SARS-cov-2 inhibitors for treating coronavirus infections

Abstract

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

Description

[Previous Technology]

[0001] SARS-CoV-2 (also known as 2019-nCoV or COVID-19) first appeared in 2019. Symptoms associated with the disease include fever, myalgia, cough, dyspnea, and fatigue (Huang et al., 2020). Currently, there is no treatment available for SARS-CoV-2. However, treatment with well-known drugs such as chloroquine or experimental drugs such as remdesivir has been suggested (Colson et al., 2020; Wang et al., 2020). A mixture of the human immunodeficiency virus (HIV) drugs lopinavir / ritonavir has also been investigated as a treatment for SARS-CoV-2 because it has shown anticoronavirus effects in vitro (Que et al., 2003; Chu et al., 2004; Chan et al., 2015; Li and De Clercq, 2020).

[0002] SARS-CoV-2 is a β-coronavirus and a member of the Coronaviridae family, which contains the largest positive-sense single-stranded RNA viruses (Cui et al., 2019). This virus contains four non-structural proteins: papain-like (PL pro) and chymotrypsin-like (3CL pro) proteases, RNA polymerase, and helicase (Zumla et al., 2016). Both proteases (PL pro and 3CL pro) are involved in viral transcription and replication. Of these four types, 3CL pro is considered to be primarily involved in viral replication (de Wit et al., 2016). During coronavirus replication, 3CL pro hydrolyzes the viral polymerases pp1a and pp1ab to produce functional proteins. Studies have reported that the SARS-CoV-2 cysteine ​​protease 3CL pro shows 96% sequence similarity to the SARS-CoV cysteine ​​protease 3CL pro (Xu et al., 2020). Due to its highly conserved sequence and basic functional characteristics, 3CL pro has been validated as a potential target for developing drugs to treat SARS-CoV-2.

[0003] As feasible treatments remain elusive, there is a need for compounds and / or methods for inhibiting SARS-CoV-2 and for treating individuals infected with SARS-CoV-2. [Summary of the Invention]

[0004] This document discloses a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: Formula (I), wherein: R1 is a halogen; R2 is a halogen; ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3 is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)OR b. -C(=O)NR cR d. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, depending on the case, independently substituted by one or more R3a; or two R3s on the same atom together form a side oxygen group; each R3a is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NR cR d. -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R 3a on the same atom together form a side oxygen group; n is 0 to 4; L is -(CR 4R 4) p-; each R 4 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C 6-hydroxyalkyl, C1-C6 aminealkyl or C1-C6 heteroalkyl; or two R4s on the same carbon together to form a cycloalkyl or heterocycloalkyl, each of which is substituted by one or more R4a as appropriate;Each R 4a is independently a halogen, -CN, -NO 2, -OH, -OR a, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR 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; each R 6 is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b、-OC(=O)NR cR d、-SH、-SR a、-S(=O)R a、-S(=O) 2R a、-S(=O) 2NR cR d、-NR cR d、-NR bC(=O)NR cR d、-NR bC(=O)R a、-NR bC(=O)OR b、-NR bS(=O) 2R a、-C(=O)R a、-C(=O)OR b、-C(=O)NR cR d、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C 6. Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is, as appropriate, and independently substituted by one or more R 6a; or two R 6a on the same atom together form a side oxygen group; each R 6a is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R6a on the same atom together form a side oxygen group; m is 0 to 4;R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are, as appropriate, independently substituted by one or more R8a; each R 8a is independently a halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 6. Acynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 8a on the same atom together forming a side oxygen group; or R 7 and R 8 together forming a heterocycloalkyl group, which is, as appropriate, independently substituted by one or more R 7a; each R 7a is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R 7a on the same atom together forming a side oxygen group;Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more Rs as appropriate; each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkylene (cycloalkyl), C2-C6 alkylene (heteroaryl), C2-C6 alkylene (cycloalkyl), C1-C6 alkylene (heteroalkyl), C2-C6 alkylene (cycloalkyl), C1 ... 6-Alkenyl, C2-C6yneyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylyl (cycloalkyl), C1-C6 alkylyl (heterocycloalkyl), C1-C6 alkylyl (aryl), or C1-C6 alkylyl (heteroaryl); wherein each alkyl, alkylyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted by one or more R, as appropriate; each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylyl (cycloalkyl), C1-C6 alkylyl (heterocycloalkyl), C 1-C 6-alkyl (aryl) or C 1-C 6-alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted by one or more Rs as appropriate; or Rc and Rd together with the atoms they are attached to form a heterocycloalkyl group substituted by one or more Rs as appropriate; and each R is independently a halogen, -CN, -OH, -OC 1-C 6 alkyl, -S(=O)C 1-C 6 alkyl, -S(=O) 2C 1-C 6 alkyl, -S(=O) 2NH 2, -S(=O) 2NHC 1-C 6 alkyl, -S(=O) 2N(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)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;Or two R atoms on the same atom can together form a side oxygen group.

[0005] This article also discloses a pharmaceutical composition comprising a therapeutically effective amount of the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient.

[0006] This article also discloses a method for treating or preventing coronavirus infection in a patient in need, comprising administering to the patient a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0007] This article also discloses a method for treating or preventing SARS-CoV-2 infection in a patient in need, comprising administering to the patient a compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, or a pharmaceutical composition disclosed herein.

[0008] In some embodiments, the compound or the pharmaceutical composition is administered to a patient until the infection is reduced or eliminated. In some embodiments, the method includes treating one or more symptoms of SARS-CoV-2 in patients in need.

[0009] This article also discloses an in vivo method for inhibiting a protease of SARS-CoV-2, which involves contacting the protease with the compound disclosed herein or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

[0010] In some embodiments, the compound binds to a cysteine ​​residue of the protease. In some embodiments, the compound binds to a cysteine ​​residue reversibly or irreversibly. In some embodiments, the compound binds to a cysteine ​​residue irreversibly. In some embodiments, the compound covalently binds to a 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.

[0011] This article also discloses a modified SARS-CoV-2 MPRO protein, which includes the SARS-CoV-2 MPRO protein and the compound disclosed herein that is covalently bound to the SARS-CoV-2 MPRO protein.

Implementation Method

[0012] Cross-reference

[0013] This patent application claims the benefits of International Application No. PCT / CN2021 / 128243, filed November 2, 2021, and International Application No. PCT / CN2022 / 117034, filed September 5, 2022, which are incorporated herein by reference in their entirety.

[0014] All publications, patents, and patent applications mentioned in this specification are incorporated herein by reference to the same extent that each individual publication, patent, or patent application was specifically and individually instructed to be incorporated by reference. Definitions

[0015] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments. However, those skilled in the art will understand that the invention may be practiced without using these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessary obscurity in the description of the embodiments. Unless the context otherwise requires, throughout this specification and in the claims below, the term "comprise" and its variations (such as "comprises" and "comprising") shall be considered to have an open-ended inclusive meaning, that is, "including but not limited to". In addition, the headings provided herein are for convenience only and do not constitute an explanation of the scope or meaning of the claimed disclosures.

[0016] Throughout this specification, the references to "some embodiments" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment. Therefore, the phrases "in one embodiment" or "in one embodiment" appearing in different places throughout this specification do not necessarily refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any suitable manner in one or more embodiments. In addition, unless the context clearly indicates otherwise, as used in this specification and the appended claims, the singular forms "a / an" and "the" include a plural of indicators. It should also be noted that unless the context clearly indicates otherwise, the term "or" is generally used to include the meaning of "and / or".

[0017] Unless otherwise indicated, the following terms have the following meanings as used herein:

[0018] "Side group" refers to =O.

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

[0020] "Cyano" refers to -CN.

[0021] "alkyl" refers to a straight-chain or branched saturated hydrocarbon single radical having one to ten carbon atoms, more preferably one to six 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, secondary butyl, tertiary butyl, n-pentyl, isopentyl, neopentyl, tertiary pentyl and hexyl, as well as longer alkyl groups, such as heptyl, octyl and similar groups. Whenever it appears herein, numerical ranges such as "C1-C6 alkyl" or "C1-6 alkyl" mean that an alkyl group can consist of 1, 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "alkyl" where no numerical range is specified. In some embodiments, the alkyl group is C1-10 alkyl. In some embodiments, the alkyl group is C1-6 alkyl. In some embodiments, the alkyl group is C1-5 alkyl. In some embodiments, the alkyl group is C1-4 alkyl. In some embodiments, the alkyl group is C1-3 alkyl. Unless otherwise specifically stated in this specification, the alkyl group may be substituted as appropriate with, for example, a syl group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and similar groups. In some embodiments, the alkyl group may be substituted as appropriate with a syl group, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl group is substituted with a halogen, -CN, -OH, or -OMe, depending on the specific embodiment. In some embodiments, the alkyl group is substituted with a halogen, depending on the specific embodiment.

[0022] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. The group may be configured in cis or trans around the double bond, and should be understood to include both isomers. Examples include, but are not limited to, vinyl (-CH=CH 2), 1-propenyl (-CH 2CH=CH 2), isopropenyl [-C(CH 3)=CH 2], butenyl, 1,3-butadienyl and similar groups. Whenever it appears herein, numerical ranges such as “C 2-C 6 alkenyl” or “C 2-6 alkenyl” mean that the alkenyl may consist of 2, 3, 4, 5 or 6 carbon atoms, but the definition of this invention also covers the presence of the term “alkenyl” where no numerical range is specified. Unless otherwise specifically stated in this specification, the alkenyl group may be substituted, as appropriate, with groups such as oxy, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the alkenyl group may be substituted, as appropriate, with oxy, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, the alkenyl group may be substituted, as appropriate, with halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl group may be substituted, as appropriate, with halogen.

[0023] "Alynyl" refers to a straight-chain or branched hydrocarbon single radical having one or more carbon-carbon triple bonds and having two to ten carbon atoms, more preferably two to six carbon atoms. Examples include, but are not limited to, acetylenyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and similar groups. Whenever it appears herein, numerical ranges such as "C 2-C 6 ynyl" or "C 2-6 ynyl" mean that the ynyl group can consist of 2, 3, 4, 5, or 6 carbon atoms, but the definition of this invention also covers the presence of the term "ynyl" where no numerical range is specified. Unless otherwise specifically stated in this specification, the ynyl group may be substituted as appropriate with, for example, a side oxygen group, halogen, amino group, nitrile, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxyl group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group and similar groups. In some embodiments, the alkynyl group is substituted with a side oxygen, halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂, depending on the situation. In some embodiments, the alkynyl group is substituted with a halogen, -CN, -OH, or -OMe, depending on the situation. In some embodiments, the alkynyl group is substituted with a halogen, depending on the situation.

[0024] "Alkyl" refers to a straight-chain or branched divalent hydrocarbon chain. Unless otherwise specifically stated in this specification, alkyl groups may be substituted as appropriate with, for example, oxy groups, halogens, amino groups, nitriles, hydroxyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and similar groups. In some embodiments, alkyl groups may be substituted as appropriate with oxy groups, halogens, -CN, -COOH, COOMe, -OH, -OMe, -NH₂, or -NO₂. In some embodiments, alkyl groups may be substituted as appropriate with halogens, -CN, -OH, or -OMe. In some embodiments, alkyl groups may be substituted as appropriate with halogens.

[0025] "Alkoxy" refers to a free radical of the formula -ORa, wherein Ra is an alkyl group as defined. Unless otherwise specifically stated in this specification, an alkoxy group may be substituted as appropriate with, for example, a side oxygen group, halogen, amino group, nitrile group, nitro group, hydroxyl group, haloalkyl group, alkoxy group, carboxyl group, carboxylate group, aryl group, cycloalkyl group, heterocycloalkyl group, heteroaryl group, and similar groups. In some embodiments, an alkoxy group may be substituted as appropriate with a halogen, -CN, -COOH, COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, an alkoxy group may be substituted as appropriate with a halogen, -CN, -OH, or -OMe. In some embodiments, an alkoxy group may be substituted as appropriate with a halogen.

[0026] "Aryl" refers to a free radical derived from a hydrocarbon ring system, comprising 6 to 30 carbon atoms and at least one aromatic ring. Aryl groups can be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, and can include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the aryl group is bonded via aromatic ring atoms) or bridged ring systems. In some embodiments, the aryl group is a 6- to 10-membered aryl group. In some embodiments, the aryl group is a 6-membered aryl (phenyl). Aryl groups include, but are not limited to, aryl groups derived from the following hydrocarbon ring systems: anthracene, anthracene, anthracene, anthracene, benzene, propylene, arsenyl, arsenyl, α-dicyclopentadienylbenzene, α-dicyclopentadienylbenzene, indane, indene, naphthalene, phenanthrene, pleiadene, pyrene, and terphenyl. Unless otherwise specified in this specification, the aryl group may be substituted as appropriate with, for example, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, the aryl group may be substituted as appropriate with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl group may be substituted as appropriate with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl group may be substituted as appropriate with halogen.

[0027] "Cycloalkyl" refers to a partially or fully saturated monocyclic or polycyclic carbon ring, which may include fused (when fused with an aryl or heteroaryl ring, the cycloalkyl is bonded via non-aromatic ring atoms), helical, or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyl groups include, but are not limited to, cycloalkyl groups having three to fifteen carbon atoms (C3-C15 fully saturated cycloalkyl groups or C3-C15 cycloalkenyl groups), three to ten carbon atoms (C3-C10 fully saturated cycloalkyl groups or C3-C10 cycloalkenyl groups), three to eight carbon atoms (C3-C8 fully saturated cycloalkyl groups or C3-C8 cycloalkenyl groups), three to six carbon atoms (C3-C6 fully saturated cycloalkyl groups or C3-C6 cycloalkenyl groups), three to five carbon atoms (C3-C5 fully saturated cycloalkyl groups or C3-C5 cycloalkenyl groups), or three to four carbon atoms (C3-C4 fully saturated cycloalkyl groups or C3-C4 cycloalkenyl groups). In some embodiments, the cycloalkyl group is a 3- to 10-membered fully saturated cycloalkyl group or a 3- to 10-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 3- to 6-membered fully saturated cycloalkyl group or a 3- to 6-membered cycloalkenyl group. In some embodiments, the cycloalkyl group is a 5- to 6-membered fully saturated cycloalkyl group or a 5- to 6-membered cycloalkenyl group. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl groups include, for example, adamantyl, norbornyl, decahydronaphthyl, bicyclo[3.3.0]octane, bicyclo[4.3.0]nonane, cis-decahydronaphthyl, trans-decahydronaphthyl, bicyclo[2.1.1]hexane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.2]decane, and 7,7-dimethyl-bicyclo[2.2.1]heptyl. Partially saturated cycloalkyl groups include, for example, cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless otherwise specifically stated in this specification, cycloalkyl groups are substituted as such by, for example, oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and similar groups. In some embodiments, cycloalkyl groups are substituted as such by, oxy, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, cycloalkyl groups are substituted as such by, oxy, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, cycloalkyl groups are substituted as such by, halogen.

[0028] "Halogen" or "halogen" refers to bromine, chlorine, fluorine or iodine. In some embodiments, the halogen is fluorine or chlorine. In some embodiments, the halogen is fluorine.

[0029] "Halogenated alkyl" means an alkyl group as defined above that has been substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and similar groups.

[0030] "Hydroxyalkyl" means an alkyl group as defined above that is substituted with one or more hydroxyl groups. In some embodiments, the alkyl group is substituted with one hydroxyl group. In some embodiments, the alkyl group is substituted with one, two, or three hydroxyl groups. Hydroxyalkyl groups include, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl group is hydroxymethyl.

[0031] "Aminoalkyl" means an alkyl group as defined above that is substituted with one or more amines. In some embodiments, the alkyl group is substituted with one amine. In some embodiments, the alkyl group is substituted with one, two, or three amines. Aminoalkyl groups include, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl group is aminomethyl.

[0032] "Heteroalkyl" means an alkyl group in which one or more alkyl skeleton atoms are selected from atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof. The heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. In one state, the heteroalkyl group is a C1-C6 heteroalkyl group, wherein the heteroalkyl group consists of 1 to 6 carbon atoms and one or more atoms other than carbon, such as oxygen, nitrogen (e.g., -NH-, -N(alkyl)-), sulfur, phosphorus, or combinations thereof, wherein the heteroalkyl group is attached to the rest of the molecule at the carbon atom of the heteroalkyl group. Examples of such heteroalkyl groups are, for example, -CH₂OCH₃, -CH₂CH₂OCH₃, -CH₂CH₂OCH₂CH₂OCH₃, -CH(CH₃)OCH₃, -CH₂NHCH₃, -CH₂N(CH₃)₂, -CH₂CH₂NHCH₃, or -CH₂CH₂N(CH₃)₂. Unless otherwise specifically stated in this specification, heteroalkyl groups may be substituted as appropriate with, for example, oxy-groups, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy-groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and similar groups. In some embodiments, heteroalkyl groups may be substituted as appropriate with oxy-groups, halogens, methyl groups, ethyl groups, -CN groups, -CF₃ groups, -OH groups, -OMe groups, -NH₂ groups, or -NO₂ groups. In some embodiments, the heteroalkyl group is substituted with a side-oxygen group, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe, depending on the specific embodiment. In some embodiments, the heteroalkyl group is substituted with a halogen, depending on the specific embodiment.

[0033] "Heterocyclic alkyl" refers to a 3- to 24-membered partially or fully saturated cyclic group comprising 2 to 23 carbon atoms and one to eight heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, silicon, and sulfur. In some embodiments, the heterocyclic alkyl is fully saturated. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocyclic alkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocyclic alkyl comprises one to three nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one or two nitrogen atoms. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom. In some embodiments, the heterocyclic alkyl comprises one nitrogen atom and one oxygen atom. Unless otherwise specified in this specification, heterocyclic alkyl groups may be monocyclic, bicyclic, tricyclic, or tetracyclic ring systems, which may include fused (when fused with aryl or heteroaryl rings, the heterocyclic alkyl group is connected via non-aromatic ring atoms), helical, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocyclic alkyl group may be oxidized as appropriate; the nitrogen atom may be quaternized as appropriate. Representative heterocyclic alkyl groups include, but are not limited to, heterocyclic alkyl groups having two to fifteen carbon atoms (C2-C15 fully saturated heterocyclic alkyl groups or C2-C15 heterocyclic alkenyl groups), two to ten carbon atoms (C2-C10 fully saturated heterocyclic alkyl groups or C2-C10 heterocyclic alkenyl groups), two to eight carbon atoms (C2-C8 fully saturated heterocyclic alkyl groups or C2-C8 heterocyclic alkenyl groups), two to seven carbon atoms (C2-C7 fully saturated heterocyclic alkyl groups or C2-C7 heterocyclic alkenyl groups), two to six carbon atoms (C2-C6 fully saturated heterocyclic alkyl groups or C2-C6 heterocyclic alkenyl groups), two to five carbon atoms (C2-C5 fully saturated heterocyclic alkyl groups or C2-C5 heterocyclic alkenyl groups), or two to four carbon atoms (C2-C4 fully saturated heterocyclic alkyl groups or C2-C4 heterocyclic alkenyl groups). Examples of such heterocyclic alkyl groups include, but are not limited to, aziridinyl, aziridine, oxadiazinyl, dioxopentyl, thienyl[1,3]dithiaalkyl, decahydroisoquinolinyl, imidazolinyl, imidazodinyl, isothiazolinyl, isothiazodinyl, piriminyl, octahydroindolyl, octahydroisoindolyl, 2-side-oxypiperidinyl, 2-side-oxypiperidinyl, 2-side-oxypyrrolidinyl, piriminyl, piperidinyl, piperidinyl, 4-piperidinoneyl, pyrrolidinyl. Pyrazolidine, pyridyl, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperanyl, thiopyrolinyl, thiapyrolinyl, 1-sideoxy-thiopyrolinyl, 1,1-disideoxy-thiopyrolinyl, 1,3-dihydroisobenzofuran-1-yl, 3-sideoxy-1,3-dihydroisobenzofuran-1-yl, methyl-2-sideoxy-1,3-m-dioxacyclopenten-4-yl, and 2-sideoxy-1,3-m-dioxacyclopenten-4-yl. The term heterocyclic alkyl also includes all cyclic forms of carbohydrates, including but not limited to monosaccharides, disaccharides, and oligosaccharides.In some embodiments, the heterocyclic alkyl group has 2 to 10 carbon atoms in the ring. It should be understood that when referring to the number of carbon atoms in a heterocyclic alkyl group, the number of carbon atoms in the heterocyclic alkyl group is not the same as the total number of atoms constituting the heterocyclic alkyl group (i.e., the skeletal atoms of the heterocyclic alkyl ring), including heteroatoms. In some embodiments, the heterocyclic alkyl group is 3 to 8-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3 to 7-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3 to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 4 to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 5 to 6-membered heterocyclic alkyl. In some embodiments, the heterocyclic alkyl group is 3 to 8-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 3 to 7-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 3 to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 4 to 6-membered heterocyclic alkenyl. In some embodiments, the heterocyclic alkyl group is 5 to 6-membered heterocyclic alkenyl. Unless otherwise specifically stated in this specification, heterocyclic alkyl groups may be substituted as described below with, for example, oxy, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocyclic alkyl, heteroaryl, and similar groups. In some embodiments, the heterocyclic alkyl group may be substituted as described below with oxy, halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocyclic alkyl group may be substituted as described below with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocyclic alkyl group may be substituted as described below with halogen.

[0034] "Heteroaryl" refers to a 5- to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorus, and sulfur, and at least one aromatic ring. In some embodiments, a heteroaryl contains one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, a heteroaryl contains one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, a heteroaryl contains one to three nitrogen atoms. In some embodiments, a heteroaryl contains one or two nitrogen atoms. In some embodiments, a heteroaryl contains one nitrogen atom. A heteroaryl can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocyclic alkyl ring, the heteroaryl is linked via aromatic ring atoms) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl may be oxidized as appropriate; the nitrogen atom may be quaternarily ammonized as appropriate. In some embodiments, a heteroaryl is a 5- to 10-membered heteroaryl. In some embodiments, a heteroaryl is a 5- to 6-membered heteroaryl. In some embodiments, the heteroaryl group is a 6-membered heteroaryl group. In some embodiments, the heteroaryl group is a 5-membered heteroaryl group. Examples include, but are not limited to, azirrolyl, acridine, benzimidazolyl, benzothiazolyl, benzoindolyl, benzo-m-dioxacyclopentenyl, benzofuranyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[b][1,4]dioxanyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzo-m-dioxacyclopentenyl, benzo-m-dioxacyclohexenyl, benzopiperanyl, benzopiperanone, benzofuranyl, benzofuranone, benzothienyl (benzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridyl, carbazole, alkinyl, dibenzofuranyl, dibenzothienyl, furanyl, furanyl Keto, isothiazolyl, imidazolyl, indazole, indole, indazole, isoindole, indolinyl, isoindolinyl, isoquinolinyl, indoleyl, isoazolyl, acetyl, diazolyl, 2-side-oxy-azapyrrolyl, acezolyl, ethylene oxide, 1-oxo-pyridyl, 1-oxo-pyrimidinyl, 1-oxo-pyridyl, 1-oxo-pyridyl, 1-oxo-pyridyl, 1 -phenyl-1H-pyrrolyl, phenanthryl, phenanthrylthiayl, phenanthryl, phthalyl, pteridinyl, purine, pyrrolyl, pyrazolyl, pyridyl, pyridine, pyrimidinyl, pyridyl, quinazolinyl, quinolinyl, quinolinyl, pyridine, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triphenyl, and thiophenyl (i.e., thienyl). Unless otherwise specifically stated in this specification, heteroaryl groups may be substituted as appropriate with, for example, halogens, amino groups, nitriles, hydroxyl groups, alkyl groups, alkenyl groups, alkynyl groups, haloalkyl groups, alkoxy groups, carboxyl groups, carboxyl groups, aryl groups, cycloalkyl groups, heterocycloalkyl groups, heteroaryl groups, and similar groups.In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -COOH, COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl group is optionally substituted with halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl group is optionally substituted with halogen.

[0035] The terms "optional" or "optionally" mean that the event or situation described below may or may not occur, and the description includes both the occurrence and non-occurrence of such event or situation. For example, "optionally substituted alkyl" means "alkyl" or "substituted alkyl" as defined above. Furthermore, optionally substituted groups may be unsubstituted (e.g., -CH₂CH₃), fully substituted (e.g., -CF₂CF₃), monosubstituted (e.g., -CH₂CH₂F), or substituted to any degree between fully substituted and monosubstituted (e.g., -CH₂CHF₂, -CH₂CF₃, -CF₂CH₃, -CFHCHF₂, etc.). Those skilled in the art will understand that for any group containing one or more substituents, such groups are not intended to introduce any spatially impractical and / or synthetically infeasible substitution or substitution pattern. Therefore, any substituents described should generally be understood to have a maximum molecular weight of about 1,000 Daltons and more usually up to about 500 Daltons.

[0036] "Effective amount" or "therapeutic effective amount" means the amount of a compound administered to a mammalian individual as a single dose or as part of a series of doses, which effectively produces the desired therapeutic effect.

[0037] "Treatment" of an individual (e.g., a mammal, such as a human) or cell is any type of intervention intended to alter the natural course of a disease in an individual or cell. In some embodiments, treatment includes administering a pharmaceutical composition after triggering a pathological event or exposure to a pathogenic agent, and includes stabilizing symptoms (e.g., preventing symptoms from worsening) or alleviating symptoms. Compound

[0038] The present invention includes compounds and / or materials used as SARS-CoV-2 inhibitors and for treating individuals infected with SARS-CoV-2.

[0039] This document discloses a compound of formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: formula (I), wherein: R1 is a halogen; R2 is a halogen; ring A is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3 is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)OR b. -C(=O)NR cR d. C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, depending on the case, independently substituted by one or more R3a; or two R3s on the same atom together form a side oxygen group; each R3a is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NR cR d. -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R 3a on the same atom together form a side oxygen group; n is 0 to 4; L is -(CR 4R 4) p-; each R 4 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C 6-hydroxyalkyl, C1-C6 aminealkyl or C1-C6 heteroalkyl; or two R4s on the same carbon together to form a cycloalkyl or heterocycloalkyl, each of which is substituted by one or more R4a as appropriate;Each R 4a is independently a halogen, -CN, -NO 2, -OH, -OR a, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR 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; each R 6 is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b、-OC(=O)NR cR d、-SH、-SR a、-S(=O)R a、-S(=O) 2R a、-S(=O) 2NR cR d、-NR cR d、-NR bC(=O)NR cR d、-NR bC(=O)R a、-NR bC(=O)OR b、-NR bS(=O) 2R a、-C(=O)R a、-C(=O)OR b、-C(=O)NR cR d、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C 6. Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is, as appropriate, and independently substituted by one or more R 6a; or two R 6a on the same atom together form a side oxygen group; each R 6a is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R6a on the same atom together form a side oxygen group; m is 0 to 4;R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are, as appropriate, independently substituted by one or more R8a; each R 8a is independently a halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 6. Acynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 8a on the same atom together forming a side oxygen group; or R 7 and R 8 together forming a heterocycloalkyl group, which is, as appropriate, independently substituted by one or more R 7a; each R 7a is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R 7a on the same atom together forming a side oxygen group;Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more Rs as appropriate; each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkylene (cycloalkyl), C2-C6 alkylene (heteroaryl), C2-C6 alkylene (cycloalkyl), C1-C6 alkylene (heteroalkyl), C2-C6 alkylene (cycloalkyl), C1 ... 6-Alkenyl, C2-C6yneyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylyl (cycloalkyl), C1-C6 alkylyl (heterocycloalkyl), C1-C6 alkylyl (aryl), or C1-C6 alkylyl (heteroaryl); wherein each alkyl, alkylyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted by one or more R, as appropriate; each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylyl (cycloalkyl), C1-C6 alkylyl (heterocycloalkyl), C 1-C 6-alkyl (aryl) or C 1-C 6-alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted by one or more Rs as appropriate; or Rc and Rd together with the atoms they are attached to form a heterocycloalkyl group substituted by one or more Rs as appropriate; and each R is independently a halogen, -CN, -OH, -OC 1-C 6 alkyl, -S(=O)C 1-C 6 alkyl, -S(=O) 2C 1-C 6 alkyl, -S(=O) 2NH 2, -S(=O) 2NHC 1-C 6 alkyl, -S(=O) 2N(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)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;Or two R atoms on the same atom can together form a side oxygen group.

[0040] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate or stereoisomer is:

[0041] In some embodiments, the compound of formula (I) or its pharmaceutically acceptable salt, solvate or stereoisomer is:

[0042] In some embodiments of the compound of formula (I), R8 is a C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, as appropriate, independently substituted by one or more R8a. In some embodiments of the compound of formula (I), R8 is a C1-C6 alkylene (aryl); wherein the alkyl and aryl are, as appropriate, independently substituted by one or more R8a. In some embodiments of the compound of formula (I), R8 is a cycloalkyl or heterocycloalkyl; wherein the cycloalkyl and heterocycloalkyl are, as appropriate, independently substituted by one or more R8a. In some embodiments of the compound of formula (I), R8 is a cycloalkyl group, optionally and independently substituted with one or more R8a. In some embodiments of the compound of formula (I), R8 is a heterocyclic alkyl group, optionally and independently substituted with one or more R8a. In some embodiments of the compound of formula (I), R8 is a heterocyclic alkyl group containing one to two heteroatoms selected from O and N. In some embodiments of the compound of formula (I), R8 is a bridged bicyclic. In some embodiments of the compound of formula (I), R8 is a fused bicyclic. In some embodiments of the compound of formula (I), R8 is a monocyclic 6-membered cycloalkyl or heterocyclic alkyl group, each optionally substituted with one or more R8a.

[0043] In some embodiments of the compound of formula (I), R8 is, wherein the ring C is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and q is 0 to 4.

[0044] In some embodiments of the compound of formula (I), R8 is .

[0045] In some embodiments of the compound of formula (I), R8 is [missing information]. In some embodiments of the compound of formula (I), R8 is [missing information]. In some embodiments of the compound of formula (I), R8 is [missing information].

[0046] In some embodiments of the compound of formula (I), R7 together with R8 forms a heterocyclic alkyl group, which is substituted by one or more R7a as appropriate and independently.

[0047] In some embodiments of the compounds of formula (I), each R 7a is independently a halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of the compounds of formula (I), each R 7a is independently a halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, or C1-C6 haloalkyl.

[0048] In some embodiments of the compound of formula (I), the compound has formula (Ia): Formula (Ia); wherein: the ring C is cycloalkyl, heterocycloalkyl, aryl or heteroaryl; and q is 0 to 4.

[0049] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt, solvate or stereoisomer is:

[0050] In some embodiments, the compound of formula (Ia) or its pharmaceutically acceptable salt, solvate or stereoisomer is:

[0051] In some embodiments of compounds of formula (I) or (Ia), ring C is a cycloalkyl or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia), ring C is a cycloalkyl. In some embodiments of compounds of formula (I) or (Ia), ring C is a heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia), ring C is a 6-membered ring.

[0052] 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.

[0053] In some embodiments of the compound of formula (I) or (Ia), R1 is fluorine or chlorine. In some embodiments of the compound of formula (I) or (Ia), R2 is fluorine or chlorine. In some embodiments of the compound of formula (I) or (Ia), R1 is fluorine and R2 is chlorine. In some embodiments of the compound of formula (I) or (Ia), R1 is chlorine and R2 is fluorine.

[0054] In some embodiments of compounds of formula (I) or (Ia), ring A is aryl or heteroaryl. In some embodiments of compounds of formula (I) or (Ia), ring A is phenyl. In some embodiments of compounds of formula (I) or (Ia), ring A is a 6-membered heteroaryl. In some embodiments of compounds of formula (I) or (Ia), ring A is monocyclic. In some embodiments of compounds of formula (I) or (Ia), ring A is bicyclic. In some embodiments of compounds of formula (I) or (Ia), ring A is tricyclic.

[0055] In some embodiments of compounds of formula (I) or (Ia), each R3 is independently a halogen, -CN, -OH, -ORa, -SRa, -SF5, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are, as appropriate and independently, substituted by one or more R3a. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently a halogen, -CN, -ORa, -SRa, -SF5, -S(=O)2Ra, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, as appropriate, independently substituted by one or more R3a. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently a halogen, -CN, -ORa, -SRa, -SF5, -S(=O)2Ra, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heteroaryl; wherein the alkyl, cycloalkyl, and heteroaryl are, as appropriate, independently substituted by one or more R3a. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently a halogen, -ORa, -SRa, -SF5, -S(=O)2Ra, C1-C6 haloalkyl, cycloalkyl, or heteroaryl. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently -ORa or -SRa. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently -ORa. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently -SRa. In some embodiments of compounds of formula (I) or (Ia), each R3 is independently heteroaryl.

[0056] In some embodiments of compounds of formula (I) or (Ia), each R 3a is independently a halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R 3a is independently a halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R 3a is independently a halogen, C1-C6 alkyl, or C1-C6 haloalkyl.

[0057] 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 compounds of formula (I) or (Ia), p is 0 to 2. In some embodiments of compounds of formula (I) or (Ia), p is 0 or 1. In some embodiments of compounds of formula (I) or (Ia), p is 1 or 2. In some embodiments of compounds of formula (I) or (Ia), p is 0 (i.e., L is a bond).

[0058] In some embodiments of compounds of formula (I) or (Ia), it is . In some embodiments of compounds of formula (I) or (Ia), it is . In some embodiments of compounds of formula (I) or (Ia), it is . In some embodiments of compounds of formula (I) or (Ia), it is .

[0059] In some embodiments of compounds of formula (I) or (Ia), it is .

[0060] In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is .

[0061] In some embodiments of compounds of formula (I) or (Ia), each R4 is independently hydrogen, halogen, or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia), each R4 is independently hydrogen or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia), each R4 is independently hydrogen or halogen. In some embodiments of compounds of formula (I) or (Ia), each R4 is hydrogen.

[0062] In some embodiments of compounds of formula (I) or (Ia), two R4s on the same carbon together form a cycloalkyl or heterocycloalkyl group, each of which is substituted by one or more R4a as appropriate.

[0063] In some embodiments of compounds of formula (I) or (Ia), each R 4a is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R 4a is independently a halogen, -OH, C1-C6 alkyl, or C1-C6 haloalkyl.

[0064] In some embodiments of compounds of formula (I) or (Ia), each R5 is deuterium or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia), each R5 is deuterium, C1-C6 alkyl, or C1-C6 deuterium alkyl. In some embodiments of compounds of formula (I) or (Ia), each R5 is C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia), each R5 is C1-C3 alkyl. In some embodiments of compounds of formula (I) or (Ia), each R5 is methyl. In some embodiments of compounds of formula (I) or (Ia), each R5 is CD3. In some embodiments of compounds of formula (I) or (Ia), each R5 is deuterium.

[0065] In some embodiments of compounds of formula (I) or (Ia), ring B is a heterocyclic alkyl or heteroaryl. In some embodiments of compounds of formula (I) or (Ia), ring B is a heteroaryl. In some embodiments of compounds of formula (I) or (Ia), ring B is a 5-membered or 6-membered heteroaryl. In some embodiments of compounds of formula (I) or (Ia), ring B is a 6-membered heteroaryl. In some embodiments of compounds of formula (I) or (Ia), ring B is pyridyl, pyrimidinyl, or pyridyl. In some embodiments of compounds of formula (I) or (Ia), ring B is pyridyl or pyrimidinyl. In some embodiments of compounds of formula (I) or (Ia), ring B is pyridyl. In some embodiments of compounds of formula (I) or (Ia), ring B is pyrimidinyl.

[0066] In some embodiments of compounds of formula (I) or (Ia), each R6 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R6 is independently a halogen or C1-C6 alkyl. In some embodiments of compounds of formula (I) or (Ia), each R6 is independently a halogen.

[0067] In some embodiments of compounds of formula (I) or (Ia), each R 6a is independently a halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R 6a is independently a halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, or C1-C6 haloalkyl.

[0068] 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.

[0069] In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is . In some embodiments of compounds of formula (I) or (Ia), is .

[0070] In some embodiments of compounds of formula (I) or (Ia), R7 is hydrogen or a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia), R7 is a C1-C6 alkyl group. In some embodiments of compounds of formula (I) or (Ia), R7 is hydrogen.

[0071] In some embodiments of compounds of formula (I) or (Ia), each R 8a is independently a halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)Ra, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R 8a is independently a halogen, -CN, -OH, -OR a, -NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl. In some embodiments of compounds of formula (I) or (Ia), each R 8a is independently a halogen, -OH, -ORa, C1-C6 alkyl, or C1-C6 haloalkyl.

[0072] In some embodiments of the compound of formula (Ia), it is .

[0073] In some embodiments of the compound of formula (Ia), it is . In some embodiments of the compound of formula (Ia), it is . In some embodiments of the compound of formula (Ia), it is .

[0074] In some embodiments of the compound of formula (Ia), R1 is fluorine or chlorine; R2 is fluorine or chlorine; R5 is C1-C3 alkyl (e.g., methyl); and R3 is halogen, -CN, -OH, -ORa, -SRa, -SF5, -S(=O)2Ra, C1-C6 alkyl or C1-C6 haloalkyl, wherein Ra is C1-C6 alkyl or C1-C6 haloalkyl; L is -(CR4R4)p- and p is 0 (i.e. L is a bond); ring B is a 6-membered heteroaryl, each R6 is independently halogen or C1-C6 alkyl and m is 0, 1 or 2; ring C is a 6-membered cycloalkyl or heterocycloalkyl; and each R8a is independently halogen, -OH, -ORa, C1-C6 alkyl or C1-C6 haloalkyl.

[0075] In some embodiments of the compounds disclosed herein, each Ra is independently a 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); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each Ra is 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, each Ra is independently C1-C6 alkyl, C1-C6 haloalkyl, or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Ra is independently C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each Ra is independently a C1-C6 haloalkyl group.

[0076] In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene(cycloalkyl), C1-C6 alkylene(heterocycloalkyl), C1-C6 alkylene(aryl), or C1-C6 alkylene(heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl, and heterocycloalkyl is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each Rb is 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, each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rb is independently hydrogen or C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each Rb is hydrogen. In some embodiments of the compounds disclosed herein, each Rb is independently a C1-C6 alkyl group.

[0077] In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl or cycloalkyl, heterocycloalkyl; wherein each alkyl, cycloalkyl and heterocycloalkyl is independently substituted with one or more Rs as appropriate. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, 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, each Rc and Rd is independently hydrogen, a C1-C6 alkyl, a C1-C6 haloalkyl or cycloalkyl, or a heterocyclic alkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen, a C1-C6 alkyl, or a C1-C6 haloalkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently hydrogen or a C1-C6 alkyl. In some embodiments of the compounds disclosed herein, each Rc and Rd is hydrogen. In some embodiments of the compounds disclosed herein, each Rc and Rd is independently a C1-C6 alkyl.

[0078] In some embodiments of the compounds disclosed herein, Rc and Rd together with the atoms to which they are attached form heterocyclic alkyl groups that are substituted with one or more Rs, as appropriate.

[0079] In some embodiments of the compounds disclosed herein, each R is independently a 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 a 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.

[0080] In some embodiments of the compounds disclosed herein, the rings formed when two R4s are bonded together, R7 and R8 are bonded together, and Rc and Rd are bonded together, are, as appropriate and independently, substituted with one, two, three, or four substituents as defined herein. In some embodiments of the compounds disclosed herein, the rings formed when two R4s are bonded together, R7 and R8 are bonded together, and Rc and Rd are bonded together, are, as appropriate and independently, substituted with one, two, or three substituents as defined herein. In some embodiments of the compounds disclosed herein, each of the R3, R6, R8, Ra, Rb, Rc, and Rd, when two R4s are bonded together, R7 and R8 are bonded together, and Rc and Rd are bonded together, forms a ring, which may be substituted by one or two substituents as defined herein, as appropriate and independently.

[0081] In some embodiments of the compounds disclosed herein, one or more hydrogens on ring A, ring B or ring C are replaced by one or more deuteriums.

[0082] In some embodiments of the compounds disclosed herein, one or more of the R, R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc and / or Rd groups contain a percentage of deuterium higher than the natural abundance of deuterium.

[0083] In some embodiments of the compounds disclosed herein, one or more hydrogens in one or more of the following groups R, R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc and / or Rd are replaced by one or more deuterium groups.

[0084] In some embodiments of the compounds disclosed herein, the abundance of deuterium in each R, R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc and / or Rd 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.

[0085] This document considers any combination of the groups described above with respect to various variables. Throughout the specification, those skilled in the art will select groups and their substituents to provide stable moieties and compounds.

[0086] In some embodiments, the compounds disclosed herein, or their pharmaceutically acceptable salts, solvates, or stereoisomers, are one of the compounds in Table 1. Table 1* Stereochemistry is arbitrarily specified, except as otherwise provided. Other isomers / stereoisomers of the compounds disclosed herein

[0087] In some embodiments, the compounds described herein exist in 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, engegen (E), and zusammen (Z) isomers and their corresponding mixtures. In some cases, the compounds described herein have one or more palmar centers, each center existing in an R or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms and their corresponding mixtures. In other embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereomeric compounds produced by a single preparation step, combination, or interconversion can be used for the applications described herein. In some embodiments, the compounds described herein are prepared in their individual stereoisomer forms by reacting a racemic mixture other than the compound with an optically active resolving agent to form diastereomeric compound pairs, separating the diastereomeric compounds, and recovering the optically pure enantiomers. In some embodiments, a dissociable complex is preferred. In some embodiments, diastereomers have different physical properties (e.g., melting point, boiling point, solubility, reactivity, etc.) and are separated using these differences. In some embodiments, diastereomers are separated by diaphoretic chromatography or preferably by separation / resolving techniques based on differences in solubility. In some embodiments, the optically pure enantiomers are subsequently recovered along with the resolving agent by any practical means that do not cause racemization. Labeled compounds

[0088] In some embodiments, the compounds described herein are present in their isotopically labeled form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such isotopically labeled compounds in the form of a pharmaceutical composition. Thus, in some embodiments, the compounds disclosed herein include isotopically labeled compounds that are the same as those listed herein, but in fact have one or more atoms replaced by atomic masses or mass numbers different from those normally found in nature. Examples of isotopes that may be incorporated into the compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, such as 2H(D), 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F, and 36Cl, respectively. Compounds described herein containing the aforementioned isotopes and / or other isotopes of other atoms, as well as their pharmaceutically acceptable salts, solvates, or stereoisomers, are within the scope of this invention. Certain isotopically labeled compounds, such as those containing radioactive isotopes like 3H and 14C, can be used in pharmaceutical and / or tissue distribution analysis. Tritium (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability.

[0089] 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 hydrogens and deuterium. In some embodiments, one or more of the substituents disclosed herein contain a percentage of deuterium higher than the native abundance of deuterium. In some embodiments, in one or more of the substituents disclosed herein, one or more hydrogens are substituted with one or more deuteriums.

[0090] In some embodiments, the compounds described herein are labeled by other means, including but not limited to the use of chromophores or fluorescent portions, bioluminescent labeling, or chemiluminescent labeling. Pharmaceutically acceptable salts

[0091] In some embodiments, the compounds described herein are present in their pharmaceutically acceptable salt form. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating a disease by administering such pharmaceutically acceptable salts in the form of a pharmaceutical composition.

[0092] In some embodiments, the compounds described herein have acidic or basic groups and therefore react with a variety of inorganic or organic bases and any of inorganic and organic acids to form pharmaceutically acceptable salts. In some embodiments, such salts are prepared in situ during the final separation and purification of the compounds disclosed herein or their solvates or stereoisomers, or by reacting the purified compound in its free form with a suitable acid or base alone and separating the salts formed therefrom.

[0093] Examples of pharmaceutically acceptable salts include those prepared by reacting the compounds described herein with inorganic acids, organic acids, or inorganic bases. Such salts include acetates, acrylates, adipates, alginates, aspartates, benzoates, benzenesulfonates, bisulfates, bisulfites, bromides, butyrates, butyn-1,4-dicitates, camphorates, camphorsulfonates, hexanoates, octanoates, chlorobenzoates, chlorides, citrates, cyclopentanepropionate, decanoates, diglucose, dihydrophosphates, dinitrobenzoates, dodecyl sulfates, ethanesulfonates, formates, transbutenedioic acid, glucoheptanoate, glycerophosphates, glycolate, hemisulfates, heptanoates, hexyn-1,6-dicitates, hydroxybenzoates, γ-hydroxy Butyrate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, iodide, isobutyrate, lactate, maleate, malonate, methanesulfonate, amygdalinate metaphosphate, methanesulfonate, methoxybenzoate, methylbenzoate, monohydrophosphate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, dihydroxynaphthalate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pentanoate, propionate, pyrosulfonate, pyrophosphate, propynate, phthalate, phenylacetate, phenylbutyrate, propanesulfonate, salicylate, succinate, sulfate, sulfite, succinate, octanoate, sebacic acid salt, sulfonate, tartrate, thiocyanate, toluenesulfonate, undecanoate, and xylenesulfonate.

[0094] Furthermore, the compounds described herein can be prepared in a pharmaceutically acceptable salt form by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including but not limited to inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, metaphosphoric acid and similar acids; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, etc. Trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)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-en-1-carboxylic acid, glucohepanoic acid, 4,4'-methylenebis-(3-hydroxy-2-en-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tributylacetic acid, lauryl sulfate, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, and mucoconic acid. In some embodiments, other acids, such as oxalic acid, although pharmaceutically unacceptable on their own, are used to prepare salts that serve as intermediates for obtaining the compounds, solvates, or stereoisomers thereof disclosed herein and their pharmaceutically acceptable acid addition salts.

[0095] In some embodiments, the compounds described herein containing free acid groups react with suitable bases (such as hydroxides, carbonates, bicarbonates, and sulfates of pharmaceutically acceptable metal cations), ammonia, or pharmaceutically acceptable primary, secondary, tertiary, or quaternary organic amines. Representative salts include alkali metal or alkaline earth metal salts, such as lithium, sodium, potassium, calcium, and magnesium salts, as well as aluminum salts and similar salts. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-4 alkyl)4, and the like.

[0096] Representative organic amines that can be used to form base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, and their analogues. It should be understood that the compounds described herein also include quaternary ammoniation of any basic nitrogen-containing group they contain. In some embodiments, such quaternary ammoniation yields water-soluble, oil-soluble, or dispersible products. Solvents

[0097] In some embodiments, the compounds described herein are present in the form of solvates. The present invention provides a method for treating a disease by administering such solvates. The present invention further provides a method for treating a disease by administering such solvates in the form of a pharmaceutical composition.

[0098] Solvents contain stoichiometric or non-stoichiometric solvents and, in some embodiments, are formed during crystallization with a pharmaceutically acceptable solvent such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcohols are formed when the solvent is an alcohol. Solvents of the compounds described herein are preferably prepared or formed during the processes described herein. Only, for example, are hydrates of the compounds described herein preferably prepared by recrystallization from an aqueous / organic solvent mixture, the organic solvents used including, but not limited to, dialkyl, tetrahydrofuran, or methanol. Additionally, the compounds provided herein may exist in both solvated and non-solventized forms. Generally, for the purposes of the compounds and methods provided herein, the solvated form is considered equivalent to the non-solventized form. Tautomers

[0099] In some cases, compounds exist as tautomers. The compounds described herein include all possible tautomers of the formulas described herein. Tautomers are compounds that can interconvert through the migration of hydrogen atoms, which involves the conversion of single bonds with adjacent double bonds. A chemical equilibrium of tautomers will exist in the bond arrangements in which tautomerization may occur. All tautomer forms of the compounds disclosed herein are covered. The exact ratio of tautomers depends on several factors, including temperature, solvent, and pH. Treatment methods

[0100] This document discloses a method for treating or preventing coronavirus infection in a patient in need, comprising administering to the patient a compound or a pharmaceutical composition comprising a compound described herein, such as a compound of formula (I). In some embodiments, the coronavirus infection is caused by SARS-CoV-2 virus. In some embodiments, the coronavirus infection is caused by MERS-CoV virus. In some embodiments, the coronavirus infection is caused by SARS-CoV virus. In some embodiments, the coronavirus infection is caused by HCoV-229E virus. In some embodiments, the coronavirus infection is caused by HCoV-OC43 virus. In some embodiments, the coronavirus infection is caused by HCoV-NL63 virus. In some embodiments, the coronavirus infection is caused by HCoV-HKU1 virus.

[0101] In another embodiment, this article provides a method for treating or preventing SARS-CoV-2 infection in a patient in need, comprising administering to the patient a compound or a pharmaceutical composition comprising a compound described herein, such as a compound of formula (I).

[0102] In some embodiments, an individual is given a prophylactic dose of the compound disclosed herein. In some embodiments, an individual is suspected of having SARS-CoV-2 infection prior to a diagnosis of SARS-CoV-2 infection.

[0103] In some embodiments, an individual is given the compound of the present invention until the infection is treated, suppressed, or alleviated. In some embodiments, an individual is given the compound until one or more symptoms of SARS-CoV-2 infection are alleviated.

[0104] In another embodiment, this document provides a method for inhibiting viral infection, comprising providing the infection with the compounds disclosed herein 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.

[0105] In another embodiment, this document provides a method for inhibiting SARS-CoV-2 by binding to a protein of SARS-CoV-2, comprising providing the 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, the compound disclosed herein binds to a cysteine ​​residue of a major protease, thereby inhibiting SARS-CoV-2. In some embodiments, the cysteine ​​residue is located at position 145 of the major protease. In some embodiments, the protease is 3CL. Dosage

[0106] In some embodiments, a composition containing a compound described herein is administered for preventative and / or therapeutic treatment. In some therapeutic applications, the composition is administered to a patient with the disease or symptom in an amount sufficient to cure or at least partially suppress at least one symptom of the disease or symptom. The effective amount for this purpose depends on the severity and course of the disease or symptom, prior therapy, the patient's health status, weight, and response to the drug, as well as the judgment of the treating physician. The therapeutically effective amount may be determined, as appropriate, by methods including, but not limited to, dose escalation and / or dose range clinical trials.

[0107] In prophylactic use, a composition containing a compound described herein is administered to a patient who is susceptible to or otherwise at risk of developing a particular disease, condition, or symptom. This amount is defined as a "preventative effective amount or dose." In this use, the precise amount also depends on the patient's health condition, weight, and the like. When used in a patient, the effective amount for this purpose will depend on the severity and course of the disease, condition, or symptom, prior therapy, the patient's health condition and response to the drug, and the diagnosis of the treating physician. In one instance, prophylactic treatment comprises administering a pharmaceutical composition to a mammal who has previously experienced at least one symptom or risk factor of a treated disease and is currently in remission to prevent recurrence of symptoms of the disease or symptom, the pharmaceutical composition comprising a compound described herein or a pharmaceutically acceptable salt thereof.

[0108] In some embodiments where the patient’s condition has not improved, the compound is administered for a long period of time, i.e., for a longer period of time, including the entire duration of the patient’s life, in order to improve or otherwise control or limit the symptoms of the patient’s disease or condition, based on the doctor’s judgment.

[0109] In some embodiments where the patient's condition improves, the dosage of the medication being administered is temporarily reduced or temporarily suspended for a certain period of time (i.e., a "medication holiday"). In specific embodiments, the length of the medication holiday is between 2 days and 1 year, including, for example, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. The dosage reduction during the medication holiday is, for example, 10% to 100%, including, for example, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, and 100%.

[0110] Once the patient's condition improves, a maintenance dose is administered if necessary. Subsequently, in certain embodiments, the dose or frequency, or both, is reduced according to the symptoms to maintain the improvement in the disease, condition, or symptom. However, in some embodiments, the patient requires long-term intermittent or daily treatment whenever any symptoms recur.

[0111] The amount of a given reagent corresponding to this amount varies depending on factors such as the specific compound, the disease symptoms and their severity, and the identity (e.g., weight, sex) of the individual or host requiring treatment, but is still determined based on the specific circumstances surrounding the following: for example, the specific reagent administered, the route of administration, the disease being treated, and the individual or host being treated.

[0112] However, generally speaking, the dosage for adult treatment is typically in the range of 0.01 mg to 5000 mg per day. In one embodiment, the dosage for adult treatment is about 1 mg to about 1000 mg per day. In one embodiment, the desired dose is preferably presented as a single dose or as divided doses administered simultaneously or at appropriate intervals (e.g., as two, three, four or more sub-dose per day).

[0113] In one embodiment, a suitable daily dose of the compound described herein or a pharmaceutically acceptable salt thereof is about 0.01 to about 50 mg per kilogram of body weight. In some embodiments, the daily dose or amount of the active ingredient in the dosage form may be lower or higher than the range indicated herein, depending on many variables relating to individual treatment regimens. In various embodiments, the daily and unit doses vary depending on many variables, including but not limited to the activity of the compound used, the disease or condition to be treated, the mode of administration, the individual's needs, the severity of the disease or condition being treated, and the physician's judgment.

[0114] The toxicity and therapeutic efficacy of such treatment regimens are determined by standard pharmaceutical procedures in cell cultures or laboratory animals, including but not limited to the determination of LD10 and ED90. The dose ratio between toxicity and therapeutic effect is the therapeutic index, expressed as the ratio between LD50 and ED50. In some embodiments, data obtained from cell culture analysis and animal studies are used when formulating therapeutically effective daily dose ranges and / or therapeutically effective unit doses for mammals, including humans. In some embodiments, the daily dose of the compounds described herein is within a cyclic concentration range including the ED50 with minimal toxicity. In some embodiments, the daily dose range and / or unit dose vary within this range depending on the dosage form and route of administration used.

[0115] Any of the foregoing embodiments is an other embodiment in which an effective amount of the compound described herein or a pharmaceutically 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 to a mammal by injection; and / or (e) administered locally to a mammal; and / or (f) administered non-systemic or locally to a mammal.

[0116] Any of the foregoing states is another embodiment of a compound that includes a single dose of an effective amount, including (i) a single dose of the compound per day; or (ii) a multiple dose of the compound to a mammal per day.

[0117] Any of the foregoing embodiments is another example of administering an effective amount of the compound multiple times, including the following other examples, wherein (i) the compound is administered continuously or intermittently, such as with a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to a mammal every 8 hours; (iv) the compound is administered to an individual every 12 hours; (v) the compound is administered to an individual every 24 hours. In other or alternative embodiments, the method includes a drug holiday, wherein administration of the compound is temporarily suspended or the dose of the compound administered is temporarily reduced; administration of the compound is resumed at the end of the drug holiday. In one embodiment, the duration of the drug holiday ranges from 2 days to 1 year. Administration Route

[0118] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, non-enteral, ocular, pulmonary, mucosal, percutaneous, vaginal, ear, nose, and local administration. Additionally, non-enteral delivery includes, for example, intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intrathecal, direct intracardiac, intraperitoneal, intralymphatic, and intranasal injection.

[0119] In some embodiments, the compounds described herein are administered locally rather than systemically, for example, typically in the form of reservoir formulations or sustained-release formulations by direct injection into an organ. In certain embodiments, long-acting formulations are administered by implantation (e.g., subcutaneously or intramuscularly) or by intramuscular injection. Furthermore, in other embodiments, the drug is delivered in a targeted drug delivery system, such as in liposomes coated with organ-specific antibodies. In such embodiments, the liposomes target the organ and are selectively absorbed by the organ. In other embodiments, the compounds described herein are provided in the form of rapid-release formulations, extended-release formulations, or intermediate-release formulations. 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 disclosed herein are formulated for intranasal administration. Such formulations include nasal sprays, nasal atomizers, and the like. Pharmaceutical Compositions / Formulations

[0120] In accordance with standard pharmaceutical guidelines, the compounds described herein may be administered, alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, as a pharmaceutical composition to an individual in need. In one embodiment, the compounds of the present invention may be administered to animals. The compounds may be administered orally or non-enterally, including via intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and local routes of administration.

[0121] In another embodiment, this document provides a pharmaceutical composition comprising the compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. The pharmaceutical composition is formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate the processing of the active compound into a pharmaceutically usable formulation. Suitable formulations depend on the chosen route of administration. An overview of the pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, 19th edition (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, HA and Lachman, L., eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, NY, 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th edition (Lippincott Williams & Wilkins 1999), the disclosures of which are incorporated herein by reference.

[0122] In some embodiments, pharmaceutically acceptable excipients are selected from carriers, binders, fillers, suspending agents, flavoring agents, sweeteners, disintegrants, dispersants, surfactants, lubricants, colorants, diluents, solubilizers, wetting agents, plasticizers, stabilizers, penetration enhancers, wetting agents, defoamers, antioxidants, preservatives, and any combination thereof.

[0123] The pharmaceutical compositions described herein may be administered to an individual via appropriate routes of administration, including but not limited to oral, non-enteric (e.g., intravenous, subcutaneous, intramuscular), intranasal, buccal, topical, rectal, or percutaneous administration. The pharmaceutical formulations described herein include, but are not limited to, aqueous liquid dispersions, liquids, gels, syrups, elixirs, slurries, suspensions, self-emulsifying dispersions, solid solutions, liposome dispersions, aerosols, solid oral dosage forms, powders, immediate-release formulations, controlled-release formulations, rapidly dissolving formulations, tablets, capsules, pills, powders, sugar-coated pills, foaming formulations, lyophilized formulations, delayed-release formulations, extended-release formulations, pulsatile-release formulations, multi-particle formulations, and mixed immediate-release and controlled-release formulations.

[0124] Pharmaceutical compositions comprising the compounds described herein or their pharmaceutically acceptable salts, solvates or stereoisomers are manufactured in a conventional manner, such as by means of conventional methods of mixing, dissolving, granulating, forming sugar-coated pills, water milling, emulsifying, encapsulating, coating or compressing.

[0125] Pharmaceutical compositions for oral use are obtained by mixing one or more solid excipients with one or more compounds described herein, grinding the resulting mixture as appropriate, and, if necessary, adding suitable adjuvants, processing the mixture into granules to obtain a tablet or sugar-coated pill core. 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, hydroxypropyl methylcellulose, sodium carboxymethylcellulose; or other excipients such as polyvinylpyrrolidone (PVP or povidone) or calcium phosphate. If necessary, disintegrants such as cross-linked croscarmellose sodium, polyvinylpyrrolidone, agar, or alginate or its salts, such as sodium alginate, are added. In some embodiments, dyes or pigments are added to the coating of the tablets or sugar-coated pills to identify or characterize different combinations of active compound dosages.

[0126] Orally administered pharmaceutical compositions include incorporation inserts made of gelatin and soft-sealable capsules made of gelatin and plasticizers such as glycerin or sorbitol. The incorporation insert contains the active ingredient mixed with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc or magnesium stearate, and, where appropriate, a stabilizer. In the soft capsule, the active compound is dissolved or suspended in a suitable liquid such as fatty oil, liquid paraffin, or liquid polyethylene glycol. In some embodiments, a stabilizer is added.

[0127] Pharmaceutical compositions intended for non-enteral use are formulated as infusion or injection solutions. In some embodiments, pharmaceutical compositions suitable for injection or infusion include sterile aqueous solutions or dispersions, or sterile powders containing compounds described herein or their pharmaceutically acceptable salts, solvates, or stereoisomers. In some embodiments, the pharmaceutical composition includes a liquid carrier. In some embodiments, the liquid carrier is a solvent or liquid dispersion medium, including, for example, water, saline, ethanol, polyols (e.g., glycerol, propylene glycol, liquid polyethylene glycol, and the like), vegetable oils, non-toxic glycerides, and any combination thereof. In some embodiments, the pharmaceutical composition further includes a preservative to prevent microbial growth.

[0128] This article discloses methods for treating diseases or conditions associated with SARS-CoV-2 by using the compounds disclosed herein or their pharmaceutically acceptable salts, solvates or stereoisomers in combination with other therapeutic agents.

[0129] In some embodiments, other therapeutic agents are administered simultaneously with the compounds disclosed herein. In some embodiments, other therapeutic agents and the compounds disclosed herein are administered sequentially. In some embodiments, other therapeutic agents are administered less frequently than the compounds disclosed herein. In some embodiments, other therapeutic agents are administered more frequently than the compounds disclosed herein. In some embodiments, other therapeutic agents are administered before the compounds disclosed herein. In some embodiments, other therapeutic agents are administered after the compounds disclosed herein.

[0130] In some embodiments, other therapeutic agents are interferons, such as interferon alpha; or pegylated interferons, such as PEG introns or Pegasus. In some embodiments, this combination provides greater clinical benefit than administration of interferon, pegylated interferon, or the compounds disclosed herein alone. Examples of greater clinical benefit include greater symptom relief, faster symptom resolution, reduced lung lesions, greater reduction in the amount of SARS coronavirus (viral load) in the patient, and lower mortality.

[0131] SARS coronavirus infection of cells expressing p-glycoprotein. In some embodiments, the compounds disclosed herein are p-glycoprotein receptors. In some embodiments, compounds that inhibit SARS coronavirus are also p-glycoprotein receptors and are administered co-administered with a p-glycoprotein inhibitor. Examples of p-glycoprotein inhibitors include verapamil, vinblastine, ketoconazole, nelfinavir, ritonavir, and cyclosporine. P-glycoprotein inhibitors work by inhibiting the efflux of the compounds disclosed herein from cells. Inhibition of p-glycoprotein-based efflux prevents a decrease in the intracellular concentration of the compounds disclosed herein due to p-glycoprotein efflux. Inhibition of p-glycoprotein efflux results in a greater intracellular concentration of the compounds disclosed herein. In some embodiments, administration of the compounds 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.

[0132] Among pharmaceutical agents that can be used to increase mammalian exposure to the compounds disclosed herein are those that inhibit at least one isoform of the cytochrome P450 (CYP450) enzyme. CyP450 isoforms that can be advantageously inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19, and CYP3A4. In some embodiments, the compounds disclosed herein include compounds that act as CYP3A4 receptors and are metabolized by CYP3A4. In some embodiments, administration to a patient infected with SARS coronavirus of compounds that act as CYP3A4 receptors and CYP3A4 inhibitors, such as ritonavir, nelfinavir, or delavirdine, will reduce the metabolism of the compounds by CYP3A4. This will result in a decrease in the clearance of the compounds and an increase in plasma concentration. In some embodiments, the reduced clearance and higher plasma concentration result in a lower effective dose of the compounds disclosed herein. Examples 1a and 1b:

[0133] A mixture of compound 1-1 (1 g, 5.67 mmol), 1-(pyrimidin-5-yl)acetone (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 three times with N2, and then the mixture was heated under reflux for 16 hours while water was removed using a Dean-Stark separator under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (0 to 80% ethyl acetate / petroleum ether gradient solvent) to give compound 1-3 (944 mg, 56.38% yield). 1H NMR (400 MHz, DMSO- d 6): δ 9.38 - 9.29 (m, 3H), 9.06 (s, 1H), 8.31 (s, 1H), 7.72 (d, J= 8.4 Hz, 2H), 6.95 (d, J= 8.4 Hz, 2H), 2.31 (s, 3H).

[0134] (2R)-2-chloro-2-fluoroacetic acid (909 mg, 4.04 mmol, 50% purity) and 4,4-difluorocyclohexanenitrile (489 mg, 3.37 mmol) were added to a solution of compounds 1-3 (944 mg, 3.37 mmol) in CF3CH2OH (10 mL). The mixture was stirred at 25 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent) and further purified by preparative HPLC (Welch Xtimate C18 150*30mm*5µm; mobile phase: A: water (FA) B: ACN; gradient conditions: 35% B to 65% B; flow rate: 60 mL / min) to give compounds 1-4 (204 mg, 11.26% yield). LCMS: (M+H) = 538.1. SFC: Residence time: 1.420 min and 2.366 min, AD-3_EtOH (DEA)_40_25ML_5MI. 1H NMR (400 MHz, DMSO- d 6): 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). 19F NMR (376 MHz, DMSO- d 6): δ-91.95 (br dd, J= 90.2, 232.3 Hz, 1F), -98.51 ~ -100.31 (m, 1F), -141.93 (br d, J= 173.4 Hz, 1F).

[0135] 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 ratio: A:B = 60:40; flow rate: 80 mL / min) to obtain two dissociated fractions.

[0136] Example 1a obtained: (64 mg, 32.00% yield). LCMS: (M+H) = 538.2. SFC: Retention time: 1.424 min, AD-3_EtOH (DEA)_40_25ML_5MI. 1H NMR (400 MHz, DMSO- d 6): δ9.14 (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). 19F NMR (376 MHz, DMSO- d 6): δ-91.81 (br d, J= 234.6 Hz, 1F), -99.36 (br d, J= 234.6 Hz, 1F), -142.20 (s, 1F).

[0137] Example 1b obtained: (79 mg, 38.25% yield). LCMS: (M+H) = 538.2. SFC: Residence time: 2.446 min, AD-3_EtOH (DEA)_40_25ML_5MI. 1H NMR (400 MHz, DMSO- d 6): δ9.13 (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). 19F NMR (376 MHz, DMSO-d 6): δ -92.04 (br d, J = 237.5 Hz, 1F), -99.15 (br d, J = 240.3 Hz, 1F), -141.73 (br s, 1F). Examples 2a and 2b

[0138] The following compounds were prepared according to a similar procedure to that described for examples 1a and 1b of compounds.

[0139] Example 2a obtained: (12 mg). LCMS: (M+H) = 522.2. SFC: Retention time: 3.651 min, AD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.07 (s, 1 H), 8.87 (s, 2 H), 8.71 (d, J= 2.00 Hz, 1 H), 8.01 (d, J= 8.00 Hz, 1 H), 7.83 - 7.94 (m, 2 H), 7.75 (d, J= 8.00 Hz, 1 H), 7.35 (d, J= 9.20 Hz, 1 H), 7.15 (d, J= 1.80 Hz, 1 H), 6.26 - 6.50 (m, 1 H), 3.81 - 4.02 (m, 1 H), 1.95 - 2.06 (m, 2 H), 1.74 - 1.93 (m, 4 H), 1.68 (s, 3 H), 1.49 - 1.65 (m, 2 H). 19F NMR (376 MHz, DMSO- d 6): δ-142.25 (s, 1 F), -99.36 (br d, J= 234.61 Hz, 1 F), -91.83 (br d, J= 234.61 Hz, 1 F).

[0140] Example 2b obtained: (27.01 mg). LCMS: (M+H) = 522.1. SFC: Residence time: 4.920 min, AD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): 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, 12.8 Hz, 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= 7.3 Hz, 1H), 2.09 -1.87 (m, 4H), 1.82 (s, 3H), 1.78 - 1.52 (m, 4H). 19F NMR (376 MHz, DMSO-d6): δ -91.15 - -92.81 (m, 1F), -98.38 - -100.04 (m, 1F), -141.30 - -142.85 (m, 1F). Examples 3a and 3b

[0141] A solution of compound 3-1 (2 g, 16.12 mmol) and N-methoxymethylamine (1.98 g, 20.31 mmol) in DCM (40 mL) was degassed and purged three times with N2, followed by the addition of EDCI (3.71 g, 19.34 mmol) and DMAP (2.95 g, 24.17 mmol). The mixture was stirred at 25 °C under a N2 atmosphere for 18 hours. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to give the residue. The reaction mixture was diluted with H2O (50 mL) and extracted with DCM (3 × 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). 1H NMR (400 MHz, CDCl 3): δ 9.28 (s, 1H), 9.09 (s, 2H), 3.59 (s, 3H), 3.41 (s, 3H).

[0142] A mixture of LiAlD4 (250 mg, 6.59 mmol) in THF (3 mL) was degassed and purged three times with N2, followed by the addition of a solution of compound 3-2 (500 mg, 2.99 mmol) in THF (2 mL). The mixture was stirred at -78 °C under a N2 atmosphere for 2 hours. The reaction mixture was quenched at 0 °C with 1 N HCl (15 mL), followed by dilution with H2O (10 mL) and extraction with EA (6 × 20 mL) and DCM (4 × 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. ¹H NMR (400 MHz, DMSO-d6): δ 9.43 (s, 1H), 8.81 (s, 2H).

[0143] Compound 3-3 (85 mg, 779.07 µmol) was added to a solution of compound 3-4 (138 mg, 779.12 µmol) in DCM (2 mL). The mixture was degassed and purged three times with N2, and then TEA (237 mg, 2.34 mmol) and TiCl4 (74 mg, 390.13 mol) were added to the mixture at 0 °C. The reaction mixture was stirred at 25 °C under a N2 atmosphere for 2 hours. The reaction mixture was diluted with ice-cold water (15 mL) and extracted with DCM (3 × 20 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to give compound 3-5 (186 mg, crude substance), which was used in the next step without further purification.

[0144] A solution of compound 3-5 (180 mg, 671.11 µmol) in CF3CH2OH (3 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (151 mg, 805.42 µmol, 60% purity) and 4,4-difluorocyclohexanecarboxynitrile (98 mg, 675.17 µmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC. The pure solvent was collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to give compound 3-6 (145 mg, 40.45% yield). LCMS: (M+H) = 526.2.

[0145] Compounds 3-6 (149 mg, 283.35 µmol) were separated by SFC (DAICEL CHIRALCEL OD-H (250 mm * 30 mm, 5 µm)); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A:B = 60:40; flow rate: 80 mL / min) to obtain two dissociated fractions.

[0146] Example 3a was obtained: (52 mg, 34.12% yield). LCMS: (M+H) = 526.2. SFC: residence time: 2.957 min, OD_3_IPA_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): 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). 19F NMR (376 MHz, DMSO- d 6): 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).

[0147] Example 3b obtained: (56 mg, 37.35% yield). LCMS: (M+H) = 526.2. SFC: Residence time: 5.542 min, OD_3_IPA_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 8.99 (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 (376 MHz, DMSO- d 6): δ -56.98 (s, 3F), -93.33 (br d, J= 243.2 Hz, 1F), -97.70 (br d, J= 211.7 Hz, 1F), -142.72 (s, 1F). Examples 4a and 4b

[0148] A mixture of compound 4-1 (2 g, 11.29 mmol), compound 4-2 (1.66 g, 13.56 mmol), and AcOH (4.20 g, 69.94 mmol, 4.00 mL) in toluene (30 mL) was degassed and purged three times with N2. The mixture was then heated under reflux (120 °C) for 48 hours, while water was removed using a Dean-Stark separator 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. 1H NMR (400 MHz, DMSO- d 6): δ9.34 - 9.24 (m, 3H), 7.39 (d, J= 8.4 Hz, 2H), 6.96 (d, J= 8.8 Hz, 2H), 2.38 - 2.17 (m, 3H).

[0149] A solution of compound 4-3 (1 g, 3.56 mmol) in CF3CH2OH (10 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (667 mg, 3.56 mmol) and 4,4-difluorocyclohexanenitrile (517 mg, 3.56 mmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (0 to 70% ethyl acetate / petroleum ether gradient) to give the product. The product was purified by preparative HPLC. The pure solvent was collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to give compound 4-4 (87 mg, 4.44% yield). LCMS: (M+H) = 539.1.

[0150] Compound 4-4 (87 mg, 161.45 µmol) was separated into two dissociated fractions by SFC (DAICEL CHIRALPAK AD (250 mm * 30 mm, 10 µm)); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic ratio: A:B = 90:10; flow rate: 50 mL / min).

[0151] Example 4a obtained: (28 mg, 30.94% yield). LCMS: (M+H) = 539.1. SFC: Retention time: 1.816 min, AD-3_MeOH (DEA)_ 5_40_25 mL. 1H NMR (400 MHz, DMSO- d 6): 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). 19F NMR (376 MHz, DMSO- d 6): 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).

[0152] Example 4b was obtained: (34 mg, 61.78 µmol, 38.26% yield). LCMS: (M+H) = 539.1. SFC: Retention time: 2.406 min, AD-3_MeOH (DEA)_5_40_25 mL. 1H NMR (400 MHz, DMSO- d 6): δ9.03 (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). 19F 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). Examples 5a and 5b

[0153] The following compounds were prepared according to a similar procedure to that described for Examples 4a and 4b.

[0154] Example 5a obtained: (17 mg). LCMS: (M+H) = 505.2. SFC: Residence time: 2.558 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ9.03 (s, 1H), 8.82 (s, 2H), 7.79 (d, J= 8.0 Hz, 2H), 7.45 (d, J= 8.4 Hz, 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). 19F NMR (376 MHz, DMSO- d 6): δ -56.85 (s, 3F), -142.33 (s, 1F).

[0155] Example 5b obtained: (20 mg). LCMS: (M+H) = 505.2. SFC: Residence time: 3.349 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): 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). 19F NMR (376 MHz, DMSO-d6): δ -56.90 (s, 3F), -142.06 (s, 1F). Examples 6a, 6b, 6c and 6d.

[0156] The following compounds were prepared according to a similar procedure to that described for Examples 4a and 4b.

[0157] Example 6a was obtained: (6 mg). LCMS: (M+H) = 491.1. SFC: Residence time: 2.504 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.84 (s, 2H), 8.04 (d, J= 6.8 Hz, 1H), 7.86 (d, J= 8.8 Hz, 1H), 7.49 (d, J= 8.4 Hz, 1H), 7.43 - 7.30 (m, 2H), 6.49 - 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). 19F NMR (376 MHz, DMSO-d 6): δ-142.27 (s, 3 F) -56.82 (s, 1 F).

[0158] Example 6b obtained: (4 mg). LCMS: (M+H) = 491.1. SFC: Residence time: 2.773 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ9.12 - 9.06 (m, 1H), 8.86 - 8.83 (m, 2H), 8.06 (d, J= 6.4 Hz, 1H), 7.90 (dd, J= 2.4, 8.8 Hz, 1H), 7.50 (d, J= 8.4 Hz, 1H), 7.40 (d, J= 8.8 Hz, 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, 9.0 Hz, 1H), 2.12 - 2.03 (m, 1H), 1.83 - 1.76 (m, 1H), 1.68 - 1.60 (m, 3H). 19F NMR (376 MHz, DMSO-d 6): δ-56.62 ~ -56.97 (m, 3F), -141.95 ~ -143.49 (m, 1F).

[0159] Example 6c obtained: (7 mg). LCMS: (M+H) = 491.1. SFC: Residence time: 3.504 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ9.02 (s, 1H), 8.81 (s, 2H), 7.95 (d, J= 6.8 Hz, 1H), 7.68 (dd, J= 2.4, 8.8 Hz, 1H), 7.51 (dd, J= 2.0, 8.8 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ-54.84 - -58.54 (m, 3F), -140.69 - -146.03 (m, 1F).

[0160] Example 6d obtained: (6 mg). LCMS: (M+H) = 491.1. SFC: Residence time: 4.030 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ9.03 (s, 1 H), 8.82 (s, 2 H), 7.93 (d, J= 6.40 Hz, 1 H), 7.67 - 7.78 (m, 1 H), 7.33 - 7.55 (m, 3 H), 6.20 - 6.43 (m, 1 H), 4.33 (br s, 1 H), 3.73 - 3.83 (m, 2 H), 3.62 - 3.70 (m, 1 H), 3.52 - 3.59 (m, 1 H), 2.01 - 2.11 (m, 1 H), 1.79 (s, 3 H), 1.72 - 1.78 (m, 1H). 19F NMR (376 MHz, DMSO-d6): δ -141.85 (s, 3 F), -57.32 - -56.43 (m, 1 F). Example 8

[0161] (2R)-2-chloro-2-fluoroacetic acid (48.00 mg, 426.69 μmol) and (1R,4R)-1-isocyano-4-(trifluoromethoxy)cyclohexane (68.69 mg, 355.58 μmol) were added to a solution of compound 4-3 (100 mg, 355.58 μmol) in CF3CH2OH (1 mL). 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 preparative HPLC (column: Boston Green ODS 150×30 mm×5 μm; mobile phase: [water(FA)-ACN]; B%: 55%-85%, 6 min) to give compound 8 (2.30 mg, 1.08% yield). LCMS: (M+H) = 587.0. HPLC: Retention time: 5.290 min, 10-80AB_8 min. 1H NMR (400 MHz, CD 3OD): δ 9.04 ( d, J= 13.6 Hz, 1H), 8.92 ( d, J= 9.6 Hz, 2H), 7.76 - 7.65 (m, 1H), 7.47 - 7.28 (m, 3H), 6.30 - 6.11 (m, 1H), 4.29 - 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). 19F NMR (376 MHz, CD 3OD): δ -145.470 - -145.311 (m, 1F), -59.572 - -59.277 (m, 6F). Examples 11a and 11b

[0162] 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 sieve (3 g, 7.19 mmol) in toluene (20 mL) was degassed and purged three times with N2, and then stirred at 125 °C under N2 atmosphere for 18 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). Compound 11-2 (1.3 g, 49.05% yield) was given. LCMS: Retention time: 4.398 min, (M+H) = 299.1

[0163] (2R)-2-chloro-2-fluoroacetic acid (405 mg, 2.02 mmol, 56% purity) and 1,1-difluoro-4-isocyanocyclohexane (252 mg, 1.68 mmol, 97% purity) were added to a solution of 11-2 (500 mg, 1.68 mmol, CF3CH2OH (5 mL). The mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative 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). The pure solvent was collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to give the title compound 11-3 (144 mg, 15.34% yield). 1H NMR (400 MHz, DMSO- d 6): δ 8.51 - 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). 19F NMR (376 MHz, DMSO- d 6): δ -56.93 (br d, J= 20.0 Hz, 3F), -91.93 (br dd, J= 55.8, 233.2 Hz, 1F), -99.31 (br dd, J= 42.9, 228.9 Hz, 1F), -128.08 (br d, J= 14.3 Hz, 1F), -141.88 (br d, J= 14.3 Hz, 1F). 11-3 (198 mg, 356.20 μmol) was separated into two dissociated fractions by SFC (DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 90:10; flow rate: 60 mL / min).

[0164] Example 11a obtained: (29 mg, 14.65% yield). LCMS: (M+H) = 556.2. SFC: Residence time: 1.773 min, OD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): 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 (br s, 1H), 2.01 (br s, 3H), 1.90 (br s, 1H), 1.76 (s, 5H), 1.65 - 1.50 (m, 2H). 19F NMR (376 MHz, DMSO- d 6): δ -56.90 (s, 3F), -91.84 (br d, J= 231.7 Hz, 1F), -99.36 (br d, J= 231.7 Hz, 1F), -128.10 (s, 1F), -141.91 (s, 1F).

[0165] Example 11b obtained: (61 mg, 29.95% yield). LCMS: (M+H) = 556.2. SFC: Residence time: 2.257 min, OD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.49 - 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.32 - -57.54 (m, 3F), -91.99 (br d, J = 234.6 Hz, 1F), -99.25 (br d, J = 226.0 Hz, 1F), -128.06 (s, 1F), -141.88 (s, 1F). Examples 13a and 13b

[0166] Tributyl(1-ethoxyvinyl)stanane (9.56 g, 26.47 mmol, 8.93 mL) and Pd(PPh3)2Cl2 (1.49 g, 2.13 mmol) were added to a solution of 4-bromo-1-methylpyridin-2-one (4.0 g, 21.27 mmol) in toluene (80 mL). The mixture was heated and stirred at 100 °C for 12 hours under N2. Before cooling the mixture to room temperature, it was quenched with a saturated KF solution (40 mL), then treated with 5% hydrochloric acid (40 mL), and the reactants were extracted with ethyl acetate (20 mL × 3). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give the crude substance. The crude material was purified by column chromatography (SiO₂, petroleum ether / ethyl acetate = 0 / 1 to 1 / 0, TLC: petroleum ether:ethyl acetate = 0:1, Rf = 0.2) to give compound 13-2 (2.1 g, 13.89 mmol, 65.30% yield). ¹H NMR (400 MHz, CDCl₃) δ 7.36 (d, J = 7.2 Hz, 1H), 7.06 (d, J = 1.6 Hz, 1H), 6.60 (dd, J = 2.0, 7.2 Hz, 1H), 3.57 (s, 3H), 2.52 (s, 3H).

[0167] 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 three times with N2, and then stirred at 120 °C under N2 atmosphere for 12 h. The reaction mixture was concentrated under reduced pressure to give a crude product. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min) to give 13-3 (1.4 g, 4.51 mmol, 32.48% yield). 1H NMR (400 MHz, CDCl 3) δ7.32 (d, J= 7.2 Hz, 1H), 7.23 (d, J= 8.0 Hz, 2H), 6.99 - 6.89 (m, 2H), 6.80 - 6.75 (m, 2H), 3.59 (s, 3H), 2.16 (s, 3H).

[0168] (2R)-2-chloro-2-fluoroacetic acid (233.07 mg, 1.16 mmol, 56% purity) and 1,1-difluoro-4-isocyanocyclohexane (154.38 mg, 1.06 mmol) were added to a solution of 13-3 (300.00 mg, 966.90 μmol) in CF3CH2OH (4 mL). The mixture was stirred at 25 °C for 2 hours. The mixture was concentrated under reduced pressure to give crude compound 13. The residue was purified by preparative 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, 97% purity).

[0169] Compound 13 was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [Neu-ETOH]; B%: 15% to 15%) to obtain two dissociated fractions.

[0170] Example 13a obtained: (20 mg, 3.55% yield). LCMS: (M+H) = 568.2. SFC: Retention time: 2.647 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 7.79 - 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).

[0171] Example 13b obtained: (15 mg, 2.61% yield). LCMS (M+H) = 568.2. SFC: Residence time: 2.991 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. ¹H NMR (400 MHz, DMSO-d⁶): δ 7.60–7.52 (m, 2H), 7.49 (d, J = 7.2 Hz, 2H), 7.41–7.34 (m, 2H), 6.45–6.27 (m, 2H), 6.22 (dd, J = 2.0, 7.2 Hz, 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). Examples 14a and 14b

[0172] H₃PO₄ (26 mg, 225.52 μmol, 15.48 μL, 85% purity) was added to a solution of compound 11-2 (350 mg, 1.17 mmol) in CF₃CH₂OH (3 mL). The mixture was stirred at 25 °C for 30 min. Subsequently, 4-isocyanotetrahydropiperanone (153 mg, 1.17 mmol, 85% purity) and (2R)-2-chloro-2-fluoroacetic acid (240 mg, 1.41 mmol, 66% purity) were added to the mixture. The mixture was stirred at 25 °C for 5 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative HPLC (Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: A: water (FA) B: ACN; gradient conditions: 45% B to 75% B; flow rate: 35 mL / min). The pure solvent was collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to give the title compound. Compound 14 was given (127 mg, 20.80% yield). LCMS (M+H) = 522.1. 1H NMR (400 MHz, DMSO- d 6): δ 8.53 - 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). 19F NMR (376 MHz, DMSO- d 6): δ -56.93 (br d, J= 20.0 Hz, 3F), -128.12 (br d, J= 17.2 Hz, 1F), -141.87 (s, 1F).

[0173] Compound 14 (127 mg, 243.36 µmol) was separated into two fractions by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 85:15; flow rate: 60 mL / min).

[0174] Example 14a obtained: (44 mg, 34.65% yield). LCMS (M+H) = 522.2. SFC: Residence time: 2.272 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.53 - 8.42 (m, 2H), 7.75 (d, J= 8.4 Hz, 1H), 7.72 - 7.65 (m, 2H), 7.42 (d, J= 7.6 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.90 (s, 3F), -128.14 (s, 1F), -141.87 (s, 1F).

[0175] Example 14b obtained: (44 mg, 34.65% yield). LCMS (M+H) = 522.2. SFC: Residence time: 2.762 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.45 (s, 1H), 8.42 (d, J= 2.4 Hz, 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). 19F NMR (376 MHz, DMSO-d6): δ -56.95 (s, 3F), -128.09 (s, 1F), -141.86 (s, 1F). Examples 17a and 17b

[0176] Pd(PPh3)2Cl2 (1.83 g, 2.60 mmol) was added to a solution of 17-1 (9 g, 52.02 mmol) and tributyl(1-ethoxyvinyl)stanane (22.37 g, 61.94 mmol, 20.91 mL) in toluene (100 mL). The mixture was stirred at 110 °C under N2 for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give compound 5-(1-ethoxyvinyl)-4-methylpyrimidine (10 g, crude). HCl (2 M, 82.21 mL) was added to a solution of 5-(1-ethoxyvinyl)-4-methylpyrimidine (10 g). The mixture was stirred at 20 °C for 3 hours. The reaction mixture was extracted with EtOAc (30 mL × 5). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 17-2 was obtained (5.5 g, crude substance).

[0177] A mixture of 17-2 (7.49 g, 42.31 mmol, 5.72 mL), 1-(4-methylpyrimidin-5-yl)acetone (3 g, 21.15 mmol), and p-TsOH (546.39 mg, 3.17 mmol) in toluene (60 mL) was degassed and purged three times with N2, and then stirred at 140 °C for 16 h under N2 atmosphere. The mixture was cooled to room temperature and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / dichloromethane solvent, at 40 mL / min). Compound 17-3 (3.74 g) was given.

[0178] Add (2R)-2-chloro-2-fluoroacetic acid (464.92 mg, 2.44 mmol) and 1,1-difluoro-4-isocyanocyclohexane (327.73 mg, 2.03 mmol) to a solution of 17-3 (600 mg, 2.03 mmol) in CF3CH2OH (2 mL). Stir the mixture at 20 °C for 16 h. Concentrate the reaction mixture under reduced pressure. Purify the residue by rapid silica gel chromatography (0 to 20% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). Purify the residue by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 50% to 80%, 7 min). Compound 17 was obtained (51 mg, 89.94 μmol, 4.43% yield, 97.51% purity).

[0179] Compound 17 (51 mg) was separated into two dissociated fractions by SFC (DAICEL CHIRALPAK AS (250 mm × 30 mm, 10 µm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 90:10; flow rate: 60 mL / min).

[0180] Example 17a obtained: (12.85 mg, 24.83% yield). LCMS: (M+H) = 553.1. SFC: Residence time: 1.174 min, AS_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.89 (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= 10.6 Hz, 2H), 1.46 (br d, J= 12.5 Hz, 2H). 19F NMR (376 MHz, DMSO- d 6): δ -56.87 (s, 3F), -92.16 (br d, J= 235.8 Hz, 1F), -99.27 (br d, J= 242.8 Hz, 1F), -141.49 (br s, 1F)

[0181] Example 17b obtained: (12.79 mg, 25.08% yield). LCMS (M+H) = 553.1. SFC: Residence time: 1.834 min, AS_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.92 (s, 1H), 8.74 (s, 1H), 7.83 (br d, J= 7.0Hz, 1H), 7.63 (d, J= 7.6 Hz, 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= 10.8 Hz, 2H). 19F NMR (376 MHz, DMSO-d 6): δ -56.87 (s, 3F), -91.75 - -93.12 (m, 1F), -99.13 (br d, J= 194.2 Hz, 1F), -141.01 (br s, 1F) Examples 18a and 18b

[0182] TEA (10.57 g, 104.48 mmol, 14.54 mL) was added to a solution of 18-1 (5 g, 34.83 mmol, HCl salt) in ethyl formate (60 mL). The mixture was stirred at 80 °C for 16 hours. The mixture was concentrated under 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 under vacuum. 18-2 (4.28 g, crude substance) was obtained. 1H NMR (400 MHz, CDCl 3): δ 8.20 - 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).

[0183] PPh 3 (8.31 g, 31.68 mmol), TEA (3.21 g, 31.68 mmol, 4.41 mL), and CCl 4 (4.87 g, 31.68 mmol, 3.05 mL) were added to a solution of 18-2 (4.28 g, 31.68 mmol, 4.41 mL) in DCM (20 mL). The mixture was stirred at 45 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. Subsequently, MTBE (30 mL) and PE (30 mL) were added, and the mixture was stirred at 20 °C for 2 hours. The reaction mixture was filtered, and the filter cake was washed with MTBE (20 mL × 3). The combined filtrates were concentrated under reduced pressure. Compound 18-3 (7.35 g, crude substance) was obtained.

[0184] (2R)-2-chloro-2-fluoroacetic acid (1.03 g, 5.12 mmol) and 18-3 (999.28 mg, 4.27 mmol) were added to a solution of compound 4-1 (2 g, 4.27 mmol) in CF3CH2OH (20 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). The product was further purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 43% to 73%, 6 min). Compound 18 was given (160 mg, 311.25 μmol, 7.29% yield).

[0185] Compound 18 (160 mg) was separated by a palmar 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: 60 mL / min), and then concentrated under vacuum to obtain two dissociated fractions.

[0186] Example 18a obtained: (16.52 mg). LCMS: (M+H) = 511.0. SFC: Retention time: 1.820 min, OD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.08 (s, 1H), 8.84 (s, 2H), 8.20 (d, J= 6.4 Hz, 1H), 7.87 (dd, J= 2.4, 8.5 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.82 (br s, 3F), -81.28 - -82.71 (m, 1F), -96.15 - -97.48 (m, 1F), -142.44 (s, 1F).

[0187] Example 18b obtained: (19.34 mg, 32.06% yield). LCMS (M+H) = 511.0. SFC: Residence time: 2.467 min, OD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.04 (s, 1H), 8.83 (s, 2H), 8.16 (d, J= 6.4 Hz, 1H), 7.70 (dd, J= 2.4, 8.6 Hz, 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, 19.8 Hz, 2H), 1.79 (s, 3H). 19F NMR (376 MHz, DMSO-d6): δ -56.86 (s, 3F), -81.37 to -82.55 (m, 1F), -96.17 to -97.35 (m, 1F), -141.95 (s, 1F). Examples 22a and 22b

[0188] p-TsOH (294.63 mg, 1.71 mmol) was added to a solution of 22-1 (2.5 g, 11.41 mmol) and 1-pyrimidin-5-ylethyl ketone (1.39 g, 11.41 mmol) in toluene (70 mL). The mixture was stirred at 136 °C for 16 h while water was removed using a Dean-Stark separator under N2 atmosphere. The reaction mixture 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 rapid silica gel chromatography (0 to 10% DCM / EtOAc solvent, at 20 mL / min). 22-2 (2.02 g, 5.62 mmol, 49.30% yield, 90% purity) was obtained. 1HNMR (400 MHz, DMSO- d 6) δ 9.38 - 9.28 (m, 3H), 7.92 (d, J= 8.8 Hz, 2H), 7.05 (d, J= 8.8 Hz, 2H), 2.28 (s, 3H).

[0189] H₃PO₄ (58.72 mg, 509.31 μmol, 34.95 μL) was added to a solution of 22-2 (1 g, 2.78 mmol) in CF₃CH₂OH (12 mL). The mixture was stirred at 20 °C for 30 min. Subsequently, 1,1-difluoro-4-isocyanocyclohexane (448.35 mg, 2.78 mmol) and (2R)-2-chloro-2-fluoroacetic acid (521.19 mg, 2.78 mmol) were added. The mixture was stirred at 20 °C for 17 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0-50% ethyl acetate / petroleum ether gradient solvent, 35 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water (FA)-ACN]; B%: 52%-82%, 7 min). Example 22 (100 mg, 5.94% yield) was obtained. LCMS: (M+H) = 580.7. 1HNMR (400 MHz, DMSO- d 6) δ9.07 (d, J= 11.4 Hz, 1H), 8.87 (d, J= 6.4 Hz, 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). 19F NMR (376 MHz, DMSO-d6) δ 64.03 (d, J = 152.6 Hz, 3F), -92.01 (dd, J = 64.2, 234.1 Hz, 1F), -99.25 (dd, J = 57.2, 234.1 Hz, 1F), -142.27 (d, J = 190.7 Hz, 1F). Compound 22 (100 mg, 172.14 μmol) was separated into two fractions by SFC (WHELK-O1 (250 mm × 30 mm, 5 μm)); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A: B = 80:20; flow rate: 60 mL / min).

[0190] Example 22a was obtained: (20 mg, 33.85 μmol, 19.67% yield). LCMS: (M+H) = 580.9. SFC: Retention time: 4.861 min, SS Whelk O1_IPA_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.08 (s, 1H), 8.87 (s, 2H), 8.15 - 7.88 (m, 3H), 7.78 (d, J= 8.0 Hz, 1H), 7.47 (s, 1H), 6.53 - 6.34 (m, 1H), 3.86 (d, J= 7.6 Hz, 1H), 2.01 (s, 3H), 1.89 - 1.69 (m, 3H), 1.65 (s, 3H), 1.62 - 1.43 (m, 2H). 19F NMR (376 MHz, DMSO- d 6): δ 64.02 (d, J= 152.6 Hz, 5F), -91.89 (d, J= 235.8 Hz, 1F), -99.40 (d, J= 232.3 Hz, 1F), -141.21 - -145.92 (m, 1F).

[0191] Example 22b obtained: (30 mg, 29.59% yield). LCMS (M+H) = 580.9. SFC: residence time: 5.270 min, SS Whelk O1_IPA_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.86 (s, 2H), 7.98 (m, 2H), 7.84 (d, J= 7.2 Hz, 1H), 7.70 (d, J= 8.0 Hz, 1H), 7.61 (d, J= 8.2 Hz, 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). 19F NMR (376 MHz, DMSO-d6): δ 64.01 (d, J = 152.6 Hz, 5F), -92.06 (d, J = 232.4 Hz, 1F), -97.67 - -102.77 (m, 1F), -142.09 (s, 1F). Examples 23a and 23b

[0192] (2R)-2-chloro-2-fluoroacetic acid (208.77 mg, 1.11 mmol) and 4-isocyanotetrahydropiperanone (145.14 mg, 1.11 mmol, 85% purity) were added to a solution of 22-2 (358.85 mg, 1.11 mmol) in CF3CH2OH (1 mL). The mixture was stirred at 20 °C for 16 h. Fresh (2R)-2-chloro-2-fluoroacetic acid (208.77 mg, 1.11 mmol) and 4-isocyanotetrahydropiperanone (145.14 mg, 1.11 mmol) were added. The mixture was stirred again at 20 °C for 48 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 30% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). The residue was further purified by preparative HPLC (column: Welch Xtimate C18 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 49%-79%, 7min) to obtain two soluble fractions.

[0193] Example 23a obtained: (1.08 mg, 0.2% yield). LCMS (M+H) = 547.0. SFC: Residence time: 3.536 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6) δ 9.19 - 8.99 (m, 2H), 8.94 - 8.79 (m, 2H), 7.61 (d, J= 9.4 Hz, 2H), 7.31 - 7.14 (m, 3H), 3.97 - 3.60 (m, 4H), 3.26 (br d, J= 4.2 Hz, 1H), 2.43 (br dd, J= 4.4, 12.6 Hz, 1H), 2.27 - 2.11 (m, 4H), 1.78 (br d, J= 12.3 Hz, 1H), 1.52 (br d, J= 11.0 Hz, 1H).

[0194] Example 23b was obtained: (4.85 mg, 7.98 µmol, 7.19e-1% yield). LCMS: (M+H) = 547.0. HPLC: Retention time: 2.522 min, 10-80AB_4min.1cm. SFC: Retention time: 2.818 min, AD_3_IPA_DEA_5_40_25ML_6MIN. ¹H NMR (400 MHz, DMSO-d⁶) δ 9.15 (s, ¹H), 9.10 (d, J = 3.0 Hz, ¹H), 8.94 (s, 2H), 7.65 (d, J = 9.5 Hz, 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 = 9.0 Hz, 1H), 1.53 (br d, J = 13.1 Hz, 1H). Examples 26a and 26b

[0195] A mixture of 26-1 (2 g, 10.25 mmol), 1-pyrimidin-5-ylethyl ketone (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 hours, and water was removed using a Dean-Stark separator. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography (0 to 30% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). Compound 26-2 was given (1.88 g, 5.97 mmol, 58.23% yield, 95% purity). 1H NMR (400 MHz, DMSO- d 6): δ 9.49 - 9.22 (m, 3H), 7.52 (dd, J= 2.0, 10.6 Hz, 1H), 7.29 (td, J= 1.2, 8.7 Hz, 1H), 7.13 (t, J= 8.9 Hz, 1H), 2.31 (d, J= 1.1 Hz, 3H).

[0196] H₃PO₄ (52.33 mg, 534.00 μmol, 31.15 μL) was added to a solution of 26-2 (800 mg, 2.67 mmol) in CF₃CH₂OH (5 mL). The reaction mixture was stirred at 15 °C for 30 min. Subsequently, 1,1-difluoro-4-isocyanocyclohexane (430.61 mg, 2.67 mmol) and (2R)-2-chloro-2-fluoroacetic 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 rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). The residue was further purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 53% to 83%, 7 min). Compound 26 was given (87 mg, 5.71% yield). LCMS: (M+H) = 557.0. HPLC: retention time: 4.783 min, 10-80AB_8min.lcm. 1H NMR (400 MHz, DMSO- d 6): δ 9.13 - 9.01 (m, 1H), 8.90 (d, J= 2.1 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -54.66 - -62.10 (m, 3F), -87.95 - -92.80 (m, 1F), -99.34 (br d, J=231.7 Hz, 1F), -107.02 - -114.13 (m, 1F), -139.66 - -144.18 (m, 1F). Compound 26 (85 mg, 152.64 µmol) was separated into two fractions by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 90:10; flow rate: 60 mL / min).

[0197] Example 26a was obtained: (30 mg, 34.45% yield). LCMS: (M+H) = 557.2. SFC: Retention time: 1.744 min, AD-3-EtOH (DEA) 5-40-25 mL. 1H NMR (400 MHz, DMSO-d6): δ 9.11 - 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). 19F NMR (376 MHz, DMSO- d 6): δ -52.95 - -60.01 (m, 3F), -91.95 (d, J= 235.8 Hz, 1F), -97.67 - -101.99 (m, 1F), -108.26 - -112.58 (m, 1F), -140.03 - -144.35 (m, 1F).

[0198] Example 26b obtained: (32 mg, 37.22% yield). LCMS (M+H) = 557.2. SFC: Retention time: 2.004 min, AD-3-EtOH (DEA) 5-40-25 mL. 1H NMR (400 MHz, DMSO-d6): δ 9.11 - 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). 19F NMR (376 MHz, DMSO-d6): δ -56.67 - -57.85 (m, 3F), -92.12 (d, J = 228.9 Hz, 1F), -98.91 (s, 1F), -106.68 - -112.98 (m, 1F), -141.07 - -143.17 (m, 1F). Examples 27a and 27b

[0199] H₃PO₄ (19.65 mg, 200.52 μmol, 85%) was added dropwise to a solution of 26-2 (300 mg, 1.00 mmol) in CF₃CH₂OH (5 mL). After addition, the mixture was stirred at 25 °C for 0.5 h, followed by the addition of 4-isocyanotetrahydropiperanone (136.19 mg, 1.10 mmol) and (2R)-2-chloro-2-fluoroacetic acid (225.56 mg, 1.20 mmol). The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 60% ethyl acetate / petroleum ether gradient solvent, 30 mL / min) to give a crude product, which was further purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water (FA)-ACN]; B%: 34% to 64%, 7 min) to give compound 27 (75 mg, 13.70% yield). LCMS: (M+H) = 523.0.

[0200] Compound 27 (75 mg, 143.44 µmol) was separated into two dissociated fractions by SFC DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A: B = 85:15.

[0201] Example 27a obtained: (15 mg, 19.76% yield). LCMS: (M+H) = 523.2. SFC: Retention time: 1.440 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO-d 6): δ 9.21 - 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.40 - -58.36 (m, 3F), -107.43 - -112.20 (m, 1F), -140.80 - -143.60 (m, 1F).

[0202] Example 27b obtained: (15 mg, 19.79% yield). LCMS (M+H) = 533.2. SFC: Retention time: 1.579 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO-d 6): δ 9.10 - 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.40 - -58.92 (m, 3F), -108.36 - -113.53 (m, 1F), -143.56 (br d, J=313.5 Hz, 1F). Examples 28a and 28b

[0203] A mixture of 28-1 (1 g, 3.77 mmol), tributyl carbamate (1.77 g, 15.12 mmol), Xantphos (663 mg, 1.15 mmol), and Cs₂CO₃ (7.38 g, 22.64 mmol) in dimethyl ether (20 mL) was degassed and purged three times with Ar, followed by the addition of Pd₂(dba)₃ (363 mg, 396.41 μmol). The mixture was stirred at 115 °C under an Ar atmosphere for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 10% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). Compound 28-2 (740 mg, 2.46 mmol, 65.10% yield) was given. 1H NMR (400 MHz, DMSO- d 6): δ 9.42 (s, 1H), 7.44 (d, J= 8.6 Hz, 2H), 7.32 (d, J= 8.6 Hz, 2H), 1.47 (s, 9H), 1.30 - 1.26 (m, 2H), 1.04 (s, 2H).

[0204] HCl / dimethyl alkylene (4 M, 8.96 mL) was added to a solution of compound 28-2 (900 mg, 2.99 mmol) in DCM (20 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with 20 mL of DCM. The solution was alkalized with saturated Na₂CO₃ aqueous solution and adjusted to 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 substance) was obtained. LCMS: (M+H) = 202.8. 1H NMR (400 MHz, DMSO- d 6): δ 7.06 (d, J= 8.3 Hz, 2H), 6.54 - 6.49 (m, 2H), 5.18 (s, 2H), 1.23 - 1.18 (m, 2H), 0.95 (s, 2H).

[0205] A solution of compound 28-3 (771 mg, 3.83 mmol) and 1-(pyrimidin-5-yl)ethyl-1-one (468.01 mg, 3.83 mmol) in toluene (30 mL) was added with 4A MS (2 g) and AcOH (2.02 g, 33.70 mmol, 1.93 mL, 8.79 eq). The mixture was stirred at 125 °C under a nitrogen atmosphere for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the residue. Compound 28-4 (1.19 g, crude substance) was obtained. 1H NMR (400 MHz, DMSO- d 6): δ 9.33 - 9.28 (m, 3H), 7.47 (d, J= 8.2 Hz, 2H), 6.86 (d, J= 8.3 Hz, 2H), 2.30 (s, 3H), 1.37 - 1.30 (m, 2H), 1.13 (br s, 2H).

[0206] (2R)-2-chloro-2-fluoroacetic acid (939.55 mg, 4.68 mmol) and 1,1-difluoro-4-isocyanocyclohexane (665.61 mg, 3.90 mmol) were added to a solution of compound 28-4 (1.19 g, 3.90 mmol) in CF3CH2OH (15 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). The residue was purified by preparative HPLC (column: Xtimate C18 150×40 mm×10 μm; mobile phase: [water (FA)-ACN]; B%: 45% to 75%, 7 min). Compound 28 was obtained (340 mg, 603.98 μmol, 15.50% yield). LCMS (M+H) = 563.1. 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (d, J= 14.4 Hz, 1H), 8.82 (d, J= 7.3 Hz, 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= 6.6 Hz, 2H).

[0207] Compound 28 (340 mg) was separated by a palmar SFC (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), and then concentrated under vacuum to obtain two dissociated fractions.

[0208] Example 28a obtained: (130.08 mg, 38.26% yield). LCMS (M+H) = 563.1. SFC: Residence time: 0.770 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO- d 6): δ 9.05 (s, 1H), 8.83 (s, 2H), 7.77 - 7.67 (m, 2H), 7.59 - 7.44 (m, 2H), 7.22 (br d, J= 8.7 Hz, 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). 19F NMR (376 MHz, DMSO- d 6): δ-68.33 (br s, 3F), -91.86 (br d, J= 235.8 Hz, 1F), -99.41 (br d, J= 235.8 Hz, 1F), -142.19 (br s, 1F).

[0209] Example 28b obtained: (131.71 mg, 37.87% yield). LCMS (M+H) = 563.1. SFC: Residence time: 1.077 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO- d 6): δ 9.01 (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= 8.0 Hz, 1H), 6.30 - 6.11 (m, 1H), 3.80 (br d, J= 8.1 Hz, 1H), 1.96 (br d, J= 8.6 Hz, 4H), 1.78 (s, 4H), 1.69 - 1.47 (m, 3H), 1.38 - 1.32 (m, 2H), 1.10 (br s, 2H). 19F NMR (376 MHz, DMSO-d6): δ -68.39 (s, 3F), -91.35 - -92.65 (m, 1F), -98.74 --99.72 (m, 1F), -141.82 (s, 1F). Examples 29a and 29b

[0210] (2R)-2-chloro-2-fluoroacetic acid (318.49 mg, 1.67 mmol) and 4-isocyanotetrahydropiperanone (182.02 mg, 1.39 mmol) were added to a solution of 28-4 (425 mg, 1.39 mmol) in CF3CH2OH (2 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 55% to 85%, 7 min). Compound 29 was given (120 mg, 209.75 µmol, 15.07% yield). LCMS (M+H) = 529.1. 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (d, J= 14.5 Hz, 1H), 8.83 (d, J= 8.2 Hz, 2H), 7.73 (br d, J= 8.1 Hz, 1H), 7.67 - 7.31 (m, 4H), 6.38 - 6.09 (m, 1H), 3.83 (br, d, J= 8.5 Hz, 3H), 3.30 - 3.19 (m, 2H), 1.84 - 1.62 (m, 4H), 1.61 - 1.41 (m, 3H),1.40 - 1.32 (m, 2H), 1.11 (br, d, J= 7.9 Hz, 2H).

[0211] Compound 29 (120 mg) was separated by a palmar SFC (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), and then concentrated under vacuum to obtain two dissociated fractions.

[0212] Example 29a obtained: (36.48 mg, 30.02% yield). LCMS (M+H) = 529.0. SFC: Residence time: 2.417 min, AD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.04 (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= 7.7 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -68.30 (s, 3F), -142.12 (s, 1F).

[0213] Example 29b obtained: (40.19 mg, 33.14% yield). LCMS (M+H) = 529.1. SFC: Residence time: 3.378 min, AD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.01 (s, 1H), 8.82 (s, 2H), 7.62 (d, J= 7.6 Hz,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= 8.3 Hz, 3H), 3.31 - 3.27 (m, 2H), 1.80 (s, 3H), 1.67 (br d, J=13.1 Hz, 1H), 1.57 - 1.40 (m, 3H), 1.39 - 1.30 (m, 2H), 1.10 (br s, 2H). 19F NMR (376 MHz, DMSO-d 6): δ -68.38 (s, 3F), -141.79 (s, 1F). Examples 32a and 32b

[0214] H₃PO₄ (16 mg, 138.78 μmol, 9.52 μL) was added to a solution of 90-2 (230 mg, 694.36 μmol) in CF₃CH₂OH (2 mL). The mixture was stirred at 25 °C for 30 min. After 30 min, 4-isocyanotetrahydropiperanone (92 mg, 703.61 μmol) and (2R)-2-chloro-2-fluoroacetic acid (142 mg, 833.16 μmol) were added to the reaction mixture. The mixture was stirred at 25 °C for 18 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min) to obtain the product. The product was purified by preparative HPLC (Welch Xtimate C18 150×30mm×5μm; mobile phase: A: water (FA) B: ACN; gradient conditions: 46% B to 76% B; flow rate: 25 mL / min). The pure solvent was collected and volatile solvents were removed by evaporation. The aqueous residue was lyophilized to give compound 32 (28 mg, 7.27% yield).

[0215] Compound 32 (28 mg, 50.46 µmol) was separated into two dissociated fractions by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm)); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic ratio: A: B = 85:15; flow rate: 60 mL / min).

[0216] Example 32a was obtained: (6 mg, 20.89% yield). LCMS (M+H) = 555.1. SFC: Retention time: 2.107 min, AD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.85 (s, 2H), 7.85 (d, J= 8.4 Hz, 1H), 7.77 (d, J= 8.0 Hz, 1H), 7.49 (d, J= 8.8 Hz, 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 (376 MHz, DMSO-d 6): δ -85.32 (s, 3F), -87.18 (s, 2F), -142.26 (s, 1F).

[0217] Example 32b obtained: (5 mg, 17.40% yield). LCMS (M+H) = 555.1. SFC: Retention time: 2.653 min, AD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.02 (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 - 6.17 (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). 19F NMR (376 MHz, DMSO-d6): δ -85.30 (s, 3F), -87.17 (br s, 2F), -141.89 (s, 1F). Examples 33a and 33b

[0218] p-TsOH (267.41 mg, 1.55 mmol) was added to a solution of 33-1 (2 g, 10.35 mmol) and 1-pyrimidin-5-ylethyl ketone (1.26 g, 10.35 mmol) in toluene (30 mL). The mixture was stirred at 136 °C for 16 h while water was removed using a Dean-Stark separator under N2 atmosphere. The reaction mixture 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 rapid silica gel chromatography (0 to 16% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). Compound 33-2 (1.85 g, 48.09% yield) was given. 1H NMR (400 MHz, DMSO- d 6): δ 9.36 - 9.30 (m, 3H), 7.74 (d, J= 8.4 Hz, 2H), 7.10 - 6.96 (m, 2H), 2.34 - 2.21 (m, 3H).

[0219] (2R)-2-chloro-2-fluoroacetic acid (253 mg, 1.35 mmol) and 1,1-difluoro-4-isocyanocyclohexane (217.73 mg, 1.35 mmol) were added to a solution of 33-2 (500 mg, 1.35 mmol) in CF3CH2OH (5 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). Compound 33 was given (83 mg, 10.95% yield). LCMS (M+H) = 554.9. 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (d, J= 14.4 Hz, 1H), 8.83 (d, J= 5.2 Hz, 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). 19F NMR (376 MHz, DMSO- d 6): δ -41.68 (d, J= 27.7 Hz, 3F), -91.36 - -92.52 (m, 1F), -98.15 - -99.86 (m, 1F), -142.00 (d, J= 114.4 Hz, 1F).

[0220] Compound 33 (80 mg, 144.16 μmol, 1 eq) was separated into two dissociated fractions by SFC (DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 85:15; flow rate: 60 mL / min).

[0221] Example 33a was obtained: (27 mg, 32.63% yield). LCMS (M+H) = 555.1. SFC: Retention time: 0.775 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO-d 6): δ 9.05 (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). 19F NMR (376 MHz, DMSO- d 6): δ -40.01 - -44.72 (m, 3F), -91.89 (d, J= 235.8 Hz, 1F), -99.38 (d, J= 232.4 Hz, 1F), -142.16 (s, 1F).

[0222] Example 33b obtained: (43 mg, 50.82% yield). LCMS (M+H) = 555.1. SFC: Retention time: 0.944 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO-d 6): δ 9.01 (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=7.2 Hz, 1H), 1.98 - 1.45 (m, 11H). 19F NMR (376 MHz, 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). Examples 34a and 34b

[0223] H₃PO₄ (31.13 mg, 270.00 μmol, 18.53 μL) was added to a solution of compound 33-2 (500 mg, 1.35 mmol) in CF₃CH₂OH (5 mL). The mixture was stirred at 20 °C for 30 min. Subsequently, 4-isocyanotetrahydropiperanone (214.34 mg, 1.35 mmol) and (2R)-2-chloro-2-fluoroacetic acid (253 mg, 1.35 mmol) were added. The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by rapid silica gel chromatography and further purified by preparative HPLC to give compound 34 (73 mg, 10.23% yield). Compound 34 (98 mg, 188.13 µmol) was separated into two fractions by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 75:25; flow rate: 60 mL / min).

[0224] Example 34a obtained: (15 mg, 15.17% yield). LCNS (M+H) = 521.0. SFC: Retention time: 0.930 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO- d 6): δ 9.04 (s, 1H), 8.84 (s, 2H), 7.90 - 7.70 (m, 4H), 7.43 (d, J= 6.4 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -39.23 - -44.32 (m, 3F), -142.12 (s, 1F).

[0225] Example 34b obtained: (21 mg, 21.26% yield). LCMS (M+H) = 521.0. SFC: Residence time: 1.215 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO- d 6): δ 9.00 (s, 1H), 8.82 (s, 2H), 7.79 - 7.65 (m, 4H), 7.58 (d, J= 7.6 Hz, 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= 12.4 Hz, 1H), 1.62 - 1.55 (m, 1H), 1.54 - 1.41 (m, 2H). 19F NMR (376 MHz, DMSO-d6): δ -41.72 (s, 3F), -141.85 (s, 1F). Examples 36a and 36b

[0226] TEA (7.27 g, 71.85 mmol, 10.00 mL) was added to a solution of 36-1 (5 g, 35.93 mmol, 4.67 mL) in ethyl formate (50 mL). The mixture was stirred at 80 °C for 16 hours. 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 substance) was obtained. LCMS (M+H) = 167.8.

[0227] PPh 3 (7.91 g, 30.14 mmol), TEA (3.05 g, 30.14 mmol, 4.20 mL), and CCl 4 (4.64 g, 30.14 mmol, 2.90 mL) were added to a solution of 36-2 (6.46 g, 30.14 mmol, 4.20 mL) in DCM (60 mL). The mixture was stirred at 45 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. Subsequently, MTBE (40 mL) and PE (40 mL) were added, and the mixture was stirred at 20 °C for 16 hours. The reaction mixture 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 rapid silica gel chromatography (0 to 10% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). Compound 36-3 (3.8 g, 25.48 mmol, 84.52% yield) was given.

[0228] (2R)-2-chloro-2-fluoroacetic acid (1.29 g, 6.40 mmol) and compound 36-3 (837.47 mg, 5.33 mmol) were added to a solution of compound 4-3 (1.5 g, 5.33 mmol) in CF3CH2OH (20 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). The residue was purified by preparative HPLC (column: Xtimate C18 150×40 mm×10 μm; mobile phase: [water(FA)-ACN]; B%: 45% to 75%, 7 min). Compound 36 was given (530 mg, 976.27 μmol, 18.30% yield). LCMS (M+H) = 543.1. 1HNMR (400 MHz, DMSO- d 6) δ 9.09 - 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).

[0229] 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 ratio: A: B = 75:25; flow rate: 60 mL / min), and concentrated under vacuum to obtain two fractions. The residue was further purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 55% to 85%, 7 min).

[0230] Example 36a was obtained: (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_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.82 (s, 2H), 8.13 (t, J= 5.7 Hz,1H), 7.76 (br d, J= 8.7 Hz, 1H), 7.46 (br d, J= 9.2 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.81 (s, 3F), -113.74 (s, 1F), -142.49 (s, 1F).

[0231] Example 36b was obtained: (51.98 mg, 95.75 µmol, 31.31% yield). LCMS (M+H) = 543.4. SFC: Retention time: 4.244 min, C2_MeOH_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.00 (s, 1H), 8.77 (s, 2H), 8.02 (t, J= 5.5 Hz, 1H), 7.61 (br d, J= 8.7 Hz, 1H), 7.53 (br d, J= 8.6 Hz, 1H), 7.38 (br t, J= 7.2 Hz, 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, 7.1 Hz, 2H), 1.74 (s, 3H). 19F NMR (376 MHz, DMSO-d6): δ -56.87 (s, 3F), -113.68 (s, 1F), -141.73 (s, 1F). Examples 76a, 76b, 76c and 76d

[0232] TEA (916 mg, 9.05 mmol, 1.26 mL) was added to a solution of compound 76-1 (500 mg, 3.02 mmol HCl) in ethyl formate (20 mL). The mixture was stirred at 80 °C for 18 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then diluted with DCM (10 mL). The organic layer was washed with H₂O (10 mL × 2) and brine (10 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. The crude product was used in the next step without further purification. Compound 76-2 (159 mg, 809.11 μmol, 26.81% yield) was obtained. 1H NMR (400 MHz, CDCl 3): δ 8.23 ​​(s, 1H), 4.12 - 3.90 (m, 2H), 3.59 - 3.40 (m, 2H), 3.26 - 3.09 (m, 1H), 1.72 -1.61 (m, 2H), 1.01 - 0.95 (m, 3H), 0.87 (s, 3H).

[0233] A mixture of compound 76-2 (159 mg, 1.01 mmol), PPh 3 (266 mg, 1.01 mmol), TEA (103 mg, 1.02 mmol, 141.68 μL), and CCl 4 (156 mg, 1.01 mmol, 97.50 μL) in DCM (1 mL) was stirred at 45 °C under a N 2 atmosphere for 18 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the residue. The crude product was used in the next step without further purification. Compound 76-3 (140 mg, crude substance) was obtained.

[0234] (2R)-2-chloro-2-fluoroacetic acid (122.03 mg, 640.04 μmol) and compound 76-3 (140 mg, 533.07 μmol) were added to a solution of compound 4-3 (150 mg, 533.37 μmol) in CF3CH2OH (2 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 53% to 83%, 7 min). Compound 76 was given (24 mg, 43.45 μmol, 8.15% yield). LCMS (M+H) = 533.1.

[0235] Compound 76 (24 mg) was separated into two fractions by SFC (DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 85:15; flow rate: 60 mL / min). Fraction 1 (17 mg) was separated into two fractions by SFC (Phenomenex-Cellulose-2 (250 mm × 30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 60:40; flow rate: 80 mL / min). The two dissociated fractions 2 (14 mg) were further separated by SFC (DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm)); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A: B = 75:25; flow rate: 70 mL / min) to obtain two dissociated fractions.

[0236] Example 76a was obtained: (2.50 mg, 14.62% yield). LCMS (M+H) = 533.1. SFC: Residence time: 1.228 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (s, 1H), 8.80 (s, 2H), 7.77 (br d, J= 8.9 Hz,1H), 7.50 - 7.36 (m, 4H), 6.45 - 6.27 (m, 1H), 3.88 (br d, J= 9.7 Hz, 2H), 3.40 -3.36 (m, 2H), 3.09 (d, J= 11.3 Hz, 1H), 1.76 (s, 4H), 1.40 (br d, J= 15.3 Hz, 1H), 0.85 (s, 3H), 0.77 (s, 3H). 19F NMR (376 MHz, DMSO-d 6): δ -56.84 (s, 3F), -141.89 (br s, 1F).

[0237] Example 76b obtained: (1.55 mg, 9.00% yield). LCMS (M+H) = 533.1. SFC: Residence time: 1.315 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.09 (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= 11.2 Hz, 2H), 3.09 (d, J= 11.4 Hz, 1H), 1.74 (br dd, J= 5.2, 12.9 Hz, 1H), 1.60(s, 3H), 1.31 (br d, J= 11.6 Hz, 1H), 0.91 (s, 3H), 0.77 (s, 3H). 19F NMR (376 MHz, DMSO-d 6): δ -56.78 (s, 3F), -142.45 (s, 1F)

[0238] Example 76c obtained: (2.07 mg, 14.79% yield). LCMS (M+H) = 533.1. SFC: Residence time: 1.528 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.93 (s, 2H), 7.69 - 7.54 (m, 2H), 7.45 (br dd, J= 8.8, 13.5 Hz, 2H), 7.33 (d, J= 9.1 Hz, 1H), 6.41 - 6.21 (m, 1H), 3.90 - 3.80 (m, 2H), 3.39 (br d, J= 11.2 Hz, 2H), 3.09 (d, J= 11.2 Hz, 1H), 1.69 (s,4H), 1.33 (br d, J= 13.1 Hz, 1H), 0.88 (s, 3H), 0.79 (s, 3H). 19F NMR (376 MHz, DMSO-d 6): δ -56.84 (s, 3F), -141.58 (s, 1F).

[0239] Example 76d obtained: (1.18 mg, 8.26% yield). LCMS (M+H) = 533.1 SFC: residence time: 1.637 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.01 (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= 8.9 Hz, 1H), 6.41 - 6.25 (m, 1H), 3.95 -3.83 (m, 2H), 3.41 - 3.36 (m, 2H), 3.09 (d, J= 11.3 Hz, 1H), 1.86 (s, 3H), 1.73 (dt, J= 7.3, 12.5 Hz, 1H), 1.37 (br d, J= 11.1 Hz, 1H), 0.87 (s, 3H), 0.75 (s, 3H). 19F NMR (376 MHz, DMSO-d6): δ-56.40 - -57.12 (m, 3F), -141.77 (s, 1F). Examples 77a, 77b, 77c and 77d: TEA (2.35 g, 23.22 mmol, 3.23 mL) was added to a solution of compound 77-1 (1 g, 7.74 mmol) in ethyl formate (10 mL). The mixture was heated and stirred at 80 °C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give compound 77-2 (1.2 g), which was used directly in the next step.

[0240] TEA (772.40 mg, 7.63 mmol, 1.06 mL), PPh 3 (2.00 g, 7.63 mmol), and CCl 4 (1.17 g, 7.63 mmol, 733.83 μL) were added to a solution of compound 77-2 (1.2 g, 7.63 mmol) in DCM (14 mL). The mixture was heated and stirred at 45 °C for 12 hours. The mixture was concentrated under reduced pressure at 20 °C to give crude material. The mixture was wet-milled with MTBE (10 mL) to give product. The residue was purified by rapid silica gel chromatography (0 to 50% dichloromethane / petroleum ether gradient solvent, at 100 mL / min). Compound 77-3 (1.0 g, crude material) was obtained. 1H NMR (400 MHz, CDCl 3): δ 3.86 - 3.74 (m, 2H), 3.59 (dt, J= 2.4, 12.0 Hz, 1H), 2.06 - 1.93 (m, 2H), 1.87 - 1.60 (m, 2H), 1.32 - 1.25 (m, 3H), 1.18 (s, 3H).

[0241] (2R)-2-chloro-2-fluoroacetic acid (775.81 mg, 6.90 mmol), compound 77-3 (1.0 g, 5.75 mmol), and 4A MS (1.0 g, 5.75 mmol) were added to a solution of compound 4-1 (1.62 g, 5.75 mmol) in CF3CH2OH (10 mL). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 45 mL / min) to obtain a residue (1.0 g). The residue was purified by preparative HPLC (column: Xtimate C18 150 × 40 mm × 10 μm; mobile phase: [water (FA)-ACN]; B%: 35% to 65%, 6 min). Compound 77 was obtained (500 mg, 938.24 μmol, 16.32% yield). LCMS (M+H) = 533.2.

[0242] 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, 70 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm), yielding 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, 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm), yielding two dissociated fractions. The pure fraction 2 was further separated by supercritical fluid chromatography (separation conditions: DAICEL CHIRALPAK IG (250 mm × 30 mm, 10 μm)); mobile phase: A: supercritical CO2, B: Neu-IPA, A:B = 75:25, 70 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm) to obtain two fractions.

[0243] Example 77a was obtained: (8.11 mg). LCMS (M+H) = 532.8. SFC: Residence time: 1.694 min, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1H NMR (400MHz, DMSO- d 6): δ 9.05 (s, 1H), 8.84 (s, 2H), 7.84 (d, J= 8.8 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.48 (d, J= 8.8 Hz, 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= 12.4 Hz, 1H), 1.17 (s, 3H), 1.13 (s, 3H). 19F NMR (376 MHz, DMSO- d 6) δ -56.83 (s, 3F), -142.3 (s, 1F).

[0244] Example 77b obtained: (39.92 mg, 7.93% yield). LCMS (M+H) = 532.8. SFC: Residence time: 1.765 min, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.06 (s, 1H), 8.85 (s, 2H), 7.85 (d, J= 8.8 Hz, 1H), 7.69 (d, J=8.0 Hz, 1H), 7.48 (d, J= 8.8 Hz, 1H), 7.39 (s, 2H), 6.45 - 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). 19F NMR (376 MHz, DMSO- d 6) δ -56.83 (s, 3F), -142.3 (s, 1F).

[0245] Example 77c obtained: (33.26 mg, 6.61% yield). LCMS (M+H) = 532.9. SFC: Residence time: 1.994 min, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.02 (s, 1H), 8.83 (s, 2H), 7.69 (dd, J=2.4, 8.8 Hz, 1H), 7.61 (d, J=8.0 Hz, 1H), 7.54 (dd, J=2.4, 8.4 Hz, 1H), 7.40 (dd, J=8.8, 13.6 Hz, 2H), 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). 19F NMR (376 MHz, DMSO-d 6) δ -56.87 (s, 3F), -141.87 (s, 1F).

[0246] Example 77d obtained: (39.77 mg, 7.81% yield). LCMS (M+H) = 532.8. SFC: Residence time: 2.738 min, IG_3_EtOH_DEA_5_40_28ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (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=12.4 Hz, 1H), 1.18 (s, 3H), 1.13 (s, 3H). 19F NMR (376 MHz, DMSO-d6) δ -56.87 (s, 3F), -141.89 (s, 1F). Examples 90a and 90b

[0247] 4-Methylbenzenesulfonic acid (60.65 mg, 352.22 μmol) was added to a solution of 90-1 (400 mg, 1.76 mmol) and 1-(pyrimidin-5-yl)ethyl-1-one (322.61 mg, 2.64 mmol) in toluene (20 mL). The mixture was stirred at 140 °C for 16 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 25% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). The aqueous residue was lyophilized to give 90-2 (270 mg, 41.66% yield). 1H NMR (400 MHz, DMSO- d 6): δ 9.32 (s, 3H), 7.39 (d, J= 8.8 Hz, 2H), 7.05 - 6.94 (m, 2H), 2.29 (s, 3H).

[0248] H₃PO₄ (18.79 mg, 163.02 μmol) was added to a solution of 90-2 (270 mg, 815.12 μmol) in CF₃CH₂OH (2 mL). After addition, the mixture was stirred at 25 °C for 0.5 h, and then 1,1-difluoro-4-isocyanocyclohexane (131.46 mg, 815.12 μmol) and (2R)-2-chloro-2-fluoroacetic 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 the residue. The residue was purified by rapid silica gel chromatography (0 to 60% ethyl acetate / petroleum ether gradient solvent, 30 mL / min) to give a crude product, which was further purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water (FA)-ACN]; B%: 53% to 83%, 7 min) to give compound 90 (80 mg, 16.61% yield). LCMS (M+H) = 589.0. ¹H NMR (400 MHz, DMSO-d⁶): δ 9.05 (d, J = 12.8 Hz, 1H), 8.84 (d, J = 5.6 Hz, 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 into two fractions by SFC (WHELK-O1 (250 mm × 30 mm, 5 μm)); mobile phase: A: supercritical CO₂, B: Neu-EtOH; isocratic ratio: A: B = 80:20).

[0249] Example 90a was obtained: (12 mg, 16.59% yield). LCMS (M+H) = 589.0. SFC: Residence time: 2.367 min, (SS) Whelk-01_EtOH (DEA)_5_4. 1H NMR (400 MHz, DMSO- d 6): δ 9.12 - 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). 19F NMR (376 MHz, DMSO- d 6): 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).

[0250] Example 90b obtained: (12 mg, 16.18% yield). LCMS (M+H) = 589.1. SFC: Residence time: 2.594 min, (SS) Whelk-01_EtOH (DEA)_5_4. 1H NMR (400 MHz, DMSO- d 6): δ 9.12 - 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). 19F NMR (376 MHz, DMSO-d 6): δ -85.04 - -85.42 (m, 3F), -86.87 - -87.35 (m, 2F), -92.04 (br d, J=233.0 Hz, 1F), -97.87 - -101.44 (m, 1F), -141.92 (br s, 1F). Examples 92a and 92b

[0251] In a Dean-Stark separator, p-TsOH (210.26 mg, 1.22 mmol) and 1-pyrimidin-5-ylethyl ketone (1.15 g, 9.39 mmol) were added to a solution of compound 92-1 (2.0 g, 10.33 mmol) in toluene (60 mL). The mixture was heated and stirred at 140 °C for 12 h. The mixture was filtered, and the filter cake was washed with toluene (20 mL × 3). The organic layer was concentrated under reduced pressure to give crude material. The crude material was purified by rapid silica gel chromatography (0 to 30% ethyl acetate / petroleum ether gradient solvent, 45 mL / min, TLC: petroleum ether: ethyl acetate = 3:1, Rf = 0.4) to give compound 92-2 (1.7 g, 5.71 mmol, 60.80% yield).

[0252] H₃PO₄ (104.57 mg, 906.99 μmol, 62.24 μL) was added to a solution of compound 92-2 (1.35 g, 4.53 mmol) in CF₃CH₂OH (2 mL). The mixture was stirred at 25 °C for 1 h, followed by (2R)-2-chloro-2-fluoro-acetic acid (927.50 mg, 5.44 mmol, 66% purity) and 1,1-difluoro-4-isocyanocyclohexane (658.25 mg, 4.53 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was concentrated under reduced pressure to give crude material. The crude material was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, TLC at 40 mL / min (petroleum ether:ethyl acetate = 0:1, Rf = 0.4)) to give crude material (300 mg). The crude material was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 60% to 90%, 7 min) to give compound 92 (57 mg, 15.20% yield). LCMS (M+H) = 554.6.

[0253] Compound 92 (50 mg, 90.04 μmol) was separated by vacuum concentration using a palmar SFC column: DAICL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: [Neu-ETOH]; B%: 15% to 15%; mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B = 85:15; flow rate: 60 mL / min) to obtain two dissociated fractions.

[0254] Example 92a was obtained: (10.97 mg). LCMS (M+H) = 555.1. SFC: Residence time: 1.555 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400MHz, methanol-d 4): δ 9.04 (s, 1H), 8.92 (s, 2H), 7.70 (d, J=7.2 Hz, 1H), 7.42 (d, J=8.8 Hz, 2H), 7.38 - 7.32 (m, 1H), 6.30 - 6.12 (m, 1H), 3.95 (t, J=10.8 Hz, 1H), 2.07 (d, J=8.0 Hz, 2H), 2.01 - 1.86 (m, 4H), 1.82 (s, 3H), 1.74 - 1.58 (m, 2H). 19F NMR (376 MHz, methanol-d4) δ -27.36 (s, 2F), -94.53 - -105.14 (m, 2F), -145.33 (s, 1F).

[0255] Example 92b obtained: (6.51 mg). LCMS (M+H) = 555.1. SFC: Residence time: 1.972 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, CD 3OD): δ 9.01 (s, 1H), 8.90 (s, 2H), 7.68 (dd, J= 2.4, 8.4 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.39 - 7.31 (m, 2H), 6.27 - 6.11 (m, 1H), 3.92 (t, J= 11.2 Hz, 1H), 2.06 (dd, J= 4.0, 7.2 Hz, 2H), 1.97 - 1.89 (m, 6H), 1.88 - 1.81 (m, 1H), 1.72 - 1.58 (m, 2H). 19F NMR (376 MHz, CD 3OD): δ -25.83 - -29.74 (m, 2F), -93.88 - -104.98 (m, 2F), -145.27 (s, 1F). Examples 94a and 94b

[0256] H₃PO₄ (104.57 mg, 906.99 μmol, 62.24 μL) was added to a solution of compound 92-2 (1.35 g, 4.53 mmol) in CF₃CH₂OH (2 mL), and the mixture was stirred at 25 °C for 1 h. Then, (2R)-2-chloro-2-fluoroacetic acid (927.50 mg, 5.44 mmol, 66% purity) and 4-isocyanotetrahydropiperanone (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 obtain a crude product. The crude product was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, TLC at 40 mL / min (petroleum ether:ethyl acetate = 0:1, Rf = 0.4)) to obtain a crude product (300 mg). The crude material was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 48% to 78%, 7 min) to give compound 94 (57 mg, 2.11% yield). LCMS (M+H) = 520.7.

[0257] Compound 94 (46 mg, 88, 24 μmol) was separated by vacuum concentration using a palmar SFC column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: [Neu-ETOH]; B%: 20% to 20%, min; mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B = 80:20; flow rate: 60 mL / min) to obtain two dissociated fractions.

[0258] Example 94a obtained: (7.38 mg). LCMS (M+H) = 521.1. SFC: Residence time: 1.797 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, CD 3OD): δ 9.07 (s, 1H), 8.97 - 8.87 (m, 2H), 7.73 (d, J= 8.4 Hz, 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). 19F NMR (376 MHz, CD 3OD): δ -27.34 (s, 2F), -145.3 (s, 1F).

[0259] Example 94b obtained: (10.02 mg). LCMS (M+H) = 521.1. SFC: Residence time: 2.189 min, OD_ETOH_DEA_5_40_28ML_8MIN. ¹H NMR (400 MHz, CD 3OD): δ 9.05 (s, ¹H), 8.97 - 8.87 (m, 2H), 7.71 (d, J = 8.4 Hz, 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). ¹⁹F NMR (376 MHz, CD 3OD): δ -27.34 (s, 2F), -145.3 (s, 1F). Examples 95a and 95b.

[0260] 33-1 (1.2 g, 6.21 mmol, 888.89 μL) and 1-(5-fluoropyridin-3-yl)ethyl-1-one (576.13 mg, 4.14 mmol) were added to toluene (25 mL) with p-TsOH (106.96 mg, 621.15 μmol). 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 the residue. The residue was purified twice by rapid silica gel chromatography (0 to 20% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). Compound 95-1 was given (620 mg, 1.78 mmol, 42.87% yield).

[0261] A solution of compound 95-1 (310.00 mg, 986.32 μmol) in CF3CH2OH (2 mL) was added with H3PO4 (19.33 mg, 197.26 μmol, 11.51 μL), (2R)-2-chloro-2-fluoroacetic acid (188.05 mg, 986.32 μmol), and 1,1-difluoro-4-isocyanocyclohexane (159.07 mg, 986.32 μmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 30% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 57% to 87%, 7 min). Compound 95 was obtained (55 mg, 94.84 μmol, 9.62% yield, 98.62% purity).

[0262] Compound 95 (55 mg) was separated by a palmar 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), followed by vacuum concentration to obtain two soluble fractions. Example 95a was obtained: (19.34 mg, 34.22% yield). LCMS (M+H) = 572.1. SFC: residence time: 2.471 min, AD-3_IPA(DEA)_5_40_25 mL. 1H NMR (400 MHz, DMSO- d 6): δ 8.46 (s, 1H), 8.43 (d, J= 2.7 Hz, 1H), 7.76 (brs, 2H), 7.67 (br d, J= 8.1 Hz, 3H), 7.37 (br s, 1H), 6.45 - 6.24 (m, 1H), 3.87 (br d, J= 8.0 Hz, 1H), 2.07 - 1.87 (m, 4H), 1.84 (s, 3H), 1.78 (br s, 2H), 1.63 - 1.50 (m,2H). 19F NMR (376 MHz, DMSO- d 6): δ -41.83 (s, 3F), -91.86 (br d, J= 232.4 Hz, 1F), -99.37 (br d, J= 232.4 Hz, 1F), -128.08 (br s, 1F), -141.75 (s, 1F).

[0263] Example 95b was obtained: (18.37 mg, 31.42% yield). LCMS (M+H) = 572.1. SFC: Residence time: 2.630 min, AD-3_IPA(DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 8.44 (s, 1H), 8.38 (d, J= 2.6 Hz, 1H), 7.71 -7.62 (m, 4H), 7.55 (br d, J= 8.2 Hz, 2H), 6.44 - 6.22 (m, 1H), 3.86 (br s, 1H), 2.07- 1.81 (m, 7H), 1.75 (br t, J= 15.1 Hz, 2H), 1.65 - 1.45 (m, 2H). 19F NMR (376 MHz, DMSO-d 6): δ -40.85 - -44.01 (m, 3F), -91.97 (br d, J = 232.4 Hz, 1F), -99.29 (br d, J = 235.8 Hz, 1F), -128.06 (s, 1F), -141.86 (s, 1F). Examples 96a and 96b

[0264] To a solution of compound 95-1 (310.00 mg, 986.32 μmol) in CF3CH2OH (2 mL), 85% H3PO4 (19.33 mg, 197.26 μmol, 11.51 μL), 4-isocyanotetrahydropiperanone (128.97 mg, 986.32 μmol) and (2R)-2-chloro-2-fluoroacetic acid (188.05 mg, 986.32 μmol) were added. The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 70% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). The residue was purified by preparative HPLC (column: Welch Xtimate C18 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 50% to 80%, 7 min). Compound 96 was obtained (75 mg, 139.42 μmol, 14.14% yield, 100% purity). LCMS (M+H) = 538.0. 1H NMR (400 MHz, DMSO- d 6): δ 8.48 - 8.43 (m, 1H), 8.40 (dd, J= 2.6, 15.1 Hz,1H), 7.74 (br s, 1H), 7.71 - 7.64 (m, 3H), 7.55 (d, J= 8.0 Hz, 1H), 7.35 (br d, J= 8.6Hz, 1H), 6.43 - 6.24 (m, 1H), 4.01 - 3.79 (m, 3H), 3.31 - 3.24 (m, 2H), 2.01 - 1.82(m, 3H), 1.69 - 1.58 (m, 2H), 1.55 - 1.43 (m, 2H).

[0265] Compound 96 (75 mg) was separated by a palmar 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 then concentrated under vacuum to obtain two dissociated fractions.

[0266] Example 96a was obtained: (16.65 mg, 22.20% yield). LCMS (M+H) = 549.1. SFC: Residence time: 2.228 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.46 (s, 1H), 8.42 (d, J = 2.6 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -41.13 - -43.31 (m, 3F), -128.11 (s, 1F), -141.68 (s, 1F).

[0267] Example 96b obtained: (13.02 mg, 25.89% yield). LCMS (M+H) = 537.9. SFC: Residence time: 2.909 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.45 (s, 1H), 8.38 (d, J= 2.5 Hz, 1H), 7.70 -7.63 (m, 4H), 7.55 (d, J= 8.0 Hz, 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). 19F NMR (376 MHz, DMSO-d6): δ -39.70 - -46.27 (m, 3F), -128.10 (s, 1F), -141.82 (s, 1F). Examples 97a and 97b

[0268] p-TsOH (109.99 mg, 638.76 μmol) was added to a solution of compound 22-1 (1.4 g, 6.39 mmol) and 1-(5-fluoro-3-pyridyl)acetone (600 mg, 4.31 mmol) in toluene (70 mL). The mixture was stirred at 135 °C for 16 h while water was removed using a Dean-Stark separator under N2 atmosphere. The reaction mixture 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 rapid silica gel chromatography (0 to 100% DCM / petroleum ether gradient solvent, at 20 mL / min). Compound 97-1 (357 mg, 23.40% yield). 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (s, 1H), 8.75 (d, J= 2.8 Hz, 1H), 8.22 (d, J= 9.8 Hz, 1H), 7.91 (d, J= 8.8 Hz, 2H), 7.03 (d, J= 8.2 Hz, 2H), 2.27 (s, 3H).

[0269] A solution of compound 97-1 (357 mg, 1.05 mmol) in CF3CH2OH (2 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (211 mg, 1.05 mmol). Subsequently, 4-isocyanotetrahydropiperanone (167 mg, 1.05 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 rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 25 mL / min). Compound 97 (100 mg, 16.71% yield). LCMS (M+H) = 563.9. 1H NMR (400 MHz, DMSO- d 6): 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).

[0270] Compound 97 (100 mg, 177.33 μmol) was separated into two fractions by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A: B = 85:15; flow rate: 80 mL / min). The two fractions were further purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 53% to 83%, 7 min).

[0271] Example 97a was obtained: (15 mg, 14.83% yield). LCMS (M+H) = 564.2. SFC: Residence time: 2.389 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.59 - 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). 19F NMR (376 MHz, DMSO-d 6): δ 63.99 (br d, J= 151.6 Hz, 5F), -128.02 (s, 1F), -142.20 (s, 1F).

[0272] Example 97b obtained: (20 mg, 19.75% yield). LCMS (M+H) = 564.2. SFC: Residence time: 2.701 min, AD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.56 - 8.41 (m, 2H), 7.92 (d, J= 8.4 Hz, 2H), 7.82 - 7.57 (m, 4H), 6.49 - 6.27 (m, 1H), 3.84 (d, J= 11.2 Hz, 3H), 3.30 (s, 2H), 1.90 (s, 3H), 1.67 (d, J= 12.4 Hz, 1H), 1.62 - 1.55 (m, 1H), 1.55 - 1.40 (m, 2H). 19F NMR (376 MHz, DMSO-d 6): δ 63.96 (br d, J = 148.8 Hz, 5F), -127.95 (s, 1F), -142.05 (s, 1F). Examples 98a and 98b

[0273] In a Dean-Stark separator, p-TsOH (192.71 mg, 1.12 mmol) and 1-(5-fluoropyridin-3-yl)ethyl-1-one (1.20 g, 8.61 mmol) were added to a solution of compound 92-1 (2.0 g, 10.33 mmol) in toluene (60 mL). The mixture was heated and stirred at 140 °C for 12 hours. The mixture was filtered, and the filter cake was washed with toluene (30 mL × 3). The organic layer was concentrated under reduced pressure to give crude material. The crude material was purified by rapid silica gel chromatography (0 to 25% ethyl acetate / petroleum ether gradient solvent, 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). 1H NMR (400 MHz, CDCl 3) δ8.87 (t, J= 1.6 Hz, 1H), 8.51 (d, J= 2.8 Hz, 1H), 8.02 - 7.96 (m, 1H), 7.22 - 7.15 (m, 2H), 6.76 - 6.71 (m, 2H), 2.22 (s, 3H).

[0274] To a solution of compound 98-1 (230 mg, 730.88 μmol) in CF3CH2OH (2 mL), (2R)-2-chloro-2-fluoroacetic acid (167.22 mg, 877.05 μmol, 59% purity), 4-isocyanotetrahydropiperanone (81.23 mg, 730.88 μmol) and 4A MS (200 mg, 730.88 μmol) were added. The mixture was stirred at 25 °C for 2 hours. The mixture was filtered, and the organic layer was concentrated under reduced pressure to obtain the crude substance. The crude material was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, 30 mL / min, TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.2) and further purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 55% to 85%, 7 min) to give compound 98 (60 mg, 111.46 μmol, 15.25% yield). LCMS (M+H) = 539.8. Residue compound 98 (60 mg, 111.4 μmmol) 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, 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm), yielding two fractions. The 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.

[0275] Example 98a obtained: (16.05 mg, 24.16% yield). LCMS (M+H) = 538.0 SFC: residence time: 2.425 min, AD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, CD 3OD): δ 8.54 (s, 1H), 8.39 (d, J= 2.4 Hz, 1H), 7.77 (td, J= 2.4, 10.2 Hz, 1H), 7.67 - 7.59 (m, 1H), 7.46 - 7.36 (m, 2H), 7.31 (d, J= 8.8 Hz, 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). 19F NMR (376MHz, CD 3OD) δ-27.29 (s, 2F), -128.11 (s, 1F), -141.97 - -146.50 (m, 1F).

[0276] Example 98b obtained: (20.35 mg, 31.70% yield). LCMS (M+H) = 538.4. SFC: Residence time: 2.866 min, AD_3_EtOH_DEA_5_40_25ML_7MIN. 1H NMR (400 MHz, CD 3OD): δ8.49 (s, 1H), 8.32 (d, J=2.4 Hz, 1H), 7.76 - 7.73 (m, 1H), 7.58 - 7.52 (m, 1H), 7.46 - 7.40 (m, 1H), 7.28 (d, J= 8.8 Hz, 2H), 6.28 - 6.13 (m, 1H), 4.07 - 4.00 (m, 1H), 3.95 (t, J= 9.2 Hz, 2H), 3.53 - 3.45 (m, 2H), 2.06 (s, 3H), 1.89 - 1.76 (m, 2H), 1.68 - 1.50 (m, 2H). 19F NMR (376 MHz, CD 3OD): δ -26.51 - -28.09 (m, 2F), -128.20 (s, 1F), -143.35 - -147.88 (m, 1F). Examples 99a and 99b

[0277] A solution of compound 98-1 (230 mg, 730.88 mmol) in CF3CH2OH (2 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (167.22 mg, 877.05 μmol), 1,1-difluoro-4-isocyanocyclohexane (106.09 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 obtain the crude substance. The crude material was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, 30 mL / min, TLC: petroleum ether: ethyl acetate = 1:1, Rf = 0.5) and further purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 62% to 92%, 7 min) to give compound 99 (60 mg, 104.84 μmol, 14.34% yield). LCMS (M+H) = 572.2.

[0278] Residual compound 99 (60 mg, 104.8 μmmol) 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, 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm), yielding two fractions. The 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 give the title compound.

[0279] Example 99a obtained: (14.88 mg, 24.80% yield). LCMS (M+H) = 573.8. SFC: Residence time: 1.935 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, CD 3OD): δ 8.41 (s, 1H), 8.26 (d, J= 2.4 Hz, 1H), 7.65 (td, J=2.4, 10.4 Hz, 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= 11.2 Hz, 1H), 2.04 - 1.84 (m, 5H), 1.81 (s, 3H), 1.79 - 1.71 (m, 1H), 1.65 - 1.48 (m, 2H). 19F NMR (376 MHz, CD 3OD) δ-24.74 - -30.45 (m, 2F), -93.89 - -107.68 (m, 2F), -125.61 - -131.72 (m, 1F), -145.01 (br. s, 1F).

[0280] Example 99b obtained: (6.19 mg, 10.27% yield). LCMS (M+H) = 573.9. SFC: Residence time: 2.400 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, CD 3OD): δ8.48 (s, 1H), 8.32 (d, J= 2.4 Hz, 1H), 7.74 (td, J= 2.4, 10.4 Hz, 1H), 7.58 - 7.52 (m, 1H), 7.46 - 7.38 (m, 1H), 7.28 (d, J= 8.8 Hz, 2H), 6.29 - 6.11 (m, 1H), 3.94 (t, J= 10.8 Hz, 1H), 2.05 (s, 5H), 1.99 - 1.82 (m, 4H), 1.74 - 1.57 (m, 2H). 19F NMR (376 MHz, CD 3OD) δ -27.05 - -27.53 (m, 2F), -91.31 - -107.89 (m, 2F), -128.18 (s, 1F), -145.24 (s, 1F). Examples 100a and 100b

[0281] Na₂CO₃ (16.15 g, 152.42 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (2.49 g, 3.05 mmol) were added to a solution of compound 100-1 (10 g, 60.97 mmol) and [4-(tributoxycarbonylamino)phenyl] acid (14.60 g, 61.58 mmol) in dimethyl ether (100 mL) and water (10 mL). The mixture was stirred at 90 °C under N₂ for 16 hours. The mixture was filtered and concentrated under reduced pressure to obtain a crude substance, which was diluted with ethyl acetate (150 mL) and water (150 mL). The aqueous layer was extracted with ethyl acetate (150 mL × 5), and the organic layer was dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to obtain a crude substance. The residue was purified by rapid silica gel chromatography (0 to 30% ethyl acetate / petroleum ether gradient solvent, at 85 mL / min) to give compound 100-2 (7.18 g, 16.38% yield). LCMS (M+H) = 276.9. ¹H NMR (400 MHz, DMSO-d 6): δ 1.47 - 1.49 (m, 9H) 7.44 (br d, J = 8.34 Hz, 2H) 7.73 (d, J = 8.34 Hz, 2H) 7.83 (s, 1H) 9.19 - 9.51 (m, 1H).

[0282] HCl / dimethyl alkylene (4 M, 50 mL, 7.70 eq) was added to a solution of 100-2 (7.18 g, 25.97 mmol) in DCM (70 mL). The reaction mixture was concentrated, and water (50 mL) was added to the residue. The mixture was adjusted to pH 8 with saturated Na₂CO₃ solution and 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 crude compound 100-3 (1.0 g, crude compound), which was used in the next step without further purification.

[0283] p-TsOH (117.25 mg, 680.90 μmol) was added to a solution of compound 100-3 (1 g, 4.54 mmol) and 1-pyrimidin-5-ylethyl ketone (550 mg, 4.50 mmol) in toluene (70 mL). The mixture was stirred at 140 °C for 16 h while water was removed using a Dean-Stark separator under N2 atmosphere. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 10% ethyl acetate / petroleum ether gradient solvent, at 25 mL / min). Compound 100-4 (688 mg, 51.36% yield). 1H NMR (400 MHz, DMSO- d 6): δ 9.38 - 9.30 (m, 3H), 8.05 - 7.94 (m, 2H), 7.92 (d, J= 3.2 Hz, 1H), 7.76 (d, J= 3.2 Hz, 1H), 6.99 (d, J= 8.4 Hz, 2H), 2.33 (s, 3H).

[0284] A solution of compound 100-4 (344 mg, 1.23 mmol) in CF3CH2OH (1.5 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (230.05 mg, 1.23 mmol). Then, 1,1-difluoro-4-isocyanocyclohexane (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 the residue. The residue was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). Compound 100 (234 mg, 33.47% yield) was given. LCMS (M+H) = 537.9. 1H NMR (400 MHz, DMSO- d 6): δ 9.03 (d, J= 18.4 Hz, 1H), 8.85 (d, J= 7.6 Hz, 2H), 7.99 - 7.90 (m, 3H), 7.85 (t, J= 3.6 Hz, 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).

[0285] Compound 100 (120 mg, 223.05 µmol) was separated into two dissociated fractions by SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 µm)); mobile phase: A: supercritical CO2, B: Neu-MeOH; isocratic ratio: A: B = 60:40; flow rate: 80 mL / min).

[0286] Example 100a was obtained: (45 mg, 37.10% yield). LCMS (M+H) = 538.0. SFC: Residence time: 1.556 min, AD_3_EtOH_DEA_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 9.07 (s, 1H), 8.87 (s, 2H), 8.07 (d, J= 9.6Hz, 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). 19F NMR (376 MHz, DMSO- d 6): δ -91.81 (d, J= 231.7 Hz, 1F), -99.38 (d, J= 234.6 Hz, 1F), -142.24 (s, 1F).

[0287] Example 100b obtained: (43 mg, 34.60% yield). LCMS (M+H) = 538.0. SFC: Residence time: 2.085 min, AD_3_EtOH_DEA_40_25ML. 1H NMR (400 MHz, DMSO- d 6): 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). 19F 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). Examples 101a and 101b

[0288] A solution of compound 100-4 (4 mg, 1.23 mmol) in CF3CH2OH (1.5 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (230.60 mg, 1.23 mmol). Subsequently, 4-isocyanotetrahydropiperanone (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 rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). Compound 101 (200 mg, 31.56% yield). LCMS (M+H) = 503.9. 1H NMR (400 MHz, DMSO- d 6): δ 9.04 (d, J= 18.0 Hz, 1H), 8.87 (d, J= 8.0 Hz, 2H), 8.02 - 7.92 (m, 4H), 7.85 - 7.76 (m, 1H), 7.68 (d, J= 7.6 Hz, 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).

[0289] Compound 101 (100 mg) was separated by a palmar 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 then concentrated under vacuum to obtain two dissociated fractions.

[0290] Example 101 a was obtained: (37 mg, 35.22% yield). LCMS (M+H) = 503.7. SFC: Residence time: 1.801 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO- d 6): δ 9.07 (s, 1H), 8.88 (s, 2H), 8.06 (d, J= 8.8 Hz, 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= 8.4 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -140.82 - -145.53 (m, 1F).

[0291] Example 101b obtained: (20 mg, 18.65% yield). LCMS (M+H) = 504.2. SFC: Residence time: 2.178 min, AD_ETOH_DEA_5_40_4ML_4MIN_5CM. 1H NMR (400 MHz, DMSO- d 6): δ 9.02 (s, 1H), 8.86 (s, 2H), 8.04 - 7.90 (m, 3H), 7.86 (d, J= 3.2 Hz, 1H), 7.75 - 7.60 (m, 2H), 7.49 (d, J= 8.2 Hz, 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). 19F NMR (376 MHz, DMSO-d6): δ -141.73 (s, 1F). Examples 102a and 102b

[0292] To a solution of 100-3 (1.4 g, 7.94 mmol) in toluene (30 mL), p-TsOH (227.99 mg, 1.32 mmol) and 1-(5-fluoro-3-pyridyl)acetone (921.00 mg, 6.62 mmol) were added. The mixture was stirred in a Dean-Stark separator at 140 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (0 to 20% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). Compound 102-1 was given (814 mg, 2.19 mmol, 33.08% yield, 80% purity). To a solution of 102-1 (400.00 mg, 1.08 mmol) in CF3CH2OH (1 mL), (2R)-2-chloro-2-fluoroacetic acid (302.64 mg, 1.61 mmol) and 1,1-difluoro-4-isocyanocyclohexane (234.31 mg, 1.29 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 rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 50%–80%, 7 min). Compound 102 was given (34 mg, 61.26 μmol, 5.69% yield). Compound 102 (34 mg, 61.26 μmol) was further separated by SFC (column: DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: [Neu-ETOH]; B%: 35% to 35%, min) to obtain two soluble fractions.

[0293] Example 102a was obtained: (9.56 mg, 28.12% yield). LCMS (M+H) = 555.0. SFC: Residence time: 1.280 min, AD_3_EtOH_DEA_40_25ML. 1H NMR (400 MHz, DMSO- d 6) δ 8.52 (s, 1H), 8.48 (d, J= 2.6 Hz, 1H), 8.03 (br d, J= 7.4 Hz, 1H), 7.97 (d, J= 3.2 Hz, 1H), 7.93 (br d, J= 8.6 Hz, 1H), 7.87 (d, J= 3.2 Hz, 1H), 7.82 - 7.73 (m, 2H), 7.68 (d, J= 8.0 Hz, 1H), 7.29 (br d, J= 8.0 Hz, 1H), 6.51 - 6.31 (m, 1H), 3.90 (br d, J= 7.5 Hz, 1H), 2.15 - 1.79 (m, 6H), 1.74 (s, 3H), 1.66 - 1.54 (m, 2H). 19F NMR (376 MHz, DMSO- d 6): δ -91.81 (br d, J= 232.4 Hz, 1F), -99.34 (br d, J= 235.8 Hz, 1F), -127.99 (s, 1F), -141.87 (br s, 1F).

[0294] Example 102b was obtained: (10.77 mg, 31.68% yield). LCMS (M+H) = 555.0. SFC: Residence time: 1.600 min, AD_3_EtOH_DEA_40_25ML. 1H NMR (400 MHz, DMSO- d 6) δ 8.49 (s, 1H), 8.42 (d, J= 2.6 Hz, 1H), 7.97 - 7.89 (m, 3H), 7.85 (d, J= 3.2 Hz, 1H), 7.76 (br d, J= 10.7 Hz, 1H), 7.64 (d, J= 7.9 Hz, 1H), 7.58 (br d, J= 7.7 Hz, 1H), 7.47 (br d, J= 7.9 Hz, 1H), 6.47 - 6.26 (m, 1H), 3.87 (br s, 1H), 2.08 - 1.76 (m, 9H), 1.69 - 1.49 (m, 2H). 19F NMR (376 MHz, DMSO-d6): δ -91.99 (br d, J = 228.9 Hz, 1F), -99.17 (br d, J = 221.9 Hz, 1F), -127.86 (s, 1F), -141.67 (s, 1F). Examples 103a and 103b

[0295] (2R)-2-chloro-2-fluoroacetic acid (378.30 mg, 2.02 mmol) and 4-isocyanotetrahydropiperanone (224.26 mg, 1.61 mmol) were added to CF 3CH 2OH (1 mL) containing compound 102-1 (400 mg, 1.35 mmol). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water (FA)-ACN]; B%: 42%-72%, 7 min). Compound 103 was obtained (65 mg, 113.54 μmol, 8.44% yield, 91% purity).

[0296] 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% to 40%, min) to obtain two dissociated fractions.

[0297] Example 103a was obtained: (15.77 mg, 23.54% yield). LCMS (M+H) = 521.1. SFC: Residence time: 1.727 min, AD_3_EtOH_DEA_40_25ML. 1H NMR (400 MHz, DMSO- d 6) δ 8.59 - 8.44 (m, 2H), 8.02 (br d, J= 8.0 Hz, 1H), 7.98 (d, J=2.9 Hz, 1H), 7.94 (br d, J= 8.1 Hz, 1H), 7.87 (d, J= 3.1 Hz, 1H), 7.76 (br d, J= 10.7 Hz, 2H), 7.71 (d, J= 7.7 Hz, 1H), 7.33 (br d, J= 7.3 Hz, 1H), 6.50 - 6.27 (m, 1H), 4.02 - 3.81 (m, 3H), 3.39 (br s, 2H), 1.91 - 1.49 (m, 7H). 19F NMR (376 MHz, DMSO-d6): δ -128.00 (br s, 1F), -141.83 (br s, 1F). Example 103b obtained: (26.96 mg, 40.24% yield). LCMS (M+H) = 521.0. SFC: Retention time: 2.471 min, AD_3_EtOH_DEA_40_25ML. 1H NMR (400 MHz, DMSO- d 6) δ 8.50 (s, 1H), 8.42 (d, J= 2.6 Hz, 1H), 7.96 (d, J= 3.2 Hz, 1H), 7.93 (br d, J= 8.0 Hz, 2H), 7.86 (d, J= 3.2 Hz, 1H), 7.77 (dd, J= 2.1, 10.6 Hz, 1H), 7.66 (d, J= 7.7 Hz, 1H), 7.57 (br d, J= 7.4 Hz, 1H), 7.51 (br d, J= 7.7 Hz, 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).19F NMR (376 MHz, DMSO-d6): δ -127.87 (s, 1F), -141.67 (s, 1F). Examples 104a and 104b.

[0298] pTsOH (178.27 mg, 1.04 mmol) was added to a solution of compound 22-1 (2 g, 10.35 mmol, 1.48 mL) and 1-(pyrimidin-5-yl)ethyl-1-one (836.05 mg, 6.90 mmol, 760.04 μL) in toluene (30 mL). 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 the residue. The residue was purified by rapid silica gel chromatography (0 to 100% DCM / petroleum ether gradient solvent, at 35 mL / min). Compound 104-1 (590 mg, 1.69 mmol, 24.52% yield) was given.

[0299] (2R)-2-chloro-2-fluoroacetic acid (227.78 mg, 1.19 mmol) and 1,1-difluoro-4-isocyanocyclohexane (160.56 mg, 995.58 μmol) were added to a solution of compound 104-1 (295 mg, 995.58 μmol) in CF3CH2OH (2 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 50% to 80%, 7 min). Compound 104 was obtained (125 mg, 224.95 μmol, 22.60% yield). LCMS (M+H) = 554.0.

[0300] Compound 104 (125 mg) was separated by a palmar SFC (DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 80:20; flow rate: 70 mL / min), and then concentrated under vacuum to obtain two dissociated fractions.

[0301] Example 104a was obtained: (15.02 mg, 12.02% yield). LCMS (M+H) = 554.0. SFC: Retention time: 2.578 min, OD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 8.52 (d, J= 2.3 Hz, 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, 8.2 Hz, 1H), 6.39 -6.20 (m, 1H), 3.88 (br d, J= 7.7 Hz, 1H), 1.99 (br s, 3H), 1.89 (s, 4H), 1.77 (br s,2H), 1.64 - 1.47 (m, 2H). 19F NMR (376 MHz, DMSO- d 6): δ -41.80 (s, 3F), -91.88 (br d, J= 232.3 Hz, 1F), -99.30 (br d, J= 232.4 Hz, 1F), -141.40 (s, 1F).

[0302] Example 104b was obtained: (16.79 mg, 13.43% yield). LCMS (M+H) = 554.0. SFC: Retention time: 2.872 min, OD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 8.52 (d, J= 2.1 Hz, 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, 8.0 Hz, 1H), 6.43 - 6.17 (m, 1H), 3.84 (br d, J= 7.3 Hz, 1H), 2.08 - 1.82 (m, 7H), 1.75 (br s, 2H), 1.67 - 1.42 (m, 2H). 19F NMR (376 MHz, DMSO-d6): δ -41.86 (s, 3F), -91.95 (br d, J = 232.3 Hz, 1F), -99.26 (br d, J = 235.8 Hz, 1F), -141.74 (br s, 1F). Examples 105a and 105b

[0303] (2R)-2-chloro-2-fluoroacetic acid (227.78 mg, 1.19 mmol) and 4-isocyanotetrahydropiperanone (130.18 mg, 995.58 μmol) were added to a solution of compound 104-1 (295 mg, 995.58 μmol) in CF3CH2OH (2 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 47% to 77%, 7 min). Compound 105 was obtained (112 mg, 215.41 μmol, 21.64% yield). LCMS (M+H) = 520.0.

[0304] Compound 105 (112 mg) was separated by a palmar SFC (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic: A:B = 75:25; flow rate: 60 mL / min), and then concentrated under vacuum to obtain two dissociated fractions.

[0305] Example 105a was obtained: (15.48 mg, 13.70% yield). LCMS (M+H) = 519.9. SFC: Retention time: 3.301 min, AD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 8.54 (d, J= 2.0 Hz, 1H), 8.34 (d, J= 4.9 Hz,1H), 7.77 - 7.54 (m, 5H), 7.37 (br s, 1H), 7.21 (dd, J= 4.6, 8.0 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -41.80 (s, 3F), -141.37 (s, 1F).

[0306] Example 105b was obtained: (15.96 mg, 14.18% yield). LCMS (M+H) = 520.0. SFC: Residence time: 3.803 min, AD-3_EtOH (DEA)_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6): δ 8.55 (d, J= 2.0 Hz, 1H), 8.30 (d, J= 3.5 Hz,1H), 7.71 - 7.58 (m, 4H), 7.57 - 7.42 (m, 2H), 7.16 (dd, J= 4.8, 8.0 Hz, 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). 19F NMR (376 MHz, DMSO-d6): δ -41.87 (s, 3F), -141.72 (br s, 1F). Examples 106a and 106b.

[0307] TEA (345.55 mg, 3.41 mmol, 475.32 μL) was added to a solution of compound 106-1 (200 mg, 1.14 mmol HCl) in ethyl formate (20 mL). The mixture was stirred at 80 °C for 16 hours. 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 product) was obtained. LCMS (M+H) = 167.8.

[0308] 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 to a solution of compound 106-2 (185 mg, 1.11 mmol) in DCM (10 mL). The mixture was stirred at 45 °C for 16 hours. The mixture was diluted with DCM (10 mL), filtered, and concentrated under vacuum. The crude product was wet-milled at 20 °C with PE (10 mL) and MTBE (10 mL) for 60 minutes. The mixture was filtered and the filter cake was washed with MTBE (10 mL × 3). The filtrate was concentrated under reduced pressure to obtain compound 106-3 (384 mg, crude product).

[0309] (2R)-2-chloro-2-fluoroacetic acid (119.99 mg, 640.04 μmol) and compound 106-3 (159.19 mg, 533.37 μmol) were added to a solution of compound 4-3 (150 mg, 533.37 μmol) in CF3CH2OH (2 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 63% to 93%, 7 min). Compound 106 was given (19 mg, 34.60 μmol, 6.49% yield). LCMS (M+H) = 543.0.

[0310] Compound 106 (19 mg) was separated by a palmar SFC (DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm)); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 85:15; flow rate: 80 mL / min), and then concentrated under vacuum to obtain two dissociated fractions.

[0311] Example 106a was obtained: (3.68 mg, 19.37% yield). LCMS (M+H) = 543.1. SFC: Residence time: 2.168 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.05 (s, 1H), 8.84 (s, 2H), 7.83 (br d, J= 8.9 Hz,1H), 7.63 (d, J= 8.1 Hz, 1H), 7.47 (br d, J= 8.8 Hz, 1H), 7.39 (br s, 2H), 6.44 -6.27 (m, 1H), 3.57 (br d, J= 3.8 Hz, 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). 19F NMR (376 MHz, DMSO-d 6): δ -56.85 (s, 3F), -142.13 (br s, 1F).

[0312] Example 106b obtained: (5.80 mg, 30.53% yield). LCMS (M+H) = 543.1. SFC: Residence time: 2.858 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.02 (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). 19F NMR (376MHz, DMSO-d6): δ -56.88 (s, 3F), -141.87 (s, 1F). Examples 107a and 107b

[0313] A solution of compound 107-1 (100 mg, 708.16 μmol) in ethyl formate (10 mL) was stirred at 80 °C for 16 hours. The mixture was concentrated under vacuum, diluted with water (20 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 107-2 (130 mg, crude substance) was obtained. LCMS (M+H) = 169.8.

[0314] TEA (77.74 mg, 768.23 μmol, 106.93 μL), PPh 3 (201.50 mg, 768.23 μmol), and CCl 4 (118.17 mg, 768.23 μmol, 73.86 μL) were added to a solution of compound 107-2 (130 mg, 768.23 μmol, 10 mL) in DCM (10 mL). The mixture was stirred at 45 °C for 16 hours. The mixture was diluted with DCM (10 mL), filtered, and concentrated under vacuum. The crude product was wet-milled at 2 °C with PE (10 mL) and MTBE (10 mL) for 60 minutes. The mixture was filtered and the filter cake was washed with MTBE (10 mL × 3). The filtrate was concentrated under reduced pressure to obtain compound 107-3 (116 mg, crude product).

[0315] (2R)-2-chloro-2-fluoroacetic acid (159.99 mg, 853.39 μmol) and compound 107-3 (107.53 mg, 711.15 μmol) were added to a solution of compound 4-3 (200 mg, 711.15 μmol) in CF3CH2OH (2 mL). The mixture was stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by reverse-phase silica column (C18, 40 g) using water and acetonitrile as solvents (mobile phase A: water (0% FA), mobile phase B: acetonitrile, mobile phase B: 30% to 60%). The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 40% to 70%, 6 min). Compound 107 was obtained (28 mg, 49.84 μmol, 7.01% yield). LCMS (M+H) = 545.1.

[0316] Compound 107 (28 mg) was separated by a palmar SFC (column: DAICEL CHIRALCEL OD-H (250 mm × 30 mm, 5 μm); mobile phase: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A: B = 75:25; flow rate: 70 mL / min), and then concentrated under vacuum to obtain two dissociated fractions.

[0317] Example 107a obtained: (3.30 mg, 11.43% yield). LCMS (M+H) = 545.1. SFC: Residence time: 2.832 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.05 (s, 1H), 8.83 (s, 2H), 7.83 (br d, J= 9.2 Hz,1H), 7.62 (d, J= 8.1 Hz, 1H), 7.48 (br d, J= 9.3 Hz, 1H), 7.39 (s, 2H), 6.47 - 6.26 (m, 1H), 4.31 (s, 2H), 4.21 (s, 2H), 3.60 (br d, J= 8.1 Hz, 1H), 2.06 (br d, J= 13.6Hz, 2H), 1.66 (s, 5H), 1.46 (br dd, J= 3.5, 7.6 Hz, 2H), 1.29 - 1.20 (m, 2H). 19F NMR (376 MHz, DMSO-d 6): δ-56.84 (s, 3F), -142.20 (br s, 1F).

[0318] Example 107b obtained: (5.85 mg, 19.78% yield). LCMS (M+H) = 545.1. SFC: Residence time: 3.516 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.02 (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, 12.9 Hz, 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= 6.1 Hz, 2H), 1.78 (s,3H), 1.70 - 1.53 (m, 2H), 1.51 - 1.40 (m, 2H), 1.26 – 1.17 (m, 2H). 19F NMR (376 MHz, DMSO-d6): δ -56.81 – -57.11 (m, 3F), -141.91 (s, 1F). Examples 108a and 108b

[0319] A solution of compound 108-1 (500 mg, 2.368 mmol) in toluene (30 mL) was added with 1-(pyrimidin-5-yl)ethyl-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 for 18 hours under a nitrogen atmosphere. The mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (20% acetone / petroleum ether gradient solvent, at 20 mL / min) to give compound 108-2 (400 mg, crude substance).

[0320] A solution of compound 108-2 (500 mg, 0.952 mmol) in CF3CH2OH (3 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (214.07 mg, 0.952 mmol) and 4-isocyanotetrahydropiperanone (88.14 mg, 0.793 mmol). The mixture was stirred at 25 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by preparative 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). The pure solvent was collected and the volatile solvent was removed by evaporation. The aqueous residue was lyophilized to give compound 108 (90 mg, 20.43% yield). LCMS (M+H) = 539.1.

[0321] Compound 108 (90 mg, 0.167 mmol) was separated into two fractions by SFC (Chiralcel OD-3 100×4.6 mm ID, 3 μm; mobile phase: A: CO 2 B: ethanol (0.05% DEA); gradient: 5% to 40% B, 4 min, and maintained at 40% for 2.5 min, followed by 5% B for 1.5 min; flow rate: 2.8 mL / min).

[0322] Example 108a obtained: (1.80 mg, 2.00% yield). LCMS (M+H) = 539.0. SFC: Retention time: 1.542 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO-d 6): δ 1.39 - 1.77 (m, 7 H), 3.29 (s, 2 H), 3.78 - 3.93 (m, 3 H), 6.32 - 6.46 (m, 1 H), 7.48 - 7.58 (m, 1 H), 7.79 (d, 3 H), 7.95 (s, 1 H), 8.85 (s, 2 H), 9.04 (s, 1 H). 19F NMR (376 MHz, DMSO-d 6): δ -142.32 (s, 1F), -113.59 (br s, 2F), -84.02 (s, 3F).

[0323] Example 108b obtained: (3.45 mg, 3.78% yield). LCMS (M+H) = 539.2. SFC: Residence time: 1.879 min, OD_ETOH_DEA_5_40_28ML_8MIN. 1H NMR (400 MHz, DMSO- d 6): δ 1.46 (s, 2 H), 1.51 - 1.60 (m, 1 H), 1.64 - 1.74 (m, 1 H), 1.85 (s, 3 H), 3.29 (s, 2 H), 3.74 - 3.94 (m, 3 H), 6.25 - 6.41 (m, 1 H), 7.64 - 7.69 (m, 1 H), 7.72 (s, 3 H), 7.77 - 7.82 (m, 1 H), 8.82 (s, 2 H), 9.00 (s, 1 H). 19F NMR (376 MHz, DMSO-d6): δ -142.01 (s, 1 F), -113.68 (s, 2 F), -84.07 (s, 3 F). Examples 109a and 109b

[0324] TEA (1.97 g, 19.47 mmol, 2.71 mL) was added to a solution of compound 109-1 (1.3 g, 6.49 mmol) in ethyl formate (10 mL). The mixture was heated and stirred at 80 °C for 12 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to give crude compound 109-2 (1.5 g, crude substance).

[0325] PPh 3 (1.72 g, 6.57 mmol), TEA (664.88 mg, 6.57 mmol, 914.55 μL, 1 eq), and CCl 4 (1.01 g, 6.57 mmol, 631.70 μL) were added to a solution of compound 109-2 (1.5 g, 6.57 mmol) in DCM (8 mL). The mixture was heated and stirred at 45 °C for 12 h. The mixture was cooled to room temperature and concentrated under reduced pressure to give crude material, which was purified at 20 °C by rapid silica gel chromatography (0 to 100% dichloromethane / petroleum ether gradient solvent, at 35 mL / min). TLC (petroleum ether:dichloromethane = 0:1, Rf = 0.4) was performed. Compound 109-3 (500 mg, 2.38 mmol, 36.19% yield) was obtained. 1H NMR (400 MHz, CDCl 3): δ 4.65 (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).

[0326] A solution of compound 11-2 in CF3CH2OH (2 mL) was added with (2R)-2-chloro-2-fluoroacetic 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 hours. The mixture was concentrated under reduced pressure to obtain a crude substance, which was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min) to give the residue compound 109-4 (500 mg, 791.07 μmol, 33.27% yield). LCMS (M+H) = 620.8.

[0327] TFA (0.308 mL, 4.026 mmol) was added to a solution of compound 109-4 (500 mg, 0.805 mmol) in DCM (5 mL), and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with dichloromethane (40 mL) and adjusted to pH 12 with sodium hydroxide solution (3 M, 8 mL), and extracted with dichloromethane (10 mL × 2). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to give compound 109-5 (300 mg, crude). The crude was used directly in the next step without further purification. DMAP (35.18 mg, 0.288 mmol) and ethyl 2,2,2-trifluoroacetate (245.49 mg, 1.728 mmol) were added to a solution of compound 109-5 (300 mg, 0.576 mmol) in DCM (10 mL). The mixture was stirred at 25 °C for 12 hours, and then concentrated under reduced pressure to obtain a crude substance. This crude substance was purified by preparative 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 55% B to 85%) to give compound 109 (60 mg, 16.89% yield). LCMS (M+H) = 616.8.

[0328] Residual 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-ETOH, A: B = 85:15, 60 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm), yielding two dissociated fractions. Example 109a was obtained: (12.77 mg). LCMS (M+H) = 617.1. SFC: Retention time: 2.590 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, CD 3OD): δ 9.49 (d, J =6.8 Hz, 1H), 8.47 - 8.41 (m, 2H), 7.83 (d, J =7.2 Hz, 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). 19F NMR (376 MHz, CD 3OD) δ -56.92 (s, 3F), -74.19 (s, 3F), -128.04 (s, 1F), -141.92 (s, 1F).

[0329] Example 109b obtained: (20.53 mg). LCMS (M+H) = 617.1. SFC: Residence time: 2.849 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, CD 3OD): δ 9.47 (d, J =6.8 Hz, 1H), 8.49 - 8.41 (m, 2H), 7.80 - 7.64 (m, 2H), 7.54 (dd, J =4.8, 8.4 Hz, 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). 19F NMR (376 MHz, CD 3OD) 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). Examples 110a and 110b

[0330] A solution of 110-1 (2 g, 13.74 mmol, 1.53 mL) in ethyl formate (20 mL) was stirred at 20 °C for 4 hours. The reaction mixture was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 5% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). Compound 110-2 was given (921 mg, 5.15 mmol, 37.46% yield).

[0331] TEA (536.92 mg, 5.31 mmol, 738.55 μL), PPh 3 (1.39 g, 5.31 mmol), and CCl 4 (816.21 mg, 5.31 mmol, 510.13 μL) were added to a solution of 110-2 (921 mg, 5.31 mmol) in DCM (10 mL). The mixture was stirred at 45 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by rapid silica gel chromatography (0 to 5% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min). Compound 110-3 (4.2 g, crude substance) was obtained.

[0332] (2R)-2-chloro-2-fluoroacetic acid (319.98 mg, 1.71 mmol) and 110-3 (442.50 mg, 1.42 mmol) were added to a solution of 4-3 (400 mg, 1.42 mmol) in CF3CH2OH (1 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The residue was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 20 mL / min) and further purified by preparative HPLC (column: Welch Xtimate C18 150×30 mm×5 μm; mobile phase: [water(FA)-ACN]; B%: 56%-86%, 7 min). Compound 110 was given (35 mg, 62.45 μmol, 4.39% yield).

[0333] 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% to 35%, min) to obtain two dissociated fractions.

[0334] Example 110a was obtained: (8.13 mg, 23.23% yield). LCMS (M+H) = 549.0. SFC: Retention time: 3.470 min, (SS)Whelk-01_IPA(DEA)_5_40. 1H NMR (400 MHz, DMSO-d 6) δ 9.76 (s, 1H), 9.13 (s, 1H), 8.99 - 8.87 (m, 2H), 7.99 (dd, J= 2.8, 8.8 Hz, 1H), 7.60 - 7.41 (m, 4H), 7.37 - 7.22 (m, 2H), 6.56 - 6.34 (m, 1H), 1.72 (s, 3H).

[0335] Example 110b was obtained: (9.89 mg, 28.26% yield). LCMS (M+H) = 549.1. SFC: Retention time: 3.951 min, (SS)Whelk-01_IPA(DEA)_5_40. 1H NMR (400 MHz, DMSO-d 6) δ 9.70 (s, 1H), 9.07 (s, 1H), 8.92 (s, 2H), 7.76 (dd, J= 2.4, 8.7 Hz, 1H), 7.58 - 7.40 (m, 5H), 7.34 (br d, J= 8.5 Hz, 1H), 6.49 - 6.28 (m, 1H), 1.91 (s, 3H). Examples 111a and 111b

[0336] p-TsOH (213.23 mg, 1.24 mmol) was added to a solution of 1-(pyridin-3-yl)ethyl-1-one (1 g, 8.26 mmol, 909.09 μL) and compound 92-1 (1.60 g, 8.26 mmol) in toluene (30 mL). The mixture was stirred at 140 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 20% ethyl acetate / petroleum ether gradient solvent, at 35 mL / min). Compound 111-1 was given (673 mg, 1.70 mmol, 20.61% yield).

[0337] (2R)-2-chloro-2-fluoroacetic acid (510.31 mg, 2.72 mmol) and 4-isocyanotetrahydropiperanone (296.59 mg, 2.27 mmol) were added to a solution of compound 111-1 (673 mg, 2.27 mmol) in CF3CH2OH (10 mL). The mixture was stirred at 20 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 100% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). The residue was purified by preparative HPLC (column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water (FA)-ACN]; B%: 45% to 75%, 7 min). The residue was purified by preparative HPLC (column: Boston Green ODS 150×30mm×5μm; mobile phase: [water(FA)-ACN]; B%: 40% to 70%, 7 min). Compound 111 was given (110 mg, 204.45 μmol, 53.19% yield). LCMS (M+H) = 520.0.

[0338] 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 ratio: A: B = 75:25; flow rate: 70 mL / min), and then concentrated under vacuum to obtain two dissociated fractions.

[0339] Example 111a obtained: (20.99 mg, 19.08% yield). LCMS (M+H) = 520.0. SFC: Residence time: 2.646 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.54 (d, J= 2.3 Hz, 1H), 8.35 (d, J= 4.8 Hz, 1H), 7.73 - 7.58 (m, 3H), 7.40 - 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). 19F NMR (376 MHz, DMSO-d 6): δ -24.97 (s, 2F), -141.43 (s, 1F).

[0340] Example 111b obtained: (36.34 mg, 32.19% yield). LCMS (M+H) = 520.0. SFC: Residence time: 3.482 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 8.54 (s, 1H), 8.31 (d, J= 4.6 Hz, 1H), 7.67 (brdd, J= 7.9, 16.6 Hz, 2H), 7.56 - 7.42 (m, 2H), 7.30 - 7.15 (m, 3H), 6.44 - 6.22 (m,1H), 3.85 (br d, J= 4.9 Hz, 3H), 3.31 - 3.21 (m, 2H), 2.03 (s, 3H), 1.66 (br s, 2H), 1.58 - 1.39 (m, 2H). 19F NMR (376 MHz, DMSO-d6): δ -24.95 (s, 2F), -141.76 (br s, 1F). Examples 112a and 112b

[0341] 1-(pyrimidin-5-yl)ethyl-1-one (830 mg, 6.796 mmol) and 4-methylbenzenesulfonic acid (146 mg, 0.848 mmol) were added to a solution of compound 112-1 (1.00 g, 5.646 mmol) in toluene (30 mL). The reaction mixture was stirred at 140 °C for 18 hours. The combined reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the residue. The residue was purified by rapid silica gel chromatography (0 to 60% EA / PE ether gradient solvent, at 40 mL / min) to give compound 112-2 (2.5 g, crude substance).

[0342] A solution of compound 112-2 (2.52 g, 8.960 mmol) in CF3CH2OH (18 mL) was added with (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 for 18 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 60% EA / PE ether gradient solvent, at 40 mL / min) to give the product. The residue was purified by preparative HPLC (Xtimate C18 150×40mm×10μm; mobile phase: A: water (FA) B: ACN; gradient conditions: 45% B to 75% B; flow rate: 60 mL / min) to give compound 112 (1.3 g, 26.92% yield). LCMS (M+H) = 539.1. 1H NMR (400 MHz, DMSO- d 6): δ 9.10 - 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).

[0343] Compound 112 (143.5 mg, 0.27 mmol) was separated into two fractions by SFC (DAICEL CHIRALCEL OD (250 mm × 30 mm, 10 μm) with mobile phases: A: supercritical CO2, B: Neu-IPA; isocratic ratio: A: B = 90:10; flow rate: 100 mL / min).

[0344] Example 112a was obtained: (43 mg, 38.23% yield). LCMS (M+H) = 539.1. SFC: Residence time: 2.182 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.11 - 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 (br s, 1H), 2.11 - 1.88 (m, 4H), 1.82 (br s, 4H), 1.68 (br s, 1H), 1.65 - 1.47 (m, 2H). 19F NMR (376 MHz, DMSO- d 6): δ -56.95 (br d, J= 80.5 Hz, 3F), -91.87 (br dd, J= 16.6, 233.0 Hz, 1F), -99.38 (br d, J= 237.2 Hz, 1F), -142.12 (br s, 1F).

[0345] Example 112b obtained: (48 mg, 41.43% yield). LCMS (M+H) = 539.1. SFC: Residence time: 2.498 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO- d 6): δ 9.07 - 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). 19F NMR (376 MHz, DMSO-d6): δ -56.98 (d, J = 25.0 Hz, 3F), -89.39 - -93.15 (m, 1F), -97.38 - -101.99 (m, 1F), -141.94 (d, J = 49.9 Hz, 1F). Examples 113a and 113b: 1-(pyrimidin-5-yl)ethyl-1-one (776.01 mg, 6.354 mmol) and p-TsOH (149.19 mg, 0.866 mmol) were added to a solution of 113-1 (1 g, 5.776 mmol) in toluene (30 mL). The mixture was heated and stirred at 140 °C in a Dean-Stark separator for 12 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure to give compound 113-2 (0.9 g, 56.2% yield).

[0346] A solution of compound 113-2 (200 mg, 0.721 mmol) in 2,2,2-trifluoroethanol (3 mL) was added with (2R)-2-chloro-2-fluoroacetic acid (162.29 μm, 0.866 mmol) and 1,1-difluoro-4-isocyanocyclohexane (104.71 mg, 0.721 mmol). The mixture was stirred at 25 °C for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography and further purified by preparative HPLC (Xtimate C18 150 × 40 mm × 10 μm; mobile phase: A: water (FA) B: ACN; gradient conditions: 45% B to 75% B; flow rate: 60 mL / min) to give compound 113 (100 mg).

[0347] Compound 113 (100 mg, 0.187 mmol) was separated 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, 100 mL / min; column temperature: 38 °C; nozzle pressure: 100 bar; nozzle temperature: 60 °C; evaporator temperature: 20 °C; adjustment plate temperature: 25 °C; wavelength: 220 nm), yielding two fractions. The pure fractions were collected and further purified by preparative HPLC to obtain the title compound.

[0348] Example 113a was obtained: (7.24 mg, 7.24%). LCMS (M+H) = 535.1. SFC: Residence time: 2.322 min, OD_3_IPA_DEA_5_40_25ML_6MIN. ¹H NMR (400 MHz, DMSO-d⁶) δ 9.20 (d, J = 2.0 Hz, 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). Example 113b was obtained: (5.80 mg, 0.011 mmol, 5.80%). LCMS (M+H) = 534.9. SFC: Residence time: 2.765 min, OD_3_IPA_DEA_5_40_25ML_6MIN. 1H NMR (400 MHz, DMSO-d 6) δ 9.05 (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). Examples 114a and 114b

[0349] 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 hours to obtain a colorless liquid of acetic anhydride (17.20 g, 78.129 mmol). The mixture was used in the next step without further purification. The above-mentioned acetic anhydride (11.54 g, 131.079 mmol) was added to a solution of 114-1 (2 g, 13.108 mmol) in THF (20 mL), and the reaction mixture was stirred at 20 °C for 20 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by rapid silica gel chromatography to give compound 114-2 (608 mg, 1.683 mmol, 12.84% yield).

[0350] TEA (2.8 mL, 20.144 mmol) was added to a solution of 114-2 (600 mg, 3.322 mmol) in DCM (10 mL). The mixture was degassed and purified three times with N2. POCl3 (0.4 mL, 4.305 mmol) was added dropwise at 0 °C. The mixture was stirred at 0 °C for 2 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography (0 to 50% ethyl acetate / petroleum ether gradient solvent, at 30 mL / min). Compound 114-3 was given (311 mg, 1.913 mmol, 57.58% yield).

[0351] (2R)-2-chloro-2-fluoroacetic acid (296 mg, 1.58 mmol) was added to a solution of 4-1 (370 mg, 1.32 mmol) and 114-3 (214 mg, 1.32 mmol) in CF3CH2OH (3 mL). The mixture was stirred at 20 °C for 18 hours under a N2 atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by rapid silica gel chromatography and further purified by preparative HPLC to give compound 114 (38 mg, 4.3% yield).

[0352] Compound 114 (38 mg, 0.068 mmol) was separated by a palmar SFC (Phenomenex-Cellulose-2 (250 mm × 30 mm, 10 μm); mobile phase: A: supercritical CO2, B: Neu-ETOH; isocratic ratio: A: B = 70: 30; flow rate: 150 mL / min), vacuum concentrated and lyophilized to obtain two soluble fractions.

[0353] Example 114a was obtained: (14 mg, 0.024 mmol, 33.84%). LCMS (M+H) = 556.1. SFC: Retention time: 3.470 min, C2_EtOH_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO-d 6) δ 9.94 (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 (376 MHz, DMSO-d 6): δ -56.92 (br d, J = 27.7 Hz, 3F), -142.12 (br s, 1F).

[0354] Example 114b obtained: (15 mg, 0.027 mmol, 36.88%). LCMS (M+H) = 556.1. SFC: Residence time: 4.984 min, C2_EtOH_DEA_5_40_25ML. 1H NMR (400 MHz, DMSO- d 6) δ 9.98 (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). 19F NMR (376 MHz, DMSO-d6): δ -52.61 - -58.57 (m, 3F), -139.36 - -144.28 (m, 1F). The compounds in Examples 115a and 115b were prepared according to a similar procedure to that described for Examples 94a and 94b.

[0355] Example 115a was obtained: (112.20 mg, 43% yield). LCMS (M+H) = 537.1. SFC: Retention time: 2.600 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1HNMR (400 MHz, DMSO- d 6): δ 9.03 (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 = 1.2 Hz, 3H), 3.32 - 3.31 (m, 1H), 3.31 - 3.26 (m, 1H), 1.85 - 1.38 (m, 7H). 19F NMR (376 MHz, DMSO-d 6): δ -25.05 (s, 2F).

[0356] Example 115b obtained: (110.28 mg, 42.29% yield). LCMS (M+H) = 537.1. SFC: Residence time: 3.000 min, OD_3_EtOH_DEA_5_40_25ML_6MIN. 1HNMR (400 MHz, DMSO- d 6): δ 9.03 (s, 1H), 8.81 (s, 2H), 7.80 - 7.70 (m, 2H), 7.44 (d, J = 8.2 Hz, 2H), 7.40 - 7.33 (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). 19F NMR (376 MHz, DMSO-d 6): δ -25.05 (s, 2F). Example A: In vitro analysis (SARS-CoV-2 M pro enzyme analysis)

[0357] The SARS-CoV-2 MPRO (NC_045512) with the C-His6 tag was selected, expressed in E. coli, and purified by WuXi. The acceptor of Dabcyl-KTSAVLQ‖SGFRKME-(Edans) was synthesized by Genscript. The analysis buffer contained 20 mM Tris-HCl (pH=7.3), 100 mM NaCl, 1 mM EDTA, 5 mM TCEP, and 0.1% BSA. In the MPRO enzyme assay, the final concentrations of the Mpro protein and acceptor were 25 nM and 25 μM, respectively. The reference compound GC376 was provided by WuXi AppTec and included in each pan to ensure analytical stability. The test compound was tested in single-dose or 10-dose titrations, in duplicate. The compound was added to the analysis pan (384-well format) in duplicate wells using ECHO. For single-dose experiments, the final concentration was 10 μM. For the full-dose response assay, samples were serially diluted 3-fold starting at 25 μM to obtain 10 doses, which were then added to the analysis pan in duplicate wells. 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 analysis pan containing the test compound using Multidrop. The test compound and MPRO protein were pre-incubated at room temperature for 30 minutes. Subsequently, the reactant (5 μL, 150 μM) was added to the analysis pan. For the 100% inhibition control (HPE, high percentage effect), 1 μM GC376 was added. For the no-inhibition control (ZPE, zero percentage effect), the same volume of DMSO was added. The final DMSO concentration was 1%. Each activity test site had a corresponding background control under enzyme-free conditions to remove fluorescence interference from the compounds. After incubation at 30°C for 60 minutes, fluorescence signals (RFUs) were detected using a microdisk reader M2e (SpectraMax) at Ex / Em=340nm / 490nm.

[0358] Calculate the inhibitory activity using the following formula, and calculate the IC50 value using the inhibition % data. Inhibition % = ((CPD ‒ BGHPE) ‒ (ZPE ‒ BGZPE)) / ((HPE ‒ BGHPE) ‒ (ZPE ‒ BGZPE)) × 100 Wherein, HPE is the high percentage control (1 μM GC376 + enzyme + substrate); ZPE is the zero percentage effective control (enzyme + substrate, no compound); CPD is the compound activity test well (compound + enzyme + substrate); and BG is the background control well (no enzyme).

[0359] The IC50 values ​​of the compounds were calculated using a nonlinear regression model with logarithmic (inhibitor) and response-variable slope (four parameters) in GraphPad Prism software. Representative biochemical data are presented in Table 2. Table 2 Example M pro IC 50 1a A 1b C 2a A 2b C 3a A 3b D 4a A 4b C 5a A 5b C 6a A 6b A 6c C 6d D 8 A 11a A 11b C 13a D 13b D 14a A 14b D 18a A 18b C 22a A 22b C 23a C 23b A 26a B 26b C 27a B 27b C 28a A 28b D 29a B 29b D 32a A 32b C 33a A 33b B 34a A 34b D 36a A 36b D 76a A 76b B 76c D 76d D 77a A 77b A 77c C 77d D 90a A 90b B 92a A 92b B 94a A 94b C 95a A 95b C 96a A 96b NT 97a A 97b D 98a A 98b C 99a A 99b C 100a A 100b B 101a A 101b NT 102a A 102b B 103a A 103b D 104a A 104b C 105a A 105b D 106a A 106b D 107a A 107b D 108a B 108b D 109a A 109b C 110a A 110b C 111a A 111b D 112a B 112b D 113a A 113b D 114a NT 114b NT 115a A 115b C IC50 (nM): 0 < A ≤ 100; 100 < B ≤ 1,000; 1,000 < C ≤ 10,000; 10,000 < D. Example B: CellTiter-Glo® luminescence assay for determining the CC50 of various compounds in cell cultures based on in vitro antiviral assays (live SARS-CoV-2).

[0360] Multiple cell lines can be used upon customer request. For each cell line, three copies of 4 × 10⁴ cells / well in a 96-well dish are incubated for 24, 48, and 72 hours with individual compounds at seven different concentrations (depending on their water solubility and using a 2-fold dilution). Subsequently, plasmids are added to detect cell viability, followed by brightness detection after 10 minutes. The 50% cytotoxic concentration (CC50) of the antiviral agent is calculated using SigmaPlot (Systat Software Inc., San Jose, CA, USA) in the Excel add-in ED50V10. SARS-CoV-2 viral load reduction analysis:

[0361] Multiple cell lines can be used according to customer requirements. Furthermore, different related variants (e.g., α, γ, κ, and δ) can be included upon request. For each cell line, cells will be infected with 0.1 MOI SARS-CoV-2 for 1 hour. Subsequently, the infectious inoculum will be replaced with serially diluted drug-containing medium (7 concentrations). At 48 hours post-inoculation (hpi), the culture supernatant of SARS-CoV-2-infected cells will be collected for qRT-PCR analysis of viral RNA load. A total of 140 μL of culture supernatant will be lysed with 560 μL AVL buffer, followed by extraction of total RNA using the QIAamp viral RNA microkit (Qiagen, Hilden, Germany). qRT-PCR will be used to quantify SARS-CoV-2 replication using the QuantiNova Probe RT-PCR kit (Qiagen) and the LightCycler 480 instant PCR system (Roche). Each 20 μL reaction mixture contained 10 μL of 2×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. The reaction mixture was incubated at 45°C for 10 minutes for reverse transcription, followed by incubation at 95°C for 5 minutes for denaturation, and then 45 cycles of 95°C for 5 seconds and 55°C for 30 seconds. Signal detection and measurement were performed in each cycle after the bonding step. The cycling curve ended with a cooling step at 40°C for 30 seconds. The primer and probe sequences target the RNA-dependent RNA polymerase / helicase (RdRP / Hel) gene region of SARS-CoV-2: Forward primer: 5'-CGCATACAGTCTTRCAGGCT-3'; Reverse primer: 5'-GTGTGATGTTGAWATGACATGGTC-3'; Specific probe: 5'-FAMTTAAGATGTGGTGCTTGCATACGTAGAC-IABkFQ-3'. Plaque reduction analysis.

[0362] Different related variants of SARS-CoV-2 (e.g., α, γ, δ, and κ) can be included upon customer request. One day prior to analysis, VeroE6 cells were seeded at 2 × 10⁵ cells / well in 24-well tissue culture dishes. After 24 hours of incubation, 50 plaque-forming units (PFU) of SARS-CoV-2 were added to the cell monolayer, and the dish was further incubated at 37°C in 5% CO₂ for 1 hour. Unbound viral particles were then removed by aspirating the medium and washing once with DMEM. The monolayer was then covered with DMEM containing 1.5% low-melting-point agarose (Cambrex Corporation, East Rutherford, NJ, USA) and appropriate concentrations of individual compounds (5 concentrations), inverted, and incubated for another 72 hours. The wells were then fixed overnight with 10% formaldehyde (BDH, Merck, Darmstadt, Germany). After removing the agarose stoppers, the monolayers were stained with 0.7% crystal violet (BDH, Merck), and plaques were counted. The percentage of plaque inhibition relative to the control (i.e., no compound added) wells was determined for each antiviral agent concentration. EC50 was calculated using the δ curve (SPSS) in the Excel add-in ED50V10. Plaque reduction analysis experiments were performed in triplicate. Table 3 Example Vero EC 50 (μM) 1a B IC50 (nM): 0<A≤100; 100<B≤1,000; 1,000<C≤10,000; 10,000<D

Claims

1. A compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof: formula (I), wherein: R1 is a halogen; R2 is a halogen; ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; each R3 is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -SF5, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C 6-hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, depending on the case, independently substituted by one or more R3a; or two R3s on the same atom together form a side oxygen group; each R3a is independently a halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, -OC(=O)NRcRd, -SH, -SRa, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R 3a on the same atom together forming a side oxygen group; n is 0 to 4; L is -(CR 4R 4) p-; each R 4 is independently hydrogen, halogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl or C1-C6 heteroalkyl; or two R on the same carbon 4 together form cycloalkyl or heterocycloalkyl groups, each of which is substituted by one or more R 4a as appropriate;Each R 4a is independently a halogen, -CN, -NO 2, -OH, -OR a, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR 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; each R 6 is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b、-OC(=O)NR cR d、-SH、-SR a、-S(=O)R a、-S(=O) 2R a、-S(=O) 2NR cR d、-NR cR d、-NR bC(=O)NR cR d、-NR bC(=O)R a、-NR bC(=O)OR b、-NR bS(=O) 2R a、-C(=O)R a、-C(=O)OR b、-C(=O)NR cR d、C1-C6 alkyl、C1-C6 haloalkyl、C1-C6 hydroxyalkyl、C1-C6 aminoalkyl、C1-C6 heteroalkyl、C2-C6 alkenyl、C2-C 6. Alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group is, as appropriate, and independently substituted by one or more R 6a; or two R 6a on the same atom together form a side oxygen group; each R 6a is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R6a on the same atom together form a side oxygen group; m is 0 to 4;R7 is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl; R8 is C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl groups are, as appropriate, independently substituted by one or more R8a; each R 8a is independently a halogen, -CN, -NO2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O)2R a, -S(=O)2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O)2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 6. Acynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; or two R 8a on the same atom together forming a side oxygen group; or R 7 and R 8 together forming a heterocycloalkyl group, which is, as appropriate, independently substituted by one or more R 7a; each R 7a is independently a halogen, -CN, -NO 2, -OH, -OR a, -OC(=O)R a, -OC(=O)OR b, -OC(=O)NR cR d, -SH, -SR a, -S(=O)R a, -S(=O) 2R a, -S(=O) 2NR cR d, -NR cR d, -NR bC(=O)NR cR d, -NR bC(=O)R a, -NR bC(=O)OR b, -NR bS(=O) 2R a, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; or two R 7a on the same atom together forming a side oxygen group;Each Ra is independently a C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein each alkyl, alkylene, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted with one or more Rs as appropriate; each Rb is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkylene (cycloalkyl), C2-C6 alkylene (heteroaryl), C2-C6 alkylene (cycloalkyl), C1-C6 alkylene (heteroalkyl), C2-C6 alkylene (cycloalkyl), C1 ... 6-Alkenyl, C2-C6yneyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylyl (cycloalkyl), C1-C6 alkylyl (heterocycloalkyl), C1-C6 alkylyl (aryl), or C1-C6 alkylyl (heteroaryl); wherein each alkyl, alkylyl, alkenyl, ynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently substituted by one or more R, as appropriate; each Rc and Rd is independently hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 heteroalkyl, C2-C6 alkenyl, C2-C6 ynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylyl (cycloalkyl), C1-C6 alkylyl (heterocycloalkyl), C 1-C 6-alkyl (aryl) or C 1-C 6-alkyl (heteroaryl); wherein each alkyl, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl group is independently substituted by one or more Rs as appropriate; or Rc and Rd together with the atoms they are attached to form a heterocycloalkyl group substituted by one or more Rs as appropriate; and each R is independently a halogen, -CN, -OH, -OC 1-C 6 alkyl, -S(=O)C 1-C 6 alkyl, -S(=O) 2C 1-C 6 alkyl, -S(=O) 2NH 2, -S(=O) 2NHC 1-C 6 alkyl, -S(=O) 2N(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)C1-C6alkyl, -C(=O)OH, -C(=O)OC1-C6alkyl, -C(=O)NH2, -C(=O)N(C1-C6alkyl)2, -C(=O)NHC1-C6alkyl, C1-C6alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl or C1-C6 heteroalkyl;Or two R atoms on the same atom can together form a side oxygen group.

2. The compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R8 is a C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C1-C6 alkylene (cycloalkyl), C1-C6 alkylene (heterocycloalkyl), C1-C6 alkylene (aryl), or C1-C6 alkylene (heteroaryl); wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are, as appropriate, and independently substituted by one or more R8a.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt or stereoisomer, wherein R 8 is a C1-C6 alkyl (aryl); wherein the alkyl and aryl groups are, as appropriate and independently, substituted by one or more R 8a.

4. A compound of claim 1 or 2 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 8 is a cycloalkyl or heterocycloalkyl group; wherein the cycloalkyl or heterocycloalkyl group is, as appropriate and independently substituted by one or more R 8a.

5. A compound of claim 1 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein the compound of formula (I) or a pharmaceutically acceptable salt or stereoisomer thereof has formula (Ia): Formula (Ia); wherein: The ring C is a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl group; and q is 0 to 4.

6. The compound of claim 5 or its pharmaceutically acceptable salt or stereoisomer, wherein the ring C is a cycloalkyl or heterocycloalkyl group.

7. The compound of claim 5 or 6 or its pharmaceutically acceptable salt or stereoisomer, wherein the ring C is a cycloalkyl group.

8. The compound of claim 5 or 6 or its pharmaceutically acceptable salt or stereoisomer, wherein the ring C is a heterocyclic alkyl group.

9. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, as claimed in any of claims 5 to 8, wherein q is 1 or 2.

10. A compound of any one of claims 5 to 8 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein q is 0 or 1.

11. A compound of any one of claims 1 to 10, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 1 is fluorine or chlorine.

12. A compound of any one of claims 1 to 11 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R2 is fluorine or chlorine.

13. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, as claimed in any of claims 1 to 12, wherein R1 is fluorine and R2 is chlorine.

14. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is aryl or heteroaryl.

15. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is phenyl.

16. A compound of any one of claims 1 to 13, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring A is a 6-membered heteroaryl group.

17. A compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R3 is independently a halogen, -CN, -OH, -ORa, -SRa, -SF5, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are, as appropriate and independently substituted by one or more R3a.

18. A compound of any one of claims 1 to 17 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R3 is independently a halogen, -CN, -ORa, -SRa, -SF5, -S(=O)2Ra, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl; wherein the alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are, as appropriate and independently, substituted by one or more R3a.

19. A compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R3 is independently a halogen, -CN, -ORa, -SRa, -SF5, -S(=O)2Ra, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heteroaryl; wherein the alkyl, cycloalkyl and heteroaryl are, as appropriate and independently substituted by one or more R3a.

20. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R3 is independently -ORa or -SRa.

21. A compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R3 is independently -OR a.

22. A compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R3 is independently a heteroaryl group.

23. A compound of any one of claims 1 to 22 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 3a is independently a halogen, -CN, -OH, -OR a, -NR cR d, -C(=O)R a, -C(=O)OR b, -C(=O)NR cR d, C1-C6 alkyl, C1-C6 haloalkyl, cycloalkyl or heterocycloalkyl.

24. A compound of any one of claims 1 to 23 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 3a is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl or C1-C6 haloalkyl.

25. A compound of any one of claims 1 to 24 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 3a is independently a halogen, a C1-C6 alkyl or a C1-C6 haloalkyl.

26. A compound of any one of claims 1 to 25, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein n is 1 or 2.

27. A compound of any one of claims 1 to 26, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein p is 0.

28. A compound or a pharmaceutically acceptable salt or stereoisomer thereof, as claimed in any of claims 1 to 26, wherein p is 1 to 3.

29. A compound of any one of claims 1 to 28 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 4 is hydrogen.

30. A compound of any one of claims 1 to 29 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is deuterium or C1-C6 alkyl.

31. A compound of any one of claims 1 to 30, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is a C1-C6 alkyl group.

32. The compound of any one of claims 1 to 30 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 5 is deuterium.

33. A compound of any one of claims 1 to 32, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is a heterocyclic alkyl or heteroaryl group.

34. A compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is a heteroaryl group.

35. A compound of any one of claims 1 to 34, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is a 5- or 6-membered heteroaryl group.

36. A compound of any one of claims 1 to 35, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein ring B is a 6-membered heteroaryl group.

37. A compound of any one of claims 1 to 36 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R6 is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl or C1-C6 haloalkyl.

38. A compound of any one of claims 1 to 37 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R6 is independently a halogen or a C1-C6 alkyl group.

39. A compound of any one of claims 1 to 38 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0 to 2.

40. A compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 0 or 1.

41. A compound of any one of claims 1 to 39 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein m is 1 or 2.

42. A compound of any one of claims 1 to 41 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is hydrogen or a C1-C6 alkyl group.

43. A compound of any one of claims 1 to 42, or a pharmaceutically acceptable salt or stereoisomer thereof, wherein R 7 is hydrogen.

44. A compound of any one of claims 1 to 43 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 8a is independently a halogen, -CN, -OH, -ORa, -NRcRd, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminealkyl, C1-C6 heteroalkyl, cycloalkyl, or heterocycloalkyl.

45. A compound of any one of claims 1 to 44 or a pharmaceutically acceptable salt or stereoisomer thereof, wherein each R 8a is independently a halogen, -OH, -OR a, C1-C6 alkyl or C1-C6 haloalkyl.

46. ​​The compound or its pharmaceutically acceptable salt or stereoisomer as claimed in any of the preceding claims, wherein the abundance of deuterium in each of R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc, Rd and / or R 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 amount of hydrogen and deuterium.

47. The compound or its pharmaceutically acceptable salt or stereoisomer as claimed in any of the preceding claims, wherein one or more of the R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc, Rd and / or R groups contain a percentage of deuterium higher than the natural abundance of deuterium.

48. A compound or its pharmaceutically acceptable salt or stereoisomer as claimed in any of the preceding claims, wherein one or more hydrogen atoms are replaced by one or more deuterium atoms in one or more of the following groups: R3, R3a, R4, R4a, R5, R6, R6a, R7, R7a, R8, R8a, R9, R9a, R10, Ra, Rb, Rc, Rd and / or R.

49. A compound selected from the compounds in Table 1 or their pharmaceutically acceptable salts or stereoisomers.

50. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 49 of the compound or a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable excipient.

51. A method of treating or preventing coronavirus infection in a patient in need, comprising administering to the patient a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 50.

52. A method of treating or preventing SARS-CoV-2 infection in a patient in need, comprising administering to the patient a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition of claim 50.

53. The method of claim 51 or 52, wherein the compound or the pharmaceutical composition is administered to the patient until the infection is reduced or eliminated.

54. The method of claim 51 or 52, wherein the method includes treating one or more symptoms of SARS-CoV-2 in patients in need.

55. An in vivo method for inhibiting a protease of SARS-CoV-2, comprising contacting the protease with a compound of any one of claims 1 to 49 or a pharmaceutically acceptable salt or stereoisomer thereof.

56. The method of claim 55, wherein the compound binds to the cysteine ​​residue of the protease.

57. The method of claim 55 or 56, wherein the compound is reversibly or irreversibly bound to the cysteine ​​residue.

58. The method of any one of claims 55 to 57, wherein the protease is a 3CL-protease.

59. The method of any one of claims 55 to 57, wherein the protease is SARS-CoV-2 MPRO.

60. The method of any one of claims 56 to 59, wherein the cysteine ​​is cysteine ​​145 of 3CL-protease.

61. The method of any one of claims 56 to 59, wherein the compound is covalently bound to the cysteine ​​residue.

62. A modified SARS-CoV-2 MPRO protein comprising the SARS-CoV-2 MPRO protein and a compound of any one of claims 1 to 49.