg) was obtained. LCMS: (M+H)=522.1. SFC: Retention time: 4.920 min, AD-3_EtOH(DEA)_5_40_25 ML. 1H NMR(400MHz,DMSO-d6):δ9.08-9.01(m,1H),8.89-8.83(m,2H),8.72-8.68(m,1H),7.92(br dd,J=8.3,12.8Hz,2H),7.80-7.64(m,2H),7.54-7.33(m,1H),7.18-7.10(m,1H),6.48-6.24(m,1H),3.88(br d,J=7.3Hz,1H),2.09-1.87(m,4H),1.82(s,3H),1.78-1.52(m,4H). 19 F NMR(376MHz,DMSO-d6):δ-91.15--92.81(m,1F),-98.38--100.04(m,1F),-141.30--142.85(m,1F).

[0195] Examples 3a and 3b

[0196] [ka] A solution of compound 3-1 (2 g, 16.12 mmol) and N-methoxymethanamine (1.98 g, 20.31 mmol) in DCM (40 mL) was degassed and purged with N2 three times, then EDCI (3.71 g, 19.34 mmol) and DMAP (2.95 g, 24.17 mmol) were added. The mixture was stirred under N2 atmosphere at 25 °C for 18 h. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 3-2 (1.78 g, 62.77% yield). 1 H NMR (400MHz, CDCl3): δ9.28(s,1H),9.09(s,2H),3.59(s,3H),3.41(s,3H).

[0197] A mixture of LiAlD4 (250 mg, 6.59 mmol) in THF (3 mL) was degassed and purged with N2 three times, then a solution of compound 3-2 (500 mg, 2.99 mmol) in THF (2 mL) was added. The mixture was stirred at -78 °C under N2 atmosphere for 2 h. The reaction mixture was quenched by 1N HCl (15 mL) at 0 °C, then diluted with H2O (10 mL) and extracted with EA (6 x 20 mL) and DCM (4 x 20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give compound 3-3 (176 mg, crude), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ9.43(s,1H),8.81(s,2H).

[0198] To a solution of compound 3-4 (138 mg, 779.12 μmol) in DCM (2 mL) was added compound 3-3 (85 mg, 779.07 μmol). The mixture was degassed and purged with N2 three times, then TEA (237 mg, 2.34 mmol) and TiCl4 (74 mg, 390.13 μmol) were added to the mixture at 0°C. The reaction mixture was stirred at 25°C for 2 h under N2 atmosphere. The reaction mixture was diluted with ice-cold water (15 mL) and extracted with DCM (3 x 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 3-5 (186 mg, crude), which was used in the next step without further purification.

[0199] To a solution of compound 3-5 (180 mg, 671.11 μmol) in CF3CH2OH (3 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (151 mg, 805.42 μmol, 60% purity) and 4,4-difluorocyclohexanecarbonitrile (98 mg, 675.17 μmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC. Pure fractions were collected and the volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give compound 3-6 (145 mg, 40.45% yield). LCMS: (M+H)=526.2.

[0200] Compound 3-6 (149 mg, 283.35 μmol) was separated by SFC (DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B = 60:40; flow rate: 80 mL / min) to obtain two fractions.

[0201] Example 3a: (52 mg, yield 34.12%) was obtained. LCMS: (M+H) = 526.2. SFC: retention time: 2.957 min, OD_3_IPA_DEA_5_40_25ML. 1 H NMR (400 MHz, DMSO-d6): δ8.97 (s, 1H), 8.47 (s, 2H), 8.39 (d, J = 7.6 Hz, 1H), 7.89 - 7.02 (m, 4H), 6.60 - 6.37 (m, 1H), 6.07 (s, 0.016H), 3.84 (br d, J = 8.0 Hz, 1H), 2.09 - 1.67 (m, 6H), 1.58 - 1.44 (m, 1H), 1.39 - 1.25 (m, 1H). 19 F NMR (376 MHz, DMSO-d6): δ-56.63--57.44 (m, 3F), -93.37 (br d, J = 243.2 Hz, 1F), -97.75 (br d, J = 191.7 Hz, 1F), -143.48 (s, 1F).

[0202] Example 3b: (56 mg, yield 37.35%) was obtained. LCMS: (M+H) = 526.2. SFC: retention time: 5.542 min, OD_3_IPA_DEA_5_40_25ML. 1 H NMR (400 MHz, DMSO-d6): δ8.99 (s, 1H), 8.50 (s, 2H), 8.37 (d, J = 7.2 Hz, 1H), 7.31 (br s, 4H), 6.78 - 6.44 (m, 1H), 6.00 (s, 0.025H), 3.79 (br s, 1H), 2.09 - 1.66 (m, 6H), 1.57 - 1.41 (m, 1H), 1.40 - 1.25 (m, 1H). 19F NMR(376MHz,DMSO-d6):δ-56.98(s,3F),-93.33(br d,J=243.2Hz,1F),-97.70(br d,J=211.7Hz,1F),-142.72(s,1F).

[0203] Examples 4a and 4b

[0204] [ka] A mixture of compound 4-1 (2 g, 11.29 mmol), compound 4-2 (1.66 g, 13.56 mmol), AcOH (4.20 g, 69.94 mmol, 4.00 mL) in toluene (30 mL) was degassed and purged with N2 three times, then the mixture was heated to reflux (120 °C) for 48 h to remove water with a Dean-Stark trap under N2 atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 4-3 (2.16 g, crude), which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): δ9.34-9.24(m,3H),7.39(d,J=8.4Hz,2H),6.96(d,J=8.8Hz,2H),2.38-2.17(m,3H).

[0205] To a solution of compound 4-3 (1 g, 3.56 mmol) in CF3CH2OH (10 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (667 mg, 3.56 mmol) and 4,4-difluorocyclohexanecarbonitrile (517 mg, 3.56 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-70% ethyl acetate / petroleum ether gradient) to give the product. The product was purified by prep-HPLC. Pure fractions were collected and volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give compound 4-4 (87 mg, 4.44% yield). LCMS: (M+H)=539.1.

[0206] Compound 4-4 (87 mg, 161.45 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic: A:B = 90:10; flow rate: 50 mL / min) to obtain two fractions.

[0207] Example 4a: (28 mg, yield 30.94%) was obtained. LCMS: (M+H) = 539.1. SFC: retention time: 1.816 min, AD-3_MeOH(DEA)_5_40_25ML. 1 H NMR (400 MHz, DMSO-d6): δ 9.06 (s, 1H), 8.84 (s, 2H), 7.94 - 7.67 (m, 2H), 7.54 - 7.32 (m, 3H), 6.51 - 6.21 (m, 1H), 3.97 - 3.74 (m, 1H), 2.03 - 1.72 (m, 6H), 1.66 (s, 3H), 1.64 - 1.46 (m, 2H). 19 F NMR (376 MHz, DMSO-d6): δ -56.84 (br s, 3F), -91.85 (br d, J = 234.6 Hz, 1F), -99.39 (br d, J = 234.6 Hz, 1F), -142.32 (br s, 1F).

[0208] Example 4b: (34 mg, 61.78 μmol, yield 38.26%) was obtained. LCMS: (M+H) = 539.1. SFC: retention time: 2.406 min, AD-3_MeOH(DEA)_5_40_25ML. 1 H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.83 (s, 2H), 7.80 - 7.61 (m, 2H), 7.56 - 7.33 (m, 3H), 6.47 - 6.18 (m, 1H), 3.93 - 3.74 (m, 1H), 2.09 - 1.81 (m, 5H), 1.79 (s, 3H), 1.75 - 1.65 (m, 1H), 1.62 - 1.47 (m, 2H). 19 F NMR (376 MHz, DMSO-d6): δ -56.89 (s, 3F), -92.02 (br d, J = 234.6 Hz, 1F), -99.23 (br d, J = 231.7 Hz, 1F), -141.94 (s, 1F).

[0209] Examples 5a and 5b

[0210] [ka] The following compounds were prepared following procedures similar to those described for Examples 4a and 4b.

[0211] Example 5a: (17 mg) was obtained. LCMS: (M+H)=505.2. SFC: Retention time: 2.558 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ9.03(s,1H),8.82(s,2H),7.79(d,J=8.0Hz,2H),7.45(d,J=8.4Hz,1H),7.36( s,2H),6.44-6.23(m,1H),3.87-3.80(m,3H),3.35-3.24(m,2H),1.73-1.64(m,4H),1.63-1.39(m,3H). 19 F NMR(376MHz,DMSO-d6):δ-56.85(s,3F),-142.33(s,1F).

[0212] Example 5b: (20 mg) was obtained. LCMS: (M+H)=505.2. SFC: Retention time: 3.349 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ9.00(s,1H),8.80(s,2H),7.76-7.63(m,2H),7.52-7.46(m,1H),7.43-7.32(m,2H), 6.38-6.19(m,1H),3.86-3.79(m,3H),3.35-3.27(m,2H),1.81(s,3H),1.71-1.61(m,1H),1.59-1.38(m,3H). 19 F NMR(376MHz,DMSO-d6):δ-56.90(s,3F),-142.06(s,1F).

[0213] Examples 6a, 6b, 6c, and 6d

[0214] [ka] The following compounds were prepared following procedures similar to those described for Examples 4a and 4b.

[0215] Example 6a: (6 mg) was obtained. LCMS: (M+H)=491.1. SFC: Retention time: 2.504 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ9.06(s,1H),8.84(s,2H),8.04(d,J=6.8Hz,1H),7.86(d,J=8.8Hz,1H),7.49(d,J=8.4Hz,1H),7.43-7.30(m,2H),6.4 9-6.24(m,1H),4.44-4.29(m,1H),3.85-3.74(m,2H),3.70-3.62(m,1H) ,3.51-3.47(m,1H),2.20-2.05(m,1H),1.91-1.78(m,1H),1.67(s,3H). 19 F NMR(376MHz,DMSO-d6):δ-142.27(s,3F)-56.82(s,1F).

[0216] Example 6b: (4 mg) was obtained. LCMS: (M+H)=491.1. SFC: Retention time: 2.773 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ9.12-9.06(m,1H),8.86-8.83(m,2H),8.06(d,J=6.4Hz,1H ),7.90(dd,J=2.4,8.8Hz,1H),7.50(d,J=8.4Hz,1H),7.40(d,J=8.8Hz,1H),7.35-7 .28(m,1H),6.50-6.28(m,1H),4.39-4.31(m,1H),3.84-3.76(m,2H),3.68(m,1H),3 .58(dd,J=4.0,9.0Hz,1H),2.12-2.03(m,1H),1.83-1.76(m,1H),1.68-1.60(m,3H).19 F NMR (376MHz, DMSO-d6): δ-56.62 ~-56.97(m,3F),-141.95~-143.49(m,1F).

[0217] Example 6c: (7 mg) was obtained. LCMS: (M+H) = 491.1. SFC: retention time: 3.504 minutes, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.81(s,2H),7.95(d,J=6.8Hz,1H),7.68(dd,J=2.4,8.8Hz,1H),7.51(dd,J=2.0,8.8Hz,1H),7.43-7.36(m,2H ),6.42-6.17(m,1H),4.36-4.29(m,1H),3.83-3.73(m,2H),3.71-3.64(m, 1H),3.49-3.47(m,1H),2.17-2.02(m,1H),1.88-1.83(m,1H),1.82(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-54.84--58.54(m,3F),-140.69--146.03(m,1F).

[0218] Example 6d: (6 mg) was obtained. LCMS: (M+H) = 491.1. SFC: retention time: 4.030 minutes, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR (400MHz, DMSO-d6): δ9.03(s,1H),8.82(s,2H),7.93(d,J=6.40Hz,1H),7.67-7.78(m,1H),7.33-7.55(m,3H),6.20-6.43(m,1H),4.33(br s,1H),3.73-3.83(m,2H),3.62-3.70(m,1H),3.52-3.59(m,1H),2.01-2.11(m,1H),1.79(s,3H),1.72-1.78(m,1H). 19 F NMR (376MHz, DMSO-d6): δ-141.85 (s, 3F), -57.32--56.43 (m, 1F).

[0219] Example 8

[0220] [ka] To a solution of compound 4-3 (100 mg, 355.58 μmol) in CF3CH2OH (1 mL), (2R)-2-chloro-2-fluoro-acetic acid (48.00 mg, 426.69 μmol) and (1R,4R)-1-isocyano-4-(trifluoromethoxy)cyclohexane (68.69 mg, 355.58 μmol) were added. The mixture was stirred at 25° C. for 2 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 55%-85%, 6 min) to give the desired compound 8 (2.30 mg, 1.08% yield). LCMS: (M+H)=587.0. HPLC: retention time: 5.290 min, 10-80AB_8 min. 1 H NMR(400MHz,CD3OD):δ9.04(d,J=13.6Hz,1H),8.92(d,J=9.6Hz,2H),7.76-7.65(m,1H),7.47-7.28(m,3H),6.30-6.11(m,1H),4.2 9-4.18(m,1H),3.89-3.75(m,1H),2.17-2.07(m,2H),2.05-1.95(m,2H),1.92-1.75(m,3H),1.70-1.58(m,2H),1.52-1.40(m,2H). 19 F NMR(376MHz,CD3OD):δ-145.470--145.311(m,1F),-59.572--59.277(m,6F).

[0221] Examples 11a and 11b

[0222] [ka] A mixture of compound 4-1 (1.27 g, 7.19 mmol, 971.84 μL), compound 11-1 (1 g, 7.19 mmol), AcOH (2.63 g, 43.71 mmol, 2.5 mL) and 4A molecular sieves (3 g, 7.19 mmol) in toluene (20 mL) was degassed and purged with N2 three times, then the mixture was stirred under N2 atmosphere at 125 °C for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient eluent @35 mL / min). Compound 11-2 (1.3 g, 49.05% yield) was obtained. LCMS: Retention time: 4.398 min, (M+H)=299.1

[0223] To a solution of 11-2 (500 mg, 1.68 mmol) in CF3CH2OH (5 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (405 mg, 2.02 mmol, 56% purity) and 1,1-difluoro-4-isocyano-cyclohexane (252 mg, 1.68 mmol, 97% purity). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: A: water (FA) B: ACN; gradient conditions: 37% B to 67% B; flow rate: 25 mL / min). Pure fractions were collected and volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give the title compound 11-3 (144 mg, 15.34% yield). 1 H NMR(400MHz,DMSO-d6):δ8.51-8.40(m,2H),7.81-7.54(m,3H),7.52-7.40(m,1H),7.39-7.27(m,2H),6.47-6.21(m,1H),3.86(br s,1H),1.99(br s,3H),1.93-1.68(m,6H),1.66-1.43(m,2H). 1919F NMR (376 MHz, DMSO-d6): δ -56.93 (broad d, J = 20.0 Hz, 3F), -91.93 (broad dd, J = 55.8, 233.2 Hz, 1F), -99.31 (broad dd, J = 42.9, 228.9 Hz, 1F), -128.08 (broad d, J = 14.3 Hz, 1F), -141.88 (broad d, J = 14.3 Hz, 1F). 11-3 (198 mg, 356.20 μmol) was separated by SFC (DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B = 90:10; flow rate: 60 mL / min) to obtain two fractions.

[0224] Example 11a: (29 mg, yield 14.65%) was obtained. LCMS: (M + H) = 556.2. SFC: retention time: 1.773 min, OD_3_EtOH_DEA_5_40_25ML_7MIN. 1 1H NMR (400 MHz, DMSO-d6): δ 8.52 - 8.41 (m, 2H), 7.82 - 7.73 (m, 1H), 7.73 - 7.62 (m, 2H), 7.49 - 7.39 (m, 1H), 7.39 - 7.26 (m, 2H), 6.46 - 6.23 (m, 1H), 3.86 (broad s, 1H), 2.01 (broad s, 3H), 1.90 (broad s, 1H), 1.76 (s, 5H), 1.65 - 1.50 (m, 2H). 19 19F NMR (376 MHz, DMSO-d6): δ -56.90 (s, 3F), -91.84 (broad d, J = 231.7 Hz, 1F), -99.36 (broad d, J = 231.7 Hz, 1F), -128.10 (s, 1F), -141.91 (s, 1F).

[0225] Example 11b: (61 mg, yield 29.95%) was obtained. LCMS: (M + H) = 556.2. SFC: retention time: 2.257 min, OD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR(400MHz,DMSO-d6):δ8.49-8.40(m,2H),7.75-7.67(m,1H),7.66-7.61(m,1H),7 .61-7.54(m,1H),7.52-7.45(m,1H),7.41-7.30(m,2H),6.43-6.20(m,1H),3.85(br s,1H),1.99(br s,3H),1.90(s,3H),1.88-1.68(m,3H),1.67-1.44(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-56.32--57.54(m,3F),-91.99(br d,J=234.6Hz,1F),-99.25(br d,J=226.0Hz,1F),-128.06(s,1F),-141.88(s,1F).

[0226] Examples 13a and 13b

[0227] [ka] To a solution of 4-bromo-1-methyl-pyridin-2-one (4.0 g, 21.27 mmol) in toluene (80 mL) was added tributyl(1-ethoxyvinyl)stannane (9.56 g, 26.47 mmol, 8.93 mL) and Pd(PPh3)2Cl2 (1.49 g, 2.13 mmol). The mixture was heated and stirred at 100 °C under N2 atmosphere for 12 h. After the mixture was quenched with a saturated solution of KF (40 mL), the mixture was cooled to room temperature, and then the mixture was treated with 5% hydrochloric acid (40 mL), the reaction was extracted with ethyl acetate (20 mL × 3), the organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 0 / 1 to 1 / 0, TLC: petroleum ether:ethyl acetate = 0:1, R f =0.2) to give compound 13-2 (2.1 g, 13.89 mmol, yield 65.30%). 1H NMR(400MHz,CDCl3)δ7.36(d,J=7.2Hz,1H),7.06(d,J=1.6Hz,1H),6.60(dd,J=2.0,7.2Hz,1H),3.57(s,3H),2.52(s,3H).

[0228] A mixture of 13-2 (2.1 g, 13.89 mmol), 4-(trifluoromethoxy)aniline (3.69 g, 20.84 mmol, 2.82 mL), 4A MS (500 mg, 13.89 mmol) and acetic acid (5.01 g, 83.35 mmol, 4.77 mL) in toluene (100 mL) was degassed and purged with N2 three times, then the mixture was stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give the crude product. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @20 mL / min) to give 13-3 (1.4 g, 4.51 mmol, 32.48% yield). 1 H NMR(400MHz,CDCl3)δ7.32(d,J=7.2Hz,1H),7.23(d,J=8.0Hz,2H),6.99-6.89(m,2H),6.80-6.75(m,2H),3.59(s,3H),2.16(s,3H).

[0229] To a solution of 13-3 (300.00 mg, 966.90 μmol) in CF3CH2OH (4 mL), (2R)-2-chloro-2-fluoro-acetic acid (233.07 mg, 1.16 mmol, purity 56%) and 1,1-difluoro-4-isocyano-cyclohexane (154.38 mg, 1.06 mmol) were added. The mixture was stirred at 25 °C for 2 h. The mixture was concentrated under reduced pressure to give crude compound 13. The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 6 min) to give the desired compound (53 mg, purity 97%).

[0230] Compound 13 was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [Neu-ETOH]; B%: 15%-15%) to obtain two fractions.

[0231] Obtained Example 13a: (20 mg, 3.55% yield). LCMS: (M+H)=568.2. SFC: Retention time: 2.647 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ7.79-7.63(m,1H),7.54(s,1H),7.51-7.46(m,1H),7.44-7.36(m,2H),6.45-6.28(m,2H), 6.27-6.20(m,1H),.3.90-3.76(m,1H),3.33-3.28(m,3H),2.07-1.93(m,3H),1.92-1.68(m,4H),1.64-1.50(m,4H).

[0232] Obtained Example 13b: (15 mg, 2.61% yield). LCMS (M+H) = 568.2. SFC: Retention time: 2.991 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ7.60-7.52(m,2H),7.49(d,J=7.2Hz,2H),7.41-7.34(m,2H),6.45-6.27(m,2H),6.2 2(dd,J=2.0,7.2Hz,1H),3.81(s,1H),3.30(s,3H),2.07-1.92(m,3H),1.91-1.65(m,7H),1.63-1.46(m,2H).

[0233] Examples 14a and 14b

[0234] [ka] To a solution of compound 11-2 (350 mg, 1.17 mmol) in CF3CH2OH (3 mL), H3PO4 (26 mg, 225.52 μmol, 15.48 μL, purity 85%) was added. The mixture was stirred at 25° C. for 30 min. Then, 4-isocyanotetrahydropyran (153 mg, 1.17 mmol, purity 85%) and (2R)-2-chloro-2-fluoro-acetic acid (240 mg, 1.41 mmol, purity 66%) were added to the mixture. The mixture was stirred at 25° C. for 5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by prep-HPLC (Boston Green ODS 150*30 mm*5 μm; mobile phase: A: water (FA) B: ACN; gradient condition: 45% B to 75% B; flow rate: 35 mL / min). Pure fractions were collected and volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give the title compound. Compound 14 was obtained (127 mg, 20.80% yield). LCMS (M+H)=522.1. 1 H NMR(400MHz,DMSO-d6):δ8.53-8.38(m,2H),7.82-7.61(m,3H),7.60-7.49(m,1H),7.47-7.30(m,2H),6.49-6.23(m,1H),4.01-3.77(m,3H),3.36(br s,2H),1.98-1.73(m,3H),1.72-1.58(m,2H),1.57-1.40(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-56.93(br d,J=20.0Hz,3F),-128.12(br d,J=17.2Hz,1F),-141.87(s,1F).

[0235] Compound 14 (127 mg, 243.36 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm), mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=85:15; flow rate: 60 mL / min) to obtain two fractions.

[0236] Example 14a: (44 mg, yield 34.65%) was obtained. LCMS (M+H) = 522.2. SFC: retention time: 2.272 minutes, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR (400MHz, DMSO-d6): δ8.53-8.42(m,2H),7.75(d,J=8.4Hz,1H),7.72-7.65(m,2H),7.42(d,J=7.6Hz,1H),7.35(br s,2H),6.47-6.24(m,1H),3.98-3.79(m,3H),3.40-3.34(m,2H),1.78(s,3H),1.72-1.59(m,2H),1.57-1.44(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-56.90(s,3F),-128.14(s,1F),-141.87(s,1F).

[0237] Example 14b: (44 mg, yield 34.65%) was obtained. LCMS (M+H) = 522.2. SFC: retention time: 2.762 minutes, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR (400MHz, DMSO-d6): δ8.45(s,1H),8.42(d,J=2.4Hz,1H),7.75-7.62(m,2H),7.60-7.47(m,2H),7.35(br s,2H),6.47-6.22(m,1H),3.95-3.79(m,3H),3.38-3.33(m,2H),1.91(s,3H),1.73-1.57(m,2H),1.57-1.39(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-56.95(s,3F),-128.09(s,1F),-141.86(s,1F).

[0238] Example 17a and Example 17b

[0239]

change

[0240] A mixture of 17-2 (7.49 g, 42.31 mmol, 5.72 mL), 1-(4-methylpyrimidin-5-yl)ethanone (3 g, 21.15 mmol) and p-TsOH (546.39 mg, 3.17 mmol) in toluene (60 mL) was degassed and purged with N2 three times, then the mixture was stirred at 140 °C under N2 atmosphere for 16 h. The mixture was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / dichloromethane @ 40 mL / min). Compound 17-3 (3.74 g) was obtained.

[0241] To a solution of 17-3 (600 mg, 2.03 mmol) in CF3CH2OH (2 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (464.92 mg, 2.44 mmol) and 1,1-difluoro-4-isocyano-cyclohexane (327.73 mg, 2.03 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient @20 mL / min). The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 7 min). Compound 17 (51 mg, 89.94 μmol, yield 4.43%, purity 97.51%) was obtained.

[0242] Compound 17 (51 mg) was separated by SFC (DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=90:10; flow rate: 60 mL / min) to obtain two fractions.

[0243] Obtained Example 17a: (12.85 mg, 24.83% yield). LCMS: (M+H)=553.1. SFC: Retention time: 1.174 min, AS_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ8.89(s,1H),8.65(s,1H),7.67(br t,J=7.0Hz,3H),7.44(br s,2H),6.43-6.25(m,1H),3.80(br s,1H),3.30(br s,3H),2.02-1.81(m,4H),1.75(s,3H),1.66(br d,J=10.6Hz,2H),1.46(br d,J=12.5Hz,2H). 19 F NMR(376MHz,DMSO-d6):δ-56.87(s,3F),-92.16(br d,J=235.8Hz,1F),-99.27(br d,J=242.8Hz,1F),-141.49(br s,1F)

[0244] Obtained Example 17b: (12.79 mg, 25.08% yield). LCMS (M+H) = 553.1. SFC: Retention time: 1.834 min, AS_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR(400MHz,DMSO-d6):δ8.92(s,1H),8.74(s,1H),7.83(br d,J=7.0Hz,1H),7.63(d,J=7.6Hz,1H),7.54-7.42(m,3H),6.44-6.24(m,1H),3.80(brs,1H),3.31(br s,3H),2.02-1.68(m,6H),1.65(s,3H),1.47(br d,J=10.8Hz,2H). 19 F NMR(376MHz,DMSO-d6):δ-56.87(s,3F),-91.75--93.12(m,1F),-99.13(br d,J=194.2Hz,1F),-141.01(br s,1F)

[0245] Examples 18a and 18b

[0246] [ka] To a solution of 18-1 (5 g, 34.83 mmol, HCl salt) in ethyl formate (60 mL) was added TEA (10.57 g, 104.48 mmol, 14.54 mL). The mixture was stirred at 80° C. for 16 h. The mixture was concentrated in vacuum, diluted with water (30 mL), and extracted with DCM (30 mL×2). The organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuum. 18-2 (4.28 g, crude) was obtained. 1 H NMR (400MHz, CDCl3): δ8.20-8.08(m,1H),6.16(br s,1H),4.43-4.27(m,1H),3.03-2.91(m,2H),2.59-2.44(m,2H).

[0247] To a solution of 18-2 (4.28 g, 31.68 mmol) in DCM (20 mL) was added PPh3 (8.31 g, 31.68 mmol), TEA (3.21 g, 31.68 mmol, 4.41 mL) and CCl4 (4.87 g, 31.68 mmol, 3.05 mL). The mixture was stirred at 45 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Then MTBE (30 mL) and PE (30 mL) were added and the mixture was stirred at 20 °C for 2 h. The reaction was filtered and the filter cake was washed with MTBE (20 mL × 3). The combined filtrate was concentrated under reduced pressure. Compound 18-3 (7.35 g, crude) was obtained.

[0248] To a solution of compound 4-1 (2 g, 4.27 mmol) in CF3CH2OH (20 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (1.03 g, 5.12 mmol) and 18-3 (999.28 mg, 4.27 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @35 mL / min). The product was further purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 43%-73%, 6 min). Compound 18 (160 mg, 311.25 μmol, yield 7.29%) was obtained.

[0249] Compound 18 (160 mg) was separated by chiral SFC and concentrated under vacuum to give two fractions (DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=85:15; flow rate: 60 mL / min).

[0250] Example 18a: (16.52 mg) was obtained. LCMS: (M+H)=511.0. SFC: Retention time: 1.820 min, OD-3_EtOH(DEA)_5_40_25 ML. 1H NMR (400MHz, DMSO-d6): δ9.08(s,1H),8.84(s,2H),8.20(d,J=6.4Hz,1H),7.87(dd,J=2.4,8.5Hz,1H),7. 54-7.27(m,3H),6.50-6.32(m,1H),4.17-4.05(m,1H),2.97-2.80(m,2H),2.66-2.52(m,2H),1.64(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.82(br s,3F),-81.28--82.71(m,1F),-96.15--97.48(m,1F),-142.44(s,1F).

[0251] Example 18b: (19.34 mg, yield 32.06%) was obtained. LCMS (M+H) = 511.0. SFC: retention time: 2.467 minutes, OD-3_EtOH(DEA)_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ9.04(s,1H),8.83(s,2H),8.16(d,J=6.4Hz,1H),7.70(dd,J=2.4,8. 6Hz,1H),7.50-7.35(m,3H),6.43-6.23(m,1H),4.16-4.03(m,1H),2.98-2.77(m,2H),2.60(br dd,J=5.4,19.8Hz,2H),1.79(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.86(s,3F),-81.37--82.55(m,1F),-96.17--97.35(m,1F),-141.95(s,1F).

[0252] Example 22a and Example 22b

[0253]

change

[0254] To a solution of 22-2 (1 g, 2.78 mmol) in CF3CH2OH (12 mL) was added H3PO4 (58.72 mg, 509.31 μmol, 34.95 μL). The mixture was stirred at 20° C. for 30 min. Then, 1,1-difluoro-4-isocyano-cyclohexane (448.35 mg, 2.78 mmol) and (2R)-2-chloro-2-fluoro-acetic acid (521.19 mg, 2.78 mmol) were added. The mixture was stirred at 20° C. for 17 h. The reaction was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether gradient @35mL / min), and the residue was further purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water(FA)-ACN]; B%: 52%-82%, 7min). Example 22 (100mg, yield 5.94%) was obtained. LCMS:(M+H)=580.7.1HNMR(400MHz,DMSO-d6)δ9.07(d,J=11.4Hz,1H),8.87(d,J=6.4Hz,2H),8.15-7.80(m,3H),7.80-7 .66(m,1H),7.63-7.37(m,1H),6.52-6.26(m,1H),3.86(s,1H),2.10-1.83(m,5H),1.81-1.66(m,4H),1.63-1.40(m,2H). 19 F NMR(376MHz,DMSO-d6)δ64.03(d,J=152.6Hz,3F),-92.01(dd,J=64.2,234.1Hz,1F),-99.25(dd,J=57.2,234.1Hz,1F),-142.27(d,J=190.7Hz,1F). Compound 22 (100 mg, 172.14 μmol) was separated by SFC (WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B=80:20; flow rate: 60 mL / min) to obtain two fractions.

[0255] Example 22a: (20 mg, 33.85 μmol, yield 19.67%) was obtained. LCMS: (M+H) = 580.9. SFC: retention time: 4.861 minutes, SS Whelk O1_IPA_DEA_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ9.08(s,1H),8.87(s,2H),8.15-7.88(m,3H),7.78(d,J=8.0Hz,1H),7.47(s,1H), 6.53-6.34(m,1H),3.86(d,J=7.6Hz,1H),2.01(s,3H),1.89-1.69(m,3H),1.65(s,3H),1.62-1.43(m,2H). 19 F NMR (376MHz, DMSO-d6): δ64.02(d,J=152.6Hz,5F),-91.89(d,J=235.8Hz,1F),-99.40(d,J=232.3Hz,1F),-141.21--145.92(m,1F).

[0256] Example 22b: (30 mg, yield 29.59%) was obtained. LCMS (M+H) = 580.9. SFC: retention time: 5.270 minutes, SS Whelk O1_IPA_DEA_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ9.06(s,1H),8.86(s,2H),7.98(m,2H),7.84(d,J=7.2Hz,1H),7.70(d,J=8.0Hz,1H),7.61 (d,J=8.2Hz,1H),6.49-6.29(m,1H),3.85(s,1H),2.11-1.82(m,5H),1.78(s,3H),1.66(m,1H),1.61-1.46(m,2H). 19 F NMR (376MHz, DMSO-d6): δ64.01(d,J=152.6Hz,5F),-92.06(d,J=232.4Hz,1F),-97.67--102.77(m,1F),-142.09(s,1F).

[0257] Example 23a and Example 23b

[0258]

change

[0259] Obtained Example 23a: (1.08 mg, 0.2% yield). LCMS (M+H) = 547.0. SFC: Retention time: 3.536 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR(400MHz,DMSO-d6)δ9.19-8.99(m,2H),8.94-8.79(m,2H),7.61(d,J=9.4Hz,2H),7.31-7.14(m,3H),3.97-3.60(m,4H),3.26(br d,J=4.2Hz,1H),2.43(br dd,J=4.4,12.6Hz,1H),2.27-2.11(m,4H),1.78(br d,J=12.3Hz,1H),1.52(br d,J=11.0Hz,1H).

[0260] Obtained Example 23b: (4.85 mg, 7.98 μmol, 7.19e-1% yield). LCMS: (M+H)=547.0. HPLC: Retention time: 2.522 min, 10-80AB_4 min. 1 cm. SFC: Retention time: 2.818 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR(400MHz,DMSO-d6)δ9.15(s,1H),9.10(d,J=3.0Hz,1H),8.94(s,2H),7.65(d,J=9.5Hz,2H),7.21-7.02(m,3H),4.07-3.80(m,4H),2.93(br s,1H),2.25-2.13(m,1H),2.04(s,3H),1.80(br d,J=9.0Hz,1H),1.53(br d,J=13.1Hz,1H).

[0261] Examples 26a and 26b

[0262] [ka] A mixture of 26-1 (2 g, 10.25 mmol), 1-pyrimidin-5-ylethanone (1.50 g, 12.30 mmol) and 4-methylbenzenesulfonic acid (264.77 mg, 1.54 mmol) in toluene (50 mL) was heated to reflux (140 °C) for 16 h and water was removed by Dean-Stark trap. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 26-2 (1.88 g, 5.97 mmol, 58.23% yield, 95% purity) was obtained. 1 H NMR(400MHz,DMSO-d6):δ9.49-9.22(m,3H),7.52(dd,J=2.0,10.6Hz,1H),7.29(td,J=1.2,8.7Hz,1H),7.13(t,J=8.9Hz,1H),2.31(d,J=1.1Hz,3H).

[0263] To a solution of 26-2 (800 mg, 2.67 mmol) in CF3CH2OH (5 mL) was added H3PO4 (52.33 mg, 534.00 μmol, 31.15 μL). The reaction mixture was stirred at 15° C. for 30 min. Then, 1,1-difluoro-4-isocyano-cyclohexane (430.61 mg, 2.67 mmol) and (2R)-2-chloro-2-fluoro-acetic acid (500.57 mg, 2.67 mmol) were added. The reaction mixture was stirred at 15° C. for 17 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient eluent @35 mL / min). The residue was further purified by prep-HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water(FA)-ACN]; B%: 53%~83%, 7min). Compound 26 (87mg, yield 5.71%) was obtained. LCMS: (M+H)=557.0. HPLC: retention time: 4.783min, 10-80AB_8min.1cm. 1 H NMR(400MHz,DMSO-d6):δ9.13-9.01(m,1H),8.90(d,J=2.1Hz,1H),8.81-8.67( m,1H),8.10-7.21(m,4H),6.69-6.44(m,1H),3.84(s,1H),2.15-1.47(m,11H). 19 F NMR(376MHz,DMSO-d6):δ-54.66--62.10(m,3F),-87.95--92.80(m,1F),-99.34(br d,J=231.7Hz,1F),-107.02--114.13(m,1F),-139.66--144.18(m,1F). Compound 26 (85 mg, 152.64 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=90:10; flow rate: 60 mL / min) to obtain two fractions.

[0264] Example 26a: (30 mg, yield 34.45%) was obtained. LCMS: (M+H) = 557.2. SFC: retention time: 1.744 minutes, AD-3_EtOH(DEA) 5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ9.11-9.00(m,1H),8.94-8.68(m,2H),8.07-7.18(m,4H),6.67-6.41(m,1H),3.83(s,1H),2.13-1.46(m,11H). 19 F NMR (376MHz, DMSO-d6): δ-52.95--60.01(m,3F),-91.95(d,J=235.8Hz,1F),- 97.67--101.99(m,1F),-108.26--1112.58(m,1F),-140.03--144.35(m,1F).

[0265] Example 26b: (32 mg, yield 37.22%) was obtained. LCMS (M+H) = 557.2. SFC: retention time: 2.004 minutes, AD-3_EtOH (DEA) 5_40_25mL. 1 H NMR (400MHz, DMSO-d6): δ9.11-8.96(m,1H),8.92-8.73(m,2H),7.93-7.74(m,1H),7.73 -7.55(m,1H),7.55-7.22(m,2H),6.69-6.42(m,1H),3.83(s,1H),2.13-1.53​​(m,11H). 19 F NMR (376MHz, DMSO-d6): δ-56.67--57.85(m,3F),-92.12(d,J=228.9Hz,1F),-98.91(s,1F),-106.68--112.98(m,1F),-141.07--143.17(m,1F).

[0266] Example 27a and Example 27b

[0267]

change

[0268] Compound 27 (75 mg, 143.44 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 um), mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B=85:15) to obtain two fractions.

[0269] Obtained Example 27a: (15 mg, 19.76% yield). LCMS: (M+H)=523.2. SFC: Retention time: 1.440 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR(400MHz,DMSO-d6):δ9.21-8.97(m,1H),8.93-8.68(m,2H),8.13-7.11(m,4H),6.73-6.43(m,1H),3.92-3.76(m,3H),3.30(br s,2H),2.14(s,1H),1.83-1.31(m,6H). 19 F NMR(376MHz,DMSO-d6):δ-56.40--58.36(m,3F),-107.43--112.20(m,1F),-140.80--143.60(m,1F).

[0270] Obtained Example 27b: (15 mg, 19.79% yield). LCMS (M+H) = 533.2. SFC: Retention time: 1.579 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR(400MHz,DMSO-d6):δ9.10-8.99(m,1H),8.97-8.73(m,2H),7.94-7.25(m,4H),6.73-6.43(m,1H),3.83(br s,3H),3.31(br s,2H),2.14-1.69(m,3H),1.68-1.30(m,4H). 19 F NMR(376MHz,DMSO-d6):δ-56.40--58.92(m,3F),-108.36--113.53(m,1F),-143.56(br d,J=313.5Hz,1F).

[0271] Examples 28a and 28b

[0272] [ka] A mixture of 28-1 (1 g, 3.77 mmol), tert-butyl carbamate (1.77 g, 15.12 mmol), Xantphos (663 mg, 1.15 mmol), and Cs2CO3 (7.38 g, 22.64 mmol) in dioxane (20 mL) was degassed and purged with Ar three times, then Pd2(dba)3 (363 mg, 396.41 μmol) was added. The mixture was stirred at 115 °C under Ar atmosphere for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 28-2 (740 mg, 2.46 mmol, 65.10% yield) was obtained. 1 H NMR (400MHz, DMSO-d6): δ9.42(s,1H),7.44(d,J=8.6Hz,2H),7.32(d,J=8.6Hz,2H),1.47(s,9H),1.30-1.26(m,2H),1.04(s,2H).

[0273] To a solution of compound 28-2 (900 mg, 2.99 mmol) in DCM (20 mL) was added HCl / dioxane (4 M, 8.96 mL). The mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with 20 mL of DCM. The solution was basified with saturated Na2CO3 to adjust pH=10. The solution was extracted with DCM (30 mL×3). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. 28-3 (712 mg, crude) was obtained. LCMS: (M+H)=202.8. 1 H NMR (400MHz, DMSO-d6): δ7.06(d,J=8.3Hz,2H),6.54-6.49(m,2H),5.18(s,2H),1.23-1.18(m,2H),0.95(s,2H).

[0274] To a solution of compound 28-3 (771 mg, 3.83 mmol) and 1-(pyrimidin-5-yl)ethan-1-one (468.01 mg, 3.83 mmol) in toluene (30 mL) was added 4A MS (2 g) and AcOH (2.02 g, 33.70 mmol, 1.93 mL, 8.79 equiv). The mixture was stirred at 125 °C under N2 atmosphere for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. Compound 28-4 (1.19 g, crude) was obtained. 1 H NMR (400MHz, DMSO-d6): δ9.33-9.28(m,3H),7.47(d,J=8.2Hz,2H),6.86(d,J=8.3Hz,2H),2.30(s,3H),1.37-1.30(m,2H),1.13(br s,2H).

[0275] To a solution of compound 28-4 (1.19 g, 3.90 mmol) in CF3CH2OH (15 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (939.55 mg, 4.68 mmol) and 1,1-difluoro-4-isocyano-cyclohexane (665.61 mg, 3.90 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @35 mL / min). The residue was purified by prep-HPLC (column: Xtimate C18 150*40 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 7 min). Compound 28 (340 mg, 603.98 μmol, 15.50% yield) was obtained. LCMS(M+H)=563.1. 1 H NMR(400MHz,DMSO-d6):δ9.03(d,J=14.4Hz,1H),8.82(d,J=7.3Hz,2H),7.77- 7.65(m,1H),7.62-7.42(m,3H),7.40-7.19(m,1H),6.36-6.10(m,1H),3.82(br s,1H),1.99(br s,4H),1.83-1.73(m,3H),1.70-1.50(m,4H),1.41-1.30(m,2H),1.10(br d,J=6.6Hz,2H).

[0276] Compound 28 (340 mg) was separated by chiral SFC and concentrated under vacuum to give two fractions (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=80:20; flow rate: 70 mL / min).

[0277] Obtained Example 28a: (130.08 mg, 38.26% yield). LCMS (M+H)=563.1. SFC: Retention time: 0.770 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400MHz, DMSO-d6): δ9.05(s,1H),8.83(s,2H),7.77-7.67(m,2H),7.59-7.44(m,2H),7.22(br d,J=8.7Hz,1H),6.35-6.18(m,1H),3.84(br s,1H),2.08-1.87(m,4H),1.85-1.65(m,3H),1.63(s,3H),1.57-1.46(m,1H),1.40-1.33(m,2H),1.12(br s,2H). 19 F NMR (376MHz, DMSO-d6): δ-68.33(br s,3F),-91.86(br d,J=235.8Hz,1F),-99.41(br d,J=235.8Hz,1F),-142.19(br s,1F).

[0278] Example 28b: (131.71 mg, yield 37.87%) was obtained. LCMS (M+H) = 563.1. SFC: retention time: 1.077 minutes, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1 H NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.82(s,2H),7.60(br t,J=8.6Hz,2H),7.53-7.42(m,2H),7.37(br d,J=8.0Hz,1H),6.30-6.11(m,1H),3.80(br d,J=8.1Hz,1H),1.96(br d,J=8.6Hz,4H),1.78(s,4H),1.69-1.47(m,3H),1.38-1.32(m,2H),1.10(br s,2H). 19 F NMR (376MHz, DMSO-d6): δ-68.39(s,3F),-91.35--92.65(m,1F),-98.74--99.72(m,1F),-141.82(s,1F).

[0279] Example 29a and Example 29b

[0280]

change

[0281] Compound 29 (120 mg) was separated by chiral SFC and concentrated under vacuum to give two fractions (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=75:25; flow rate: 70 mL / min).

[0282] Obtained Example 29a: (36.48 mg, 30.02% yield). LCMS (M+H) = 529.0. SFC: Retention time: 2.417 min, AD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400MHz, DMSO-d6): δ9.04(s,1H),8.84(s,2H),7.72(br d,J=7.9Hz,2H),7.60-7.44(m,2H),7.26(br d,J=7.7Hz,1H),6.35-6.16(m,1H),3.92-3.78(m,3H),3.31-3.28(m,2H),1.65(s,4H),1.62-1.41(m,3H),1.40-1.34(m,2H),1.12(br s,2H). 19 F NMR (376MHz, DMSO-d6): δ-68.30(s,3F),-142.12(s,1F).

[0283] Example 29b: (40.19 mg, yield 33.14%) was obtained. LCMS (M+H) = 529.1. SFC: retention time: 3.378 minutes, AD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.82(s,2H),7.62(d,J=7.6Hz,1H),7.59 -7.54(m,1H),7.52-7.44(m,2H),7.43-7.37(m,1H),6.30-6.12(m,1H),3.82(br t,J=8.3Hz,3H),3.31-3.27(m,2H),1.80(s,3H),1.67(br d,J=13.1Hz,1H),1.57-1.40(m,3H),1.39-1.30(m,2H),1.10(br s,2H). 19 F NMR (376MHz, DMSO-d6): δ-68.38(s,3F),-141.79(s,1F).

[0284] Example 32a and Example 32b

[0285]

change

[0286] Compound 32 (28 mg, 50.46 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic: A:B=85:15; flow rate: 60 mL / min) to give two fractions.

[0287] Obtained Example 32a: (6 mg, 20.89% yield). LCMS (M+H) = 555.1. SFC: Retention time: 2.107 min, AD-3_EtOH(DEA)_5_40_25 ML. 1 H NMR(400MHz,DMSO-d6):δ9.06(s,1H),8.85(s,2H),7.85(d,J=8.4Hz,1H),7.77(d,J=8.0Hz,1H),7.49(d,J=8.8Hz,1H),7 .39(s,2H),6.49-6.25(m,1H),4.01-3.73(m,3H),3.41-3.37(m,2H),1.69(s,4H),1.66-1.59(m,1H),1.58-1.41(m,2H). 19F NMR(376MHz,DMSO-d6):δ-85.32(s,3F),-87.18(s,2F),-142.26(s,1F).

[0288] Obtained Example 32b: (5 mg, 17.40% yield). LCMS (M+H) = 555.1. SFC: Retention time: 2.653 min, AD-3_EtOH(DEA)_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.83(s,2H),7.75-7.62(m,2H),7.59-7.49(m,1H),7.47-7.34(m,2H),6.43-6.1 7(m,1H),3.97-3.78(m,3H),3.39-3.35(m,2H),1.82(s,3H),1.73-1.64(m,1H),1.64-1.56(m,1H),1.55-1.41(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-85.30(s,3F),-87.17(brs,2F),-141.89(s,1F).

[0289] Examples 33a and 33b

[0290] [ka] To a solution of 33-1 (2 g, 10.35 mmol, 1.48 mL) and 1-pyrimidin-5-ylethanone (1.26 g, 10.35 mmol) in Tol. (30 mL) was added p-TsOH (267.41 mg, 1.55 mmol). The mixture was stirred at 136 °C for 16 h and water was removed by Dean-Stark trap under N2 atmosphere. The reaction was filtered and the filter cake was washed with toluene (10 mL * 2). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-16% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 33-2 (1.85 g, yield 48.09%) was obtained. 1H NMR (400MHz, DMSO-d6): δ9.36-9.30(m,3H),7.74(d,J=8.4Hz,2H),7.10-6.96(m,2H),2.34-2.21(m,3H).

[0291] To a solution of 33-2 (500 mg, 1.35 mmol) in CF3CH2OH (5 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (253 mg, 1.35 mmol) and 1,1-difluoro-4-isocyano-cyclohexane (217.73 mg, 1.35 mmol). The mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient eluent @30 mL / min). Compound 33 (83 mg, 10.95% yield) was obtained. LCMS (M+H)=554.9. 1 H NMR (400MHz, DMSO-d6): δ9.03(d,J=14.4Hz,1H),8.83(d,J=5.2Hz,2H),7.93-7.62(m,4H),7.58-7. 33(m,1H),6.46-6.15(m,1H),3.85(s,1H),2.12-1.91(m,3H),1.90-1.63(m,6H),1.61-1.45(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-41.68(d,J=27.7Hz,3F),-91.36--92.52(m,1F),-98.15--99.86(m,1F),-142.00(d,J=114.4Hz,1F).

[0292] Compound 33 (80 mg, 144.16 μmol, 1 equiv.) was separated by SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=85:15; flow rate: 60 mL / min) to give two fractions.

[0293] Example 33a: (27 mg, yield 32.63%) was obtained. LCMS (M+H) = 555.1. SFC: retention time: 0.775 minutes, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1 H NMR (400MHz, DMSO-d6): δ9.05(s,1H),8.83(s,2H),7.89-7.68(m,4H),7.41(s,1H),6.51-6.24(m,1H),3.87(s,1H),2.04-1.57(m,11H). 19 F NMR (376MHz, DMSO-d6): δ-40.01--44.72(m,3F),-91.89(d,J=235.8Hz,1F),-99.38(d,J=232.4Hz,1F),-142.16(s,1F).

[0294] Example 33b: (43 mg, yield 50.82%) was obtained. LCMS (M+H) = 555.1. SFC: retention time: 0.944 minutes, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1 H NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.82(s,2H),7.83-7.63(m,4H),7.55(br s,1H),6.44-6.20(m,1H),3.84(br d,J=7.2Hz,1H),1.98-1.45(m,11H). 19 F NMR (376MHz, DMSO-d6): δ-39.62--45.89(m,3F),-89.04--93.36(m,1F),-97.28--102.38(m,1F),-141.86(s,1F).

[0295] Example 34a and Example 34b

[0296]

change

[0297] Obtained Example 34a: (15 mg, 15.17% yield). LCNS (M+H) = 521.0. SFC: Retention time: 0.930 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1 H NMR(400MHz,DMSO-d6):δ9.04(s,1H),8.84(s,2H),7.90-7.70(m,4H),7.43(d,J=6.4Hz,1H ),6.46-6.24(m,1H),3.96-3.82(m,3H),3.31-3.18(m,2H),1.73(s,3H),1.69-1.41(m,4H). 19 F NMR(376MHz,DMSO-d6):δ-39.23--44.32(m,3F),-142.12(s,1F).

[0298] Obtained Example 34b: (21 mg, 21.26% yield). LCMS (M+H) = 521.0. SFC: Retention time: 1.215 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR(400MHz,DMSO-d6):δ9.00(s,1H),8.82(s,2H),7.79-7.65(m,4H),7.58(d,J=7.6Hz,1H),6.42-6.23(m,1H) ),3.95-3.78(m,3H),3.22(m,2H),1.86(s,3H),1.68(d,J=12.4Hz,1H),1.62-1.55(m,1H),1.54-1.41(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-41.72(s,3F),-141.85(s,1F).

[0299] Examples 36a and 36b

[0300] [ka] To a solution of 36-1 (5 g, 35.93 mmol, 4.67 mL) in ethyl formate (50 mL) was added TEA (7.27 g, 71.85 mmol, 10.00 mL). The mixture was stirred at 80° C. for 16 h. The mixture was concentrated under vacuum, diluted with water (20 mL), and extracted with DCM (20 mL*2). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Compound 36-2 (6.46 g, crude) was obtained. LCMS (M+H)=167.8.

[0301] To a solution of 36-2 (6.46 g, 30.14 mmol) in DCM (60 mL) was added PPh3 (7.91 g, 30.14 mmol), TEA (3.05 g, 30.14 mmol, 4.20 mL) and CCl4 (4.64 g, 30.14 mmol, 2.90 mL). The mixture was stirred at 45 °C for 16 h. The reaction mixture was concentrated under reduced pressure. Then MTBE (40 mL) and PE (40 mL) were added and the mixture was stirred at 20 °C for 16 h. The reaction was filtered and the filter cake was washed with MTBE (20 mL*3). The filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient @35 mL / min). Compound 36-3 (3.8 g, 25.48 mmol, 84.52% yield) was obtained.

[0302] To a solution of compound 4-3 (1.5 g, 5.33 mmol) in CF3CH2OH (20 mL), (2R)-2-chloro-2-fluoro-acetic acid (1.29 g, 6.40 mmol) and compound 36-3 (837.47 mg, 5.33 mmol) were added. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @35 mL / min). The residue was purified by prep-HPLC (column: Xtimate C18 150*40 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 7 min). Compound 36 (530 mg, 976.27 μmol, yield 18.30%) was obtained. LCMS(M+H)=543.1.1HNMR(400MHz,DMSO-d6)δ9.09-8.73(m,3H),8.18-7.98(m,1H),7.81-7.57(m,1H),7.56-7.43(m,1H),7.42- 7.35(m,2H),7.34-7.27(m,1H),7.08-6.98(m,3H),6.46-6.23(m,1H),3.53-3.38(m,2H),2.84-2.72(m,2H),1.84-1.43(m,3H).

[0303] Compound 36 (530 mg, 976.27 μmol) was separated by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic: A:B=75:25; flow rate: 60 mL / min) and concentrated under vacuum to obtain two fractions. The residue was further purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 55%~85%, 7 min).

[0304] Obtained Example 36a: (84.11 mg, 154.93 μmol, 46.73% yield). LCMS (M+H)=543.4. SFC: Retention time: 3.656 min, C2_MeOH_DEA_5_40_25 ML. 1H NMR (400MHz, DMSO-d6): δ9.06(s,1H),8.82(s,2H),8.13(t,J=5.7Hz,1H),7.76(br d,J=8.7Hz,1H),7.46(br d,J=9.2Hz,1H),7.40(s,2H),7.36-7.27(m,1H),7.08-6.99(m,3H),6.45-6.26(m,1H),3.53-3.39(m,2H),2.83-2.76(m,2H),1.51(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.81(s,3F),-113.74(s,1F),-142.49(s,1F).

[0305] Example 36b: (51.98 mg, 95.75 μmol, yield 31.31%) was obtained. LCMS (M+H) = 543.4. SFC: retention time: 4.244 minutes, C2_MeOH_DEA_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ9.00(s,1H),8.77(s,2H),8.02(t,J=5.5Hz,1H),7.61(br d,J=8.7Hz,1H),7.53(br d,J=8.6Hz,1H),7.38(br t,J=7.2Hz,2H),7.33-7.26(m,1H),7.07-6.97(m,3H),6.41-6.25(m,1H),3.48-3.36(m,2H),2.76(dt,J=3.2,7.1Hz,2H),1.74(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.87(s,3F),-113.68(s,1F),-141.73(s,1F).

[0306] Examples 76a, 76b, 76c, and 76d

[0307]

change

[0308] A mixture of compound 76-2 (159 mg, 1.01 mmol), PPh3 (266 mg, 1.01 mmol), TEA (103 mg, 1.02 mmol, 141.68 μL), and CCl4 (156 mg, 1.01 mmol, 97.50 μL) in DCM (1 mL) was stirred at 45 °C under N2 atmosphere for 18 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 76-3 (140 mg, crude) was obtained.

[0309] To a solution of compound 4-3 (150 mg, 533.37 μmol) in CF3CH2OH (2 mL), (2R)-2-chloro-2-fluoro-acetic acid (122.03 mg, 640.04 μmol) and compound 76-3 (140 mg, 533.07 μmol) were added. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @30 mL / min). The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 53%-83%, 7 min). Compound 76 (24 mg, 43.45 μmol, yield 8.15%) was obtained. LCMS (M+H) = 533.1.

[0310] Compound 76 (24 mg) was separated by SFC (DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=85:15; flow rate: 60 mL / min) to obtain two fractions. Fraction 1 (17 mg) was separated by SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=60:40; flow rate: 80 mL / min) to obtain two fractions. Fraction 2 (14 mg) was further separated by SFC (DAICEL CHIRALPAK IG (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B=75:25; flow rate: 70 mL / min) to obtain two fractions.

[0311] Obtained Example 76a: (2.50 mg, 14.62% yield). LCMS (M+H) = 533.1. SFC: Retention time: 1.228 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400MHz, DMSO-d6): δ9.03(s,1H),8.80(s,2H),7.77(br d,J=8.9Hz,1H),7.50-7.36(m,4H),6.45-6.27(m,1H),3.88(br d,J=9.7Hz,2H),3.40-3.36(m,2H),3.09(d,J=11.3Hz,1H),1.76(s,4H),1.40(br d,J=15.3Hz,1H),0.85(s,3H),0.77(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.84(s,3F),-141.89(br s,1F).

[0312] Example 76b: (1.55 mg, yield 9.00%) was obtained. LCMS (M+H) = 533.1. SFC: retention time: 1.315 minutes, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR (400MHz, DMSO-d6): δ9.09(s,1H),8.96(s,2H),7.87(br d,J=8.7Hz,1H),7.56-7.33(m,4H),6.43-6.27(m,1H),3.92-3.82(m,2H),3.40(br d,J=11.2Hz,2H),3.09(d,J=11.4Hz,1H),1.74(br dd,J=5.2,12.9Hz,1H),1.60(s,3H),1.31(br d,J=11.6Hz,1H),0.91(s,3H),0.77(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.78(s,3F),-142.45(s,1F)

[0313] Example 76c: (2.07 mg, yield 14.79%) was obtained. LCMS (M+H) = 533.1. SFC: retention time: 1.528 minutes, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400MHz, DMSO-d6): δ9.06(s,1H),8.93(s,2H),7.69-7.54(m,2H),7.45(br dd,J=8.8,13.5Hz,2H),7.33(d,J=9.1Hz,1H),6.41-6.21(m,1H),3.90-3.80(m,2H),3.39(br d,J=11.2Hz,2H),3.09(d,J=11.2Hz,1H),1.69(s,4H),1.33(br d,J=13.1Hz,1H),0.88(s,3H),0.79(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.84(s,3F),-141.58(s,1F).

[0314] Example 76d: (1.18 mg, yield 8.26%) was obtained. LCMS (M+H) = 533.1 SFC: retention time: 1.637 minutes, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR (400MHz, DMSO-d6): δ9.01(s,1H),8.79(s,2H),7.60(dd,J=4.8,8.4Hz,2H),7.43-7.36(m,2H),7.32(d,J=8.9Hz,1H),6.41 -6.25(m,1H),3.95-3.83(m,2H),3.41-3.36(m,2H),3.09(d,J=11.3Hz,1H),1.86(s,3H),1.73(dt,J=7.3,12.5Hz,1H),1.37(br d,J=11.1Hz,1H),0.87(s,3H),0.75(s,3H). 19 F NMR (376MHz, DMSO-d6): δ-56.40--57.12(m,3F),-141.77(s,1F)

[0315] Examples 77a, 77b, 77c, and 77d

[0316]

change

[0317] To a solution of compound 77-2 (1.2 g, 7.63 mmol) in DCM (14 mL) was added TEA (772.40 mg, 7.63 mmol, 1.06 mL), PPh3 (2.00 g, 7.63 mmol), CCl4 (1.17 g, 7.63 mmol, 733.83 μL). The mixture was heated and stirred at 45 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product at 20 °C. The mixture was triturated with MTBE (10 mL) to give the product. The residue was purified by flash silica gel chromatography (0-50% dichloromethane / petroleum ether gradient @ 100 mL / min). Compound 77-3 (1.0 g, crude) was obtained. 1 H NMR (400MHz, CDCl3): δ3.86-3.74(m,2H),3.59(dt,J=2.4,12.0Hz,1H),2.06-1.93(m,2H),1.87-1.60(m,2H),1.32-1.25(m,3H),1.18(s,3H).

[0318] To a solution of compound 4-1 (1.62 g, 5.75 mmol) in CF3CH2OH (10 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (775.81 mg, 6.90 mmol), compound 77-3 (1.0 g, 5.75 mmol), 4A MS (1.0 g, 5.75 mmol). The mixture was stirred at 25°C for 12 h. The mixture was concentrated under reduced pressure to give the crude product. The crude was purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether gradient @45 mL / min) to give a residue (1.0 g), which was purified by HPLC (column: Xtimate C18 150*40 mm*10 μm; mobile phase: [water (FA)-ACN]; B%: 35%-65%, 6 min). Compound 77 was obtained (500 mg, 938.24 μmol, 16.32% yield). LCMS (M+H)=533.2.

[0319] Compound 77 (500 mg, 0.948 mmol) was separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-IPA, A:B=80:20 at 70 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm) to give two fractions. Pure fraction 1 was collected and the solvent was evaporated under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to obtain title P1 (100 mg), which was separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK IC (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-IPA, A:B=80:20 at 60 mL / min; column temperature: 38°C; nozzle pressure: 100 bar; nozzle temperature: 60°C; evaporator temperature: 20°C; trimmer temperature: 25°C; wavelength: 220 nm) to obtain two fractions. The pure fraction 2 was further separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A: supercritical CO2, B: Neu-IPA, A:B=75:70 at 25mL / min; column temperature: 38℃; nozzle pressure: 100 bar; nozzle temperature: 60℃; evaporator temperature: 20℃; trimmer temperature: 25℃; wavelength: 220nm) to obtain two fractions.

[0320] Example 77a: (8.11 mg) was obtained. LCMS (M+H) = 532.8. SFC: Retention time: 1.694 min, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1H NMR (400MHz, DMSO-d6): δ9.05(s,1H),8.84(s,2H),7.84(d,J=8.8Hz,1H),7.69(d,J=8.0Hz,1H),7.48(d,J=8.8Hz,1H),7.39(s,2H),6.45- 6.25(m,1H),4.12-3.96(m,1H),3.71-3.55(m,2H),1.72-1.57(m,5H) ,1.47-1.34(m,1H),1.26(t,J=12.4Hz,1H),1.17(s,3H),1.13(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.83(s,3F),-142.3(s,1F).

[0321] Example 77b: (39.92 mg, yield 7.93%) was obtained. LCMS (M+H) = 532.8. SFC: retention time: 1.765 minutes, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.06(s,1H),8.85(s,2H),7.85(d,J=8.8Hz,1H),7.69(d,J=8.0Hz,1H),7.48(d,J=8.8Hz,1H),7.39(s,2H),6.4 5-6.28(m,1H),4.12-3.99(m,1H),3.66-3.53(m,2H),1.73-1.64(m,4H),1.63-1.55(m,1H),1.40-1.28(m,2H),1.18(s,3H),1.15(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.83(s,3F),-142.3(s,1F).

[0322] Example 77c: (33.26 mg, yield 6.61%) was obtained. LCMS (M+H) = 532.9. SFC: retention time: 1.994 minutes, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.83(s,2H),7.69(dd,J=2.4,8.8Hz,1H) ,7.61(d,J=8.0Hz,1H),7.54(dd,J=2.4,8.4Hz,1H),7.40(dd,J=8.8,13.6Hz,2 H),6.38-6.22(m,1H),4.10-3.96(m,1H),3.66-3.52(m,2H),1.79(s,3H),1.71 -1.65(m,1H),1.59-1.51(m,1H),1.41-1.24(m,2H),1.18(s,3H),1.13(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.87(s,3F),-141.87(s,1F).

[0323] Example 77d: (39.77 mg, yield 7.81%) was obtained. LCMS (M+H) = 532.8. SFC: retention time: 2.738 minutes, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.03(s,1H),8.83(s,2H),7.71-7.51(m,3H),7.46-7.35(m,2H),6.40-6.22(m,1H),4.10-3.98(m,1H),3.67-3 .54(m,2H),1.82(s,3H),1.71-1.62(m,1H),1.61-1.53​​(m,1H),1.43-1.32(m,1H),1.27(t,J=12.4Hz,1H),1.18(s,3H),1.13(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-56.87(s,3F),-141.89(s,1F).

[0324] Example 90a and Example 90b

[0325]

change

[0326] To a solution of 90-2 (270 mg, 815.12 μmol) in CF3CH2OH (2 mL) was added H3PO4 (18.79 mg, 163.02 μmol). After addition, the mixture was stirred at 25° C. for 0.5 h, and then 1,1-difluoro-4-isocyano-cyclohexane (131.46 mg, 815.12 μmol) and (2R)-2-chloro-2-fluoro-acetic acid (183.38 mg, 978.14 μmol) were added. The resulting mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-60% ethyl acetate / petroleum ether gradient eluent @30mL / min) to give crude product, which was further purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water(FA)-ACN]; B%: 53%-83%, 7min) to give compound 90 (80mg, 16.61% yield). LCMS(M+H)=589.0. 1 H NMR(400MHz,DMSO-d6):δ9.05(d,J=12.8Hz,1H),8.84(d,J=5.6Hz,2H),7.98-7.63(m,2H),7.57-7.31(m,3H),6.50-6.12(m,1H),3.86(br s,1H),2.11-1.46(m,11H). Compound 90 (70.0 mg, 118.8 μmol) was separated by SFC (WHELK-O1 (250 mm*30 mm, 5 μm), mobile phase A: supercritical CO2, B: Neu-EtOH; isocratic: A:B=80:20) to obtain two fractions.

[0327] Example 90a: (12 mg, 16.59% yield) was obtained. LCMS (M+H) = 589.0. SFC: Retention time: 2.367 min, (SS) Whelk-01_EtOH(DEA)_5_4. 1 H NMR(400MHz,DMSO-d6):δ9.12-9.04(m,1H),8.94-8.81(m,2H),7.96-7.69(m,2H),7.62- 7.32(m,3H),6.50-6.28(m,1H),3.98-3.79(m,1H),2.20-1.96(m,2H),1.94-1.47(m,9H). 19 F NMR(376MHz,DMSO-d6):δ-85.31(s,3F),-87.18(s,2F),-90.50--92.79(m,1F),-98.64--101.39(m,1F),-142.09--142.89(m,1F).

[0328] Obtained Example 90b: (12 mg, 16.18% yield). LCMS (M+H) = 589.1. SFC: Retention time: 2.594 min, (SS) Whelk-01_EtOH(DEA)_5_4. 1 H NMR (400MHz, DMSO-d6): δ9.12~9.04(m, 1H), 8.94~8.81(m, 2H), 7.96~7.69(m, 2H), 7.62~ 7.32(m, 3H), 6.50~6.28(m, 1H), 3.98~3.79(m, 1H), 2.20-1.96(m, 2H), 1.94-1.47(m, 9H). 19 F NMR (376MHz, DMSO-d6): δ-85.04--85.42(m, 3F), -86.87--87.35(m, 2F), -92.04(Brd,J=233.0Hz,1F), -97.87--101.44(m, 1F), -141.92(brs, 1F).

[0329] Examples 92a and 92b

[0330] [ka] To a solution of compound 92-1 (2.0 g, 10.33 mmol) in toluene (60 mL), p-TsOH (210.26 mg, 1.22 mmol) and 1-pyrimidin-5-ylethanone (1.15 g, 9.39 mmol) were added with a Dean-Stark trap, and the mixture was heated and stirred at 140 °C for 12 h. The mixture was filtered, the filter cake was washed with toluene (20 mL * 3), and the organic layer was concentrated under reduced pressure to give the crude product. The crude was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient @ 45 mL / min, TLC: petroleum ether: ethyl acetate = 3:1, Rf = 0.4) to give compound 92-2 (1.7 g, 5.71 mmol, yield 60.80%).

[0331] To a solution of compound 92-2 (1.35 g, 4.53 mmol) in CF3CH2OH (2 mL), H3PO4 (104.57 mg, 906.99 μmol, 62.24 μL) was added, the mixture was stirred at 25 °C for 1 h, then (2R)-2-chloro-2-fluoro-acetic acid (927.50 mg, 5.44 mmol, 66% purity) and 1,1-difluoro-4-isocyano-cyclohexane (658.25 mg, 4.53 mmol) were added. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @40 mL / min, TLC (petroleum ether:ethyl acetate = 0:1, Rf = 0.4)) to give the crude product (300 mg). The crude product was subjected to prep-HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 60%-90%, 7min) to give compound 92 (57mg, yield 15.20%). LCMS (M+H)=554.6.

[0332] Compound 92 (50 mg, 90.04 μmol) was separated by chiral SFC column (DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 um); Mobile phase: [Neu-ETOH]; B%: 15%-15%; Mobile phase: A: Supercritical CO2, B: Neu-ETOH; Isocratic: A:B=85:15; Flow rate: 60 mL / min) and concentrated under vacuum to obtain two fractions.

[0333] Obtained Example 92a: (10.97 mg). LCMS (M+H) = 555.1. SFC: Retention time: 1.555 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR(400MHz,METHANOL-d4):δ9.04(s,1H),8.92(s,2H),7.70(d,J=7.2Hz,1H),7.42(d,J=8.8Hz,2H),7.38-7.32(m,1H ),6.30-6.12(m,1H),3.95(t,J=10.8Hz,1H),2.07(d,J=8.0Hz,2H),2.01-1.86(m,4H),1.82(s,3H),1.74-1.58(m,2H). 19 F NMR(376MHz,METHANOL-d4)δ-27.36(s,2F),-94.53--105.14(m,2F),-145.33(s,1F).

[0334] Example 92b: (6.51 mg) was obtained. LCMS (M+H) = 555.1. SFC: Retention time: 1.972 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR(400MHz,CD3OD):δ9.01(s,1H),8.90(s,2H),7.68(dd,J=2.4,8.4Hz,1H),7.43-7.39(m,1H),7.39-7.31(m,2H),6.27- 6.11(m,1H),3.92(t,J=11.2Hz,1H),2.06(dd,J=4.0,7.2Hz,2H),1.97-1.89(m,6H),1.88-1.81(m,1H),1.72-1.58(m,2H). 19F NMR(376MHz,CD3OD):δ-25.83--29.74(m,2F),-93.88--104.98(m,2F),-145.27(s,1F).

[0335] Examples 94a and 94b

[0336] [ka] To a solution of compound 92-2 (1.35 g, 4.53 mmol) in CF3CH2OH (2 mL), H3PO4 (104.57 mg, 906.99 μmol, 62.24 μL) was added, the mixture was stirred at 25 °C for 1 h, and then (2R)-2-chloro-2-fluoro-acetic acid (927.50 mg, 5.44 mmol, 66% purity) and 4-isocyanotetrahydropyran (504.02 mg, 4.53 mmol) were added. The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @40 mL / min, TLC (petroleum ether:ethyl acetate = 0:1, Rf = 0.4)) to give the crude product (300 mg). The crude product was subjected to prep-HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 48%~78%, 7min) to give compound 94 (57mg, yield 2.11%). LCMS (M+H)=520.7.

[0337] Compound 94 (46 mg, 88, 24 μmol) was separated by chiral SFC column (DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: [Neu-ETOH]; B%: 20%-20%, min; mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=80:20; flow rate: 60 mL / min) and concentrated under vacuum to obtain two fractions.

[0338] Example 94a: (7.38 mg) was obtained. LCMS (M+H) = 521.1. SFC: retention time: 1.797 minutes, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR (400MHz, CD3OD): δ9.07(s,1H),8.97-8.87(m,2H),7.73(d,J=8.4Hz,1H),7.48-7.29(m,3H) ,6.32-6.15(m,1H),4.11-3.91(m,3H),3.56-3.45(m,2H),1.91-1.74(m,5H),1.71-1.55(m,2H). 19 F NMR (376MHz, CD3OD): δ-27.34(s,2F),-145.3(s,1F).

[0339] Example 94b: (10.02 mg) was obtained. LCMS(M+H)=521.1.SFC: Holding time: 2.189 minutes, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR (400MHz, CD3OD): δ9.05 (s, 1H), 8.97~8.87 (m, 2H), 7.71 (d, J=8.4Hz, 1H), 7.47~7.30 (m, 3H) , 6.30~6.12(m, 1H), 4.08~3.91(m, 3H), 3.55-3.44(m, 2H), 1.83-1.74(m, 5H), 1.71-1.54(m, 2H). 19 F NMR (376MHz, CD3OD) δ -27.34 (s, 2F), -145.3 (s, 1F).

[0340] Example 95a and Example 95b

[0341]

change

[0342] To a solution of compound 95-1 (310.00 mg, 986.32 μmol) in CF3CH2OH (2 mL) was added H3PO4 (19.33 mg, 197.26 μmol, 11.51 μL), (2R)-2-chloro-2-fluoro-acetic acid (188.05 mg, 986.32 μmol) and 1,1-difluoro-4-isocyano-cyclohexane (159.07 mg, 986.32 μmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-30% ethyl acetate / petroleum ether gradient @ 30 mL / min). The residue was purified by prep-HPLC (column: Welch Xtimate C18 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 57%-87%, 7 min). Compound 95 (55mg, 94.84μmol, yield 9.62%, purity 98.62%) was obtained.

[0343] Compound 95 (55 mg) was separated by chiral SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B=90:10; flow rate: 80 mL / min) and concentrated under vacuum to give two fractions. Obtained Example 95a: (19.34 mg, 34.22% yield). LCMS (M+H) = 572.1. SFC: Retention time: 2.471 min, AD-3_IPA(DEA)_5_40_25ML.1 H NMR (400MHz, DMSO-d6): δ8.46(s,1H),8.43(d,J=2.7Hz,1H),7.76(brs,2H),7.67(br d,J=8.1Hz,3H),7.37(br s,1H),6.45-6.24(m,1H),3.87(br d,J=8.0Hz,1H),2.07-1.87(m,4H),1.84(s,3H),1.78(br s,2H),1.63-1.50(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-41.83(s,3F),-91.86(br d,J=232.4Hz,1F),-99.37(br d,J=232.4Hz,1F),-128.08(br s,1F),-141.75(s,1F).

[0344] Example 95b: (18.37 mg, yield 31.42%) was obtained. LCMS (M+H) = 572.1. SFC: retention time: 2.630 minutes, AD-3_IPA(DEA)_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ8.44(s,1H),8.38(d,J=2.6Hz,1H),7.71-7.62(m,4H),7.55(br d,J=8.2Hz,2H),6.44-6.22(m,1H),3.86(br s,1H),2.07-1.81(m,7H),1.75(br t,J=15.1Hz,2H),1.65-1.45(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-40.85--44.01(m,3F),-91.97(br d,J=232.4Hz,1F),-99.29(br d,J=235.8Hz,1F),-128.06(s,1F),-141.86(s,1F).

[0345] Example 96a and Example 96b

[0346]

change

[0347] Compound 96 (75 mg) was separated by chiral SFC (DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=80:20; flow rate: 80 mL / min) and concentrated under vacuum to give two fractions.

[0348] Obtained Example 96a: (16.65 mg, 22.20% yield). LCMS (M+H) = 549.1. SFC: Retention time: 2.228 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400MHz, DMSO-d6): δ8.46(s,1H),8.42(d,J=2.6Hz,1H),7.74(br s,2H),7.70-7.63(m,3H),7.40(br s,1H),6.44-6.24(m,1H),3.95-3.80(m,3H),3.29(br s,2H),1.85(s,3H),1.71-1.60(m,2H),1.56-1.45(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-41.13--43.31(m,3F),-128.11(s,1F),-141.68(s,1F).

[0349] Example 96b: (13.02 mg, yield 25.89%) was obtained. LCMS (M+H) = 537.9. SFC: retention time: 2.909 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ8.45(s,1H),8.38(d,J=2.5Hz,1H),7.70-7.63(m,4H),7.55(d,J=8.0Hz,2H),6.42-6.23(m,1H),3.93-3.80(m,3H),3.29(br s,2H),1.98(s,3H),1.70-1.59(m,2H),1.57-1.43(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-39.70--46.27(m,3F),-128.10(s,1F),-141.82(s,1F).

[0350] Example 97a and Example 97b

[0351]

change

[0352] To a solution of compound 97-1 (357 mg, 1.05 mmol) in CF3CH2OH (2 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (211 mg, 1.05 mmol). 4-isocyanotetrahydropyran (167 mg, 1.05 mmol) was then added and the mixture was stirred at 15° C. for 16 h. The reaction was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient eluent @25 mL / min). Compound 97 (100 mg, 16.71% yield). LCMS (M+H)=563.9. 1 H NMR(400MHz,DMSO-d6):8.54-8.40(m,2H),8.04-7.40(m,6H),6.52-6.27(m,1H ),3.97-3.76(m,3H),3.30-3.10(m,2H),1.93-1.71(m,3H),1.71-1.38(m,4H).

[0353] Compound 97 (100 mg, 177.33 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B=85:15; flow rate: 80 mL / min) to obtain two fractions. The two fractions were further purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 53%-83%, 7 min).

[0354] Obtained Example 97a: (15 mg, 14.83% yield). LCMS (M+H) = 564.2. SFC: Retention time: 2.389 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR(400MHz,DMSO-d6):δ8.59-8.45(m,2H),8.11-7.81(m,3H),7.80-7.67(m,2H),7.47(s,1H),6.58- 6.26(m,1H),3.98-3.75(m,3H),3.31-3.18(m,2H),1.76(s,3H),1.71-1.59(m,2H),1.59-1.42(m,2H). 19 F NMR(376MHz,DMSO-d6):δ63.99(br d,J=151.6Hz,5F),-128.02(s,1F),-142.20(s,1F).

[0355] Obtained Example 97b: (20 mg, 19.75% yield). LCMS (M+H) = 564.2. SFC: Retention time: 2.701 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR(400MHz,DMSO-d6):δ8.56-8.41(m,2H),7.92(d,J=8.4Hz,2H),7.82-7.57(m,4H),6.49-6.27(m,1H),3.8 4(d,J=11.2Hz,3H),3.30(s,2H),1.90(s,3H),1.67(d,J=12.4Hz,1H),1.62-1.55(m,1H),1.55-1.40(m,2H). 19F NMR(376MHz,DMSO-d6):δ63.96(br d,J=148.8Hz,5F),-127.95(s,1F),-142.05(s,1F).

[0356] Examples 98a and 98b

[0357] [ka] To a solution of compound 92-1 (2.0 g, 10.33 mmol) in toluene (60 mL), p-TsOH (192.71 mg, 1.12 mmol) and 1-(5-fluoropyridin-3-yl)ethan-1-one (1.20 g, 8.61 mmol) were added with a Dean-Stark trap, and the mixture was heated and stirred at 140 °C for 12 h. The mixture was filtered, the filter cake was washed with toluene (30 mL × 3), and the organic layer was concentrated under reduced pressure to give the crude product. The crude was purified by flash silica gel chromatography (eluent of 0-25% ethyl acetate / petroleum ether gradient @45 mL / min TLC: petroleum ether; ethyl acetate = 3:1 Rf = 0.5) to give compound 98-1 (1.3 g, 4.13 mmol, 47.99% yield). 1 H NMR (400MHz, CDCl3) δ8.87(t,J=1.6Hz,1H),8.51(d,J=2.8Hz,1H),8.02-7.96(m,1H),7.22-7.15(m,2H),6.76-6.71(m,2H),2.22(s,3H).

[0358] To a solution of compound 98-1 (230 mg, 730.88 μmol) in CF3CH2OH (2 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (167.22 mg, 877.05 μmol, 59% purity), 4-isocyanotetrahydropyran (81.23 mg, 730.88 μmol), and 4A MS (200 mg, 730.88 μmol). The mixture was stirred at 25° C. for 2 hours. The mixture was filtered and the organic layer was concentrated under reduced pressure to give the crude product. The crude product was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @30mL / min, TLC: petroleum ether:ethyl acetate=1:1, Rf=0.2) and purified by prep-HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water(FA)-ACN]; B%: 55%-85%, 7min) to give compound 98 (60mg, 111.46μmol, yield 15.25%). LCMS (M+H)=539.8. The residue compound 98 (60 mg, 111.4 μmol) was separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH, A:B=80:20 at 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm) to obtain two fractions. Pure fractions were collected and the solvent was evaporated under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to obtain the title compound.

[0359] Obtained Example 98a: (16.05 mg, 24.16% yield). LCMS (M+H) = 538.0 SFC: Retention time: 2.425 min, AD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400MHz, CD3OD): δ8.54(s,1H),8.39(d,J=2.4Hz,1H),7.77(td,J=2.4,10. 2Hz,1H),7.67-7.59(m,1H),7.46-7.36(m,2H),7.31(d,J=8.8Hz,1H),6.32-6. 15(m,1H),4.13-4.02(m,1H),4.00-3.93(m,2H),3.58-3.46(m,2H),1.94(s,3H ),1.91-1.82(m,2H),1.70-1.54(m,2H),1.70-1.54(m,1H),1.70-1.54(m,2H). 19 F NMR (376MHz, CD3OD) δ-27.29(s,2F),-128.11(s,1F),-141.97--146.50(m,1F).

[0360] Example 98b: (20.35 mg, yield 31.70%) was obtained. LCMS (M+H) = 538.4. SFC: retention time: 2.866 minutes, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1 H NMR (400MHz, CD3OD): δ8.49(s,1H),8.32(d,J=2.4Hz,1H),7.76 * 7.73(m,1H),7.58-7.52(m,1H),7.46-7.40(m,1H),7.28(d,J=8.8Hz,2H),6.28-6.13(m,1H),4.07-4.00(m,1H),3.95(t,J=9.2Hz,2H),3.53 * 3.45(m,2H),2.06(s,3H),1.89-1.76(m,2H),1.68-1.50(m,2H). 19 F NMR (376MHz, CD3OD): δ-26.51--28.09(m,2F),-128.20(s,1F),-143.35--147.88(m,1F).

[0361] Example 99a and Example 99b

[0362]

change

[0363] The residue compound 99 (60 mg, 104.8 μmol) was separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH, A:B=90:10 at 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm) to obtain two fractions. Pure fractions were collected and the solvent was evaporated under vacuum. The residue was partitioned between acetonitrile (2 mL) and water (10 mL). The solution was lyophilized to dryness to obtain the title compound.

[0364] Obtained Example 99a: (14.88 mg, 24.80% yield). LCMS (M+H) = 573.8. SFC: Retention time: 1.935 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400MHz, CD3OD): δ8.41(s,1H),8.26(d,J=2.4Hz,1H),7.65(td,J=2.4,10.4Hz,1H),7.56-7.47(m,1H),7.34-7.23(m,2H),7. 22-7.14(m,1H),6.21-6.04(m,1H),3.86(t,J=11.2Hz,1H),2.04-1.84(m,5H),1.81(s,3H),1.79-1.71(m,1H),1.65-1.48(m,2H). 19 F NMR (376MHz, CD3OD) δ-24.74--30.45(m,2F),-93.89--107.68(m,2F),-125.61--131.72(m,1F),-145.01(br.s,1F).

[0365] Example 99b: (6.19 mg, yield 10.27%) was obtained. LCMS (M+H) = 573.9. SFC: retention time: 2.400 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, CD3OD): δ8.48(s,1H),8.32(d,J=2.4Hz,1H),7.74(td,J=2.4,10.4Hz,1H),7.58-7.52(m,1H),7.46-7.38(m, 1H),7.28(d,J=8.8Hz,2H),6.29-6.11(m,1H),3.94(t,J=10.8Hz,1H),2.05(s,5H),1.99-1.82(m,4H),1.74-1.57(m,2H). 19 F NMR (376MHz, CD3OD) δ-27.05--27.53(m,2F),-91.31--107.89(m,2F),-128.18(s,1F),-145.24(s,1F).

[0366] Example 100a and Example 100b

[0367]

change

[0368] To a solution of 100-2 (7.18 g, 25.97 mmol) in DCM (70 mL) was added HCl / dioxane (4 M, 50 mL, 7.70 equiv). The reaction was concentrated and water (50 mL) was added to the residue. The mixture was adjusted to pH=8 with saturated Na2CO3, then extracted with DCM (100 mL×3), the organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give the crude product. Compound 100-3 (1.0 g, crude) was used in the next step without further purification.

[0369] To a solution of compound 100-3 (1 g, 4.54 mmol) and 1-pyrimidin-5-ylethanone (550 mg, 4.50 mmol) in Tol. (70 mL) was added p-TsOH (117.25 mg, 680.90 μmol). The mixture was stirred at 140 °C for 16 h and water was removed by Dean-Stark trap under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-10% ethyl acetate / petroleum ether gradient @25 mL / min). Compound 100-4 (688 mg, 51.36% yield) 1 H NMR (400MHz, DMSO-d6): δ9.38-9.30(m,3H),8.05-7.94(m,2H),7.92(d,J=3.2Hz,1H),7.76(d,J=3.2Hz,1H),6.99(d,J=8.4Hz,2H),2.33(s,3H).

[0370] To a solution of compound 100-4 (344 mg, 1.23 mmol) in CF3CH2OH (1.5 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (230.05 mg, 1.23 mmol). Then 1,1-difluoro-4-isocyano-cyclohexane (197.90 mg, 1.23 mmol) was added and the mixture was stirred at 15° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient eluent @20 mL / min). Compound 100 (234 mg, 33.47% yield) was obtained. LCMS (M+H)=537.9. 1 H NMR(400MHz,DMSO-d6):δ9.03(d,J=18.4Hz,1H),8.85(d,J=7.6Hz,2H),7.99-7.90(m,3H),7.85(t,J=3.6Hz,1H),7.77-7 .62(m,2H),7.50-7.27(m,1H),6.49-6.25(m,1H),3.87(s,1H),1.97-1.82(m,5H),1.79-1.65(m,3H),1.64-1.38(m,3H).

[0371] Compound 100 (120 mg, 223.05 μmol) was separated by SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic: A:B = 60:40; flow rate: 80 mL / min) to obtain two fractions.

[0372] Example 100a: (45 mg, yield 37.10%) was obtained. LCMS (M+H) = 538.0. SFC: retention time: 1.556 min, AD_3_EtOH_DEA_40_25ML. 1 H NMR (400 MHz, DMSO-d6): δ 9.07 (s, 1H), 8.87 (s, 2H), 8.07 (d, J = 9.6 Hz, 1H), 8.01 - 7.94 (m, 2H), 7.92 - 7.82 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H) 7.31 (d, J = 6.8 Hz, 1H), 6.52~6.31 (m, 1H), 3.91 (s, 1H), 2.02 (m, 4H), 1.81 (m, 2H), 1.66 (s, 3H), 1.63~1.47 (m, 2H). 19 F NMR (376 MHz, DMSO-d6): δ -91.81 (d, J = 231.7 Hz, 1F), -99.38 (d, J = 234.6 Hz, 1F), -142.24 (s, 1F).

[0373] Example 100b: (43 mg, yield 34.60%) was obtained. LCMS (M+H) = 538.0. SFC: retention time: 2.085 min, AD_3_EtOH_DEA_40_25ML. 1 H NMR (400 MHz, DMSO-d6): δ 9.03 (s, 1H), 8.86 (s, 2H), 8.05 - 7.91 (m, 3H), 7.86 (d, J = 3.2 Hz, 1H), 7.74 - 7.64 (m, 2H), 7.46 (d, J = 7.2 Hz, 1H), 6.48 - 6.22 (m, 1H), 3.88 (br s, 1H), 2.10 - 1.90 (m, 4H), 1.85 - 1.73 (m, 5H), 1.60 (m, 2H). 19 F NMR (376 MHz, DMSO-d6): δ -92.04 (d, J = 234.6 Hz, 1F), -99.16 (d, J = 231.7 Hz, 1F), -141.73 (s, 1F).

[0374] Examples 101a and 101b

[0375] [ka] To a solution of compound 100-4 (4 mg, 1.23 mmol) in CF3CH2OH (1.5 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (230.60 mg, 1.23 mmol). Then, 4-isocyanotetrahydropyran (195.29 mg, 1.23 mmol) was added and the mixture was stirred at 15 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient eluent @ 20 mL / min). Compound 101 (200 mg, 31.56% yield). LCMS (M+H) = 503.9. 1 H NMR (400MHz, DMSO-d6): δ9.04(d,J=18.0Hz,1H),8.87(d,J=8.0Hz,2H),8.02-7.92(m,4H),7.85-7.76(m,1H),7.68(d ,J=7.6Hz,1H),7.55-7.28(m,1H),6.51-6.26(m,1H),3.81(s,3H),3.51-3.39(m,2H),1.83(s,3H),1.55-1.37(m,4H).

[0376] Compound 101 (100 mg) was separated by chiral SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=60:40; flow rate: 80 mL / min) and concentrated under vacuum to give two fractions.

[0377] Obtained Example 101a: (37 mg, 35.22% yield). LCMS (M+H)=503.7. SFC: Retention time: 1.801 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400MHz, DMSO-d6): δ9.07(s,1H),8.88(s,2H),8.06(d,J=8.8Hz,1H),8.02-7.93(m,2H),7.90-7.83(m,2H),7.79(d,J=8.0 Hz,1H),7.34(d,J=8.4Hz,1H),6.49-6.30(m,1H),4.00-3.81(m,3H),3.43-3.34(m,2H),1.77-1.63(m,5H),1.61-1.42(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-140.82--145.53(m,1F).

[0378] Example 101b: (20 mg, yield 18.65%) was obtained. LCMS (M+H) = 504.2. SFC: retention time: 2.178 minutes, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1 H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.86(s,2H),8.04-7.90(m,3H),7.86(d,J=3.2Hz,1H),7.75-7.60(m,2H),7.49(d,J =8.2Hz,1H),6.48-6.24(m,1H),4.00-3.80(m,3H),3.47-3.37(m,2H),1.83(s,3H),1.74-1.61(m,2H),1.58-1.44(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-141.73 (s, 1F).

[0379] Example 102a and Example 102b

[0380]

change

[0381] Obtained Example 102a: (9.56 mg, 28.12% yield). LCMS (M+H) = 555.0. SFC: Retention time: 1.280 min, AD_3_EtOH_DEA_40_25 ML. 1H NMR (400MHz, DMSO-d6) δ8.52(s,1H),8.48(d,J=2.6Hz,1H),8.03(br d,J=7.4Hz,1H),7.97(d,J=3.2Hz,1H),7.93(br d,J=8.6Hz,1H),7.87(d,J=3.2Hz,1H),7.82-7.73(m,2H),7.68(d,J=8.0Hz,1H),7.29(br d,J=8.0Hz,1H),6.51-6.31(m,1H),3.90(br d,J=7.5Hz,1H),2.15-1.79(m,6H),1.74(s,3H),1.66-1.54(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-91.81(br d,J=232.4Hz,1F),-99.34(br d,J=235.8Hz,1F),-127.99(s,1F),-141.87(br s,1F).

[0382] Example 102b: (10.77 mg, yield 31.68%) was obtained. LCMS(M+H)=555.0.SFC: Holding time: 1.600 minutes, AD_3_EtOH_DEA_40_25ML. 1 H NMR(400MHz,DMSO-d6)δ8.49(s,1H),8.42(d,J=2.6Hz,1H),7.97-7.89(m,3H),7.85(d,J=3.2Hz,1H),7.76(br d,J=10.7Hz,1H),7.64(d,J=7.9Hz,1H),7.58(br d,J=7.7Hz,1H),7.47(br d,J=7.9Hz,1H),6.47-6.26(m,1H),3.87(br s,1H),2.08-1.76(m,9H),1.69-1.49(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-91.99(br d,J=228.9Hz,1F),-99.17(br d,J=221.9Hz,1F),-127.86(s,1F),-141.67(s,1F).

[0383] Example 103a and Example 103b

[0384]

change

[0385] Compound 103 (67 mg, 128.60 μmol) was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: [Neu-ETOH]; B%: 40%-40%, min) to obtain two fractions.

[0386] Obtained Example 103a: (15.77 mg, 23.54% yield). LCMS (M+H) = 521.1. SFC: Retention time: 1.727 min, AD_3_EtOH_DEA_40_25ML. 1 H NMR(400MHz,DMSO-d6)δ8.59-8.44(m,2H),8.02(br d,J=8.0Hz,1H),7.98(d,J=2.9Hz,1H),7.94(br d,J=8.1Hz,1H),7.87(d,J=3.1Hz,1H),7.76(br d,J=10.7Hz,2H),7.71(d,J=7.7Hz,1H),7.33(br d,J=7.3Hz,1H),6.50-6.27(m,1H),4.02-3.81(m,3H),3.39(br s,2H),1.91-1.49(m,7H). 19 F NMR(376MHz,DMSO-d6):δ-128.00(br s,1F),-141.83(br s,1F). Obtained Example 103b: (26.96 mg, 40.24% yield). LCMS (M+H) = 521.0. SFC: Retention time: 2.471 min, AD_3_EtOH_DEA_40_25ML. 1 H NMR(400MHz,DMSO-d6)δ8.50(s,1H),8.42(d,J=2.6Hz,1H),7.96(d,J=3.2Hz,1H),7.93(br d,J=8.0Hz,2H),7.86(d,J=3.2Hz,1H),7.77(dd,J=2.1,10.6Hz,1H),7.66(d,J=7.7Hz,1H),7.57(br d,J=7.4Hz,1H),7.51(br d,J=7.7Hz,1H),6.52-6.23(m,1H),3.96-3.80(m,3H),3.38(s,2H),1.92(s,3H),1.79-1.63(m,2H),1.60-1.40(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-127.87(s,1F),-141.67(s,1F).

[0387] Examples 104a and 104b

[0388] [ka] To a solution of compound 22-1 (2 g, 10.35 mmol, 1.48 mL) and 1-(pyrimidin-5-yl)ethan-1-one (836.05 mg, 6.90 mmol, 760.04 μL) in toluene (30 mL), pTsOH (178.27 mg, 1.04 mmol) was added. The mixture was stirred at 140° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (0-100% DCM / petroleum ether gradient @35 mL / min). Compound 104-1 (590 mg, 1.69 mmol, 24.52% yield) was obtained.

[0389] To a solution of compound 104-1 (295 mg, 995.58 μmol) in CF3CH2OH (2 mL), (2R)-2-chloro-2-fluoro-acetic acid (227.78 mg, 1.19 mmol) and 1,1-difluoro-4-isocyano-cyclohexane (160.56 mg, 995.58 μmol) were added. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @20 mL / min). The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 50%-80%, 7 min). Compound 104 (125 mg, 224.95 μmol, yield 22.60%) was obtained. LCMS(M+H)=554.0.

[0390] Compound 104 (125 mg) was separated by chiral SFC (DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=80:20; flow rate: 70 mL / min) and concentrated under vacuum to give two fractions.

[0391] Obtained Example 104a: (15.02 mg, 12.02% yield). LCMS (M+H) = 554.0. SFC: Retention time: 2.578 min, OD-3_EtOH(DEA)_5_40_25 ML. 1 H NMR(400MHz,DMSO-d6):δ8.52(d,J=2.3Hz,1H),8.32(dd,J=1.3,4.6Hz,1H),7.73-7.55(m,5H),7.33(br s,1H),7.19(dd,J=4.8,8.2Hz,1H),6.39-6.20(m,1H),3.88(br d,J=7.7Hz,1H),1.99(br s,3H),1.89(s,4H),1.77(br s,2H),1.64-1.47(m,2H). 19F NMR (376MHz, DMSO-d6): δ-41.80(s,3F),-91.88(br d,J=232.3Hz,1F),-99.30(br d,J=232.4Hz,1F),-141.40(s,1F).

[0392] Example 104b: (16.79 mg, yield 13.43%) was obtained. LCMS (M+H) = 554.0. SFC: retention time: 2.872 minutes, OD-3_EtOH(DEA)_5_40_25ML. 1 H NMR (400MHz, DMSO-d6): δ8.52(d,J=2.1Hz,1H),8.28(dd,J=1.4,4.7Hz,1H),7.70-7. 56(m,4H),7.54-7.41(m,2H),7.15(dd,J=4.6,8.0Hz,1H),6.43-6.17(m,1H),3.84(br d,J=7.3Hz,1H),2.08-1.82(m,7H),1.75(br s,2H),1.67-1.42(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-41.86(s,3F),-91.95(br d,J=232.3Hz,1F),-99.26(br d,J=235.8Hz,1F),-141.74(br s,1F).

[0393] Example 105a and Example 105b

[0394]

change

[0395] Compound 105 (112 mg) was separated by chiral SFC (DAICEL CHIRALPAK AD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic: A:B=75:25; flow rate: 60 mL / min) and concentrated under vacuum to give two fractions.

[0396] Obtained Example 105a: (15.48 mg, 13.70% yield). LCMS (M+H) = 519.9. SFC: Retention time: 3.301 min, AD-3_EtOH(DEA)_5_40_25ML. 1 H NMR(400MHz,DMSO-d6):δ8.54(d,J=2.0Hz,1H),8.34(d,J=4.9Hz,1H),7.77-7.54(m,5H),7.37(br s,1H),7.21(dd,J=4.6,8.0Hz,1H),6.44-6.18(m,1H),3.98-3.81(m,3H),3.16(br s,2H),1.93(s,3H),1.68(br s,2H),1.59-1.43(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-41.80(s,3F),-141.37(s,1F).

[0397] Example 105b: (15.96 mg, 14.18% yield) was obtained. LCMS (M+H) = 520.0. SFC: Retention time: 3.803 min, AD-3_EtOH(DEA)_5_40_25 ML. 1 H NMR (400MHz, DMSO-d6): δ8.55(d,J=2.0Hz,1H),8.30(d,J=3.5Hz,1H),7.71-7.58(m,4H),7.57-7.42(m,2H),7.16(dd,J=4. 8,8.0Hz,1H),6.42-6.19(m,1H),3.95-3.79(m,3H),3.31-3.27(m,2H),2.05(s,3H),1.71-1.60(m,2H),1.60-1.38(m,2H). 19 F NMR(376MHz,DMSO-d6):δ-41.87(s,3F),-141.72(br s,1F).

[0398] Examples 106a and 106b

[0399] [ka] To a solution of compound 106-1 (200 mg, 1.14 mmol HCl) in ethyl formate (20 mL) was added TEA (345.55 mg, 3.41 mmol, 475.32 μL). The mixture was stirred at 80° C. for 16 h. The mixture was concentrated under vacuum, diluted with water (30 mL), and extracted with DCM (10 mL*3). The organic layer was washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Compound 106-2 (185 mg, crude) was obtained. LCMS (M+H)=167.8.

[0400] To a solution of compound 106-2 (185 mg, 1.11 mmol) in DCM (10 mL), CCl4 (170.15 mg, 1.11 mmol, 106.34 μL), PPh3 (290.13 mg, 1.11 mmol), and TEA (111.93 mg, 1.11 mmol, 153.96 μL) were added. The mixture was stirred at 45 °C for 16 h. The mixture was diluted with DCM (10 mL), filtered, and concentrated under vacuum. The crude product was triturated with PE (10 mL) and MTBE (10 mL) at 20 °C for 60 min. The mixture was filtered, and the filter cake was washed with MTBE (10 mL * 3). The filtrate was concentrated under reduced pressure. Compound 106-3 (384 mg, crude) was obtained.

[0401] To a solution of compound 4-3 (150 mg, 533.37 μmol) in CF3CH2OH (2 mL), (2R)-2-chloro-2-fluoro-acetic acid (119.99 mg, 640.04 μmol) and compound 106-3 (159.19 mg, 533.37 μmol) were added. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @20 mL / min). The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 63%-93%, 7 min). Compound 106 (19 mg, 34.60 μmol, yield 6.49%) was obtained. LCMS (M+H) = 543.0.

[0402] Compound 106 (19 mg) was separated by chiral SFC (DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=85:15; flow rate: 80 mL / min) and concentrated under vacuum to give two fractions.

[0403] Obtained Example 106a: (3.68 mg, 19.37% yield). LCMS (M+H) = 543.1. SFC: Retention time: 2.168 min, OD_3_EtOH_DEA_5_40_25ML_6MIN.1 H NMR (400MHz, DMSO-d6): δ9.05(s,1H),8.84(s,2H),7.83(br d,J=8.9Hz,1H),7.63(d,J=8.1Hz,1H),7.47(br d,J=8.8Hz,1H),7.39(br s,2H),6.44-6.27(m,1H),3.57(br d,J=3.8Hz,1H),1.85-1.78(m,2H),1.77-1.70(m,4H),1.69-1.64(m,5H),1.62-1.50(m,2H),1.33-1.20(m,4H). 19 F NMR (376MHz, DMSO-d6): δ-56.85(s,3F),-142.13(br s,1F).

[0404] Example 106b: (5.80 mg, yield 30.53%) was obtained. LCMS (M+H) = 543.1. SFC: retention time: 2.858 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.82(s,2H),7.66(br d,J=8.6Hz,1H),7.58-7.49(m,2H),7.46-7.35(m,2H),6.39-6.21(m,1H),3.55(br s,1H),1.85-1.76(m,5H),1.75-1.63(m,6H),1.61-1.44(m,2H),1.31-1.20(m,4H). 19 F NMR (376MHz, DMSO-d6): δ-56.88(s,3F),-141.87(s,1F).

[0405] Example 107a and Example 107b

[0406]

change

[0407] To a solution of compound 107-2 (130 mg, 768.23 μmol) in DCM (10 mL), TEA (77.74 mg, 768.23 μmol, 106.93 μL) PPh3 (201.50 mg, 768.23 μmol), and CCl4 (118.17 mg, 768.23 μmol, 73.86 μL) were added. The mixture was stirred at 45 °C for 16 h. The mixture was diluted with DCM (10 mL), filtered, and concentrated under vacuum. The crude product was triturated with PE (10 mL) and MTBE (10 mL) for 60 min at 2 °C. The mixture was filtered, and the filter cake was washed with MTBE (10 mL * 3). The filtrate was concentrated under reduced pressure. Compound 107-3 (116 mg, crude) was obtained.

[0408] To a solution of compound 4-3 (200 mg, 711.15 μmol) in CF3CH2OH (2 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (159.99 mg, 853.39 μmol) and compound 107-3 (107.53 mg, 711.15 μmol). The mixture was stirred at 20° C. for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse phase silica gel column (C 18 , 40g) using water and acetonitrile as eluents (Mobile phase A water (0% FA), Mobile phase B acetonitrile, Mobile phase B 30%-60%). The residue was purified by prep-HPLC (Column: Boston Green ODS 150*30mm*5μm; Mobile phase: [Water (FA)-ACN]; B%: 40%-70%, 6min). Compound 107 (28mg, 49.84μmol, 7.01% yield) was obtained. LCMS (M+H)=545.1.

[0409] Compound 107 (28 mg) DAICEL CHIRALCEL OD-H (250mm*30mm, 5μm); mobile phase: A: supercritical CO2, B: Neu-IPA; イソクラティック: A:B=75:25; flow rate: 70mL / min), separation and concentration under vacuum, 2 and 2 draw points, respectively.

[0410] Example 107a: (3.30 mg, yield 11.43%) was obtained. LCMS (M+H) = 545.1. SFC: retention time: 2.832 minutes, OD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.05(s,1H),8.83(s,2H),7.83(br d,J=9.2Hz,1H),7.62(d,J=8.1Hz,1H),7.48(br d,J=9.3Hz,1H),7.39(s,2H),6.47-6.26(m,1H),4.31(s,2H),4.21(s,2H),3.60(br d,J=8.1Hz,1H),2.06(br d,J=13.6Hz,2H),1.66(s,5H),1.46(br dd,J=3.5,7.6Hz,2H),1.29-1.20(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-56.84(s,3F),-142.20(br s,1F).

[0411] Example 107b: (5.85 mg, yield 19.78%) was obtained. LCMS (M+H) = 545.1. SFC: retention time: 3.516 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.02(s,1H),8.81(s,2H),7.69-7.62(m,1H),7.56-7.49(m,2H),7.40(br dd,J=8.8,12.9Hz,2H),6.38-6.22(m,1H),4.31-4.26(m,2H),4.20(s,2H),3.63-3.52(m,1H),2.01(br d,J=6.1Hz,2H),1.78(s,3H),1.70-1.53​​(m,2H),1.51-1.40(m,2H),1.26-1.17(m,2H).19 F NMR(376MHz,DMSO-d6):δ-56.81--57.11(m,3F),-141.91(s,1F).

[0412] Examples 108a and 108b

[0413] [ka] To a solution of compound 108-1 (500 mg, 2.368 mmol) in toluene (30 mL) was added 1-(pyrimidin-5-yl)ethan-1-one (289.22 mg, 0.237 mmol) and 4-methylbenzenesulfonic acid (40.78 g, 2.046 mmol). The mixture was stirred at 140° C. under N2 atmosphere for 18 h. The mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (20% acetone / petroleum ether gradient eluent @20 mL / min) to give compound 108-2 (400 mg, crude).

[0414] To a solution of compound 108-2 (500 mg, 0.952 mmol) in CF3CH2OH (3 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (214.07 mg, 0.952 mmol) and 4-isocyanotetrahydropyran (88.14 mg, 0.793 mmol). The mixture was stirred at 25° C. for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (Phenomenex Gemini-NX C18 75*30 mm*3 μm; mobile phase: A: water (FA) B: ACN; gradient conditions: 37% B to 67% B; flow rate: 25 mL / min). Pure fractions were collected and volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give compound 108 (90 mg, 20.43% yield). LCMS (M+H)=539.1.

[0415] Compound 108 (90 mg, 0.167 mmol) was separated by SFC (Chiralcel OD-3 100 x 4.6 mm ID, 3 μm Mobile phase: A: CO2, B: Ethanol (0.05% DEA) Gradient: 5% to 40% B in 4 min, hold at 40% for 2.5 min, then 5% B for 1.5 min Flow rate: 2.8 mL / min) to give two fractions.

[0416] Obtained Example 108a: (1.80 mg, 2.00% yield). LCMS (M+H) = 539.0. SFC: Retention time: 1.542 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR(400MHz,DMSO-d6):δ1.39-1.77(m,7H),3.29(s,2H),3.78-3.93(m,3H),6.32-6 .46(m,1H),7.48-7.58(m,1H),7.79(d,3H),7.95(s,1H),8.85(s,2H),9.04(s,1H). 19 F NMR(376MHz,DMSO-d6):δ-142.32(s,1F),-113.59(brs,2F),-84.02(s,3F).

[0417] Example 108b: (3.45 mg, 3.78% yield) was obtained. LCMS (M+H)=539.2. SFC: Retention time: 1.879 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1 H NMR (400MHz, DMSO-d6): δ1.46(s,2H),1.51-1.60(m,1H),1.64-1.74(m,1H),1.85(s,3H),3.29(s,2H),3.74- 3.94(m,3H),6.25-6.41(m,1H),7.64-7.69(m,1H),7.72(s,3H),7.77-7.82(m,1H),8.82(s,2H),9.00(s,1H). 19 F NMR(376MHz,DMSO-d6):δ-142.01(s,1 F),-113.68(s,2 F),-84.07(s,3 F).

[0418] Examples 109a and 109b

[0419] [ka] To a solution of compound 109-1 (1.3 g, 6.49 mmol) in ethyl formate (10 mL) was added TEA (1.97 g, 19.47 mmol, 2.71 mL) and the mixture was heated and stirred at 80° C. for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give crude compound 109-2 (1.5 g, crude).

[0420] To a solution of compound 109-2 (1.5 g, 6.57 mmol) in DCM (8 mL) was added PPh3 (1.72 g, 6.57 mmol), TEA (664.88 mg, 6.57 mmol, 914.55 μL, 1 eq), and CCl4 (1.01 g, 6.57 mmol, 631.70 μL). The mixture was heated and stirred at 45 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure at 20 °C to give the crude product, which was purified by flash silica gel chromatography (0-100% dichloromethane / petroleum ether gradient eluent @35 mL / min). TLC (petroleum ether:dichloromethane = 0:1, Rf = 0.4)). Compound 109-3 (500 mg, 2.38 mmol, 36.19% yield) was obtained. 1 H NMR (400MHz, CDCl3): δ4.65(m,1H),4.03-3.82(m,2H),2.42-2.28(m,1H),2.09-1.82(m,3H),1.80-1.59(m,2H),1.38(s,9H).

[0421] To a solution of compound 11-2 in CF3CH2OH (2 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (560 mg, 2.94 mmol), compound 109-3 (500 mg, 2.38 mmol) and 4A MS (200 mg, 2.38 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give the crude product, which was purified by flash silica gel chromatography (0-100% ethyl acetate / petroleum ether gradient eluent @ 30 mL / min) to give the residue compound 109-4 (500 mg, 791.07 μmol, 33.27% yield). LCMS (M+H) = 620.8

[0422] To a solution of compound 109-4 (500 mg, 0.805 mmol) in DCM (5 mL) was added TFA (0.308 mL, 4.026 mmol) and the mixture was stirred at 25 °C for 1 h. The mixture was diluted with dichloromethane (40 mL), adjusted to pH = 12 by a solution of sodium hydroxide (3 M, 8 mL), and extracted with dichloromethane (10 mL * 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give compound 109-5 (300 mg, crude) as is. The crude was used directly in the next step without further purification. To a solution of compound 109-5 (300 mg, 0.576 mmol) in DCM (10 mL), DMAP (35.18 mg, 0.288 mmol) and ethyl 2,2,2-trifluoroacetate (245.49 mg, 1.728 mmol) were added, and the mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give a crude product, which was purified by prep-HPLC (column: Boston Green ODS 150 * 30 mm * 5 μm, mobile phase A: water (FA), mobile phase B: acetonitrile, flow rate: 25 mL / min, gradient conditions from 55% B to 85% B) to give compound 109 (60 mg, yield 16.89%). LCMS (M + H) = 616.8.

[0423] The residue compound 109 (60 mg, 0.097 mmol) was separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-IPA, A:B=85:15 at 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm) to obtain two fractions. Obtained Example 109a: (12.77 mg). LCMS (M+H) = 617.1. SFC: Retention time: 2.590 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400MHz, CD3OD): δ9.49(d,J=6.8Hz,1H),8.47-8.41(m,2H),7.83(d,J=7.2Hz,1H),7.75-7.64(m,2H),7.45-7.31(m,3H),6 .43-6.29(m,1H),4.18-3.96(m,2H),2.35-2.22(m,1H),1.95-1.85(m,2H),1.80(s,3H),1.73-1.64(m,2H),1.60-1.49(m,1H). 19 F NMR (376MHz, CD3OD) δ-56.92(s,3F),-74.19(s,3F),-128.04(s,1F),-141.92(s,1F).

[0424] Example 109b: (20.53 mg) was obtained. LCMS (M+H) = 617.1. SFC: retention time: 2.849 minutes, OD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, CD3OD): δ9.47(d,J=6.8Hz,1H),8.49-8.41(m,2H),7.80-7.64(m,2H),7.54(dd,J=4.8,8.4Hz,2H),7.40-7 .30(m,2H),6.45-6.23(m,1H),4.13-3.99(m,2H),2.26-2.16(m,1H),1.92(s,3H),1.89-1.78(m,2H),1.72-1.49(m,3H). 19 F NMR (376MHz, CD3OD) δ-55.25--58.93(m,3F),-73.81--74.92(m,3F),-126.74--128.76(m,1F),-140.33--142.54(m,1F).

[0425] Example 110a and Example 110b

[0426]

change

[0427] To a solution of 110-2 (921 mg, 5.31 mmol) in DCM (10 mL) was added TEA (536.92 mg, 5.31 mmol, 738.55 μL), PPh3 (1.39 g, 5.31 mmol), CCl4 (816.21 mg, 5.31 mmol, 510.13 μL). The mixture was stirred at 45 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (eluent of 0-5% ethyl acetate / petroleum ether gradient @ 20 mL / min). Compound 110-3 (4.2 g, crude) was obtained.

[0428] To a solution of 4-3 (400 mg, 1.42 mmol) in CF3CH2OH (1 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (319.98 mg, 1.71 mmol) and 110-3 (442.50 mg, 1.42 mmol). The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered and the filtrate was concentrated in vacuum. The residue was purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether gradient @20 mL / min) and further purified by prep-HPLC (column: Welch Xtimate C18 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 56%-86%, 7 min). Compound 110 (35 mg, 62.45 μmol, yield 4.39%) was obtained.

[0429] Compound 110 (35 mg, 63.72 μmol) was further separated by SFC (column: (S, S) WHELK-O1 (250 mm*30 mm, 5 μm); mobile phase: [Neu-IPA]; B%: 35%–35%, min) to obtain two fractions.

[0430] Obtained Example 110a: (8.13 mg, 23.23% yield). LCMS (M+H) = 549.0. SFC: Retention time: 3.470 min, (SS) Whelk-01_IPA(DEA)_5_40. 1 H NMR(400MHz,DMSO-d6)δ9.76(s,1H),9.13(s,1H),8.99-8.87(m,2H),7.99(dd,J=2. 8,8.8Hz,1H),7.60-7.41(m,4H),7.37-7.22(m,2H),6.56-6.34(m,1H),1.72(s,3H).

[0431] Obtained Example 110b: (9.89 mg, 28.26% yield). LCMS (M+H)=549.1. SFC: Retention time: 3.951 min, (SS) Whelk-01_IPA(DEA)_5_40. 1 H NMR(400MHz,DMSO-d6)δ9.70(s,1H),9.07(s,1H),8.92(s,2H),7.76(dd,J=2.4,8.7Hz,1H),7.58-7.40(m,5H),7.34(br d,J=8.5Hz,1H),6.49-6.28(m,1H),1.91(s,3H).

[0432] Examples 111a and 111b

[0433] [ka] To a solution of 1-(pyridin-3-yl)ethan-1-one (1 g, 8.26 mmol, 909.09 μL) and compound 92-1 (1.60 g, 8.26 mmol) in toluene (30 mL) was added p-TsOH (213.23 mg, 1.24 mmol). The mixture was stirred at 140 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-20% ethyl acetate / petroleum ether gradient @ 35 mL / min). Compound 111-1 (673 mg, 1.70 mmol, 20.61% yield) was obtained.

[0434] To a solution of compound 111-1 (673 mg, 2.27 mmol) in CF3CH2OH (10 mL) was added (2R)-2-chloro-2-fluoro-acetic acid (510.31 mg, 2.72 mmol) and 4-isocyanotetrahydropyran (296.59 mg, 2.27 mmol). The mixture was stirred at 20°C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-100% ethyl acetate / petroleum ether gradient @30 mL / min). The residue was purified by prep-HPLC (column: Boston Green ODS 150*30 mm*5 μm; mobile phase: [water (FA)-ACN]; B%: 45%-75%, 7 min). The residue was purified by prep-HPLC (column: Boston Green ODS 150*30mm*5μm; mobile phase: [water (FA)-ACN]; B%: 40%~70%, 7min). Compound 111 (110mg, 204.45μmol, yield 53.19%) was obtained. LCMS (M+H)=520.0.

[0435] Compound 111 (110 mg, 211 μmol) was separated by SFC (column: DAICEL CHIRALCEL OD-H (250 mm*30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=75:25; flow rate: 70 mL / min) and concentrated under vacuum to give two fractions.

[0436] Example 111a: (20.99 mg, 19.08% yield) was obtained. LCMS (M+H) = 520.0. SFC: retention time: 2.646 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ8.54(d,J=2.3Hz,1H),8.35(d,J=4.8Hz,1H),7.73-7.58(m,3H),7.4 0-7.20(m,4H),6.43-6.22(m,1H),3.98-3.79(m,3H),3.32-3.25(m,2H),1.91(s,3H),1.67(br s,2H),1.59-1.42(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-24.97(s,2F),-141.43(s,1F).

[0437] Example 111b: (36.34 mg, 32.19% yield) was obtained. LCMS (M+H) = 520.0. SFC: retention time: 3.482 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ8.54(s,1H),8.31(d,J=4.6Hz,1H),7.67(brdd,J=7.9 ,16.6Hz,2H),7.56-7.42(m,2H),7.30-7.15(m,3H),6.44-6.22(m,1H),3.85(br d,J=4.9Hz,3H),3.31-3.21(m,2H),2.03(s,3H),1.66(br s,2H),1.58-1.39(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-24.95(s,2F),-141.76(br s,1F).

[0438] Example 112a and Example 112b

[0439]

change

[0440] To a solution of compound 112-2 (2.52 g, 8.960 mmol) in CF3CH2OH (18 mL) was added (2R)-2-chloro-2-fluoroacetic acid (2.42 g, 10.752 mmol) and 1,1-difluoro-4-isocyanocyclohexane (1.30 g, 8.960 mmol). The mixture was stirred at 20 °C under N2 atmosphere for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (0-60% EA / PE ether gradient @40 mL / min) to give the product. The residue was purified by prep-HPLC (Xtimate C18 150*40 mm*10 μm; mobile phase: A: water (FA) B: ACN; gradient condition: 45% B to 75% B; flow rate: 60 mL / min) to give compound 112 (1.3 g, 26. Yield 92%). LCMS(M+H)=539.1. 1 H NMR(400MHz,DMSO-d6):δ9.10-8.97(m,1H),8.89-8.71(m,2H),7.87-7.63(m,2H),7.62-7.21(m,3H),6.52-6.13(m,1H),3.89(br s,1H),2.12-1.43(m,11H).

[0441] Compound 112 (143.5 mg, 0.27 mmol) was separated by SFC (DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm), mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic: A:B=90:10; flow rate: 100 mL / min)) to obtain two fractions.

[0442] Example 112a: (43 mg, yield 38.23%) was obtained. LCMS (M+H) = 539.1. SFC: retention time: 2.182 minutes, OD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.11-8.96 (m, 1H), 8.88-8.73 (m, 2H), 7.88-7.66 (m, 2H), 7.64-7.39 (m, 2H), 7.34-7.20 (m, 1H), 6.58-6.20 (m, 1H), 3.89 (brs, 1H), 2.11-1.88 (m, 4H), 1.82 (brs, 4H), 1.68 (brs, 1H), 1.65-1.47 (m, 2H). 19 F NMR (376MHz, DMSO-d6): δ-56.95(Brd,J=80.5Hz,3F), -91.87(Brdd,J=16.6,233.0Hz,1F), -99.38(Brd,J=237.2Hz,1F), -142.12(brs,1F).

[0443] Example 112b: (48 mg, yield 41.43%) was obtained. LCMS (M+H) = 539.1. SFC: retention time: 2.498 minutes, OD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR (400MHz, DMSO-d6): δ9.07-8.96(m,1H),8.89-8.74(m,2H),7.78-7.49(m,3H),7.48-7.36(m,2H),6.46-6.14(m,1H),3.87(br s,1H),2.11-1.95(m,3H),1.89(s,2H),1.86-1.71(m,4H),1.68-1.45(m,2H). 19 F NMR (376MHz, DMSO-d6): δ-56.98(d,J=25.0Hz,3F),-89.39--93.15(m,1F),-97.38--101.99(m,1F),-141.94(d,J=49.9Hz,1F).

[0444] Example 113a and Example 113b

[0445]

change

[0446] To a solution of compound 113-2 (200 mg, 0.721 mmol) in 2,2,2-trifluoroethanol (3 mL), (2R)-2-chloro-2-fluoroacetic acid (162.29 mg, 0.866 mmol) and 1,1-difluoro-4-isocyanocyclohexane (104.71 mg, 0.721 mmol) were added. The mixture was stirred at 25° C. for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography and further purified by prep-HPLC (Xtimate C18 150*40 mm*10 μm; mobile phase: A: water (FA) B: ACN; gradient condition: 45% B to 75% B; flow rate: 60 mL / min) to give compound 113 (100 mg).

[0447] Compound 113 (100 mg, 0.187 mmol) was separated into two fractions by supercritical fluid chromatography (separation conditions: DAICEL CHIRALCEL OD (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-IPA, A:B=85:15 at 100 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; trimmer temperature: 25 °C; wavelength: 220 nm). Pure fractions were collected and further purified by prep-HPLC to give the title compound.

[0448] Obtained Example 113a: (7.24 mg, 7.24%). LCMS (M+H) = 535.1. SFC: Retention time: 2.322 min, OD_3_IPA_DEA_5_40_25ML_6MIN.1 H NMR(400MHz,DMSO-d6)δ9.20(d,J=2.0Hz,1H),8.82(s,1H),8.79(s,1H),7.24-7.14(m,2H),7.09-7.04 (m,1H),6.13-5.95(m,1H),4.06-3.85(m,1H),2.14-2.04(m,4H),1.97-1.80(m,2H),1.59-1.50(m,5H). Obtained Example 113b: (5.80 mg, 0.011 mmol, 5.80%). LCMS (M+H) = 534.9. SFC: Retention time: 2.765 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1 H NMR(400MHz,DMSO-d6)δ9.05(s,1H),8.88-8.82(m,2H),7.64-7.57(m,1H),7.48-7.40(m,2H), 6.48-6.29(m,1H),3.89-3.81(m,1H),2.06-1.89(m,6H),1.78-1.74(m,3H),1.63-1.52(m,2H).

[0449] Examples 114a and 114b

[0450] [ka] A mixture of formic acid (8.3 mL, 217.297 mmol) and acetic anhydride (18.9 mL, 201.237 mmol) was stirred at 55° C. for 2 h. The mixture was used in the next step without further purification. To a solution of 114-1 (2 g, 13.108 mmol) in THF (20 mL), the above formic acid·acetic anhydride (11.54 g, 131.079 mmol) was added and the reaction was stirred at 20° C. for 20 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give compound 114-2 (608 mg, 1.683 mmol, 12.84% yield).

[0451] To a solution of 114-2 (600 mg, 3.322 mmol) in DCM (10 mL) was added TEA (2.8 mL, 20.144 mmol). The mixture was degassed and purged with N2 three times. POCl3 (0.4 mL, 4.305 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent of 0-50% ethyl acetate / petroleum ether gradient @ 30 mL / min). Compound 114-3 (311 mg, 1.913 mmol, 57.58% yield) was obtained.

[0452] To a solution of 4-1 (370 mg, 1.32 mmol) and 114-3 (214 mg, 1.32 mmol) in CF3CH2OH (3 mL) was added (2R)-2-chloro-2-fluoroacetic acid (296 mg, 1.58 mmol). The mixture was stirred at 20 °C under N2 atmosphere for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash silica gel chromatography and further purified by prep-HPLC to give compound 114 (38 mg, 4.3% yield).

[0453] Compound 114 (38 mg, 0.068 mmol) was separated by chiral SFC (Phenomenex-Cellulose-2 (250 mm*30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B=70:30; flow rate: 150 mL / min), concentrated under vacuum, and lyophilized to give two fractions.

[0454] Obtained Example 114a: (14 mg, 0.024 mmol, 33.84%). LCMS (M+H) = 556.1. SFC: Retention time: 3.470 min, C2_EtOH_DEA_5_40_25 ML. 1 H NMR(400MHz,DMSO-d6)δ9.94(s,1H),9.16(s,1H),8.89(s,2H),8.18(s,1H),8.03-7.65(m,3H),7.61-7.21(m,3H),6.60-6.19(m,1H),1.87(s,3H). 19F NMR(376MHz,DMSO-d6):δ-56.92(br d,J=27.7Hz,3F),-142.12(br s,1F).

[0455] Example 114b: (15 mg, 0.027 mmol, 36.88%) was obtained. LCMS(M+H)=556.1.SFC: Retention time: 4.984 min, C2_EtOH_DEA_5_40_25ML. 1 H NMR(400MHz,DMSO-d6)δ9.98(s,1H),9.18(s,1H),8.91(s,2H),8.20(s,1H),8.07-7.86(m,2H),7.82- 7.70(m,1H),7.62-7.49(m,1H),7.48-7.37(m,1H),7.36-7.23(m,1H),6.62-6.37(m,1H),1.77(s,3H). 19 F NMR(376MHz,DMSO-d6):δ-52.61--58.57(m,3F),-139.36--144.28(m,1F).

[0456] Examples 115a and 115b

[0457] [ka] The following compounds were prepared following procedures similar to those described for Examples 94a and 94b.

[0458] Obtained Example 115a: (112.20 mg, 43% yield). LCMS (M+H) = 537.1. SFC: Retention time: 2.600 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1 HNMR(400MHz,DMSO-d6):δ9.03(s,1H),8.81(s,2H),7.84-7.65(m,2H),7.53-7.31(m,3H),6 .10(s,1H),3.85(d,J=1.2Hz,3H),3.32-3.31(m,1H),3.31-3.26(m,1H),1.85-1.38(m,7H). 19F NMR (376MHz, DMSO-d6): δ-25.05 (s, 2F).

[0459] Example 115b: (110.28 mg, yield 42.29%) was obtained. LCMS (M+H) = 537.1. SFC: retention time: 3.000 minutes, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1HNMR (400MHz, DMSO-d6): δ9.03(s,1H),8.81(s,2H),7.80-7.70(m,2H),7.44(d,J=8.2Hz,2H),7.40-7.3 3(m,1H),6.10(s,1H),3.94-3.78(m,3H),3.33-3.32(m,1H),3.30(s,1H),1.79(s,3H),1.75-1.41(m,4H). 19 F NMR (376MHz, DMSO-d6): δ-25.05 (s, 2F).

[0460] Example A: in vitro SARS-CoV-2 M pro Enzyme アッセイ) C-His6 tagged SARS-CoV-2 MPRO (NC_045512) was cloned, expressed in E. coli and purified by WuXi. Substrate Dabcyl-KTSAVLQ||SGFRKME-(Edans) was synthesized by Genscript. Assay buffer contained 20 mM Tris-HCl (pH=7.3), 100 mM NaCl, 1 mM EDTA, 5 mM TCEP and 0.1% BSA. In MPRO enzyme assay, final concentrations of Mpro protein and substrate were 25 nM and 25 μM, respectively. Control compound GC376 was provided by WuXi AppTec and included in each plate to confirm assay robustness. Test compounds were tested in duplicate at a single dose or at a titration of 10 doses. Compounds were added in replicate wells using ECHO to the assay plate (384w format). The final concentration is 10 μM for single dose experiments. For all dose response experiments, samples were serially diluted 3-fold starting at 25 μM across 10 doses and added in duplicate wells to the assay plate. The final concentrations (μM) of each compound were 25, 8.33, 2.778, 0.926, 0.309, 0.103, 0.034, 0.011, 0.0038, and 0.0013. MPRO protein (25 μL, 30 nM) was added to the assay plate containing the test compound using a Multidrop. The test compound and MPRO protein were pre-incubated at room temperature for 30 minutes. Then, substrate (5 μL, 150 μM) was added to the assay plate. For 100% inhibition control (HPE, high percent effect), 1 μM of GC376 was added. For no inhibition control (ZPE, zero percent effect), the same volume of DMSO was added. The final DMSO concentration was 1%. Each activity test point had an associated background control containing no enzyme to eliminate the fluorescence interference of the compounds. After incubation at 30°C for 60 min, the activity was measured using a microplate reader M2e (SpectraMax). Ex / Em=340nm / 490nm The fluorescent signal (RFU) was detected.

[0461] The inhibitory activity was calculated using the following formula, and the % inhibition data was used to calculate IC50 values. Inhibition %=((CPD-BGHPE)-(ZPE-BGZPE)) / ((HPE-BGHPE)-(ZPE-BGZPE))×100 where HPE is the high percent effect control (1 μM GC376+enzyme+substrate), ZPE is the zero percent effect control (enzyme+substrate, no compound), CPD is the compound activity test well (compound+enzyme+substrate), and BG is the background control well (no enzyme).

[0462] Compound IC50 values ​​were calculated using a nonlinear regression model of log(inhibitor) vs. response-variable slope (four parameters) in GraphPad Prism software. Representative biochemical data are shown in Table 2.

[0463] [Table 2-1] [Table 2-2]

[0464] Example B: In vitro antiviral cell-based assay (live SARS-CoV-2) CellTiter-Glo® Luminescent Assay to Determine the CC50 of Each Compound in Cell Culture: Multiple cell lines can be used depending on customer requirements. For each cell line, 4 × 104 cells / well in 96-well plates are incubated with individual compounds at seven concentrations (depending on their water solubility, and using 2-fold dilutions) in triplicates for 24, 48, and 72 h, respectively. This is followed by the addition of substrate for cell viability and luminance detection after 10 min. The 50% cytotoxic concentration (CC50) of antiviral agents is calculated by SigmaPlot (Systat Software Inc., San Jose, CA, USA) in Excel add-in ED50V10.

[0465] SARS-CoV-2 Viral Load Reduction Assay: Multiple cell lines can be used according to customer requirements. Also, different variants of interest (e.g., alpha, gamma, kappa, and delta, etc.) can be included according to customer requirements. For each cell line, cells are infected with 0.1 MOI SARS-CoV-2 for 1 h. The infectious inoculum is then replaced with serially diluted (seven concentrations) drug-containing medium. Culture supernatants of SARS-CoV-2-infected cells are harvested 48 hours post inoculation (hpi) for qRT-PCR analysis of viral RNA load. A total of 140 μL of culture supernatant is lysed in 560 μL AVL buffer, followed by total RNA extraction using the QIAamp viral RNA mini kit (Qiagen, Hilden, Germany). For quantification of SARS-CoV-2 replication, qRT-PCR will be used, using the QuantiNova Probe RT-PCR kit (Qiagen) with the LightCycler 480 Real-Time PCR System (Roche). Each 20 μL reaction mixture contains 10 μL of 2x QuantiNova Probe RT-PCR Master Mix, 1.2 μL of RNase-free water, 0.2 μL of QuantiNova Probe RT-Mix, 1.6 μL each of 10 μM forward and reverse primers, 0.4 μL of 10 μM probe, and 5 μL of extracted RNA as template. Reactions are incubated at 45 °C for 10 min for reverse transcription and 95 °C for 5 min for denaturation, followed by 45 cycles of 95 °C for 5 s and 55 °C for 30 s. Signal detection and measurement are performed in each cycle after the annealing step. The cycling profile is terminated with a cooling step at 40 °C for 30 s. The primer and probe sequences are directed to the RNA-dependent RNA polymerase / helicase (RdRP / Hel) gene region of SARS-CoV-2, the forward primer is 5'-CGCATACAGTCTTRCAGGCT-3', the reverse primer is 5'-GTGTGATGTTGAWATGACATGGTC-3', and the specific probe is 5'-FAM TTAAGATGTGGTGCTTGCATACGTAGAC-IABkFQ-3'.

[0466] Plaque reduction assay Different variants of interest of SARS-CoV-2 (e.g., alpha, gamma, delta, and kappa) can be included according to customer requirements. VeroE6 cells are seeded at 2 × 105 cells / well in 24-well tissue culture plates the day before performing the assay. After 24 h of incubation, 50 plaque-forming units (PFU) of SARS-CoV-2 are added to the cell monolayer and the plate is further incubated for 1 h at 37 °C in 5% CO2, after which unbound viral particles are removed by aspirating the medium and washing once with DMEM. The monolayer is then covered with medium containing 1.5% low melting point agarose (CAMBREX Corporation, East Rutherford, NJ, USA) in DMEM and appropriate concentrations of individual compounds (five concentrations), inverted, and incubated for another 72 h as above. The wells are then fixed overnight with 10% formaldehyde (BDH, Merck, Darmstadt, Germany). After removing the agarose plugs, the monolayers are stained with 0.7% crystal violet (BDH, Merck) and the plaques are counted. The percentage of plaque inhibition relative to control (i.e., no compound added) wells is determined for each antiviral concentration. EC50 was calculated using sigma plot (SPSS) in Excel add-in ED50V10. Plaque reduction assay experiments are performed in triplicate.

[0467] [Table 3]

Claims

1. Formula (I) 【Chemical 1】 or a pharmaceutically acceptable salt or stereoisomer thereof, During the ceremony, R １ is a halogen, R ２ is a halogen, Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ３ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -SF ５ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ３ａ is replaced by Or two R on the same atom ３ together to form an oxo R ３ａ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom ３ａ together to form an oxo n is 0 to 4; L is - (CR ４ R ４ ) ｐ - and R ４ are each independently hydrogen, halogen, or C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, Or two R on the same carbon ４ are combined together to form one or more R ４ａ forming a cycloalkyl or heterocycloalkyl optionally substituted with R ４ａ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , -NR ｃ R ｄ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, p is 0 to 4; R ５ is deuterium, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; Ring B is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; R ６ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ６ａ is replaced by Or two R on the same atom ６ together to form an oxo R ６ａ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom ６ａ together to form an oxo m is 0 to 4; R ７ is hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ heteroalkyl, cycloalkyl, or heterocycloalkyl; R ８ is C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene (heteroaryl), where alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are optionally independently selected from one or more R ８ａ is replaced by R ８ａ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom ８ａ together to form an oxo Or R ７ and R ８ together and optionally independently one or more R ７ａ forming a heterocycloalkyl substituted with R ７ａ are each independently a halogen, —CN, or —NO ２ , —OH, —OR ａ , —OC(═O)R ａ , -OC(=O)OR ｂ , -OC(=O)NR ｃ R ｄ , -SH, -SR ａ , -S(=O)R ａ , -S(=O) ２ R ａ , -S(=O) ２ NR ｃ R ｄ , -NR ｃ R ｄ , -NR ｂ C(=O)NR ｃ R ｄ , -NR ｂ C(=O)R ａ , -NR ｂ C(=O)OR ｂ , -NR ｂ S (= O) ２ R ａ , -C(=O)R ａ , -C(=O)OR ｂ , —C(═O)NR ｃ R ｄ , C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; Or two R on the same atom ７ａ together to form an oxo R ａ are each independently C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R ｂ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; R ｃ and R ｄ are each independently hydrogen, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ Aminoalkyl, C １ -C ６ Heteroalkyl, C ２ -C ６ Alkenyl, C ２ -C ６ Alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C １ -C ６ Alkylene (cycloalkyl), C １ -C ６ Alkylene (heterocycloalkyl), C １ -C ６ Alkylene (aryl), or C １ -C ６ alkylene(heteroaryl), wherein alkyl, alkylene, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are each independently optionally substituted with one or more R; Or R ｃ and R ｄ together with the atom to which they are attached form a heterocycloalkyl optionally substituted with one or more R; and R is independently a halogen, —CN, —OH, or —OC １ -C ６ Alkyl, —S(═O)C １ -C ６ Alkyl, —S(═O) ２ C １ -C ６ Alkyl, —S(═O) ２ NH ２ , -S(=O) ２ NHC １ -C ６ Alkyl, —S(═O) ２ N (C １ -C ６ alkyl) ２ , -NH ２ , -NHC １ -C ６ Alkyl, —N(C １ -C ６ alkyl) ２ , -NHC(=O)OC １ -C ６ Alkyl, —C(═O)C １ -C ６ Alkyl, —C(═O)OH, —C(═O)OC １ -C ６ Alkyl, —C(═O)NH ２ , -C(=O)N(C １ -C ６ alkyl) ２ , -C(=O)NHC １ -C ６ Alkyl, C １ -C ６ Alkyl, C １ -C ６ Haloalkyl, C １ -C ６ Hydroxyalkyl, C １ -C ６ aminoalkyl, or C １ -C ６ is heteroalkyl, or two R on the same atom together form oxo; The compound, or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, is represented by formula (Ia): 【Chemistry 2】 It is of During the ceremony, Ring C is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, and q is 0 to 4; 10. The compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring C is cycloalkyl or heterocycloalkyl.

4. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is fluoro and R 2 is chloro.

5. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is phenyl.

6. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 or 2, and R 3 is each independently halogen, -CN, -OR a , -SR a , -SF 5 , -S(═O) 2 R a , C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, cycloalkyl, or heteroaryl, wherein the alkyl, cycloalkyl, and heteroaryl are optionally independently substituted with one or more R 3a .

7. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0.

8. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is deuterium or C 1 -C 6 alkyl.

9. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is methyl.

10. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is a 6-membered heteroaryl.

11. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0.

12. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 1 and R 6 is halogen or C 1 -C 6 alkyl.

13. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is hydrogen or C 1 -C 6 alkyl.

14. The compound of claim 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is hydrogen.

15. The compound of claim 2, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is 0, 1, or 2, and each R 8a is independently halogen, —OH, —OR a , C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

16. The following 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof.

17. The following 【Table 2】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt or stereoisomer thereof.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

19. Use of a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt or stereoisomer thereof, in the manufacture of a medicament for treating a coronavirus infection.

20. Use of the pharmaceutical composition of claim 18 in the manufacture of a medicament for treating coronavirus infection.

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