Molecular glues and uses thereof

Abstract

Provided are molecular glue compounds of Formula (I) and pharmaceutically acceptable salts and compositions thereof, which are useful for treating a variety of conditions associated with increased protein levels of target proteins.

Description

MOLECULAR GLUES AND USES THEREOF RELATEDAPPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisonal Application No. 63 / 555,527, filed February 20, 2024, U.S. Provisonal Application No. 63 / 706,906, filed October 14, 2024, and U.S. Provisonal Application No. 63 / 723,200, filed November 21, 2024, the entire contents of each of which are incorporated herein by reference. BACKGROUND

[0002] Targeted protein degradation is an attractive area for the development of therapeutics to treat diseases driven by the accumulation or inappropriate expression of proteins that remodel cellular physiology. The ubiquitin-proteasome system (UPS) is a major pathway for regulating cellular protein abundance that involves tagging target proteins with ubiquitin for recognition and degradation by the proteasome.

[0003] Synthetic small molecules which enhance the ubiquitination of a target protein by inducing and / or stabilizing the interaction between the target protein and an E3 ligase have been reported and are referred to as “molecular glues”. See e.g., Guoqiang Dong et al., J. Med. Chem. 2021, 64, 15, 10606–10620. Molecular glues are distinct from PROTACS in that PROTACS are bifunctional molecules, i.e., the molecules have one moiety that selectively binds a target protein and another moiety that recruits an E3 ubiquitin ligase, each moiety being separated from each other on the molecule by a linker. Molecular glues, on the other hand, are small chemical entities made up of a single molecule. While both PROTACS and molecular glues are effective, molecular glues are inherently more advantageous than PROTACs because they resemble traditional small molecule drug design principles. Being a smaller molecule, a molecular glue intrinsically poses qualities such as better solubility and membrane permeability, based on basic druggability principles.

[0004] Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription factor that regulates cellular defense against oxidative stress and toxicity. In nonpathological circumstances, the protein level of NRF2 is tightly regulated by the redox-sensitive E3 ligase KEAP1 and is transiently stabilized to promote cellular antioxidant mechanisms. In multiple cancers, NRF2 is ectopically stabilized by mutations in KEAP1 or NRF2 itself that prevent recognition by KEAP1 even in the absence of oxidative stress. Other mechanisms resulting in high expression of NRF2 protein can include transcriptional downregulation (as by promoter methylation) of KEAP1 and increased transcription of the NRF2 gene locus. Continuous highexpression of NRF2 results in activation of multiple transcriptional networks that support tumor progression, metastasis, and resistance to chemotherapeutic agents. Inhibition of NRF2 function is thus a relevant therapeutic strategy for cancer and other diseases in which NRF2 protein levels are high. As a transcription factor with no enzymatic activity and no validated binary ligands for bifunctional degraders, NRF2 is strongly suited for degradation using a molecular glue to recruit a non-KEAP1 E3 ligase.

[0005] β-catenin is a transcriptional coregulator that plays important roles in embryonic patterning and tissue homeostasis. Protein levels of transcriptionally active β-catenin are tightly regulated by the multi-protein destruction complex, which promotes β-catenin phosphorylation and recruits β-TRCP for ubiquitination and degradation. In the majority of colorectal cancers, the destruction complex is dysfunctional, resulting in inadequate phosphorylation and accumulation of β-catenin. Sustained accumulation of active β-catenin results in the activation of pro-tumorigenic transcriptional programs and is a critical driver of colorectal cancers. Oncogenesis via accumulated β-catenin is also observed in other cancers via mutation of the β-TRCP binding site. Restoration of β-TRCP recognition and degradation of β-catenin via molecular glue degrader thus represents an attractive therapeutic option for multiple cancers.

[0006] Therefore, molecular glues targeting NRF2 and / or β-catenin represent an attractive and unique approach for targeting conditions associated with increased protein levels of either of these oncogenic drivers. SUMMARY

[0007] Provided herein are compounds having the Formula I:and pharmaceutically acceptable salts and compositions thereof, wherein R1, R2, R3, R4X, X1, X2, X3, Y, Y1, Y2and p are as described herein. In one aspect, the described compounds of Formula I induce or facilitate ubiquitination and degradation of NRF2 or β-catenin, or both. Therefore, in one aspect, the described compounds are useful in a variety of therapeutic applications such as, for example, in treating conditions associated with increased protein levels of NRF2 and / or β-catenin such as cancers.

[0008] Pharmaceutical compositions comprising the described compounds and pharmaceutically acceptable salts of the described compounds, as well as methods for their preparation are also included. DETAILED DESCRIPTION 1. General Description of Compounds

[0009] Provided herein is a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein Y is C(O) or CRx1Ry1; Y1is C(O) or CRxRy; Y2is C(O) or CRx2Ry2; X, X1, X2, and X3are each independently is N or CH; R1is phenyl, carbocyclyl, heterocyclyl, or heteroaryl, each of which are substituted with 1 to 4 groups selected from Ra; R2is (C1-C4)alkyl or halo(C1-C4)alkyl; R3is hydrogen, halo, (C1-C4)alkyl, -(C1-C4)alkylcycloalkyl, cycloalkyl, -(C1-C4)alkyl heterocyclyl, and heterocyclyl, wherein each heterocyclyl and cycloalkyl alone, or as connected to (C1-C4)alkyl, are optionally substituted with one or more groups selected from halo, oxo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; each R4is independently selected from halo, (C1-C4)alkyl, (C2-C4)alkynyl, (C2- C4)alkenyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkoxyNRcRd, -(C1-C4)alkylC(O)ORc, -(C1- C4)alkoxyC(O)ORc, -(C1-C4)alkylC(O)Rc, -(C1-C4)alkoxyC(O)Rc, -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkoxyheterocyclyl, -(C1-C4)alkoxyheteroaryl, -(C1- C4)alkylcycloalkyl, -(C1-C4)alkoxycycloalkyl, -NRc(C1-C4)alkylheteroaryl, -NRc(C1- C4)alkylheterocyclyl, -NRc(C1-C4)alkylcycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, - NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -(C1- C4)alkylNRcC(O)Rd, -(C1-C4)alkylNRcC(O)ORd, -(C1-C4)alkylNRc(C1-C4)alkylC(O)NRdRe, - (C1-C4)alkylNRcC(O)NRdRe, -(C1-C4)alkoxyNRcC(O)Rd, -(C1-C4)alkoxyNRcC(O)ORd, -(C1- C4)alkoxyNRc(C1-C4)alkylC(O)NRdRe, -(C1-C4)alkoxyNRcC(O)NRdRe, -S(C1-C4)alkyl, -O(heteroaryl), -O(heterocyclyl), -O(cycloalkyl), -C(O)NRcRd, -(C1-C4)alkylC(O)NRcRd, - (C1-C4)alkoxyC(O)NRcRd, C(O)Rc, and -C(O)ORc, wherein each heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb; each Rais independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, cyano(C2-C4)alkynyl, -(C2- C4)alkynyl heterocyclyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, cyano, -(C1- C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylNRc1Rd1, -(C1-C4)alkoxyNRc1Rd1, -(C1- C4)alkylC(O)ORc1, -(C1-C4)alkoxyC(O)ORc1, -(C1-C4)alkylC(O)Rc1, -(C1-C4)alkoxyC(O)Rc1, -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkoxy heterocyclyl, -(C1- C4)alkoxyheteroaryl, -(C1-C4)alkylcycloalkyl, -(C1-C4)alkoxycycloalkyl, -NRc(C1- C4)alkylheteroaryl, -NRc1(C1-C4)alkylheterocyclyl, -NRc1(C1-C4)alkylcycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRc1Rd1, -NRc1C(O)Rd1, -NRc1C(O)ORd1, -NRc1(C1- C4)alkylC(O)NRd1Re1, -NRc1C(O)NRd1Re1, -(C1-C4)alkylNRc1C(O)Rd1, -(C1- C4)alkylNRc1C(O)ORd1, -(C1-C4)alkylNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1- C4)alkylNRc1C(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)Rd1, -(C1-C4)alkoxyNRc1C(O)ORd1, - (C1-C4)alkoxyNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)NRd1Re1, -S(C1- C4)alkyl, -C(O)NRc1Rd1, -(C1-C4)alkylC(O)NRc1Rd1, -(C1-C4)alkoxyC(O)NRc1Rd1, -C(O)Rc1, and -C(O)ORc1, wherein each heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb1; Rx, Ry, Rx1, Ry1, Rx2, and Ry2are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkylaryl, (C1-C4)alkylheterocyclyl, (C1-C4)alkyl(C3- C6)cycloalkyl, -(C2-C4)alkynylC(O)Rd3, cyano(C2-C4)alkynyl, hydroxy(C1-C4)alkyl, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxy(C2-C4)alkynyl, -(C1-C4)alkylS(O)2(C1-C4)alkyl, -(C1- C4)alkylS(O)(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, cyano(C1-C4)alkyl, - (C1-C4)alkylNRc3Rd3, -(C1-C4)alkoxyNRc3Rd3, -(C1-C4)alkylC(O)ORc3, -(C1- C4)alkoxyC(O)ORc3, -(C1-C4)alkylC(O)Rc3, -(C1-C4)alkoxyC(O)Rc3, -(C1- C4)alkylNRc3C(O)Rd3, -(C1-C4)alkylNRc3C(O)ORd3, -(C1-C4)alkylNRc3(C1- C4)alkylC(O)NRd3Re3, -(C1-C4)alkylNRc3C(O)NRd3Re3, -(C1-C4)alkoxyNRc3C(O)Rd3, -(C1- C4)alkoxyNRc3C(O)ORd3, -(C1-C4)alkoxyNRc3(C1-C4)alkylC(O)NRd3Re3, -(C1- C4)alkoxyNRc3C(O)NRd3Re3, -C(O)NRc3Rd3, -(C1-C4)alkylC(O)NRc3Rd3, -C(O)Rc3, - C(O)ORc3, aryl, and heteroaryl; or Rxand Ry, Rx1and Ry1, and / or Rx1and Ry1are taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl orheterocyclyl, each optionally substituted with one or more groups selected from halo, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; Rb, Rb1, Rb2, and Rb3are each independently selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, hydroxy, phenyl, heteroaryl, heterocyclyl, cycloalkyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylphenyl, -(C1- C4)alkylcycloalkyl, -NRc2Rd2, -NRc2C(O)Rd2, -NRc2C(O)ORd2, -C(O)NRc2Rd2, -C(O)ORc2, - C(O)Rc2, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylNRc2Rd2, -(C1-C4)alkylNRc2C(O)Rd2, - (C1-C4)alkylNRc2C(O)ORd2, -(C1-C4)alkylC(O)NRc2Rd2, -(C1-C4)alkylC(O)ORc2, and -(C1- C4)alkylC(O)Rc2, wherein each phenyl, heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more groups selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkenyl, halo(C1- C4)alkenyl, -S(O)2(C1-C4)alkyl, -S(O)2(C1-C4)alkenyl, cyano, phenyl, benzyl, 4- to 6- membered heterocyclyl, and 5- to 7-membered heteroaryl; Rc, Rd, Re, Rc1, Rd1, Rc2, Rd2, Re1, Rc3, Rd3, Re3, and Rf3are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl; p is 1, 2, 3 or 4; and when p is 2 or 3 or 4, two R4groups on adjacent carbon atoms may be taken together to form a 6-membered heterocyclyl or a phenyl, each of which may be optionally substituted with one or more groups selected from Rb2; provided the compound is not 4-((2,6-dichlorophenyl)thio)-3-(5,6- dimethoxyisoindoline-2-carbonyl)-6-(trifluoromethyl)pyridin-2(1H)-one or 2-(4-((2,6- dichlorophenyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonyl)isoindoline- 4-carbonitrile; or a salt thereof. 2. Definitions

[0010] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. The terminology used in the description is for describing particular embodiments only and is not intended to be limiting of the disclosure.

[0011] As used in structures herein, a wiggly line “ ” indicates the point ofattachment of the particular depicted structure or substituent group to the appropriate atom(s) in the remainder of the molecule.

[0012] The articles “a” and “an” as used herein and in the appended claims are used herein to refer to one or to more than one (e.g., to at least one) of the grammatical object of the article unless the context clearly indicates otherwise. By way of example, “an element” means one element or more than one element.

[0013] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in a country other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.

[0014] The term “pharmaceutically acceptable carrier” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0015] For use in medicines, the salts of the compounds described herein refer to non- toxic “pharmaceutically acceptable salts.” Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include e.g., salts of inorganic acids (such as hydrochloric acid, hydrobromic, phosphoric, nitric, and sulfuric acids) and of organic acids (such as, acetic acid, benzenesulfonic, benzoic, methanesulfonic, and p-toluenesulfonic acids). Compounds of the present teachings with acidic groups such as carboxylic acids can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable basic salts include e.g., ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts). Compounds with a quaternary ammonium group also contain a counteranion such as chloride, bromide, siodide, acetate, perchlorate and the like. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates and salts with amino acids such as glutamic acid.

[0016] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment of that group to the variable to which it is defined. For example, -(C1-C4)alkylheteroaryl means that the point of attachment for this group occurs on the (C1-C4)alkyl.

[0017] The term “alkyl,” when used alone or as part of a substituent group, refers to a straight- or branched-chain hydrocarbon group having from 1 to 12 carbon atoms (“C1-12”), for example 1 to 6 carbons atoms (“C1-6”), in the group. Examples of alkyl groups include methyl (C1), ethyl (C2), propyl (C3) (e.g., n-propyl, isopropyl), butyl (C4) (e.g., n-butyl, tert- butyl, sec-butyl, iso-butyl), pentyl (C5) (e.g., n-pentyl, 3-pentyl, amyl, neopentyl, 3-methyl-2- butanyl, tertiary amyl), hexyl (C6) (e.g., n-hexyl), heptyl (C7) (e.g., n-heptyl), octyl (C8) (e.g., n-octyl), and the like. In some embodiments, the alkyl group is a C1-6alkyl; in other embodiments, it is a C1-4alkyl; and in other embodiments, it is a C1-3alkyl.

[0018] When a range of carbon atoms is used herein, for example, C1-6, all ranges, as well as individual numbers of carbon atoms are encompassed. For example, “C1-4” includes C1-3, C1-2, C2-3, C1, C2, and C3.

[0019] The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, 2-4, or 3-6 carbon atoms, referred to herein as C2-6alkynyl, C2-4alkynyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, methylpropynyl, etc.

[0020] The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond. Exemplary alkynyl groups include, but are not limited to, straight or branched groups of 2-6, 2-4, or 3-6 carbon atoms, referred to herein as C2-6alkenyl, C2-4alkenyl, and C3-6alkynyl, respectively. Exemplary alkynyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc.

[0021] The term “aryl” when used alone or as part of a substituent group also refers to a mono- or bicyclic- aromatic hydrocarbon ring structure having 6 or 10 carbon atoms in the ring, wherein one or more of the carbon atoms in the ring is optionally substituted. Examples of aryl groups include phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and the like. The aryl may be unsubstituted or substituted as described herein. In some embodiments, the optionally substituted phenyl has four substituents. In further embodiments, the optionally substituted phenyl has three substituents. In yet other embodiments, the optionally substitutedphenyl has two substituents. In still further embodiments, the optionally substituted phenyl has one substituent. In other embodiments, the optionally substituted phenyl is unsubstituted.

[0022] The term “carbocyclyl” when used alone or as part of a substituent group refers to a non-aromatic, saturated or partially saturated cyclic hydrocarbon ring have from 3 to 10 ring carbon atoms (“C3-10”), for example from 3 to 6 carbon atoms (“C3-6”). Examples include cyclopropyl (C3), cyclobutyl (C4), cyclobutyene (C4), cyclopentyl (C5), cyclohexyl (C6), cyclohexene (C6), and the like.

[0023] The term “cycloalkyl” when used alone or as part of a substituent group refers to cyclic-containing, non-aromatic hydrocarbon groups having from 3 to 10 carbon atoms (“C3-10”), for example from 3 to 7 carbon atoms (“C3-7”). Examples of cycloalkyl groups include cyclopropyl (C3), cyclobutyl (C4), cyclopentyl (C5), cyclohexyl (C6), cycloheptyl (C7), and the like. In some embodiments, the cycloalkyl group is a C3-6cycloalkyl. The cycloalkyl may be unsubstituted or substituted as described herein. In some embodiments, the cycloalkyl is substituted with two substituents. In further embodiments, the cycloalkyl is substituted with one substituent. In yet other embodiments, the cycloalkyl is substituted with three substituents. In still further embodiments, the cycloalkyl is unsubstituted. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is bicyclic (e.g., a spiro, fused, or bridge bicyclic). In some embodiments, the cycloalkyl group is a spiro bicyclic cycloalkyl.

[0024] The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0025] As used herein, the term “haloalkyl” refers to an alkyl group wherein one or more of the hydrogen atoms has been replaced with one or more halogen atoms which may be the same or different. In some embodiments, the alkyl is substituted by at least one halogen. In other embodiments, the alkyl is substituted by one, two, or three F and / or Cl. Examples of haloalkyl groups include fluoromethyl (CH2F), 1-fluoroethyl (CH(CH3)F), 2-fluoroethyl, difluoromethyl (CHF2), trifluoromethyl (CF3), pentafluoroethyl, 1,1-difluoroethyl (C(CH3)F2), 2,2-difluoroethyl (CH2CHF2), 2,2,2-trifluoroethyl (CH2CF3), 2-fluoropropan-2- yl (C(CH3)2F), 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, trichloromethyl and the like. In some embodiments, the haloalkyl group is a C1-6haloalkyl; in other embodiments, it is a C1-4haloalkyl; and in other embodiments, it is a C1-3haloalkyl.

[0026] The term “cyanoalkyl” as used by itself or as part of another group refers to an alkyl as defined herein that is substituted by one or more CN. In some embodiments, the alkyl is substituted by at least one CN. In other embodiments, the alkyl is substituted by one, two,or three CN. In further embodiments, the cyanoalkyl group is a C1-6cyanoalkyl. In yet other embodiments, the cyanoalkyl is a C1-4cyanoalkyl. Examples of cyanoalkyl groups include CH2CN, CH2CH2CN, CH(CN)CH3, CH2CH2CH2CN, C(CH3)2CN, CH2CH(CN)CH3, CH(CN)CH2CH3, and the like.

[0027] The term “hydroxyalkyl” as used by itself or as part of another group refers to an alkyl group as defined herein wherein one or more of the hydrogen atoms has been replaced with one or more hydroxyl (i.e., -OH). In some embodiments, the hydroxyalkyl contains one OH. In other embodiments, the hydroxyalkyl contains two OH. In further embodiments, the hydroxyalkyl contains three OH. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl (e.g., 1-hydroxyethyl, 2-hydroxyethyl), 1,2-dihydroxyethyl, hydroxypropyl (e.g., 2-hydroxypropyl, 3-hydroxypropyl), hydroxybutyl (e.g., 3-hydroxybutyl, 4- hydroxybutyl), 2-hydroxy-1-methylpropyl, 1,3-dihydroxyprop-2-yl, and the like. In some embodiments, the hydroxyalkyl group is C1-6hydroxyalkyl; in other embodiments, it is C1-4hydroxyalkyl; and in other embodiments, it is C1-3hydroxyalkyl.

[0028] The term “alkoxy” as used by itself or as part of another group refers to an oxygen radical attached to an alkyl group by a single bond. Examples of alkoxyl groups include methoxy (OCH3), ethoxy (OCH2CH3), propoxy (e.g., -OnPr, -OiPr), or butoxy (e.g., -OnBu, - OiBu, -OsBu, -OtBu), and the like. In other embodiments, the alkoxy group is a C1-6alkoxy. In further embodiments, the alkoxy group is a C1-4alkoxy.

[0029] The term “haloalkoxy” as used by itself or as part of another group refers an oxygen radical attached to a haloalkyl group by a single bond, wherein haloalkyl is defined above. Examples of haloalkoxy groups include fluoromethoxy (OCH2F), 2-fluoroethoxy, difluoromethoxy (OCHF2), trifluoromethoxy (OCF3), pentafluoroethoxy, 1,1-difluoroethoxy (OC(CH3)F2), 2,2-difluoroethoxy, 2,2,2-trifluoroethoxy (OCH2CF3), 3,3,3-trifluoropropoxy, 4,4,4-trifluorobutoxy, trichloromethoxy groups, and the like. In some embodiments, the haloalkoxy group is a C1-6haloalkoxy; in other embodiments, it is C1-4haloalkoxy; and in other embodiments, it is C1-3haloalkoxy.

[0030] The term oxo means the group =O.

[0031] The term “heteroaryl” when used alone or as part of a substituent group refers to a mono- or bicyclic- aromatic ring structure including carbon atoms as well as up to four heteroatoms that are each independently nitrogen, oxygen, or sulfur. Heteroaryl rings can include a total of 5, 6, 9, or 10 ring atoms. In some embodiments, heteroaryl rings are characterized by the number of ring atoms in the heteroaryl group. For example, a 6- membered heteroaryl group refers to a heteroaryl group having 6 ring atoms in the group.Similarly, a 5-membered heteroaryl group refers to a heteroaryl group having 5 ring atoms in the group. The heteroaryl moiety can be unsubstituted, or one or more of the carbon atoms or nitrogen atoms in the ring can be substituted. Examples of heteroaryl groups include thienyl, benzo[b]thienyl, furanyl, benzofuryl, pyranyl, thiophenyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2H pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, quinoxalyl, phthalazinyl, naphthyridinyl, cinnolinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, quinazolinyl, pteridinyl, pyrimidinyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, furazanyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridinyl, benzoisothiazolyl, imidazol[1,5-a]pyridinyl, pyrrolo[1,2]pyridazinyl, benzo[d]thiazolyl, benzo[d]imidazolyl, benzo[d]oxazolyl, benzoisoxazolyl, isothiazolyl, tetrahydropyrazolo[1,5- a]pyridinyl and the like. In some embodiments, the heteroaryl is thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furanyl, 3-furanyl, 4-furanyl), pyrrolyl (e.g., pyrrol-2-yl, pyrrol-3- yl), imidazolyl (e.g., imidazol-2-yl, imidazol-4-yl), pyrazolyl (e.g., pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl, pyrazol-5-yl), pyridyl (e.g., pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, and pyridin- 4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thiazolyl (e.g., thiazol-2-yl, thiazol-4-yl, and thiazol-5-yl), isothiazolyl (e.g., isothiazol-3-yl, isothiazol-4-yl, and isothiazol-5-yl), oxazolyl (e.g., oxazol-2-yl, oxazol-4-yl, and oxazol-5-yl), isoxazolyl (e.g., isoxazol-3-yl, isoxazol-4-yl, and isoxazol-5-yl), pyrazinyl (e.g., pyrazin-2-yl, pyrazin-3- yl, pyrazin-5-yl, pyrazin-6-yl), triazolyl (e.g., 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4- triazol-5-yl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thidiazolyl, 1,3,4- thiadiazolyl), oxadiazolyl (e.g., 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4- oxadiazolyl), indazolyl (e.g., indazol-3-yl), pyrazolo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyridin- 3-yl, imidazol[1,5-a]pyridinyl (e.g., imidazol[1,5-a]pyridin-1-yl), pyrrolo[1,2]pyridazinyl (e.g., pyrrolo[1,2]pyridazin-5-yl, pyrrolo[1,2]pyridazin-6-yl), benzo[d]thiazolyl (e.g., benzo[d]thiazol-3-yl, benzo[d]thiazol-2-yl), benzo[d]imidazolyl (e.g., benzo[d]imidazol-2- yl), benzo[d]oxazolyl (e.g., benzo[d]oxazol-2-yl), benzo[d]isoxazolyl (e.g., benzo[d]isoxazol- 3-yl), benzo[d]isothiazolyl (e.g., benzo[d]isothiazol-3-yl), benzo[c]isoxazolyl (e.g., benzo[c]isoxazol-3-yl), and quinolinyl (e.g., quinolin-3-yl), and pyridazinyl (e.g., pyridazin- 3-yl, pyridazin-4-yl). The term “heteroaryl” is also include N-oxides. The heteroaryl may be unsubstituted or substituted as described herein. In some embodiments, the heteroaryl is substituted with two substituents. In further embodiments, the heteroaryl is substituted with one substituent. In yet other embodiments, the heteroaryl is substituted with three substituents. In still further embodiments, the heteroaryl is unsubstituted. Substitution mayoccur on any available carbon or heteroatom (e.g., nitrogen), or both, as permitted by substituent valency.

[0032] In some embodiments, the heteroaryl is a 5- or 6-membered heteroaryl. In some embodiments, the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms wherein at least one carbon atom of the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl and the like. In other embodiments, the heteroaryl is a 6-membered heteroaryl, e.g., the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms wherein at least one carbon atom of the ring is replaced with a nitrogen atom. Examples of 6-membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like.

[0033] The term “heterocyclyl” as used by itself or as part of another group refers to non- aromatic, saturated or partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two, or three rings having from three to fourteen ring members, i.e., a 3-14-membered heterocyclyl, wherein at least one carbon atom of one of the rings is replaced with a heteroatom. Each heteroatom is independently selected from oxygen, sulfur, including sulfoxide and sulfone, and / or nitrogen atoms, which can be oxidized or quaternized. The term “heterocyclyl” also includes groups wherein a ring -CH2- is replaced with a -C(O)-. The term “heterocyclyl” also includes groups having fused optionally substituted aryl groups, e.g., indolinyl or chroman-4-yl and groups having fused optionally substituted cycloalkyl groups, e.g., 6-azaspiro[2.5]octanyl. In some embodiments, the heterocyclyl group is a C4-6heterocyclyl, i.e., a 4-, 5- or 6-membered cyclic group, containing one ring and one or two oxygen and / or nitrogen atoms. In other embodiments, the heterocyclyl is a C4-6heterocyclyl containing one ring and one nitrogen atom. The heterocyclyl can be optionally linked to the rest of the molecule through any available carbon or heteroatom that results in a stable structure. Examples of heterocyclyl groups include azetidinyl, dioxanyl, tetrahydropyranyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, indolinyl, oxetanyl, tetrahydrofuranyl, tetrahydrothiophenyl, azepanyl, aziridinyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, thianyl, dithianyl, thiomorpholinyl, oxazepanyl, oxiranyl, tetrahydropyranyl, and the like. In some embodiments, the heterocyclyl group includes azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, and 6-azaspiro[2.5]octanyl. The heterocyclyl may be unsubstituted or substituted as described herein. In some embodiments, the heterocyclyl is substituted with two substituents. In further embodiments, the heterocyclyl is substituted withone substituent. In yet other embodiments, the heterocyclyl is substituted with three substituents. In still further embodiments, the heterocyclyl is unsubstituted. In some embodiments, the heterocyclyl group is monocyclic. In some embodiments, the heterocyclyl group is bicyclic (e.g., a spiro, fused, or bridge bicyclic). In some embodiments, the heterocyclyl group is a spiro bicyclic heterocyclyl.

[0034] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0035] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0036] The term “bridged” refers to two rings that share three ring atoms with one another.

[0037] The term “optionally substituted,” as used herein to describe a chemical moiety defined herein, means that the moiety may, but is not required to be, substituted with one or more suitable functional groups or other substituents as described herein.

[0038] Recitation of ranges of values herein are intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended to better illustrate the disclosure and is not a limitation on the scope of the disclosure unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the disclosure.

[0039] Compounds described herein can comprise one or more asymmetric centers, and thus can exist in various stereoisomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein can be in the form of an individual enantiomer, diastereomer or geometric isomer, or can be in the form of a mixture of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomer. Isomers can be isolated from mixtures by methods known to those skilled in the art, including supercritical fluid chromatography (SFC), chiral high-pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or preferred isomers can be prepared by asymmetric syntheses. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).

[0040] Exemplary compounds of the disclosure including a chiral center may be depicted herein as having particular stereochemistries, but for which absolute stereochemistry has not been obtained. Absolute configurations can be obtained using methods known in the art.

[0041] As used herein, the term “stereoisomers” refers to compounds which have identical chemical constitution and connectivity, but differ with regard to the arrangement of the atoms or groups in space, e.g., enantiomers or diastereomers.

[0042] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by dashed or wedge bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0043] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0044] When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that they include both E and Z geometric isomers.

[0045] In some embodiments, the compounds described herein are isotopically enriched compound, e.g., an isotopologue. The term “isotopically enriched” refers to an atom having an isotopic composition other than the naturally abundant isotopic composition of that atom. “Isotopically enriched” may also refer to a compound containing at least one atom having an isotopic composition other than the natural isotopic composition of that atom. In an isotopologue, “isotopic enrichment” refers to the percentage of incorporation of an amount of a specific isotope of a given atom in a molecule in the place of that atom’s natural isotopic composition. For example, deuterium enrichment of 1% at a given position means that 1% of the molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%.In one embodiment, one or more hydrogen atoms on a described compound may be replaced by deuterium.

[0046] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0047] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0048] As used herein, the terms “treatment,” “treat,” and “treating” refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some aspects, treatment may be administered after one or more symptoms have developed, i.e., therapeutic treatment. In other aspects, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of exposure to a particular organism, or other susceptibility factors), i.e., prophylactic treatment. Treatment may also be continued after symptoms have resolved, for example to delay their recurrence.

[0049] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that is sufficient to achieve the desired therapeutic effect (such as treatment of a condition recited herein) under the conditions of administration. 3. Compounds

[0050] In a first embodiment, Rx, Ry, Rx1, Ry1, Rx2, and Ry2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkylaryl, (C1-C4)alkylheterocyclyl, (C1- C4)alkyl(C3-C6)cycloalkyl, -(C2-C4)alkynylC(O)Rd3, cyano(C2-C4)alkynyl, hydroxy(C2- C4)alkynyl, -(C1-C4)alkylS(O)2(C1-C4)alkyl, -(C1-C4)alkylS(O)(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, cyano(C1-C4)alkyl, -(C1-C4)alkylNRc3Rd3, -(C1-C4)alkoxyNRc3Rd3, -(C1-C4)alkylC(O)ORc3, -(C1-C4)alkoxyC(O)ORc3, -(C1-C4)alkylC(O)Rc3, -(C1- C4)alkoxyC(O)Rc3, -(C1-C4)alkylNRc3C(O)Rd3, -(C1-C4)alkylNRc3C(O)ORd3, -(C1- C4)alkylNRc3(C1-C4)alkylC(O)NRd3Re3, -(C1-C4)alkylNRc3C(O)NRd3Re3, -(C1- C4)alkoxyNRc3C(O)Rd3, -(C1-C4)alkoxyNRc3C(O)ORd3, -(C1-C4)alkoxyNRc3(C1- C4)alkylC(O)NRd3Re3, -(C1-C4)alkoxyNRc3C(O)NRd3Re3, -C(O)NRc3Rd3, -(C1- C4)alkylC(O)NRc3Rd3, -C(O)Rc3, -C(O)ORc3, aryl, and heteroaryl; or Rxand Ry, Rx1and Ry1, and / or Rx1and Ry1are taken together with the carbon atom to which they are attached to forma (C3-C6)cycloalkyl or (C3-C6)alkylheterocyclyl, each optionally substituted with one or more groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1- C4)alkoxy; and Rb, Rb1, Rb2, and Rb3are each independently selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, hydroxy, phenyl, -NRc2Rd2, - NRc2C(O)Rd2, -NRc2C(O)ORd2, -C(O)NRc2Rd2, -C(O)ORc2, -C(O)Rc2, -(C1-C4)alkyl(C1- C4)alkoxy, -(C1-C4)alkylNRc2Rd2, -(C1-C4)alkylNRc2C(O)Rd2, -(C1-C4)alkylNRc2C(O)ORd2, - (C1-C4)alkylC(O)NRc2Rd2, -(C1-C4)alkylC(O)ORc2, and -(C1-C4)alkylC(O)Rc2, wherein the remaining variables are as described above for Formula I

[0051] In a second embodiment, each Rain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, cyano(C2- C4)alkynyl, -(C2-C4)alkynyl heterocyclyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRc1Rd1, -(C1-C4)alkoxyNRc1Rd1, -(C1-C4)alkylC(O)ORc1, -(C1- C4)alkoxyC(O)ORc1, -(C1-C4)alkylC(O)Rc1, -(C1-C4)alkoxyC(O)Rc1, -(C1- C4)alkylheterocyclyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkoxy heterocyclyl, -(C1- C4)alkoxyheteroaryl, -(C1-C4)alkylcycloalkyl, -(C1-C4)alkoxycycloalkyl, -NRc(C1- C4)alkylheteroaryl, -NRc1(C1-C4)alkylheterocyclyl, -NRc1(C1-C4)alkylcycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRc1Rd1, -NRc1C(O)Rd1, -NRc1C(O)ORd1, -NRc1(C1- C4)alkylC(O)NRd1Re1, -NRc1C(O)NRd1Re1, -(C1-C4)alkylNRc1C(O)Rd1, -(C1- C4)alkylNRc1C(O)ORd1, -(C1-C4)alkylNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1- C4)alkylNRc1C(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)Rd1, -(C1-C4)alkoxyNRc1C(O)ORd1, - (C1-C4)alkoxyNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)NRd1Re1, -S(C1- C4)alkyl, -C(O)NRc1Rd1, -(C1-C4)alkylC(O)NRc1Rd1, -(C1-C4)alkoxyC(O)NRc1Rd1, C(O)Rc1, and C(O)ORc1, wherein each heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb1, wherein the remaining variables are as described above for Formula I.

[0052] In a third embodiment, Y in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CRx1Ry1, wherein the remaining variables are as described above for Formula I or any one of the first or second embodiment.

[0053] In a fourth embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylC(O)ORc3, - (C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to third embodiments. Alternatively, aspart of a fourth embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, -(C1-C4)alkylC(O)ORc3, -(C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to third embodiments. In another alternative, as part of a fourth embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to third embodiments. In another alternative, as part of a fourth embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, CH3, CH2C(O)NH2, CH2C(O)OH, CH2C(O)OCH3, CH2OCH3, CH2OH, CH2NH2, CH2NHCH3, and CH2CN, wherein the remaining variables are as described above for Formula I or any one of the first to third embodiments. In another alternative, as part of a fourth embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, CH3, CH2C(O)NH2, CH2C(O)OH, CH2C(O)OCH3, and CH2CN, wherein the remaining variables are as described above for Formula I or any one of the first to third embodiments. In another alternative, as part of a fourth embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, CH2C(O)NH2, and CH2CN, wherein the remaining variables are as described above for Formula I or any one of the first to third embodiments.

[0054] In a fifth embodiment, Y in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CH2, wherein the remaining variables are as described above for Formula I or any one of the first to fourth embodiments.

[0055] In a sixth embodiment, Y2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CRx2Ry2, wherein the remaining variables are as described above for Formula I or any one of the first to fifth embodiments.

[0056] In a seventh embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylC(O)ORc3, - (C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to sixth embodiments. Alternatively, as part of a seventh embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen,(C1-C4)alkyl, -(C1-C4)alkylC(O)ORc3, -(C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to sixth embodiments. In another alternative, as part of a seventh embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, -(C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to sixth embodiments. In another alternative, as part of a seventh embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, CH3, CH2C(O)NH2, CH2C(O)OH, CH2C(O)OCH3, CH2OCH3, CH2OH, CH2NH2, CH2NHCH3, and CH2CN, wherein the remaining variables are as described above for Formula I or any one of the first to sixth embodiments. In another alternative, as part of a seventh embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, CH3, CH2C(O)NH2, CH2C(O)OH, CH2C(O)OCH3, and CH2CN, wherein the remaining variables are as described above for Formula I or any one of the first to sixth embodiments. In another alternative, as part of a seventh embodiment, Rx1and Ry1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, CH2C(O)NH2, and CH2CN, wherein the remaining variables are as described above for Formula I or any one of the first to sixth embodiments.

[0057] In an eighth embodiment, Y is CH2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I or any one of the first to seventh embodiments.

[0058] In a ninth embodiment, Y2is CRx2Ry2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the remaining variables are as described above for Formula I or any one of the first to eighth embodiments. Alternatively, as part of a ninth embodiment, Y2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CH2, wherein the remaining variables are as described above for Formula I or any one of the first to eighth embodiments.

[0059] In a tenth embodiment, X, X1, X2, and X3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each CH, wherein the remaining variables are as described above for Formula I or any one of the first to ninth embodiments.

[0060] In an eleventh embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen or CH3, wherein the remaining variables are as described above for Formula I or any one of the first to tenth embodiments.Alternatively, as part of an eleventh embodiment, R3in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is hydrogen, wherein the remaining variables are as described above for Formula I or any one of the first to tenth embodiments.

[0061] In a twelfth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is halo(C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to eleventh embodiments. Alternatively, as part of a twelfth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CF2Cl, CF3, or CF2CH3, wherein the remaining variables are as described above for Formula I or any one of the first to eleventh embodiments. In another alternative, as part of a twelfth embodiment, R2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CF2Cl, wherein the remaining variables are as described above for Formula I or any one of the first to eleventh embodiments.

[0062] In a thirteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is phenyl or heteroaryl, each of which are substituted with 1 to 4 groups selected from Ra, wherein the remaining variables are as described above for Formula I or any one of the first to twelfth embodiments. Alternatively, as part of a thirteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is phenyl or 5- to 7-membered heteroaryl, each of which are substituted with 1 to 4 groups selected from Ra, wherein the remaining variables are as described above for Formula I or any one of the first to twelfth embodiments. In another alternative, as part of a thirteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is phenyl, oxazolyl, or thiazolyl, each of which are substituted with 1 to 4 groups selected from Ra, wherein the remaining variables are as described above for Formula I or any one of the first to twelfth embodiments. In another alternative, as part of a thirteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from, wherein the remaining variables are as described above for Formula I or any one of the first to twelfth embodiments. In another alternative, as part of a thirteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptablesalt thereof, is selected from, wherein the remainingvariables are as described above for Formula I or any one of the first to twelfth embodiments. In another alternative, as part of a thirteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof,, wherein the remaining variables are as described above for Formula I or any one of the first to twelfth embodiments.

[0063] In a fourteenth embodiment, Rain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, (C1-C4)alkyl(C1-C4)alkoxy, -(C1- C4)alkyl[5- to 7-membered heterocyclyl], 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, (C1-C4)alkylNRc1Rd1, hydroxy, cyano, (C3-C6)cycloalkyl, -C(O)NRc1Rd1, and - C(O)ORc1, wherein the remaining variables are as described above for Formula I or any one of the first to thirteenth embodiments. Alternatively, as part of a fourteenth embodiment,Rain the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, - (C1-C4)alkyl[5- to 7-membered heterocyclyl], 5- to 7-membered heteroaryl, 5- to 7- membered heterocyclyl, (C1-C4)alkylNRc1Rd1, hydroxy, cyano, (C3-C6)cycloalkyl, - C(O)NRc1Rd1, and -C(O)ORc1, wherein the remaining variables are as described above for Formula I or any one of the first to thirteenth embodiments.

[0064] In a fifteenth embodiment, Rc1and Rd1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen and (C1-C4)alkyl, wherein the remaining variables are as described above for Formula I or any one of the first to fourteenth embodiments.

[0065] In a sixteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from, ,Formula I or any one of the first to fifteenth embodiments. Alternatively, as part of a sixteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptabledescribed above for Formula I or any one of the first to fifteenth embodiments. In another alternative, as part of a sixteenth embodiment, R1in the compound of Formula I, or a pharmaceutically acceptable salt thereof,wherein the remaining variables are as described above for Formula I or any one of the first to fifteenth embodiments.

[0066] In a seventeenth embodiment, Y1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is C(O) , wherein the remaining variables are as described above for Formula I or any one of the first to sixteenth embodiments.

[0067] In an eighteenth embodiment, p in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is 1 or 2, wherein the remaining variables are as described above for Formula I or any one of the first to seventeenth embodiments.

[0068] In a nineteenth embodiment, two R4groups on adjacent carbon atoms in the compound of Formula I, or a pharmaceutically acceptable salt thereof, are taken together to form 1,4-dioxanyl, 1,3-dioxolanyl, morpholinyl, or a phenyl, each of which may be optionally substituted with one or more groups selected from Rb2, wherein the remaining variables are as described above for Formula I or any one of the first to eighteenth embodiments.

[0069] In a twentieth embodiment, Rb2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is (C1-C4)alkyl, C(O)Rc2, or (C1-C4)alkylC(O)ORc2, wherein the remaining variables are as described above for Formula I or any one of the first to eighteenth embodiments. Alternatively, as part of a twentieth embodiment, Rb2in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is C(O)CH3, CH2C(O)OCH2CH3, or CH3, wherein the remaining variables are as described above for Formula I or any one of the first to ninteenth embodiments.

[0070] In a twenty-first embodiment, R4in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C2-C4)alkynyl, hydroxy, cyano, -(C1- C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1-C4)alkoxyC(O)ORc, -(C1-C4)alkyl[5- to 9- membered heteroaryl], -O[5- to 9-membered heteroaryl], (C3-C6)cycloalkyl, 5- to 9- membered heteroaryl, 4- to 9-membered heterocyclyl, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, - NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each 5- to 7-membered heteroaryl, 4- to 9-membered heterocyclyl, and (C3- C6)cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb, wherein the remaining variables are as described above for Formula I or any one of the first to twentieth embodiments. Alternatively, as part of a twenty-first embodiment, R4in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, cyano, -(C1- C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1-C4)alkoxyC(O)ORc, -(C1-C4)alkyl[5- to 7- membered heteroaryl], -O[5- to 7-membered heteroaryl], (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 9-membered heterocyclyl, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, - NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each 5- to 7-membered heteroaryl, 4- to 9-membered heterocyclyl, and (C3- C6)cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb, wherein the remaining variables are as described above for Formula I or any one of the first to twentieth embodiments. In another alternative, as part of a twenty-first embodiment, R4in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1-C4)alkoxyC(O)ORc, -(C1- C4)alkyltetrazolyl, -O(pyrimidinyl), pyrimidinyl, oxazolidinyl, cylopropyl, pyrazolyl, imidazolyl, thiophenyl, 1,2,3-triazolyl, tetrazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H-imidazo[4,5- c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, 5,6,7,8- tetrahydroimidazo[1,2-a]pyrimidinyl, imidazolidinyl, 5-azaspiro[2.5]octanyl, 2,3-dihydro- 1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, -NRcRd, - NRcC(O)Rd, -NRcC(O)ORd, -NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each, tetrazolyl, pyrimidinyl, pyrazolyl, imidazolyl, thiopheneyl, 1,2,3-triazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, oxazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H-imidazo[4,5-c]pyridinyl, 1,2,3,4- tetrahydropyrimidinyl, imidazolidinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, and cyclopropyl alone, or as connected to another group, are optionally substituted with one or more Rb, wherein the remaining variables are as described above for Formula I or any one of the first to twentieth embodiments. In another alternative, as part of a twenty-first embodiment, R4in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is independently selected from halo, (C1-C4)alkyl, hydroxy(C1- C4)alkyl, (C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1- C4)alkoxyC(O)ORc, -(C1-C4)alkyltetrazolyl, -O(pyrimidinyl), pyrimidinyl, oxazolidinyl, cylopropyl, pyrazolyl, imidazolyl, thiophenyl, 1,2,3-triazolyl, tetrazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H- imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, 5,6,7,8- tetrahydroimidazo[1,2-a]pyrimidinyl, imidazolidinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, - NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each, tetrazolyl, pyrimidinyl, pyrazolyl, imidazolyl, thiopheneyl, 1,2,3-triazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, oxazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, imidazolidinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4- diazepanyl, and cyclopropyl alone, or as connected to another group, are optionally substituted with one or more Rb, wherein the remaining variables are as described above for Formula I or any one of the first to twentieth embodiments.

[0071] In a twenty-second embodiment, Rbin the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, oxo, hydroxy, hydroxy(C1-C4)alkyl, (C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl(C3-C6)cycloalkyl, (C3- C6)cycloalkyl, and phenyl, wherein the remaining variables are as described above for Formula I or any one of the first to twenty-first embodiments. Alternatively, as part of a twenty-second embodiment, Rbin the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected from (C1-C4)alkyl, oxo, hydroxy, hydroxy(C1-C4)alkyl, (C1-C4)alkyl(C1-C4)alkoxy, and phenyl, wherein the remaining variables are as described above for Formula I or any one of the first to twenty-first embodiments.

[0072] In a twenty-third embodiment, Rc, Rd, and Rein the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl, wherein the remaining variables are as described above for Formula I or any one of the first to twenty-second embodiments. Alternatively, as part of a twenty-third embodiment, Rc, Rd, and Rein the compound of Formula I, or a pharmaceutically acceptable salt thereof, are each independently selected from hydrogen, (C1-C4)alkyl, phenyl, benzyl, morpholinyl, piperidinyl, pyrrolidinyl, pyridazinyl, and pyridinyl, wherein the remaining variables are as described above for Formula I or any one of the first to twenty-second embodiments.

[0073] In a twenty-fourth embodiment, R4in the compound of Formula I, or apharmaceutically acceptable salt thereof, is selected from, OCH3, CH2OH, OH,described above for Formula I or any one of the first to twenty-third embodiments. Alternatively, as part of a twenty-fourth embodiment, R4in the compound of Formula I, or apharmaceutically acceptable salt thereof, is selected from, OCH3, CH2OH, OH,variables are as described above for Formula I or any one of the first to twenty-third embodiments. In another alternative, as part of as part of a twenty-fourth embodiment, R4in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is selected fromwherein the remaining variables areas described above for Formula I or any one of the first to twenty-third embodiments.

[0074] In a twenty-fifth embodiment, X1in the compound of Formula I, or a pharmaceutically acceptable salt thereof, is CH, wherein the remaining variables are as described above for Formula I or any one of the first to twenty-fourth embodiments.

[0075] Additional compounds such as those described in the exemplification section are included in the present disclosure. Pharmaceutically acceptable salts thereof as well as the neutral forms of such compounds are included. 4. Uses, Formulation and Administration

[0076] The compounds and compositions described herein are generally useful for inducing or facilitating ubiquitination and degradation of NRF2 or β-catenin, or both. In some aspects, the compounds, pharmaceutical acceptable salts, and pharmaceutical compositions described herein degrade NRF2 or β-catenin, or both.

[0077] In some aspects, the compounds and pharmaceutical compositions described herein are useful in treating a disorder associated with NRF2 function and / or or β-catenin function. Thus, provided herein are methods of treating a disorder associated with NRF2 function and / or β-catenin function, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

[0078] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disorder associated with NRF2 function and / or β-catenin function. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for use in treating a disorder associated with NRF2 or β-catenin, or both.

[0079] In some aspects, the compounds and pharmaceutical compositions described herein are useful conditions associated with increased protein levels of NRF2 or β-catenin, or both. Thus, provided herein are methods of treating a condition associated with increased protein levels of NRF2 or β-catenin, or both, comprising administering to a subject in need thereof, a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof.

[0080] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition associated increased protein levels of NRF2 or β-catenin, or both. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or pharmaceuticallyacceptable salt thereof, for use in treating a condition associated increased protein levels of NRF2.

[0081] In one aspect, the condition, disease, or disorders associated with NRF2 (e.g., associated increased protein levels of NRF2) is a proliferative disease such as cancer. In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is selected from lung cancer, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, cholangiocarcinoma, hepatocellular carcinoma, uterine endometrial carcinoma, head and neck squamous cell carcinoma,esophageal adenocarcinoma, bladder urothelial carcinoma, cervical squamous carcinoma, biliary tract cancers, adenoid cystic carcinoma, colon cancer, rectal cancer, renal clear cell carcinoma, angiosarcoma, breast cancer, melanoma, cutaneous squamous cell carcinoma, meningioma, renal papillary cell carcinoma, gastric cancer, prostate adenocarcinoma, pancreatic cancer, ovarian cancer, lymphocytic leukemia, myeloid leukemia, basal cell carcinoma, and ampullary carcinoma.

[0082] In one aspect, the condition, disease, or disorders associated with β-catenin (e.g., associated increased protein levels of β-catenin) is a proliferative disease such as cancer. In some aspects, the cancer treated by the compounds, pharmaceutically acceptable salt thereof, and pharmaceutical compositions described herein is selected from colorectal adenocarcinoma, stomach adenocarcinoma, endometrial carcinoma, prostate adenocarcinoma, bladder carcinoma, lung adenocarcinoma, ovarian serous carcinoma, lung squamous cell carcinoma, esophageal adenocarcinoma, liver hepatocellular carcinoma, adrenocortical carcinoma, and melanoma.

[0083] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0084] In some aspects, the pharmaceutical compositions are administered orally.

[0085] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition. EXEMPLIFICATION Preparation of Compounds

[0086] Compounds of the disclosure can be prepared by methods described in the General Schemes, procedures, and Examples set forth within, and by related methods known in the art. Intermediates

[0087] Synthesis of ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1,2- dihydropyridine-3-carboxylate

[0089] To a solution of LiHMDS (757 mL, 757 mmol, 1M in THF) in THF (800 mL) was added dropwise ethyl acetate (68 mL, 694 mmol) at -78oC, and stirred for 1 h. Then ethyl 2- chloro-2,2-difluoroacetate (100 g, 631 mmol) in THF (200 mL) was added dropwise to the reaction at -78oC. The mixture was stirred at the temperature for 3 h. The reaction wasquenched with aq. NH4Cl and extracted with EA. The organic layer was separated, washed with brine, dried over Na2SO4, and concentrated in vacuo to give the ethyl 4-chloro-4,4- difluoro-3-oxobutanoate (212 g, 1057 mmol) as a yellow oil without further purification. LCMS (m / z): [M]+calcd, 200.01.

[0090] Step 2: ethyl 3-amino-4-chloro-4,4-difluorobut-2-enoate

[0091] To a solution of ethyl 4-chloro-4,4-difluoro-3-oxobutanoate (212 g, 1057 mmol) in EtOH / H2O=20:1 (3780 mL) was added ammonium acetate (244 g, 3171 mmol). The reaction mixture was stirred at 80oC for 4 h. The reaction was concentrated in vacuo, diluted with DCM and water. The organic layer was separated, washed with brine, and concentrated in vacuo followed by vacuum distillation to afford the title compound ethyl 3-amino-4- chloro-4,4-difluorobut-2-enoate (96 g, 481 mmol, 76.24%) as an orange oil. LCMS (m / z): [M]+calcd, 199.02. found, 200.0.1H NMR (400 MHz, DMSO) δ 7.64 (s, 2H), 4.85 (s, 1H), 4.09 (q, J = 7.1 Hz, 2H), 1.20 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, DMSO) δ -58.10 – - 59.06 (m).

[0092] Step 3: ethyl 4-chloro-3-(3-ethoxy-3-oxopropanamido)-4,4-difluorobut-2- enoate

[0093] To a solution of ethyl 3-amino-4-chloro-4,4-difluorobut-2-enoate (96 g, 481 mmol) in DCM (480 mL) was added pyridine (43 mL, 529 mmol) at 0oC. Then it was added ethyl 3-chloro-3-oxopropanoate (75 g, 500 mmol). The reaction was stirred at rt overnight. The reaction was diluted with water, washed with 1 M HCl (100 ml), sat. aq NaHCO3(500 ml), and brine. The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the ethyl 4-chloro-3-(3-ethoxy-3-oxopropanamido)-4,4- difluorobut-2-enoate (112 g, 357 mmol, 89.81 %) as an orange oil. LCMS (m / z): [M]+calcd, 313.05; found, 313.9.

[0094] Step 4: ethyl 6-(chlorodifluoromethyl)-4-hydroxy-2-oxo-1,2-dihydropyridine- 3-carboxylate

[0095] To a solution of ethyl 4-chloro-3-(3-ethoxy-3-oxopropanamido)-4,4-difluorobut- 2-enoate (112 g, 357 mmol) in ethanol (1000 mL) was added t-BuOK (80 g, 714 mmol). The reaction was stirred at 70oC for 2 h. The reaction mixture was concentrated in vacuo. The mixture was washed with H2O. The water phase was extracted with EA and washed with 1 M HCl. The organic layer was separated, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to afford ethyl 6-(chlorodifluoromethyl)-4-hydroxy-2-oxo-1,2- dihydropyridine-3-carboxylate (66 g, 247 mmol, 89.87 %) as a brown solid. LCMS (m / z): [M]+calcd, 267.01; found, 267.9.

[0096] 1H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 11.82 (s, 1H), 6.79 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.28 (s).

[0097] Step 5: ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3- carboxylate

[0098] To a solution of ethyl 6-(chlorodifluoromethyl)-4-hydroxy-2-oxo-1H-pyridine-3- carboxylate (66 g, 247 mmol) in DMF (17 mL) and ACN (800 mL) was added Oxalyl Chloride (40.69 g, 321 mmol) at 0oC, and the reaction was stirred at rt overnight. The mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to afford ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1H-pyridine-3- carboxylate (52 g, 182 mmol, 73.71%) as a white solid. LCMS (m / z): [M]+calcd, 267.01; found, 267.9.

[0099] 1H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 7.56 (s, 1H), 4.37 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.31 (s).

[0100] Synthesis of 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylic acid

[0101] Step 1: ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylate

[0102] To a solution of ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1,2- dihydropyridine-3-carboxylate (2.40 g, 8.97 mmol) and 2,6-dichlorobenzenethiol (1.50 g, 8.39 mmol) in ethanol (40 mL) was added 2-[ethyl(2-hydroxyethyl)amino]ethan-1-ol (3.30 mL, 25.17 mmol), the reaction was stirred at 80oC for 18 h. LCMS showed the reaction was completed. The mixture was cooled to rt. The solvent was removed in vacuo and extracted with EA three times. The organic layer was washed with brine, dried over Na2SO4and concentrated under reduced pressure, the residue was purified by column chromatography on silica gel to give ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylate (3.00 g, 6.65 mmol, 79.25%) as a yellow solid. LCMS (m / z): [M]+calcd, 428.66; found, 429.80.

[0103] 1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 7.80 – 7.76 (m, 2H), 7.65 (dd, J = 8.7, 7.5 Hz, 1H), 6.25 (s, 1H), 4.38 – 4.32 (m, 2H), 1.31 (d, J = 7.1 Hz, 3H).19F NMR (376 MHz, DMSO) δ -55.83 (s, 2F).

[0104] Step 2: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylic acid

[0105] To a solution of ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylate (2.70 g, 6.30 mmol) in THF: H2O (5:1) (30 mL) was added lithium hydroxide (0.45 g, 18.90 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. Then the mixture was adjusted with 1 M HCl to pH~2 and extracted with EA three times. The combined organic phase was dried over Na2SO4 and concentrated in vacuo to 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylic acid (2.00 g, 4.74 mmol, 75.30%) as a white solid. LCMS (m / z): [M]+calcd, 400.60; found, 401.70.1H NMR (400 MHz, DMSO) δ 7.78 (d, J = 7.8 Hz, 2H), 7.65 (dd, J = 8.7, 7.5 Hz, 1H), 5.97 (d, J = 1.1 Hz, 1H).19F NMR (376 MHz, DMSO) δ -55.83 (s, 2F).

[0106] Synthesis of 4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-6-(trifluoromethyl)-1H- pyridine-3-carboxylic acid

[0107] Step 1: Preparation of ethyl 3-[(3-ethoxy-1,3-dioxopropyl)amino]-4,4,4- trifluorobut-2-enoate

[0108] To a solution of ethyl 3-amino-4,4,4-trifluorobut-2-enoate (5 g, 27.303 mmol) and Py (2.59 g, 32.764 mmol) in DCM (20 mL) was added ethyl 3-chloro-3-oxopropanoate (4.93 g, 32.76 mmol) dropwise maintaining the temperature below 30℃, the reaction was stirred at rt for 24 hrs. LCMS showed the reaction was completed. The reaction was washed with 1M HCl (20 mL) and sat NaHCO3(aq) (30 mL), the organic layer was concentrated under reduced pressure to give ethyl 3-[(3-ethoxy-1,3-dioxopropyl)amino]-4,4,4-trifluorobut-2- enoate (8 g, 26.915 mmol, 98.58%) as a brown oil. LCMS(ESI)[M+1]+= 298.0 tR=1.332 min.

[0109] Step 2: Preparation of ethyl 4-hydroxy-2-oxo-6-(trifluoromethyl)-1H- pyridine-3-carboxylate

[0110] To a solution of ethyl 3-[(3-ethoxy-1,3-dioxopropyl)amino]-4,4,4-trifluorobut-2- enoate (8 g, 26.91 mmol) in EtOH (50 mL) was added Potassium tert-butoxide (40.37 mL, 40.37 mmol) dropwise that the temperature did not exceed 40℃, the reaction was stirred at 70℃ for 2 hrs. The reaction was concentrated under reduced pressure and adjusted with 1M HCl(aq) to pH~5, the suspension was filtered to give ethyl 4-hydroxy-2-oxo-6- (trifluoromethyl)-1H-pyridine-3-carboxylate (4.3 g, 17.12 mmol, 63.61%) as a pink- solid.1H NMR (400 MHz, DMSO) δ 12.09 (s, 1H), 11.83 (s, 1H), 6.81 (s, 1H), 4.25 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, DMSO) δ -67.50 (s, 3F).

[0111] Step 3: Preparation of ethyl 4-chloro-2-oxo-6-(trifluoromethyl)-1H-pyridine- 3-carboxylate

[0112] To a solution of ethyl 4-hydroxy-2-oxo-6-(trifluoromethyl)-1H-pyridine-3- carboxylate (5 g, 19.90 mmol) in DMF (20 mL) was added POCl3 (2.55 mL, 27.87 mmol) dropwise, the reaction was stirred at rt for 20 min after a light brown solution was formed, then added DIEA (3.09 g, 23.89 mmol) and stirred at 80℃ for 8 hrs. LCMS showed the reaction was completed. The reaction was quenched with ice water and extracted with EA, the organic layer was concentrated under reduced pressure and purified by column chromatography on silica gel to give ethyl 4-chloro-2-oxo-6-(trifluoromethyl)-1H-pyridine-3- carboxylate (2.1 g, 7.79 mmol, 39.13%) as a white solid.1H NMR (400 MHz, DMSO) δ 13.24 (s, 1H), 7.64 (s, 1H), 4.36 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H).

[0113] Step 4: Preparation of ethyl 4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-6- (trifluoromethyl)-1H-pyridine-3-carboxylate

[0114] To a solution of ethyl 4-chloro-2-oxo-6-(trifluoromethyl)-1H-pyridine-3- carboxylate (2.1 g, 7.789 mmol) and 2,6-dichlorobenzene-1-thiol (1.39 g, 7.79 mmol) in ethanol (30 mL) was added TEA (4.72 g, 46.74 mmol), the reaction was stirred at 80℃ for 18 hrs. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel to give ethyl 4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylate (2.6 g, 6.30 mmol, 80.98%) as a white solid. LCMS(ESI)[M+1]+= 412.2. tR=1.998 min.1H NMR (400 MHz, DMSO) δ 12.99 (s, 1H), 7.77 (d, J = 7.9 Hz, 2H), 7.65 (m, J = 8.7, 7.5 Hz, 1H), 6.28 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H).19F NMR (377 MHz, DMSO) δ -67.68 (s, 3F).

[0115] Step 5: Preparation of 4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-6- (trifluoromethyl)-1H-pyridine-3-carboxylic acid

[0116] To a solution of ethyl 4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-6-(trifluoromethyl)- 1H-pyridine-3-carboxylate (2 g, 4.85 mmol) in THF (20 mL) and H2O (2 mL) was added LiOH (0.61 g, 14.55 mmol), the reaction was stirred at rt for 4 hrs. LCMS showed the reaction was completed. The reaction was extracted with EA, the aqueous layer was adjusted with 1M HCl to pH ~3 and extracted with EA, the combined organic layer was concentrated under reduced pressure and the residue was triturated with EA:PE=1:1 and filtered to give 4- [(2,6-dichlorophenyl)sulfanyl]-2-oxo-6-(trifluoromethyl)-1H-pyridine-3-carboxylic acid (1.3 g, 3.38 mmol, 69.75%) as a white solid. LCMS(ESI)[M+1]+= 384.0. tR=1.355min.1H NMR (400 MHz, DMSO) δ 7.78 (d, J = 8.1 Hz, 2H), 7.72 – 7.58 (m, 1H), 6.01 (s, 1H).19F NMR (377 MHz, DMSO) δ -67.5 (s, 3F).

[0117] Synthesis of 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0118] Step 1: tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6- methoxyisoindoline-2-carboxylate

[0119] To a solution of 2-methylpropan-2-yl 6-amino-5-methoxy-2,3-dihydro-1H- isoindole-2-carboxylate (150.00 mg, 0.57 mmol) in Tol (5 mL) was added 3-chloropropyl chloromethanoate (89.09 mg, 0.57 mmol), the reaction was stirred at 70oC for 18 h under N2. LCMS showed about 85 % of product was detected. The solvent was removed in vacuo. The crude enamine was used directly in next step. [M]+ calcd:384.86. found:769.10.

[0120] Step 2: tert-butyl 5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2- carboxylate

[0121] To a solution of 3-chloropropyl [(6-methoxy-2-{[(2-methylprop-2- yl)oxy]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)amino]methanoate (130.00 mg, 0.34 mmol) in acetonitrile (6 mL) was added potassium carbonate (93.36 mg, 0.68 mmol), the reaction was stirred at 70oC for 24 h under N2. LCMS showed the reaction was completed. The reaction was filtered and removed in vacuo. The reaction was removed in vacuo and purified by column chromatography on silica gel to give 2-methylpropan-2-yl 5-methoxy-6-(2-oxo- 1,3-oxazinan-3-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (100.00 mg, 0.20 mmol, 59.48%) as a white solid. [M]+ calcd:348.40, found:349.00.1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 7.01 (d, J = 5.7 Hz, 1H), 4.51 (t, J = 11.3 Hz, 4H), 4.16 (t, J = 6.1 Hz, 2H), 3.79 (d, J = 3.7 Hz, 2H), 3.71 (m, 3H), 2.07 – 2.03 (m, 2H), 1.45 (s, 9H).

[0122] Step 3: 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0123] To a solution of 2-methylpropan-2-yl 5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)-2,3- dihydro-1H-isoindole-2-carboxylate (100.00 mg, 0.29 mmol) in DMC:TFA (3:1, 4 mL), the reaction was stirred at rt for 2 h. LCMS showed the reaction was completed. The reaction was removed in vacuo and purified by prep-HPLC to give 3-(6-methoxy-2,3-dihydro-1H- isoindol-5-yl)-1,3-oxazinan-2-one (10.00 mg, 0.04 mmol, 13.33%) as a white solid. [M]+ calcd:248.28, found:249.00.1H NMR (400 MHz, DMSO) δ 10.00 (s, 1H), 7.36 (s, 1H), 7.24 (s, 1H), 4.55 (t, J = 5.4 Hz, 2H), 4.49 (s, 2H), 4.44 – 4.38 (m, 2H), 3.88 (s, 3H), 3.52 (d, J = 6.1 Hz, 2H), 2.19 – 2.11 (m, 2H).

[0124] Synthesis of 4-(6-methoxyisoindolin-5-yl)morpholin-3-one

[0126] To a solution of tert-butyl 5-methoxyisoindoline-2-carboxylate (5 g, 0.02 mol) in THF / MeCN (25 mL / 25 mL) was added NBS (3.56 g, 0.02 mol). The mixture was stirred at rt for overnight. The mixture was cooled to rt and concentrated. The residue was diluted with water and extracted with EA. The organic layer was concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 50%) to obtain the desired product tert-butyl 5-bromo-6-methoxyisoindoline-2-carboxylate (3 g, 9.2 mmol, 46%) as a yellow solid. [M]+ calcd:327, found:328.

[0127] Step 2: ethyl 3-(3-ethoxy-3-oxopropanamido)-4,4,4-trifluoro-2-methylbut-2- enoate

[0128] To a solution of 2-methylpropan-2-yl 5-bromo-6-methoxy-2,3-dihydro-1H- isoindole-2-carboxylate (447 mg, 1.36 mmol) in dioxane (1 mL) at 0℃ was dropwise added 1,4-oxazinan-3-one (206.56 mg, 2.04 mmol), CuI (58.03 mg, 0.31 mmol), Cs2CO3 (297.82 mg, 0.91 mmol) and DMEDA (23.97 mg, 0.27 mmol) the resulting mixture was stirred at 150oC for 10 h under N2. The reaction mixture was quenched with sat. NH4Cl solution (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (MeOH in DCM = 0 ~ 3%) to obtain the desired product 2-methylpropan-2-yl 6-methoxy-5-(3-oxo-1,4-oxazinan-4-yl)-2,3- dihydro-1H-isoindole-2-carboxylate (173 mg, 0.50 mmol, 36.46%) as a brown solid.[M]+ calcd:347,found:348.

[0129] 1H NMR (400 MHz, DMSO) δ 7.98 (s, 1H), 7.18 (d, J = 9.0 Hz, 1H), 7.12 (d, J = 5.5 Hz, 1H), 4.58 (d, J = 10.0 Hz, 2H), 4.51 (d, J = 7.1 Hz, 2H), 3.95 – 3.91 (m, 2H), 3.78 (t, J = 7.5 Hz, 3H), 3.73 – 3.69 (m, 2H), 3.52 (s, 2H), 3.21 (dd, J = 7.6, 2.7 Hz, 2H), 1.46 (s, 9H).

[0130] Step 3: ethyl 4-hydroxy-5-methyl-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylate

[0131] To a solution of 2-methylpropan-2-yl 6-methoxy-5-(3-oxo-1,4-oxazinan-4-yl)-2,3- dihydro-1H-isoindole-2-carboxylate (173 mg, 0.5 mmol) in HCl / dioxane (10 mL) at 0oC, the resulting mixture was stirred at rt for 1 h. The reaction mixture was filtered to give the crude product 4-(6-methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,4-oxazinan-3-one (94 mg, 0.38 mmol, 76.89%) as a brown solid. [M]+ calcd:247. found: 248.

[0132] 1H NMR (400 MHz, DMSO) δ 9.73 (s, 2H), 7.23 (d, J = 30.6 Hz, 2H), 4.46 (dt, J = 25.3, 5.3 Hz, 4H), 4.18 (s, 2H), 3.95 (t, J = 5.0 Hz, 2H), 3.80 (s, 3H), 3.53 (t, J = 4.8 Hz, 2H).

[0133] Synthesis of tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate

[0134] Step 1: 5-methoxy-6-nitroisoindoline-1,3-dione

[0135] To a flask containing 4-methoxyphthalic acid (50.00 g, 255.10 mmol) was added AcOH (500 mL) followed by the addition of NH4OAc (39.20 g, 509.09 mmol) at rt. The mixture was stirred at 140oC for 18h. The reaction liquid is quenched with H2O. Strain to obtain filter cake. The filter cake is concentrated under vacuum. Get 5-methoxyisoindoline- 1,3-dione (42.00 g, 237.28 mmol, 93.02%) as a white solid. [M]+ calcd: 222.0, found: 223.0.

[0136] Step 2: 5-methoxy-6-nitroisoindoline-1,3-dione

[0137] To a flask containing 5-methoxyisoindoline-1,3-dione (10.00 g, 56.44 mmol) was added H2SO4 (100 mL) followed by the addition of KNO3 (6.28 g, 62.09 mmol) at 0oC under N2. The mixture was stirred at 20oC for 2h. The reaction liquid is quenched with H2O.Extract three times with EA and H2O. Get 5-methoxy-6-nitroisoindoline-1,3-dione (9.00 g, 40.51 mmol, 71.77%) as a yellow solid. [M]+ calcd: 222.0, found: 223.0.1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 4.10 (s, 3H).

[0138] Step 3: Preparation of 5-methoxy-6-nitroisoindoline

[0139] To a flask containing 5-methoxy-6-nitroisoindoline-1,3-dione (11.00 g, 49.51 mmol) was added THF (40 mL) followed by the addition of BH3(1mol / L) (495.13 mL, 495.13 mmol) at 0oC under N2. The mixture was stirred at 85oC for 18h. The reaction liquid is quenched with MeOH. The mixture was stirred at 85oC for 1h. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 5-methoxy-6-nitroisoindoline (8.00 g, 41.19 mmol, 83.20%) as a yellow solid. [M]+ calcd: 194.0, found: 195.0.

[0140] Step 4: tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate

[0141] To a flask containing 5-methoxy-6-nitroisoindoline (3.00 g, 15.45 mmol) was added DCM (30.00 mL) followed by the addition of TEA (6.44 mL, 46.34 mmol) and (2- methylprop-2-yl) oxidanecarboxylic anhydride (4.05 g, 18.54 mmol) at 0oC under N2. The mixture was stirred at rt for 2h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-30%) to afford the product tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate (3.50 g, 11.89 mmol, 76.98%) as a yellow solid. [M]+ calcd: 294.1, found: 280.4.1H NMR (400 MHz, DMSO) δ 7.87 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 3.8 Hz, 1H), 4.63 (d, J = 10.4 Hz, 2H), 4.55 (d, J = 8.8 Hz, 2H), 3.90 (t, J = 4.6 Hz, 3H), 1.46 (s, 9H).

[0142] Step 5: tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate

[0143] To a flask containing tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate (1400.00 mg, 4.75 mmol) was added MeOH (15 mL) followed by the addition of Pd / C (140.00 mg, 1.31 mmol). The mixture was stirred at rt for 2h under H2. Filtrate is obtained after filtration. The organic system was concentrated under vacuum. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0- 30%) to afford the product tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (1.00 g, 3.78 mmol, 79.53%) as a yellow solid. [M]+ calcd: 264.1, found: 250.0.

[0144] 1H NMR (400 MHz, DMSO) δ 6.75 (d, J = 6.7 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.69 (s, 2H), 4.41 (t, J = 10.4 Hz, 4H), 3.74 (d, J = 3.4 Hz, 3H), 1.45 (d, J = 6.5 Hz, 9H). Examples

[0145] Example 1: Synthesis of 3-(2-(4-((2-(aminomethyl)-6-chlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)-1,3-oxazinan-2-one

[0146] Step 1: 3-chloro-2-mercaptobenzonitrile

[0147] To a solution of 3-chloro-2-fluorobenzene-1-carbonitrile (2 g, 12.86 mmol) in DMF (dry, 15 mL) was added Na2S (1.1 g, 14.10 mmol) at 0oC. Then the mixture was stirred at rt for 2 hours. TLC shows the starting material was consumed. The mixture was filtered and diluted with water and extracted with EA. The organic layer was washed with brine and dried and concentrated. The residue was diluted with HCl aq. (10 % ,15 mL), then Zinc dust (8 g) was added portion at 0oC. The mixture was stirred at 0oC for 1 hour. Then EA (20 mL) was added and the mixture was stirred for 30 minutes. The mixture was filtered and the filtrate was diluted with water and extracted with EA. The organic layer was dried and concentrated to give 3-chloro-2-sulfanylbenzene-1-carbonitrile (1.6 g, 9.43 mmol, 73.36%).

[0148] Step 2: ethyl 4-((2-chloro-6-cyanophenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylate

[0149] To a solution of 3-chloro-2-sulfanylbenzene-1-carbonitrile (300 mg, 1.77 mmol) in EtOH (5 mL) was added ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1H-pyridine-3- carboxylate (269.75 mg, 0.94 mmol) and TEA (0.98 mL, 7.074 mmol). The mixture was stirred at 90oC for overnight. The mixture was cooled to rt and concentrated and purified by chromatography (silica gel, DCM: MeOH=10 :1) to give ethyl 4-[(6-chloro-2- cyanophenyl)sulfanyl]-6-(chlorodifluoromethyl)-2-oxo-1H-pyridine-3-carboxylate (310 mg, 0.74 mmol, 41.81%). [M]+calcd:417, found:418.

[0150] Step 3: 4-((2-chloro-6-cyanophenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid

[0151] To a solution of ethyl 4-[(6-chloro-2-cyanophenyl)sulfanyl]-6- (chlorodifluoromethyl)-2-oxo-1H-pyridine-3-carboxylate (318 mg, 0.76mmol) in THF / H2O (5 mL / 1 mL) was added LiOH (191.27 mg, 4.56mol),the mixture was stirred at 50oC for 3 hours. The mixture was diluted with water and acidified by HCl aq. (1 N) and extracted with EA. The organic layer was dried and concentrated to give 4-[(6-chloro-2- cyanophenyl)sulfanyl]-6-(chlorodifluoromethyl)-2-oxo-1H-pyridine-3-carboxylic acid 240 mg as a crude.[M]+calcd:391, found:392.

[0152] Step 4: 3-chloro-2-((6-(chlorodifluoromethyl)-3-(5-methoxy-6-(2-oxo-1,3- oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4-yl)thio)benzonitrile

[0153] To a solution of 4-[(6-chloro-2-cyanophenyl)sulfanyl]-6-(chlorodifluoromethyl)- 2-oxo-1H-pyridine-3-carboxylic acid (238 mg, 0.61mmol) in ACN (7 mL) was added 3-(6- methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,3-oxazinan-2-one (151 mg, 0.61mmol) and NMI (300 mg, 3.65 mmol) and TCFH (222.13 mg, 0.79 mmol).The mixture was stirred at 40oC for overnight. The mixture was concentrated and purified by prep-HPLC to give 3-chloro-2- {[6-(chlorodifluoromethyl)-3-{[5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)-2,3-dihydro-1H- isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4-yl]sulfanyl}benzene-1-carbonitrile (190 mg, 0.31 mmol, 50.25%).[M]+calcd:620, found:621.1H NMR (400 MHz, DMSO) δ 12.97 (s, 1H), 8.06 (t, J = 8.0 Hz, 2H), 7.76 (td, J = 8.0, 2.6 Hz, 1H), 7.19 (dd, J = 35.8, 31.5 Hz, 2H), 6.42 (s, 1H), 4.72 (dd, J = 55.4, 24.0 Hz, 4H), 4.31(d, J = 4.4 Hz, 2H), 3.78 (d, J = 26.2 Hz, 3H), 3.50 – 3.39 (m, 2H), 2.06 (dd, J = 10.8, 5.5 Hz, 2H).

[0154] Step 5: 3-(2-(4-((2-(aminomethyl)-6-chlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)-1,3-oxazinan-2-one

[0155] To a solution of 3-chloro-2-{[6-(chlorodifluoromethyl)-3-{[5-methoxy-6-(2-oxo- 1,3-oxazinan-3-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4- yl]sulfanyl}benzene-1-carbonitrile (170 mg, 0.27 mmol) in EtOH (4 mL) was added Pd / C(10 %, 120 mg) and drops of HCl. The mixture was stirred at rt for 8 hours. The mixture was filtered and concentrated and purified by prep-HPLC to give 3-{2-[(4-{[2-(aminomethyl)-6- chlorophenyl]sulfanyl}-6-(chlorodifluoromethyl)-2-oxo-1H-pyridin-3-yl)carbonyl]-6- methoxy-2,3-dihydro-1H-isoindol-5-yl}-1,3-oxazinan-2-one (14.3 mg, 0.023 mmol, 8.36%) and 3-chloro-2-{[6-(chlorodifluoromethyl)-3-{[5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)-2,3- dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4-yl]sulfanyl}benzene-1-carbonitrile (35 mg, 0.056 mmol, 20.47%).[M]+calcd:624, found:625.

[0156] 1H NMR (400 MHz, DMSO) δ 7.72 (dd, J = 8.8, 4.5 Hz, 1H), 7.64 (d, J = 4.6 Hz, 2H), 7.24 (d, J = 25.6 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 6.21 (s, 1H), 4.84 – 4.45 (m, 4H), 4.29 (d, J = 19.2 Hz, 4H), 3.79 (d, J = 23.6 Hz, 3H), 3.45 (dd, J = 14.4, 6.3 Hz, 2H), 2.07 (d, J = 5.4 Hz, 2H).

[0157] Example 2: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-methoxy-6-(2-oxopyrrolidin-1-yl)isoindoline-2- carbonyl)pyridin-2(1H)-one

[0158] Step 1: tert-butyl 5-(4-chlorobutanamido)-6-methoxyisoindoline-2- carboxylate

[0159] To a solution of 2-methylpropan-2-yl 5-amino-6-methoxy-2,3-dihydro-1H- isoindole-2-carboxylate (20 mg, 0.076 mmol) in Toluene (3 mL), 2-methylpropan-2-yl 5- amino-6-methoxy-2,3-dihydro-1H-isoindole-2-carboxylate (20 mg, 0.076 mmol) was added at rt, the mixture was stirred at 70oC for 16h , the mixture was concentrated in vacuo, to give 2-methylpropan-2-yl 5-[(4-chloro-4-oxobutyl)amino]-6-methoxy-2,3-dihydro-1H-isoindole- 2-carboxylate (15 mg, 0.041 mmol, crude) as a brown solid. [M]+calcd,368; found, 369.

[0160] Step 2: tert-butyl 5-methoxy-6-(2-oxopyrrolidin-1-yl)isoindoline-2- carboxylate

[0161] To a solution of 2-methylpropan-2-yl 5-[(4-chloro-4-oxobutyl)amino]-6-methoxy- 2,3-dihydro-1H-isoindole-2-carboxylate (400 mg, 1.084 mmol) in ACN (5 mL), K2CO3(449.60 mg, 3.25 mmol) was added at rt, the mixture was stirred at 80oC for 16h , The mixture was cooled to rt and the residue was diluted with water and extracted with EA. The organic layer was dried, concentrated and purified by chromatography (silica gel, PE: EA=1:1) to give 2-methylpropan-2-yl 6-methoxy-5-(2-oxotetrahydro-1H-pyrrol-1-yl)-2,3- dihydro-1H-isoindole-2-carboxylate (80 mg, 0.24 mmol, 22.19%) as a white solid. [M]+calcd, 332; found, 333.

[0162] 1H NMR (400 MHz, DMSO) δ 7.13 (t, J = 10.3 Hz, 1H), 7.09 (d, J = 5.4 Hz, 1H), 4.57 (d, J = 9.9 Hz, 2H), 4.50 (d, J = 7.8 Hz, 2H), 3.77 (d, J = 3.6 Hz, 3H), 3.62 (t, J = 7.0 Hz, 2H), 2.37 (dd, J = 15.7, 7.9 Hz, 2H), 2.15 – 2.04 (m, 2H), 1.45 (s, 9H).

[0163] Step 3: 1-(6-methoxyisoindolin-5-yl)pyrrolidin-2-one

[0164] To a solution of tert-butyl 5-(5-((tert-butyldimethylsilyl)oxy)-2- oxotetrahydropyrimidin-1(2H)-yl)isoindoline-2-carboxylate (70 mg, 0.16 mmol) in DCM (1 mL) , hydrochloric acid 1,4-dioxane (1 mL) was added at rt 16 h , the mixture was concentrated in vacuo to give 5-hydroxy-1-(isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (35 mg, 0.15 mmol) as a crude, which was without further purification [M]+calcd:232, found:233.

[0165] Step 4: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5-methoxy- 6-(2-oxopyrrolidin-1-yl)isoindoline-2-carbonyl)pyridin-2(1H)-one

[0166] To a solution of 1-(6-methoxy-2,3-dihydro-1H-isoindol-5-yl)tetrahydropyrrol-2- one (30 mg, 0.129 mmol) in ACN (2 mL), 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (480.72 mg, 1.2 mmol), 1- methylimidazole (328 mg, 4.0 mmol) and N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate (336.70 mg, 1.2 mmol) was added at rt, the mixture was stirred 16h at rt. The mixture was concentrated and the residue was dissolved in DMF (3.0 mL). The mixture was filtered and purified by prep-HPLC to give 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-methoxy-6-(2-oxopyrrolidin-1-yl)isoindoline-2-carbonyl)pyridin- 2(1H)-one (6.4 mg, 0.010 mmol, 8.06%) as a white solid. [M]+calcd,613; found,614.1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 7.76 (d, J = 8.1 Hz, 3H), 7.62 (t, J = 8.1 Hz, 2H), 7.20 (t, J = 17.5 Hz, 3H), 6.21 (s, 1H), 4.81 (d, J = 27.1 Hz, 3H), 4.74 – 4.51 (m, 3H), 3.78 (d, J = 25.0 Hz, 5H), 3.64 (dd, J = 14.6, 7.4 Hz, 3H), 2.37 (dd, J = 13.8, 7.8 Hz, 3H), 2.07 (dt, J = 15.2, 7.7 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.06 (d, J = 64.4 Hz).

[0167] Example 3: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-methoxy-6-(2-oxopiperidin-1-yl)isoindoline-2- carbonyl)pyridin-2(1H)-one

[0168] Step 1: tert-butyl 5-(5-chloropentanamido)-6-methoxyisoindoline-2- carboxylate

[0169] To a solution of 2-methylpropan-2-yl 6-amino-5-methoxy-2,3-dihydro-1H- isoindole-2-carboxylate (400 mg, 1.51 mmol) in Toluene (3 mL) was added 5- chloropentanoyl chloride (234.59 mg, 1.51 mmol) and the reaction was stirred at 70oC for overnight. LCMS was OK. Directly spin dry the reaction solution to obtain crude product 2- methylpropan-2-yl 6-[(5-chloro-1-oxopentyl)amino]-5-methoxy-2,3-dihydro-1H-isoindole-2- carboxylate (400 mg, crude) as a gray solid. [M]+calcd:382.17, found:383.2.

[0170] Step 2: tert-butyl 5-methoxy-6-(2-oxopiperidin-1-yl)isoindoline-2- carboxylate

[0171] To a solution of 2-methylpropan-2-yl 6-[(5-chloro-1-oxopentyl)amino]-5- methoxy-2,3-dihydro-1H-isoindole-2-carboxylate (400 mg, 1.045 mmol) in ACN (5 mL) was added K2CO3 (433.14 mg, 3.13 mmol) and the reaction was stirred at 100oC for overnight. The reaction was diluted with EA and water. The organic layer was separated, washed with brine, and concentrated in vacuo. The residue was purified using silica gel column chromatography to afford the title compound 2-methylpropan-2-yl 5-methoxy-6-(2- oxohexahydropyridin-1-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (120 mg, 0.35 mmol,33.15%) as a white solid. [M]+calcd:346.19, found:347.1.1H NMR (400 MHz, DMSO) δ 7.13 – 7.04 (m, 2H), 4.53 (dd, J = 29.6, 8.6 Hz, 4H), 3.75 (d, J = 3.6 Hz, 3H), 3.40 (s, 2H), 2.34 (s, 2H), 1.83 (s, 4H), 1.46 (s, 9H).

[0172] Step 3: 1-(6-methoxyisoindolin-5-yl)piperidin-2-one

[0173] To a solution of 2-methylpropan-2-yl 5-methoxy-6-(2-oxohexahydropyridin-1-yl)- 2,3-dihydro-1H-isoindole-2-carboxylate (25 mg, 0.072 mmol) in DCM (1 mL) was added HCl / dioxane (1 mL, 4 M) and the reaction was stirred at room temperature for 2 hr. Directly spin dry the reaction solution to obtain crude product 1-(6-methoxy-2,3-dihydro-1H-isoindol- 5-yl)hexahydropyridin-2-one (17 mg, crude) as a gray solid. [M]+calcd:246.14, found:247.2.

[0174] Step 4: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5-methoxy- 6-(2-oxopiperidin-1-yl)isoindoline-2-carbonyl)pyridin-2(1H)-oneE-374

[0175] To a solution of 1-(6-methoxy-2,3-dihydro-1H-isoindol-5-yl)hexahydropyridin-2- one (17 mg, 0.069 mmol) in ACN (2 mL) were added 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (27.65 mg, 0.069 mmol), TCFH (29.04 mg, 0.104 mmol), and NMI (11.32 mg, 0.14 mmol), and the reaction was stirred at room temperature for 2 hr. The mixture was purified by prep-HPLC to give 6- (chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-{[5-methoxy-6-(2- oxohexahydropyridin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2- one (17 mg, 0.027 mmol, 39.53%). as a white solid. [M]+calcd:627.04, found:628.0.1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 – 7.58 (m, 1H), 7.15 (dd, J = 18.0, 9.8 Hz, 2H), 6.26 (s, 1H), 4.92 – 4.47 (m, 4H), 3.75 (d, J = 25.2 Hz, 3H), 3.42 (s, 2H), 2.34 (d, J = 4.6 Hz, 2H), 1.83 (s, 4H).

[0176] Example 4: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- ((methylamino)methyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0177] Step 1: 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5-methoxy-6-(2-oxo-1,3- oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4-yl)thio)benzaldehyde

[0178] To a mixture of 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (57 mg, 0.13 mmol) in ACN (4.0 mL) were added NMI (33 mg, 0.401 mmol), 6-(chlorodifluoromethyl)-4- ((2,6-dichloro-3-formylphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (40 mg, 0.16 mmol) and TCFH (45 mg, 0.16 mmol), and stirred at 40 ℃ for 5 hrs. The reaction wasfiltered and purified by silica gel column chromatography to afford 2,4-dichloro-3-((6- (chlorodifluoromethyl)-3-(5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2-carbonyl)-2- oxo-1,2-dihydropyridin-4-yl)thio)benzaldehyde (68 mg, 0.104 mmol, yield: 79.62 %) as a white solid. LCMS (m / z): [M]+calcd, 657.01 (M+H)+, found: 658.2.

[0179] Step 2: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- ((methylamino)methyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0180] To a mixture of 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5-methoxy-6-(2- oxo-1,3-oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4- yl)thio)benzaldehyde (30 mg, 0.046 mmol) in MeOH (2.0 mL) were added NH2Me (0.1 mL, 0.2 mmol) (2.0 M in THF) and AcOH (5.0 mg, 0.085 mmol), and stirred at RT for 1 hr. Then NaBH4 (5 mg, 0.14 mmol) was added to the mixture at 0 ℃, and stirred at RT for 2 h. The reaction was purified by prep-HPLC to afford 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichloro-3-((methylamino)methyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (5 mg, 0.0074 mol, yield: 16.17 %) as a white solid. LCMS (m / z): [M]+calcd, 672.06 (M+H)+, found: 673.1.1H NMR (400 MHz, DMSO) δ 9.26 (s, 1H), 7.78 – 7.65 (m, 2H), 7.03 (dd, J = 33.4, 21.3 Hz, 2H), 6.16 (s, 1H), 4.69 – 4.34 (m, 4H), 4.21 – 4.03 (m, 4H), 3.60 (d, J = 24.0 Hz, 3H), 3.25 (d, J = 6.0 Hz, 2H), 2.34 – 2.31 (m, 4H), 1.95 – 1.78 (m, 2H).

[0181] Example 5: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0182] Step 1: ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0183] To a flask containing ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (4.50 mg, 0.01 mmol) was added MeOH (5 mL) followed by the addition of NaBH4(11.18 mg, 0.30 mmol) at 0oC.The mixture was stirred at 0oC for 1 h. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate (40.00 mg, 0.09 mmol, 88.50%) as a yellow solid. [M]+ calcd: 456.9, found: 458.0.

[0184] Step 2: 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0185] To a flask containing ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate (40.00 mg, 0.09 mmol) was added MeOH (0.9 mL) and H2O (0.3 mL) followed by the addition of LiOH (3.66 mg, 0.09 mmol). The mixture was stirred at 50oC for 6 h. Extract three times with EA and H2O. Turn the H2O to basic. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (35.00 mg, 0.08 mmol, 93.20%) as a yellow solid. [M]+ calcd: 428.9, found: 430.0.

[0186] Step 3: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- (hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0187] To a flask containing 6-(chlorodifluoromethyl)-4-{[1,3-dichloro-4- (hydroxymethyl)benzen-2-yl]sulfanyl}-2-oxo-1H-pyridine-3-carboxylic acid (35 mg, 0.081 mmol) was added ACN (2 mL) followed by the addition of 1-methylimidazole (23.36 mg, 0.28 mmol), 3-(6-methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,3-oxazinan-2-one (24.22 mg, 0.10 mmol) at room temperature. The mixture was stirred at room temperature for 10 min. Added [chloro(dimethylamino)methylidene]dimethylammonium hexafluoro-λ5- phosphanuide (29.65 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The system is concentrated under vacuum. Extract three times with EAand H2O. Which was purified by silica gel column to give 3-(2-(6-(chlorodifluoromethyl)-4- ((2,6-dichloro-3-(hydroxymethyl)phenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (20.00 mg, 0.03 mmol, 37.23%) as a white solid. [M]+ calcd: 659.0, found: 660.0.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 7.85 – 7.66 (m, 2H), 7.26 (d, J = 28.6 Hz, 1H), 7.17 (d, J = 7.2 Hz, 1H), 6.25 (s, 1H), 5.67 (s, 1H), 4.81 (d, J = 27.4 Hz, 2H), 4.74 – 4.50 (m, 4H), 4.32 (d, J = 4.2 Hz, 2H), 3.79 (d, J = 24.7 Hz, 3H), 3.45 (dt, J = 12.1, 6.1 Hz, 2H), 2.06 (dd, J = 10.8, 5.3 Hz, 2H).

[0188] Example 6: Synthesis of 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6- methoxy-5-(2-oxo-1,3-oxazinan-3-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H- pyridin-4-yl]sulfanyl}benzoic acid

[0189] Step 1: Preparation of ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate

[0190] To a solution of ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- vinylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (400.00 mg, 0.88 mmol), Potassium osmate(VI) dihydrate (32.41 mg, 0.09 mmol) in THF (4 mL) and H2O (0.5 mL) was addedsodium periodate (1128.98 mg, 5.28 mmol), the reaction was stirred at rt for 1 h. LCMS showed the reaction was completed.

[0191] The reaction was filtered and the filtrate was extracted with EA, the organic layer was concentrated under reduced pressure and purified by column chromatography on silica gel to give ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3-formylphenyl)sulfanyl]-2-oxo- 1H-pyridine-3-carboxylate (250.00 mg, 0.55 mmol, 62.23%) as a white solid. [M]+ calcd:456, found:458.

[0192] Step 2: Preparation of 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid

[0193] To a solution of ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (150.00 mg, 0.33 mmol) in MeOH (2.5 mL) and H2O (0.5 mL) was added LiOH (68.91 mg, 1.64 mmol), the reaction was stirred at 40oC for 18 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel to give 6- (chlorodifluoromethyl)-4-[(2,6-dichloro-3-formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3- carboxylic acid (100.00 mg, 0.23 mmol, 71.03%) as a white solid. [M]+ calcd:428, found:429.

[0194] Step 3: Preparation of 4-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-methoxy-2,3-dihydro-1H- isoindol-5-yl)-1,4-oxazinan-3-one

[0195] To a solution of 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-2-oxo-1H-pyridine-3-carboxylic acid (10.00 mg, 0.02 mmol), 5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (5.05 mg, 0.02 mmol) and NMI (57.39 mg, 0.70 mmol) in MeCN (5 mL) was added TCFH (8.45 mg, 0.03 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, the organic layer was concentrated under reduced pressure and purified by prep-TLC to give 4-(2-{[6-(chlorodifluoromethyl)-4- [(2,6-dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-methoxy-2,3-dihydro-1H- isoindol-5-yl)-1,4-oxazinan-3-one (40.00 mg, 0.06 mmol, 42.33%) as a white solid. [M]+ calcd:659, found:660.1H NMR (400 MHz, DMSO) δ 10.27 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 26.2 Hz, 1H), 7.16 (d, J = 6.5 Hz, 1H), 6.24 (s, 1H), 4.76 (d, J = 24.8 Hz, 4H), 4.31 (s, 2H), 3.79 (d, J = 23.6 Hz, 3H), 3.49 – 3.42 (m, 2H), 2.08 – 1.95 (m, 2H).

[0196] Step 4: Preparation of 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6- methoxy-5-(2-oxo-1,3-oxazinan-3-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H- pyridin-4-yl]sulfanyl}benzoic acid

[0197] To a solution of 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6-methoxy-5-(2- oxo-1,3-oxazinan-3-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4- yl]sulfanyl}benzene-1-carbaldehyde (30.00 mg, 0.05 mmol), sodium dihydrogenphosphate dihydrate (2.34 mg, 0.02 mmol) and H2O2(5.49 mg, 0.05 mmol) in MeCN (3 mL) and H2O (1 mL) was added sodium chlorite (5.66 mg, 0.05 mmol), the reaction was stirred at rt for 2h. LCMS showed the reaction was completed. The reaction was added H2O and extracted with EA, the organic layer was concentrated under reduced pressure and purified by prep-HPLC to give 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6-methoxy-5-(2-oxo-1,3-oxazinan-3-yl)- 2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4-yl]sulfanyl}benzoic acid (8.00 mg, 0.01 mmol, 26.03%) as a white solid. [M]+ calcd:675, found:6761H NMR (400 MHz, DMSO) δ 13.89 (s, 1H), 12.89 (s, 1H), 7.95 – 7.85 (m, 1H), 7.83 – 7.74 (m, 1H), 7.25 (d, J = 28.1 Hz, 1H), 7.17 (d, J = 6.0 Hz, 1H), 6.32 (s, 1H), 4.89 – 4.55 (m, 4H), 4.31 (s, 2H), 3.78 (d, J = 24.8 Hz, 3H), 3.49 – 3.40 (m, 2H), 2.06 (d, J = 5.3 Hz, 2H).19F NMR (377 MHz, DMSO) δ -54.30 – -56.13 (m).

[0198] Example 7: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxy-7- methylisoindolin-5-yl)-1,3-oxazinan-2-one

[0199] Step 1: tert-butyl 5-methoxy-4-methyl-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline- 2-carboxylate.

[0200] To a solution of 2-methylpropan-2-yl 4-bromo-5-methoxy-6-(2-oxo-1,3-oxazinan- 3-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (73 mg, 0.17 mmol) in DMF (1.0 mL) at 0oC was dropwise added methylboranediol (102.26 mg, 1.70 mmol), K2CO3 (47.15 mg, 0.34 mmol) and PdCl2dppf (12.49 mg, 0.02 mmol) the resulting mixture was stirred at 100oC for 2 h under N2. The reaction mixture was purified by prep-HPLC to obtain the desired product 2-methylpropan-2-yl 5-methoxy-4-methyl-6-(2-oxo-1,3-oxazinan-3-yl)-2,3-dihydro-1H- isoindole-2-carboxylate (50 mg, 0.13 mmol, 80.75%) as a brown solid. LC / MS (ESI) m / z: 362(M+H)+.1H NMR (400 MHz, DMSO) δ 7.09 (d, J = 10.8 Hz, 1H), 4.54 (d, J = 7.2 Hz,4H), 4.37 – 4.28 (m, 2H), 3.67 (s, 3H), 3.49 (s, 2H), 2.14 (d, J = 3.9 Hz, 3H), 2.12 – 2.06 (m, 2H), 1.46 (d, J = 3.0 Hz, 9H).

[0201] Step 2: 3-(6-methoxy-7-methylisoindolin-5-yl)-1,3-oxazinan-2-one.

[0202] To a solution of 2-methylpropan-2-yl 5-methoxy-4-methyl-6-(2-oxo-1,3- oxazinan-3-yl)-2,3-dihydro-1H-isoindole-2-carboxylate (50 mg, 0.13 mmol) at 0oC was dropwise added HCl / dioaxne (4M, 5 ml), the resulting mixture was stirred at rt for 1h under N2. The reaction mixture was concentrated to give crude desired product 3-(6-methoxy-7- methylisoindolin-5-yl)-1,3-oxazinan-2-one as a grey solid, used directly next step. LC / MS (ESI) m / z: 262(M+H)+

[0203] Step 3: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-methoxy-7-methylisoindolin-5-yl)-1,3-oxazinan-2-one.E-353-3E-353

[0204] To a solution of 3-(6-methoxy-7-methyl-2,3-dihydro-1H-isoindol-5-yl)-1,3- oxazinan-2-one (20 mg, 0.08 mmol) in MeCN (5.0 mL) at 0oC was dropwise added 6- (chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (30.54 mg, 0.08 mmol), TCFH (27.76 mg, 0.10 mmol) and NMI (21.81 mg, 0.27 mmol) the resulting mixture was stirred at 40oC for 1 h under N2. The reaction mixture was purified by prep-HPLC to obtain the desired product 3-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-methoxy-7-methyl-2,3-dihydro- 1H-isoindol-5-yl)-1,3-oxazinan-2-one (9 mg, 0.014 mmol, 18.30%) as a brown solid. LC / MS (ESI) m / z: 645(M+H)+.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 7.76 (dd, J = 8.2, 2.2Hz, 2H), 7.62 (dd, J = 8.6, 7.6 Hz, 1H), 7.16 (d, J = 36.8 Hz, 1H), 6.26 (s, 1H), 4.82 (s, 2H), 4.73 – 4.59 (m, 2H), 4.40 – 4.31 (m, 2H), 3.69 (d, J = 5.4 Hz, 3H), 3.55 – 3.48 (m, 2H), 2.22 (s, 2H), 2.09 (dd, J = 11.5, 5.6 Hz, 3H).

[0205] Example 8: Synthesis of 4-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5- yl)morpholin-3-one

[0206] Step 1: 4-(6-hydroxyisoindolin-5-yl)morpholin-3-one

[0207] At 0oC, to the solution of 4-(6-methoxyisoindolin-5-yl)morpholin-3-one (200 mg, 0.86 mmol) in DCM (5 mL) was added BBr3(0.43 mL, 4.46 mmol) dropwise, it was stirred at rt under N2 for 20 h. After which the reaction mixture was concentrated to give the crude product, it was used directly next step. [M]+ calcd: 234, found: 235. Step 2: tert-butyl 5-hydroxy-6-(3-oxomorpholino)isoindoline-2-carboxylate

[0208] To the solution of 4-(6-hydroxyisoindolin-5-yl)morpholin-3-one (crude) in DCM (10 mL) were added TEA (0.09 mL, 0.66 mmol) and Boc2O (0.06 mL, 0.26 mmol) respectively, it was stirred at rt under N2 for 30 min. After which the reaction mixture was quenched by ice water and adjust to PH=4 with 1M HCl, then it was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under pressure. The crude product was purified by prep-HPLC to give tert-butyl 5-hydroxy-6-(3-oxomorpholino)isoindoline-2-carboxylate (120 mg, 0.36 mmol) as a white solid. [M]+ calcd: 334, found: 335.1H NMR (400 MHz, DMSO) δ 9.65 (s, 1H), 7.08 (d, J = 8.6 Hz, 1H), 6.85 (s, 1H), 4.48 (dd, J = 20.3, 9.5 Hz, 4H), 4.15 (s, 2H), 3.97 – 3.91 (m, 2H), 3.53 (t, J = 4.8 Hz, 2H), 1.45 (s, 9H).

[0209] Step 3: tert-butyl 5-ethoxy-6-(3-oxomorpholino)isoindoline-2-carboxylate

[0210] To the solution of tert-butyl 5-hydroxy-6-(3-oxomorpholino)isoindoline-2- carboxylate (60 mg, 0.18 mmol) in N,N-dimethylmethanamide (3 mL) were added Cs2CO3(176 mg, 0.54 mmol) and iodoethane (140 mg, 0.90 mmol) respectively, it was stirred at 60oC under N2 for 16 h. After which the reaction mixture was quenched by ice water and extracted with EA. the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under pressure. The crude product was purified by prep-HPLC to give tert- butyl 5-ethoxy-6-(3-oxomorpholino)isoindoline-2-carboxylate (45 mg, 0.12 mmol, 69.19%) as a white solid. [M]+ calcd: 362. found: 363.1H NMR (400 MHz, DMSO) δ 7.16 (d, J = 8.8 Hz, 1H), 7.10 (d, J = 5.6 Hz, 1H), 4.57 (d, J = 10.4 Hz, 2H), 4.50 (d, J = 7.9 Hz, 2H), 4.17 (s, 2H), 4.06 – 3.99 (m, 2H), 3.93 (t, J = 5.0 Hz, 2H), 3.57 – 3.48 (m, 2H), 1.45 (s, 9H), 1.30 (t, J = 6.9 Hz, 3H).

[0211] Step 4: 4-(6-ethoxyisoindolin-5-yl)morpholin-3-one

[0212] To a solution of give tert-butyl 5-ethoxy-6-(3-oxomorpholino)isoindoline-2- carboxylate (45 mg, 0.12 mmol) in DCM (1 mL) was added HCl-dioxane (4 M, 1 mL). The resulting mixture was stirred at rt for 1.5 h. After which the reaction mixture was concentrated under pressure, it was used directly next step. [M]+ calcd: 262. found: 263.

[0213] Stepn 5: 4-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5-yl)morpholin-3-one

[0214] To the solution of 4-(6-ethoxyisoindolin-5-yl)morpholin-3-one (HCl salt) in ACN (2 mL) were added 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylic acid (24 mg, 0.06 mmol), NMI (0.02 mL, 0.30 mmol) and TCFH (21.89 mg, 0.08 mmol) respectively, it was stirred at rt under N2 for 18 h. After which the reaction mixture was quenched by ice water and extracted with EA twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by prep-HPLC to obtain 4-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5- yl)morpholin-3-one (17.8 mg, 0.03 mmol) as a white solid. [M]+ calcd: 643, found: 644.1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 7.79 – 7.73 (m, 2H), 7.66 – 7.59 (m, 1H), 7.27 –7.17 (m, 2H), 6.26 (s, 1H), 4.87 – 4.75 (m, 2H), 4.65 (t, J = 21.4 Hz, 2H), 4.17 (d, J = 4.4 Hz, 2H), 4.07 (q, J = 6.8 Hz, 1H), 4.00 (q, J = 7.0 Hz, 1H), 3.96 – 3.90 (m, 2H), 3.59 – 3.49 (m, 2H), 1.33 – 1.27 (m, 3H).19F NMR (377 MHz, DMSO) δ -55.23 (s).

[0215] Example 9: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- fluorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0216] Step 1: Preparation 2,6-dichloro-3-fluorobenzenethiol

[0217] To a solution of 2, 4-dichloro-1-fluorobenzene (8.0 g,48.5 mmol) in THF (63 mL) added dropwise n -BuLi (23.27 mL, 2.5 M, 43.6 mmol) at -78 °C and stirred for 1.5 h. Then was added sulfur (3.1 g, 72.7 mmol) at -78 °C and stirred for 2 h. The mixture was added 10% hydrochloric acid to adjust pH to 5–6, extracted the resulting mixture with EtOAc (200 mL x 3), washed the combined organic phase with brine(100 mL x 2) and dry over Na2SO4, filtered and concentrated the organic phase to dry to obtain product 2,6-dichloro-3- fluorobenzene-1-thiol (10 g) as crude. [M]+calcd:196, found:197.

[0218] Step 2: ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-fluorophenyl)thio)- 2-oxo-1,2-dihydropyridine-3-carboxylate

[0219] To a solution of 2,6-dichloro-3-fluorobenzene-1-thiol (200 mg, 1.015 mmol) as crude in EtOH (5 mL), ethyl 4-chloro-6-[dichloro(fluoro)methyl]-2-oxo-1H-pyridine-3- carboxylate (307.04 mg, 1.015 mmol) was added, TEA (0.423 mL, 3.045 mmol) was dropwise at rt 0.5h, was stirred at 80oC 16h, the mixture was filtered and concentrated in vacuo. The mixture was cooled to rt and the residue was diluted with water and extracted with EA. The organic layer was dried, concentrated and purified by chromatography (silica gel, PE: EA=1:1) to give ethyl 6-[dichloro(fluoro)methyl]-4-[(2,6-dichloro-3- fluorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (55 mg, 0.119 mmol, 11.70%) as oil. [M]+calcd:445, found:446.1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 7.84 (dd, J = 9.1, 5.0 Hz, 1H), 7.77 (t, J = 8.8 Hz, 1H), 6.36 (s, 1H), 4.51 – 4.30 (m, 2H), 1.36 – 1.28 (m, 3H).19F NMR (377 MHz, DMSO) δ -55.57 (d, J = 94.3 Hz), -110.01 (d, J = 380.6 Hz).

[0220] Step 3: 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-fluorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid

[0221] To a solution of ethyl 6-[dichloro(fluoro)methyl]-4-[(2,6-dichloro-3- fluorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (5 mg, 0.011 mmol) in THF (1 mL) and Water (0.2 mL), was added LiOH (0.91 mg, 0.022 mmol), the mixture was stirred 16h at rt. The mixture was concentrated. The residue was diluted with water, EA was added and the mixture was acidified to pH 3-4 by 3 M HCl. The organic layer was separated, dried andconcentrated to give 6-[dichloro(fluoro)methyl]-4-[(2,6-dichloro-3-fluorophenyl)sulfanyl]-2- oxo-1H-pyridine-3-carboxylic acid (2 mg, 0.005 mmol, 42.58%) as crude, without further purification [M]+calcd:417, found:418.

[0222] Step 4: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-fluorophenyl)thio)- 2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0223] To a solution of 6-[dichloro(fluoro)methyl]-4-[(2,6-dichloro-3- fluorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (40 mg, 0.092 mmol) inACN (3 mL), 3-(6-methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,3-oxazinan-2-one (27.39 mg, 0.11 mmol), 1-methylimidazole (30.16 mg, 0.37 mmol) and N,N,N',N'- Tetramethylchloroformamidinium hexafluorophosphate (38.70 mg, 0.14 mmol) was added at rt, the mixture was stirred 16h at rt. The mixture was concentrated and the residue was dissolved in DMF (3.00 mL). The mixture was filtered and purified by prep-HPLC to give 3- (2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-fluorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (15 mg, 0.023 mmol, 24.52%) as a white solid. [M]+calcd,647; found, 648.1H NMR (400 MHz, DMSO) δ 7.81 (dd, J = 9.0, 5.0 Hz, 1H), 7.72 (t, J = 8.7 Hz, 1H), 7.25 (d, J = 29.5 Hz, 1H), 7.17 (d, J = 9.6 Hz, 1H), 6.35 (s, 1H), 4.71 (dd, J = 67.5, 29.5 Hz, 4H), 4.31 (s, 2H), 3.78 (d, J = 24.7 Hz, 3H), 3.45 (dd, J = 14.9, 5.9 Hz, 2H), 2.07 (d, J = 7.4 Hz, 2H).19F NMR (377 MHz, DMSO) δ -55.12 (dd, J = 140.8, 42.7 Hz), -107.98 – -113.95 (m).

[0224] Example 10: Synthesis of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-7-cyclopropylisoindolin-5- yl)tetrahydropyrimidin-2(1H)-one

[0225] Step 1: 4-bromo-2-[(2,4-dimethoxyphenyl)methyl]-6-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole

[0226] To a solution of 4-bromo-2-[(2,4-dimethoxyphenyl)methyl]-6-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (300 mg, 0.67 mmol) in toluene / H2O (8 mL / 0.2 mL) was added cyclopropylboranediol (77.8 mg, 0.91 mmol), tricyclohexylphosphine (20.33 mg, 0.072 mmol), K3PO4 (89.74 mg, 0.42 mmol) and Pd(OAc)2(2.71 mg, 0.012 mmol). The mixture was stirred at 100oC for 3 hours.The mixture was concentrated and purified by chromatography(silica gel, DCM:MeOH=10:1) to give 4- cyclopropyl-2-[(2,4-dimethoxyphenyl)methyl]-6-(2-oxohexahydropyrimidin-1-yl)-2,3- dihydro-1H-isoindole (100 mg) as a crude. [M]+calcd:407, found:408.

[0227] Step 2: 1-(7-cyclopropylisoindolin-5-yl)tetrahydropyrimidin-2(1H)-one

[0228] To a solution of 4-cyclopropyl-2-[(2,4-dimethoxyphenyl)methyl]-6-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (104 mg, 0.26 mmol) in DCM(5 mL) was added 1-chloroethyl chloromethanoate (109 mg, 0.76 mmol).The mixture was stirred at 40oC for 3 hours. TLC shows the starting material was consumed. Then the mixture was concentrated to give 4-cyclopropyl-6-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H- isoindole (100 mg) as a crude.[M]+calcd:257,found:258.

[0229] Step 3: 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-7-cyclopropylisoindolin-5-yl)tetrahydropyrimidin-2(1H)- one

[0230] To a solution of 4-cyclopropyl-6-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro- 1H-isoindole (33 mg, 0.13 mmol) in ACN (5 mL) was added 6-(chlorodifluoromethyl)-4- [(2,6-dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (40.96 mg, 0.10 mmol), TCFH (46.68 mg, 0.17 mmol) and NMI (63.06 mg, 0.088 mmol). The mixture was stirred at 40oC for overnight. The mixture was concentrated and dissolved in DMF (3 mL) and purified by prep-HPLC to give 6-(chlorodifluoromethyl)-3-{[4-cyclopropyl-6-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-4-[(2,6- dichlorophenyl)sulfanyl]-1,2-dihydropyridin-2-one (10 mg, 0.016 mmol, 12.19%) as a white solid.[M] calcd:638,found:639.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 7.81 – 7.72 (m, 2H), 7.67 – 7.56 (m, 1H), 7.08 (d, J = 28.0 Hz, 1H), 6.76 (d, J = 23.6 Hz, 1H), 6.53 (d, J = 12.4 Hz, 1H), 6.25 (s, 1H), 4.97 – 4.52 (m, 4H), 3.57 (dd, J = 12.4, 6.2 Hz, 2H), 3.21 (d, J =4.0 Hz, 2H), 2.01 – 1.84 (m, 2H), 1.80 – 1.61 (m, 1H), 0.94 (d, J = 8.4 Hz, 1H), 0.83 (d, J = 8.2 Hz, 1H), 0.63 (t, J = 31.2 Hz, 2H).

[0231] Example 11: Synthesis of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- hydroxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one

[0232] Step 1: 2,6-dichloro-3-methoxyaniline

[0233] To a solution of 3-amino-2,4-dichlorophenol (500 mg, 2.81 mmol) in acetone (10 mL) was added KOH (522 mg, 9.30 mmol). Then dimethyl sulfate (0.24 mL, 2.56 mmol) was added at the internal temperature did not rise above 30oC. Then the mixture was stirred at rt for 1 hour. Then water (3 mL) was added to the mixture and the mixture was stirred continuously for another hours. Then the mixture was concentrated and diluted with water and extracted with EA. The organic layer was dried and concentrated and purified by chromatography (silica gel, MeOH:DCM=1:10) to give 2,6-dichloro-3-methoxyaniline (270 mg, 1.41 mmol, 50.05%). [M]+ calcd:192, found:193.

[0234] Step 2: 2,6-dichloro-3-methoxybenzenethiol

[0235] To a solution of 2,6-dichloro-3-methoxyaniline (150 mg, 0.78 mmol) in HCl (3 M, 5 mL) was added NaNO2(64.68 mg, 0.94 mmol) dropwise at -10oC. The mixture was stirred at -10oC for 1 hour. TLC shows the starting material was consumed. Then potassium O-ethyl carbonodithioate (212.86 mg, 1.33 mmol) was added dropwise, then the mixture was warmed up to 60oC and stirred for 1 hour. The mixture was cooled to rt and diluted with water (10 mL) and extracted with EA. The organic layer was dried and concentrated. The residue was dissolved in EtOH / H2O (5 mL / 1 mL), KOH (43.83 mg, 0.78 mmol) was added and the mixture was stirred at 80oC for 2 hours. The mixture was cooled to rt and dried and diluted with water, then the mixture was acidified by 3 M HCl and extracted with EA. The organic layer was dried and concentrated and purified by chromatography (silica gel, PE:EA=4:1) to give 2,6-dichloro-3-methoxybenzenethiol (110 mg, 0.53 mmol, 67.36%).

[0236] Step 3: ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- methoxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0237] To a solution of 2,6-dichloro-3-methoxybenzenethiol (114 mg, 0.55 mmol) in EtOH (5 mL) were added ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1H-pyridine-3- carboxylate (155.97 mg, 0.55 mmol) and TEA (0.08 mL, 0.55 mmol). The mixture was stirred at 90oC overnight under nitrogen. The mixture was cooled to rt and concentrated and purified by chromatography (silica gel, DCM:MeOH=10:1) to give ethyl 6- (chlorodifluoromethyl)-4-((2,6-dichloro-3-methoxyphenyl)thio)-2-oxo-1,2-dihydropyridine- 3-carboxylate (50 mg, 0.11 mmol, 19.99%). [M]+ calcd:458, found:459.

[0238] Step 4: 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-hydroxyphenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid

[0239] To a solution of ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- methoxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate (70 mg, 0.15 mmol) in DCM (4 mL) was added BBr3 (114.70 mg, 0.46 mmol), the reaction was stirred at 0oC for 2 h. LCMS showed about 60 % of product was detected. The reaction was removed in vacuo and purified by Prep-TLC (DCM:MeOH=15:1) to give 6-(chlorodifluoromethyl)-4-((2,6- dichloro-3-hydroxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (24 mg, 0.06 mmol, 35.86%) as a white solid. [M]+ calcd:416, found:417.1H NMR (400 MHz, DMSO) δ 10.84 (s, 1H), 7.52 (d, J = 8.9 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 5.85 (s, 1H).

[0240] Step 5: 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- hydroxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-oneTo A solution of 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-hydroxyphenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid (50 mg, 0.12 mmol) in MeCN (10 mL) were added 1- (isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (31.29 mg, 0.14 mmol), TCFH (43.68 mg, 0.16 mmol) and NMI (61.92 mg, 0.72 mmol), the reaction was stirred at rt for 18 h and 40oC for 4 h. LCMS showed the reaction was completed. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel and Prep-HPLC to give 1-(2-(6- (chlorodifluoromethyl)-4-((2,6-dichloro-3-hydroxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3- carbonyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (20 mg, 0.03 mmol, 26.52%) as a white solid. [M]+ calcd:616, found:617.1H NMR (400 MHz, DMSO) δ 12.80 (s, 1H), 11.01 (s, 1H), 7.54 (dd, J = 8.9, 1.9 Hz, 1H), 7.33 (d, J = 6.9 Hz, 1H), 7.23 (m, 3H), 6.59 (d, J = 7.8 Hz, 1H), 6.28 (s, 1H), 4.83 (d, J = 13.4 Hz, 2H), 4.66 (d, J = 17.4 Hz, 2H), 3.66 – 3.55 (m, 2H), 3.23 (d, J = 4.4 Hz, 2H), 1.94 (dd, J = 11.5, 5.7 Hz, 2H).19F NMR (377 MHz, DMSO) δ -54.96 – -55.24 (m, 2F).

[0241] Example 12: Synthesis of 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-3-{[5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro- 1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one

[0242] tep 1: ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- vinylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate

[0243] To a solution of ethyl 4-[(3-bromo-2,6-dichlorophenyl)sulfanyl]-6- (chlorodifluoromethyl)-2-oxo-1H-pyridine-3-carboxylate (300.00 mg, 0.59 mmol), 4,4,5,5- tetramethyl-2-vinyl-1,3,2-dioxaborolane (364.10 mg, 2.36 mmol) and Pd-118 (38.12 mg, 0.06 mmol) in H2O (2 mL) and dioxane (10 mL) was added K2CO3(245.06 mg, 1.77 mmol), the reaction was stirred at 80oC for 1 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel to give ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3-vinylphenyl)sulfanyl]-2- oxo-1H-pyridine-3-carboxylate (200.00 mg, 0.44 mmol, 74.42%) as a white solid. [M]+ calcd:455, found:456.

[0244] Step 2: ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate

[0245] To a solution of ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- vinylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (200.00 mg, 0.44 mmol), Potassium osmate(VI) dihydrate (16.21 mg, 0.04 mmol) in THF (4 mL) and H2O (0.5 mL) was added sodium periodate (564.49 mg, 2.64 mmol), the reaction was stirred at rt for 1 h. LCMS showed the reaction was completed.

[0246] The reaction was filtered and the filtrate was extracted with EA, the organic layer was concentrated under reduced pressure and purified by prep-TLC to give ethyl 6- (chlorodifluoromethyl)-4-[(2,6-dichloro-3-formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3- carboxylate (30.00 mg, 0.06 mmol, 14.93%) as a white solid. [M]+ calcd:456, found:457.

[0247] Step 3: ethyl 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-2-oxo-1H-pyridine-3-carboxylate

[0248] To a solution of ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- formylphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (20.00 mg, 0.04 mmol) in MeOH (1 mL) was added NaBH4 (4.99 mg, 0.13 mmol), the reaction was stirred at rt for 2 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, the organic layer was concentrated under reduced pressure and purified by prep-TLC to give ethyl 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3-(hydroxymethyl)phenyl]sulfanyl}-2- oxo-1H-pyridine-3-carboxylate (15.00 mg, 0.03 mmol, 74.67%) as a white solid. [M]+ calcd:458, found:460

[0249] Step 4: 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-2-oxo-1H-pyridine-3-carboxylic acid

[0250] To a solution of ethyl 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-2-oxo-1H-pyridine-3-carboxylate (15.00 mg, 0.03 mmol) in THF (2.5 mL), MeOH (2.5 mL) and H2O (0.5 mL) was added LiOH (4.62 mg, 0.11 mmol), the reaction was stirred at 40oC for 2 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep-TLC to give 6- (chlorodifluoromethyl)-4-{[2,6-dichloro-3-(hydroxymethyl)phenyl]sulfanyl}-2-oxo-1H- pyridine-3-carboxylic acid (10.00 mg, 2.00 μmol, 71.42%) as a white solid. [M]+ calcd:430, found:430

[0251] Step 5: 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-3-{[5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro- 1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one

[0252] To a solution of 6-(chlorodifluoromethyl)-4-{[2,6-dichloro-3- (hydroxymethyl)phenyl]sulfanyl}-2-oxo-1H-pyridine-3-carboxylic acid (10.00 mg, 0.02 mmol), 5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (5.05 mg, 0.02 mmol) and NMI (11.43 mg, 0.14 mmol) in MeCN (2 mL) was added TCFH (8.45 mg, 0.03 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, the organic layer was concentrated under reduced pressure and purified by prep-HPLC to give 6-(chlorodifluoromethyl)-4-{[2,6- dichloro-3-(hydroxymethyl)phenyl]sulfanyl}-3-{[5-(2-oxohexahydropyrimidin-1-yl)-2,3- dihydro-1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one (3.00 mg, 5.00 μmol, 20.51%) as a white solid. [M]+ calcd:629.88, found: NMR (400 MHz, DMSO) δ 12.84 (s,1H), 7.85 – 7.68 (m, 2H), 7.36 – 7.17 (m, 3H), 6.59 (d, J = 8.8 Hz, 1H), 6.23 (s, 1H), 5.67 (t, J = 5.3 Hz, 1H), 4.86 – 4.59 (m, 4H), 4.54 (t, J = 4.7 Hz, 2H), 3.67 – 3.54 (m, 2H), 3.23 (d, J = 4.1 Hz, 2H), 1.97 – 1.91 (m, 2H).19F NMR (377 MHz, DMSO) δ -55.08 (d, J = 44.5 Hz).

[0253] Example 13: Synthesis of 3-{[6-(aminomethyl)-5-(2-oxohexahydropyrimidin- 1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-1,2-dihydropyridin-2-one

[0254] Step 1: 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-{[6- (hydroxymethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2- yl]carbonyl}-1,2-dihydropyridin-2-one

[0255] To a solution of 2-{[6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2- oxo-1H-pyridin-3-yl]carbonyl}-6-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H- isoindole-5-carbaldehyde (85 mg, 0.14 mmol) in MeOH (3 mL) were added NaBH4 (14.6 mg, 0.40 mmol) at 0℃, and stirred at 0℃ for 1hour. The mixture was purified by perp-HPLC ((Column: YMC-C8-5um; Mobile phase: from 10% to 95% MECN with H2O(0.1%FA); flow rate: 30 mL / min; wave length: 220 nm / 254 nm；)) to give 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-3-{[6-(hydroxymethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one (50 mg, 0.08 mmol, 58.64 %) as a white solid. [M]+calcd:628, found:629.

[0256] Step 2: 2-(2-{[6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2- oxo-1H-pyridin-3-yl]carbonyl}-6-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H- isoindol-5-yl)ethane-1-sulfonic acid

[0257] To a solution of 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-{[6- (hydroxymethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2- yl]carbonyl}-1,2-dihydropyridin-2-one (10 mg, 0.02 mmol) in DCM (2 mL) were added TEA (0.007 mL, 0.05 mmol) and MsCl (3.64 mg, 0.03 mmol) at 0 ℃, and stirred at 0 ℃ for 1 hour. The mixture was concentrated to give 2-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-(2-oxohexahydropyrimidin-1- yl)-2,3-dihydro-1H-isoindol-5-yl)ethane-1-sulfonic acid (10 mg, 0.01 mmol, 88.97 %) as a white oil used for next step without further purification [M]+calcd:706, found:707

[0258] Step 3: 3-{[6-(azidomethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro- 1H-isoindol-2-yl]carbonyl}-6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]- 1,2-dihydropyridin-2-one

[0259] To a solution of 2-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-(2-oxohexahydropyrimidin-1- yl)-2,3-dihydro-1H-isoindol-5-yl)ethane-1-sulfonic acid (10 mg, 0.01 mmol) in DMF (2 mL)were added NaN3 (4.59 mg, 0.07 mmol) at 25 ℃, and stirred at 25 ℃ for 18 hours. The mixture was concentrated to give 3-{[6-(azidomethyl)-5-(2-oxohexahydropyrimidin-1-yl)- 2,3-dihydro-1H-isoindol-2-yl]carbonyl}-6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-1,2-dihydropyridin-2-one (10 mg, 0.02 mmol, 108.11%) as a white oil used next step without purification. [M]+calcd:653, found:654.

[0260] Step 4: 3-{[6-(aminomethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro- 1H-isoindol-2-yl]carbonyl}-6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]- 1,2-dihydropyridin-2-one

[0261] To a solution of 3-{[6-(azidomethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3- dihydro-1H-isoindol-2-yl]carbonyl}-6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-1,2-dihydropyridin-2-one (10 mg, 0.02 mmol) in THF / H2O=15:2 (2 mL) were added PPh3(8.01 mg, 0.03 mmol) at rt under N2. and stirred at 50 ℃ for 2 hours. The mixture was purified by perp-HPLC ((Column: YMC-C8-5um; Mobile phase: from 10 % to 95 % MECN with H2O (0.1 % HCl); flow rate: 30 mL / min; wave length: 220 nm / 254 nm ；)) to give 3-{[6-(aminomethyl)-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H- isoindol-2-yl]carbonyl}-6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-1,2- dihydropyridin-2-one (2.5 mg, 0.004 mmol, 26.03 %) as a white solid. [M]+calcd:627, found:628.1H NMR (400 MHz, DMSO)1H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 8.09 (s, 2H), 7.76 (d, J = 8.0 Hz, 2H), 7.67 – 7.56 (m, 2H), 7.45 (d, J = 28.8 Hz, 2H), 7.06 (d, J = 8.6 Hz, 1H), 6.28 (s, 1H), 5.01 – 4.56 (m, 4H), 4.06 – 3.81 (m, 2H), 3.79 – 3.55 (m, 2H), 3.29 – 3.12 (m, 2H), 2.08 – 1.87 (m, 2H).19F NMR (377 MHz, DMSO) δ -53.46 – -57.87 (m).

[0262] Example 14: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-methoxyisoindoline-2-carbonyl)pyridin-2(1H)-one

[0263] Step 1: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5- methoxyisoindoline-2-carbonyl)pyridin-2(1H)-one

[0264] To a solution of 5-methoxy-2,3-dihydro-1H-isoindole (50 mg, 0.34 mmol) in ACN (2 mL), 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine- 3-carboxylic acid (161.11 mg, 0.40 mmol), 1-methylimidazole (82.45 mg, 1.01 mmol) and N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate (112.84 mg, 0.40 mmol) was added at rt, the mixture was stirred 16h at rt. The mixture was concentrated and the residue was dissolved in DMF (3.0 mL). The mixture was filtered and purified by prep-HPLC to give 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-[(5-methoxy-2,3- dihydro-1H-isoindol-2-yl)carbonyl]-1,2-dihydropyridin-2-one (50 mg, 0.094 mmol, 28.05%) as a white solid. [M]+calcd,530.1; found, 531.0.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 7.76 (d, J = 8.4 Hz, 2H), 7.67 – 7.54 (m, 1H), 7.29 (dd, J = 19.6, 8.4 Hz, 1H), 6.99 (d, J = 10.4 Hz, 1H), 6.92 – 6.82 (m, 1H), 6.25 (s, 1H), 4.79 (d, J = 16.2 Hz, 2H), 4.71 – 4.54 (m, 2H), 3.74 (d, J = 15.2 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.17 (d, J = 19.8 Hz).

[0265] Example 15: Synthesis of 3-(7-bromo-2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0266] Step 1: tert-butyl 4-bromo-5-hydroxy-6-nitroisoindoline-2-carboxylate

[0267] To a flask containing tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate (1.20 g, 4.28 mmol) was added DCM (15.00 mL) followed by the addition of NBS (0.76 g, 4.28 mmol) and SiO2(7.20 g, 119.88 mmol) at -15oC under N2. The mixture was stirred at -15oC for 2 h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-20%) to afford the product tert-butyl 4-bromo-5-hydroxy-6-nitroisoindoline-2-carboxylate (800.00 mg, 2.22 mmol, 52.02%) as a white solid. [M]+ calcd: 358.0, found: 346.2.1H NMR (400 MHz, DMSO) δ 11.07 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H), 4.65 (d, J = 9.6 Hz, 2H), 4.56 (d, J = 9.2 Hz, 2H), 1.46 (d, J = 1.8 Hz, 9H).

[0268] Step 2: tert-butyl 4-bromo-5-methoxy-6-nitroisoindoline-2-carboxylate

[0269] To a flask containing tert-butyl 4-bromo-5-hydroxy-6-nitroisoindoline-2- carboxylate (0.85 g, 2.36 mmol) was added DMF (3 mL) followed by the addition of K2CO3 (0.98 g, 7.10 mmol) and CH3I (1.92 mL, 23.66 mmol). The mixture was stirred at 40oC for 18 h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-20%) to afford the product tert-butyl 4-bromo-5-methoxy-6-nitroisoindoline-2-carboxylate (740.00 mg, 1.98 mmol, 83.79%) as a yellow solid. [M]+ calcd: 372.0, found: 359.0.1H NMR (400 MHz, DMSO) δ 7.97 (d, J = 9.5 Hz, 1H), 4.71 (d, J = 8.7 Hz, 2H), 4.59 (d, J = 8.4 Hz, 2H), 3.92 (s, 3H), 1.46 (d, J = 2.3 Hz, 9H).

[0270] Step 3: tert-butyl 6-amino-4-bromo-5-methoxyisoindoline-2-carboxylate

[0271] To a flask containing tert-butyl 4-bromo-5-methoxy-6-nitroisoindoline-2- carboxylate (740 mg, 1.98 mmol) was added EtOH (10.00 mL) and H2O (2.5 mL) followed by the addition of Fe (885.78 mg, 15.86 mmol), NH4Cl (848.50 mg, 15.86 mmol). The mixture was stirred at 75oC for 2h. Filtrate is obtained after filtration. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-40%) to afford the product tert-butyl 6- amino-4-bromo-5-methoxyisoindoline-2-carboxylate (580.00 mg, 1.69 mmol, 85.22%) as a white solid. [M]+ calcd: 342.0, found: 384.0.1H NMR (400 MHz, DMSO) δ 6.59 (d, J = 6.8 Hz, 1H), 5.23 (s, 2H), 4.51 (d, J = 9.4 Hz, 2H), 4.36 (d, J = 9.8 Hz, 2H), 3.66 (s, 3H), 1.44 (s, 9H).

[0272] Step 4: tert-butyl 4-bromo-6-(((3-chloropropoxy) carbonyl) amino)-5- methoxyisoindoline-2-carboxylate

[0273] To a flask containing tert-butyl 6-amino-4-bromo-5-methoxyisoindoline-2- carboxylate (300.00 mg, 0.87 mmol) was added Toluene (5 mL) followed by the addition of 3-chloropropyl carbonochloridate (137.22 mg, 0.87 mmol). The mixture was stirred at 70oC for 18h. The system is concentrated under vacuum. Get tert-butyl 4-bromo-6-(((3- chloropropoxy) carbonyl) amino)-5-methoxyisoindoline-2-carboxylate (350.00 mg, 0.75 mmol, 86.34%) as a yellow solid. [M]+ calcd: 462.0, found: 450.3.

[0274] Step 5: tert-butyl 4-bromo-5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl) isoindoline-2-carboxylate

[0275] To a flask containing tert-butyl 4-bromo-6-(((3-chloropropoxy) carbonyl) amino)- 5-methoxyisoindoline-2-carboxylate (300.00 mg, 0.65 mmol) was added ACN (2 mL) followed by the addition of K2CO3 (268.20 mg, 1.94 mmol). The mixture was stirred at 75oC for 18 h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (DCM: MeOH = 0-5%) to afford the product tert-butyl 4-bromo-5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl) isoindoline-2- carboxylate (150.00 mg, 0.35 mmol, 54.27%) as a yellow solid. [M]+ calcd:426.0, found:373.3.1H NMR (400 MHz, DMSO) δ 7.33 (d, J = 12.0 Hz, 1H), 5.76 (s, 1H), 4.65 (d, J = 7.4 Hz, 2H), 4.53 (d, J = 8.2 Hz, 2H), 4.42 – 4.31 (m, 2H), 3.76 (s, 3H), 3.53 (t, J = 5.2 Hz, 2H), 2.16 – 2.04 (m, 2H).

[0276] Step 6: 3-(7-bromo-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0277] To a flask containing tert-butyl 4-bromo-5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl) isoindoline-2-carboxylate (50.00 mg, 0.12 mmol) was added DCM (2.00 mL) followed by the addition of TFA (0.20 mL, 2.61 mmol) under N2at 0oC.The mixture was stirred at rt for 2 hr. The system was adjusted to neutral by saturated sodium bicarbonate aqueous solution. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 3- (7-bromo-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (35.00 mg, 0.11 mmol, 91.42%) as a yellow oil. [M]+ calcd: 326.0, found: 328.0.

[0278] Step 7: 3-(7-bromo-2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)- 2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0279] To a flask containing 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (38.00 mg, 0.095 mmol) was added ACN (5 mL) followed by the addition of 1-methylimidazole (27.26 mg, 0.33 mmol), 3-(7-bromo-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (37.24 mg, 0.11 mmol) at room temperature. The mixture was stirred at room temperature for 10 min. Added [chloro(dimethylamino)methylidene]dimethylammonium hexafluoro-λ5-phosphanuide (34.60 mg, 0.12 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give 3-(7-bromo-2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (20.00 mg, 0.028 mmol, 29.71%) as a white solid. [M]+ calcd:706.9, found: 709.2.1H NMR (400 MHz, DMSO) δ 12.92 (s, 1H), 7.75 (dd, J = 8.2, 2.8 Hz, 2H), 7.65 – 7.56 (m, 1H), 7.40 (d, J = 38.8 Hz, 1H), 6.29 (s, 1H), 5.00 – 4.63 (m, 4H), 4.44 – 4.34 (m, 2H), 3.78 (d, J = 7.8 Hz, 3H), 3.60 – 3.50 (m, 2H), 2.10 (dt, J = 12.2, 6.1 Hz, 2H).

[0280] Example 16: Synthesis of 2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-5-methoxyisoindoline-4- carbonitrile

[0282] To a solution of NBS (938 mg, 5.21 mmol), methyl 3-bromo-4-methoxy-2- methylbenzoate (1350 mg, 5.21 mmol) in tetrachloromethane (50 mL) was added BPO (243.2 mg, 5.21 mmol) at rt. Then the mixture was stirred at 80 ℃ for 12 hours. The mixturewas filtered. The residue was concentrated in vacuo and purified by chromatography (silica gel, PE:EA=3:1) to give methyl 3-bromo-2-(bromomethyl)-4-methoxybenzoate (1.15 g, 3.40 mmol, 65.30%) as a white solid. [M]+ calcd:336, found:337.

[0283] Step 2: 4-bromo-2-(2,4-dimethoxybenzyl)-5-methoxyisoindolin-1-one

[0284] To a solution of methyl 3-bromo-2-(bromomethyl)-4-methoxybenzoate (1.6 g, 4.73 mmol) (2,4-dimethoxyphenyl)methanamine (0.84 g, 5.00 mmol) in THF (30 mL) was added TEA (2.41 g, 4.73 mmol) at rt. Then the mixture was stirred at rt for 2 hours. The mixture was cooled to rt. Then the mixture was poured into ice water and stirred for 5 minutes. Then the mixture was extracted with EA, brine. The organic phase was dried and concentrated. The residue was purified by chromatography (silica gel, PE:EA=1:1) to give 4- bromo-2-(2,4-dimethoxybenzyl)-5-methoxyisoindolin-1-one (1.5 g, 3.82 mmol, 80.78%) as a white solid. [M]+ calcd:391.04, found:392.1H NMR (400 MHz, DMSO) δ 7.68 (d, J = 8.2 Hz, 1H), 7.23 (d, J = 8.2 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.59 (d, J = 2.2 Hz, 1H), 6.49 (dd, J = 8.2, 2.2 Hz, 1H), 4.60 (s, 2H), 4.19 (s, 2H), 3.94 (s, 3H), 3.81 (s, 3H), 3.75 (s, 3H).

[0285] Step 3: 4-bromo-2-(2,4-dimethoxybenzyl)-5-methoxyisoindoline

[0286] To a solution of 4-bromo-2-(2,4-dimethoxybenzyl)-5-methoxyisoindolin-1-one (1.5 g, 4.16 mmol) in tetrahydrofuran (4 mL) was added BH3 / THF (38.6 mL) dropwise at 0 ℃ under N2. Then the mixture was stirred at 80 ℃ reflex overnight. The mixture was cooled to rt. The mixture was added MeOH slowly at 0 ℃. The mixture was heated under reflux for 2 hours. The residue was purified by chromatography (silica gel, PE:EA=3:1) to give 4- bromo-2-(2,4-dimethoxybenzyl)-5-methoxyisoindoline (1 g, 2.89 mmol, 69.36%) as a white oil.[M]+ calcd:377, found:378.1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, J = 8.2 Hz, 1H),7.16 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.2, 2.4 Hz, 1H), 3.89 (s, 2H), 3.81 (d, J = 4.6 Hz, 5H), 3.78 – 3.76 (m, 6H).

[0287] Step 4: 2-(2,4-dimethoxybenzyl)-5-methoxyisoindoline-4-carbonitrile

[0288] To a solution of 4-bromo-2-(2,4-dimethoxybenzyl)-5-methoxyisoindoline (300 mg, 0.79 mmol) in N,N-dimethylmethanamide (8 mL) was added Zn(CN)2 (560 mg, 4.77 mmol) and Pd(PPh3)4 (90 mg, 0.79 mmol) at rt under N2. Then the mixture was stirred at 120 ℃ overnight. The mixture was filtered at rt. The residue was extracted with EA, the organic layer was washed with brine and purified by pre-HPLC to give 2-(2,4-dimethoxybenzyl)-5- methoxyisoindoline-4-carbonitrile (57 mg, 0.18mmol, 22.16%) as a yellow oil. [M]+ calcd:324, found:325.1H NMR (400 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.25 (d, J = 8.2 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 6.52 (dd, J = 8.2, 2.4 Hz, 1H), 3.91 (s, 2H), 3.88 (s, 3H), 3.83 (s, 2H), 3.78 (s, 5H), 3.76 (s, 3H).

[0289] Step 5: 5-methoxyisoindoline-4-carbonitrile

[0290] To a solution of 2-(2,4-dimethoxybenzyl)-5-methoxyisoindoline-4-carbonitrile (57 mg, 0.18 mmol) in DCM (10 mL) was added 1-chloroethyl chloromethanoate (75.3 mg, 0.53 mmol) at 0 ℃. Then the mixture was stirred at 40 ℃ for 1.5 hours. The mixture was concentrated in vacuo. To the mixture was added MeOH and the mixture was stirred for 1 hour at 75 ℃.Then the mixture was concentrated in vacuo to give 5-methoxyisoindoline-4- carbonitrile (30 mg, 0.17 mmol, 98.07%) as a crude product which was a yellow oil. [M]+ calcd: 174, found:175

[0291] Step 6: 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-5-methoxyisoindoline-4-carbonitrile

[0292] To a solution of 5-methoxyisoindoline-4-carbonitrile hydrochloride (30 mg, mmol) 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3- carboxylic acid (50 mg, 0.13 mmol) in ACN (3 mL) was added NMI (58 mg, mmol) and TCFH (78 mg, mmol) at rt. Then the mixture was stirred at 40 ℃ for 2 hours. The mixture was purified by pre-HPLC to give 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)- 2-oxo-1,2-dihydropyridine-3-carbonyl)-5-methoxyisoindoline-4-carbonitrile (30 mg, 0.05 mmol, 31.37%) as a yellow solid. [M]+ calcd:555, found:556.1H NMR (400 MHz, DMSO) δ 12.93 (s, 1H), 7.76 (dd, J = 7.8, 6.4 Hz, 2H), 7.73 – 7.59 (m, 2H), 7.23 (dd, J = 14.6, 8.6 Hz, 1H), 6.29 (s, 1H), 4.95 – 4.66 (m, 4H), 3.93 (s, 3H).19F NMR (377 MHz, DMSO) δ -55.26 (d, J = 62.2 Hz).

[0293] Example 17: Synthesis of 4-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-hydroxy-2,3-dihydro-1H- isoindol-5-yl)-1,4-oxazinan-3-one

[0294] Step 1: 4-(2-{[6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2- oxo-1H-pyridin-3-yl]carbonyl}-6-methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,4-oxazinan- 3-one

[0295] To a solution of 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo- 1H-pyridine-3-carboxylic acid (60.00 mg, 0.15 mmol), ethyl 2,3,4,6,7,8- hexahydro[1,4]oxazino[3,2-f]isoindol-4-ylacetate (11.92 mg, 0.05 mmol) and NMI (73.69 mg, 0.90 mmol) in MeCN (2 mL) was added TCFH (6.36 mg, 0.02 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, the organic layer was concentrated under reduced pressure and purified by prep-TLC to give 4-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-methoxy-2,3-dihydro-1H- isoindol-5-yl)-1,4-oxazinan-3-one (40.00 mg, 0.06 mmol, 42.33%) as a white solid. [M]+ calcd:630, found:631

[0296] Step 2: 4-(2-{[6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2- oxo-1H-pyridin-3-yl]carbonyl}-6-hydroxy-2,3-dihydro-1H-isoindol-5-yl)-1,4-oxazinan-3- one

[0297] To a solution of 4-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-methoxy-2,3-dihydro-1H- isoindol-5-yl)-1,4-oxazinan-3-one (25.00 mg, 0.04 mmol) in DCM (3 mL) was added BBr3 (29.72 mg, 0.12 mmol) dropwise under N2at 0oC, the reaction was stirred at 0oC for 1 h. LCMS showed the reaction was completed. The reaction was quenched with MeOH and concentrated under reduced pressure, the residue was purified by prep-HPLC to give 4-(2- {[6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3- yl]carbonyl}-6-hydroxy-2,3-dihydro-1H-isoindol-5-yl)-1,4-oxazinan-3-one (8.30 mg, 0.01 mmol, 33.96%) as a white solid.12.84 (s, 1H), 9.77 (d, J = 28.0 Hz, 1H), 7.87 – 7.70 (m, 2H), 7.66 – 7.54 (m, 1H), 7.15 (d, J = 27.9 Hz, 1H), 6.93 (d, J = 13.1 Hz, 1H), 6.25 (s, 1H), 4.90 – 4.47 (m, 4H), 4.16 (d, J = 4.1 Hz, 2H), 4.04 – 3.85 (m, 2H), 3.57 – 3.48 (m, 2H).19F NMR (377 MHz, DMSO) δ -55.10 (d, J = 48.2 Hz).

[0298] Example 18: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0299] Step 1: tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate

[0300] To a solution of tert-butyl 5-bromo-6-nitroisoindoline-2-carboxylate (2.8 g, 8 mmol) in dioxane (150 mL) / H2O (30 mL) was added t-BuXPhos Pd G3 (635 mg, 0.8 mmol) and KOH (896 mg, 16 mmol), The resulting mixture was heated to 100°C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered andconcentrated, the residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford tert-butyl 5-hydroxy-6-nitroisoindoline-2- carboxylate (1 g, 3.5 mmol, 43%) as a yellow solid. LCMS (m / z): [M+H]+calcd, 281; found, 279 (M-H)+.1H NMR (400 MHz, CDCl3) δ 10.63 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 20.2 Hz, 1H), 6.94 (t, J = 21.8 Hz, 1H), 4.59 (dd, J = 18.4, 14.7 Hz, 4H), 1.45 (s, 9H).

[0301] Step 2: tert-butyl 5-ethoxy-6-nitroisoindoline-2-carboxylate

[0302] To a solution of tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate (200 mg, 0.7 mmol) in DMF (10 ml) was added Cs2CO3(682 mg, 2.1 mmol) and EtI (0.5 mg, 7 mmol). The resulting mixture was heated to 66°C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5-ethoxy-6-nitroisoindoline-2-carboxylate (148 mg, 0.48 mmol, 68%) as a white solid. LCMS (m / z): [M+H]+calcd, 309; found, 294 (M-56+41)+.

[0303] Step 3: tert-butyl 5-amino-6-ethoxyisoindoline-2-carboxylate

[0304] At H2 atmosphere, to a solution of tert-butyl 5-ethoxy-6-nitroisoindoline-2- carboxylate (148 mg, 0.48 mmol) in MeOH (5 mL) was added Pd / C (200 mg). After being stirred at rt for 2 hr, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5- amino-6-ethoxyisoindoline-2-carboxylate (67 mg, 0.24 mmol, 50%) as a colorless oil. LCMS (m / z): [M+H]+calcd, 279; found, 279 (M+H)+.

[0305] Step 4: tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6-ethoxyisoindoline- 2-carboxylate

[0306] To a solution of tert-butyl 5-amino-6-ethoxyisoindoline-2-carboxylate (67 mg, 0.24 mmol) in toluene (5 ml) was added 3-chloropropyl carbonochloridate (37 mg, 0.24 mmol). The resulting mixture was stirred at 70°C overnight. The reaction mixture was concentrated to afford tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6-ethoxyisoindoline- 2-carboxylate as a white solid which was used in the next step directly without further purification. LCMS (m / z): [M+H]+calcd, 400; found, 384 (M-56+41)+.

[0307] Step 5: 4-methoxynaphthalene-1,2-dicarboxylic acid

[0308] To a solution of tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6- ethoxyisoindoline-2-carboxylate (95 mg, 0.24 mmol) in MeCN (8 mL) was added K2CO3 (40 mg, 0.28 mmol). After being stirred at 90°C overnight, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford tert-butyl 5-ethoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2-carboxylate (49 mg, 0.13 mmol, 54%) as a light yellow solid. LCMS (m / z): [M+H]+calcd, 363; found, 363 (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 24.3 Hz, 1H), 6.76 (d, J = 20.2 Hz, 1H), 4.54 (t, J = 16.6 Hz, 4H), 4.39 – 4.30 (m, 2H), 3.99 (p, J = 6.6 Hz, 2H), 3.50 (s, 2H), 2.10 (dt, J = 11.4, 5.6 Hz, 2H), 1.44 (s, 9H), 1.35 (t, J = 6.9 Hz, 3H).

[0309] Step 6: 3-(6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0310] To a solution of tert-butyl 5-ethoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2- carboxylate (49 mg, 0.13 mmol) in DCM (3 mL) was added HCl (3 mL, 4 M in dioxane). After being stirred at rt for 2 hr, The reaction mixture was concentrated to afford 3-(6- ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one as a brown solid which was used in the next step directly without further purification. LCMS (m / z): [M+H]+calcd, 263; found, 263 (M+H)+.

[0311] Step 7: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0312] To a solution of 3-(6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one (34 mg, 0.13 mmol) in ACN (6 ml) was added 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (40 mg, 0.1 mmol), NMI (41 mg, 0.5 mmol) and TCFH (56 mg, 0.2 mmol). The resulting mixture was stirred at 40°C for 30 min. The residue was diluted with EtOAc, washed with NaHCO3 (aq.), the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 3-(2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)- 6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one (38 mg, 0.06 mmol, 46%) as a white solid. LCMS (m / z): [M+H]+calcd, 646; found, 646 (M+H)+.1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.62 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 27.9 Hz, 1H), 7.16 (d, J= 8.5 Hz, 1H), 6.26 (s, 1H), 4.85 – 4.57 (m, 4H), 4.31 (s, 2H), 4.09 – 3.97 (m, 2H), 3.48 – 3.42 (m, 2H), 2.09 – 2.03 (m, 2H), 1.36 – 1.29 (m, 3H).19F NMR (377 MHz, DMSO) δ -55.14 (d, J = 71.4 Hz).

[0313] Step 8: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-hydroxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0314] To a solution of 3-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-6-ethoxy-2,3-dihydro-1H- isoindol-5-yl)-1,3-oxazinan-2-one (28 mg, 0.043 mmol) in DCM (1 mL) were added BBr3 (43.51 mg, 0.174 mmol) at 0℃, and stirred at 0℃ for 2h. The mixture was purified by perp- HPLC ((Column: YMC-C8-5um; Mobile phase: from 10% to 95% MECN with H2O(0.1%FA); flow rate: 30 mL / min; wave length: 220 nm / 254 nm；)) to give 3-(2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)- 6-hydroxyisoindolin-5-yl)-1,3-oxazinan-2-one (16 mg, 0.026 mmol, 59.74%) as a white solid. [M]+calcd:615, found:616.1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 8.63 (s, 1H), 7.75 (t, J = 7.6 Hz, 2H), 7.64 – 7.42 (m, 3H), 7.13 (d, J = 12.4 Hz, 1H), 6.24 (s, 1H), 4.95 – 4.57 (m, 4H), 4.00 (s, 2H), 3.73 (d, J = 34.0 Hz, 1H), 3.42 – 3.32 (m, 4H), 2.60 (d, J = 9.6 Hz, 3H), 2.08 – 1.94 (m, 2H).19F NMR (377 MHz, DMSO) δ -55.09 (d, J = 45.2 Hz).

[0315] Example 19: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- methoxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0316] Step 1: 2,6-dichloro-3-methoxyaniline

[0317] To a solution of 3-amino-2,4-dichlorophenol (500 mg, 2.81 mmol) in acetone (10 mL) was added KOH (522 mg, 9.30 mmol). Then dimethyl sulfate (0.24 mL, 2.56 mmol) was added at the internal temperature did not rise above 30oC. Then the mixture was stirred at rt for 1 hour. Then water (3 mL) was added to the mixture and the mixture was stirred continuously for another hour. Then mixture was concentrated and diluted with water and extracted with EA. The organic layer was dried and concentrated and purified by chromatography (silica gel, MeOH:DCM=1:10) to give 2,6-dichloro-3-methoxyaniline (270 mg, 1.41 mmol, 50.05%). [M]+calcd:191, found:193.

[0318] Step 2: 42,6-dichloro-3-methoxybenzenethiol

[0319] To a solution of 2,6-dichloro-3-methoxyaniline (150 mg, 0.78 mmol) in HCl aq. (3 M, 5 mL) was added NaNO2(64.68 mg, 0.94 mmol) dropwise at -10oC. The mixture was stirred at -10oC for 1 hour. TLC shows the starting material was consumed. Then [(ethoxythioxomethyl)sulfanyl] potassium (212.86 mg, 1.33 mmol) was added dropwise, then the mixture was warmed up to 60oC and stirred at 60oC for 1 hour. The mixture was cooled to rt and diluted with water (10 mL) and extracted with EA. The organic layer was dried and concentrated. The residue was dissolved in EtOH / H2O (5 mL / 1 mL), KOH (43.83 mg, 0.78 mmol) was added and the mixture was stirred at 80oC for 2 hours. The mixture was cooled to rt and dried and diluted with water, then the mixture was acidified by 3 M HCl aq. and extracted with EA. The organic layer was dried and concentrated and purified by chromatography (silica gel, PE: EA=4:1) to give 2,6-dichloro-3-methoxybenzene-1-thiol (110 mg, 0.526 mmol, 67.36%).

[0320] Step 3: ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- methoxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0321] To a solution of 2,6-dichloro-3-methoxybenzene-1-thiol (114 mg, 0.545 mmol) in EtOH (5 mL) was added ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1H-pyridine-3- carboxylate (155.97 mg, 0.55 mmol) and TEA (0.076 mL, 0.55 mmol). The mixture was stirred at 90oC for overnight under nitrogen. The mixture was cooled to rt and concentrated and purified by chromatography (silica gel, DCM:MeOH=10:1) to give ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3-methoxyphenyl)sulfanyl]-2-oxo-1H-pyridine-3- carboxylate (50 mg, 0.11 mmol, 19.99%).[M]+calcd:457,found:459.

[0322] Step 4: 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-methoxyphenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid

[0323] To a solution of ethyl 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- methoxyphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylate (50 mg, 0.11 mmol) in THF / H2O(3 mL / 0.6 mL) was added LiOH (18.3 mg, 0.44 mmol). The mixture was stirred at 50oC for 3 hours. TM MS detected. The mixture was diluted with water and acidified by 1 N HCl aq. The mixture was extracted with EA. The organic layer was dried and concentrated to give 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3-methoxyphenyl)sulfanyl]-2-oxo-1H- pyridine-3-carboxylic acid (40 mg) as a crude. [M]+calcd:429 found:431.

[0324] Step 5: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- methoxyphenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0325] To A solution of 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- methoxyphenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (40 mg, 0.093 mmol)) in ACN (5 mL) was added 3-(6-methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,3-oxazinan-2-one (23.039 mg, 0.093 mmol), TCFH (33.88 mg, 0.12 mmol) and NMI (45.77 mg, 0.064 mmol).The mixture was stirred at 40oC for overnight. TM MS detected. The mixture was concentrated and dissolved in DMF (3 mL) and purified by prep-HPLC to give 3-(2-{[6- (chlorodifluoromethyl)-4-[(2,6-dichloro-3-methoxyphenyl)sulfanyl]-2-oxo-1H-pyridin-3- yl]carbonyl}-6-methoxy-2,3-dihydro-1H-isoindol-5-yl)-1,3-oxazinan-2-one (8 mg, 0.012 mmol, 13.03%).[M]+calcd:659,found:661.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 7.71 (d, J = 9.0 Hz, 1H), 7.40 (dd, J = 9.2, 3.6 Hz, 1H), 7.21 (dd, J = 33.2, 19.2 Hz, 2H), 6.25 (s, 1H), 4.94 – 4.44 (m, 4H), 4.31 (s, 2H), 3.90 (s, 3H), 3.78 (d, J = 24.4 Hz, 3H), 3.45 (dt, J = 12.4, 6.1 Hz, 2H), 2.07 (d, J = 7.2 Hz, 2H).

[0326] Example 20: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0327] Step 1: tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate

[0328] To a solution of tert-butyl 5-bromo-6-nitroisoindoline-2-carboxylate (2.8 g, 8 mmol) in dioxane (150 mL) / H2O (30 mL) was added t-BuXPhos Pd G3 (635 mg, 0.8 mmol) and KOH (896 mg, 16 mmol), The resulting mixture was heated to 100°C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford tert-butyl 5-hydroxy-6-nitroisoindoline-2- carboxylate (1 g, 3.5 mmol, 43%) as a yellow solid. LCMS (m / z): [M+H]+calcd, 281; found, 279 (M-H)+.1H NMR (400 MHz, CDCl3) δ 10.63 (d, J = 7.3 Hz, 1H), 7.93 (d, J = 20.2 Hz, 1H), 6.94 (t, J = 21.8 Hz, 1H), 4.59 (dd, J = 18.4, 14.7 Hz, 4H), 1.45 (s, 9H).

[0329] Step 2: tert-butyl 5-ethoxy-6-nitroisoindoline-2-carboxylate

[0330] To a solution of tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate (200 mg, 0.7 mmol) in DMF (10 ml) was added Cs2CO3(682 mg, 2.1 mmol) and EtI (0.5 mg, 7 mmol). The resulting mixture was heated to 66°C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5-ethoxy-6-nitroisoindoline-2-carboxylate (148 mg, 0.48 mmol, 68%) as a white solid. LCMS (m / z): [M+H]+calcd, 309; found, 294 (M-56+41)+.

[0331] Step 3: tert-butyl 5-amino-6-ethoxyisoindoline-2-carboxylate

[0332] At H2 atmosphere, to a solution of tert-butyl 5-ethoxy-6-nitroisoindoline-2- carboxylate (148 mg, 0.48 mmol) in MeOH (5 mL) was added Pd / C (200 mg). After beingstirred at rt for 2 hr, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~30%, ethyl acetate in petroleum ether) to afford tert-butyl 5- amino-6-ethoxyisoindoline-2-carboxylate (67 mg, 0.24 mmol, 50%) as a colorless oil. LCMS (m / z): [M+H]+calcd, 279; found, 279 (M+H)+.

[0333] Step 4: tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6-ethoxyisoindoline- 2-carboxylate

[0334] To a solution of tert-butyl 5-amino-6-ethoxyisoindoline-2-carboxylate (67 mg, 0.24 mmol) in toluene (5 ml) was added 3-chloropropyl carbonochloridate (37 mg, 0.24 mmol). The resulting mixture was stirred at 70°C overnight. The reaction mixture was concentrated to afford tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6-ethoxyisoindoline- 2-carboxylate as a white solid which was used in the next step directly without further purification. LCMS (m / z): [M+H]+calcd, 399; found, 384 (M-56+41)+.

[0335] Step 5: 4-methoxynaphthalene-1,2-dicarboxylic acid

[0336] To a solution of tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6- ethoxyisoindoline-2-carboxylate (95 mg, 0.24 mmol) in MeCN (8 mL) was added K2CO3(40 mg, 0.28 mmol). After being stirred at 90°C overnight, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford tert-butyl 5-ethoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2-carboxylate (49 mg, 0.13 mmol, 54%) as a light yellow solid. LCMS (m / z): [M+H]+calcd, 363; found, 363 (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.05 (d, J = 24.3 Hz, 1H), 6.76 (d, J = 20.2 Hz, 1H),4.54 (t, J = 16.6 Hz, 4H), 4.39 – 4.30 (m, 2H), 3.99 (p, J = 6.6 Hz, 2H), 3.50 (s, 2H), 2.10 (dt, J = 11.4, 5.6 Hz, 2H), 1.44 (s, 9H), 1.35 (t, J = 6.9 Hz, 3H).

[0337] Step 6: 3-(6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0338] To a solution of tert-butyl 5-ethoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2- carboxylate (49 mg, 0.13 mmol) in DCM (3 mL) was added HCl (3 mL, 4 M in dioxane). After being stirred at rt for 2 hr, The reaction mixture was concentrated to afford 3-(6- ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one as a brown solid which was used in the next step directly without further purification. LCMS (m / z): [M+H]+calcd, 263; found, 263 (M+H)+.

[0339] Step 7: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0340] To a solution of 3-(6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one (34 mg, 0.13 mmol) in ACN (6 ml) was added 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (40 mg, 0.1 mmol), NMI (41 mg, 0.5 mmol) and TCFH (56 mg, 0.2 mmol). The resulting mixture was stirred at 40°C for 30 min. The residue was diluted with EtOAc, washed with NaHCO3 (aq.), the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 3-(2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)- 6-ethoxyisoindolin-5-yl)-1,3-oxazinan-2-one (38 mg, 0.06 mmol, 46%) as a white solid.LCMS (m / z): [M-H] - calcd, 642; found, 642 (M-H) -.1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.62 (t, J = 8.1 Hz, 1H), 7.24 (d, J = 27.9 Hz, 1H), 7.16 (d, J = 8.5 Hz, 1H), 6.26 (s, 1H), 4.85 – 4.57 (m, 4H), 4.31 (s, 2H), 4.09 – 3.97 (m, 2H), 3.48 – 3.42 (m, 2H), 2.09 – 2.03 (m, 2H), 1.36 – 1.29 (m, 3H).19F NMR (377 MHz, DMSO) δ - 55.14 (d, J = 71.4 Hz).

[0341] Example 21: Synthesis of 3-(2-(4-((2-chloro-6-methoxyphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)-1,3-oxazinan-2-one

[0342] Step 1: 2-chloro-6-methoxybenzenethiol

[0343] At -10oC, to the solution of 2-chloro-6-methoxyaniline (500 mg, 3.18 mmol) in HCl (2.7 mL, 7.7 mmol) was added NaNO2 (264.4 mg, 3.82 mmol) with H2O (2 mL), the reaction mixture was stirred at rt for 1 h. After that, potassium O-ethyl carbonodithioate (868.7 mg, 5.42 mmol) was added to the reaction mixture dropwise, it was stirred at 60oC for another 1 h. After being cooled down to room temperature, the reaction mixture wasquenched by ice water, extracted with DCM and saturated NaHCO3, the combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to give the crude intermediate product. Then to the solution of KOH (896 mg, 16.0 mmol) in EtOH (11 mL) and H2O (2 mL) was added the intermediate product, the resulting mixture was heated to 80oC for 18 hrs. After being cooled down to room temperature, the reaction mixture was quenched by ice water and adjusted pH=2 with HCl (3M), extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by column chromatography on silica gel (0~10% ethyl acetate in petroleum ether) to give 2-chloro-6-methoxybenzenethiol (150 mg， crude) as a yellow oil. LCMS (m / z): [M+H]+calcd, 175; found, 175 (M+H)+.

[0344] Step 2: ethyl 4-((2-chloro-6-methoxyphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylate

[0345] To a solution of 2-chloro-6-methoxybenzenethiol (100 mg, 0.57 mmol) in EtOH (5 mL) was added ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3- carboxylate (193.8 mg, 0.68 mmol) and DIPEA (221 mg, 1.71. mmol). The reaction was stirred at 60oC for 16 hours. The reaction mixture was quenched with water, extracted with EA. The combined organic layer was dried, filtered and concentrated to give the residue which was purified by flash chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to afford the ethyl 4-((2-chloro-6-methoxyphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylate (40 mg, 0.1 mmol, yield：17.5%) as a colorless oil. LCMS (m / z): [M+H]+calcd, 424; found, 424 (M+H)+.

[0346] Step 3: 4-((2-chloro-6-methoxyphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid

[0347] To a mixture of ethyl 4-((2-chloro-6-methoxyphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (30 mg, 0.07 mmol) in MeOH (5 mL) and water (1 mL) was added LiOH (14 mg, 0.57 mmol) the mixture was stirred at room temperature for 3 hrs. Adjust pH to 5-6, extracted with EA and H2O, The combined organic layer was dried, filtered and concentrated to afford 4-((2-chloro-6- methoxyphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (25.0 mg, 0.06 mmol, yield: 85.7%) as a white solid. LCMS (m / z): [M+H]+calcd, 396; found, 396 (M+H)+.

[0348] Step 4: 3-(2-(4-((2-chloro-6-methoxyphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0349] To a mixture of 4-((2-chloro-6-methoxyphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (25.0 mg, 0.06 mmol) in MeCN (5 mL) were added TCFH (25.3 mg, 0.09 mmol), NMI (49.2 mg, 0.6 mmol) at room temperature under N2 atmosphere and the mixture was stirred at room temperature for 16 hrs. The reaction was purified by Prep-HPLC to afford 3-(2-(4-((2-chloro-6-methoxyphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one (4.5 mg, 0.007 mmol, yield: 12%) as a white solid. [M+H]+calcd, 626; found, 626 (M+H)+.1H NMR (400 MHz, MeOD) δ 7.50 (m, J = 8.3, 2.6 Hz, 1H), 7.33 – 6.98(m, 4H), 6.33 (s, 1H), 4.89 (d, J = 26.2 Hz, 2H), 4.84 – 4.74 (m, 2H), 4.55 – 4.33 (m, 2H), 3.87 (d, J = 19.4 Hz, 3H), 3.81 (d, J = 7.9 Hz, 3H), 3.60 (t, J = 6.1 Hz, 2H), 2.18 (dt, J = 11.6, 5.9 Hz, 2H).19FNMR (377 MHz, MeOD) δ -57.59 (s).

[0350] Example 22: Synthesis of tert-butyl (2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)carbamate

[0352] To a flask containing 5-methoxyisoindoline-1,3-dione (10.00 g, 56.44 mmol) was added H2SO4(100 mL) followed by the addition of KNO3(6.28 g, 62.09 mmol) at 0oC under N2. The mixture was stirred at 20oC for 2h. The reaction liquid is quenched with H2O. Extract three times with EA and H2O. Get 5-methoxy-6-nitroisoindoline-1,3-dione (9.00 g, 40.511 mmol, 71.77%) as a yellow solid. [M]+ calcd: 222.0, found: 223.0.1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 4.10 (s, 3H).

[0353] Step 2: 5-methoxy-6-nitroisoindoline

[0354] To a flask containing 5-methoxy-6-nitroisoindoline-1,3-dione (11.00 g, 49.51 mmol) was added THF (40 mL) followed by the addition of BH3(1mol / L) (495.13 mL, 495.13 mmol) at 0oC under N2. The mixture was stirred at 85oC for 18h. The reaction liquid is quenched with MeOH. The mixture was stirred at 85oC for 1h. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 5-methoxy-6-nitroisoindoline (8.00 g, 41.19 mmol, 83.20%) as a yellow solid. [M]+ calcd: 194.0, found: 195.0.

[0355] Step 3: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5-methoxy- 6-nitroisoindoline-2-carbonyl)pyridin-2(1H)-one

[0356] To a flask containing 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (200.00 mg, 0.5 mmol) was added ACN (5.0 mL) followed by the addition of 1-methylimidazole (143.48 mg, 1.74 mmol), 5-methoxy-6- nitroisoindoline (116.34 mg, 0.60 mmol) at room temperature. The mixture was stirred at room temperature for 10 min. Added [chloro(dimethylamino)methylidene]dimethylammonium hexafluoro-λ5-phosphanuide (182.10 mg, 0.65mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-methoxy-6-nitroisoindoline-2-carbonyl)pyridin-2(1H)-one (167.00 mg, 0.28 mmol, 57.79%) as a white solid. [M]+ calcd: 574.9, found: 576.0.

[0357] Step 4: 3-(5-amino-6-methoxyisoindoline-2-carbonyl)-6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)pyridin-2(1H)-one

[0358] To a flask containing 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5- methoxy-6-nitroisoindoline-2-carbonyl)pyridin-2(1H)-one (167.00 mg, 0.29 mmol) was added EtOH (4.0 mL) and H2O (1.0 mL)followed by the addition of NH4Cl (123.90 mg, 2.31 mmol) and Fe (129.34 mg, 2.31 mmol).The mixture was stirred at 80oC for 2hr. After filtration, the filtrate is concentrated under vacuum. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-30%) to afford the product 3-(5-amino-6-methoxyisoindoline-2-carbonyl)-6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)pyridin-2(1H)-one (130.00 mg, 0.238 mmol, 82.11%) as a yellow solid. [M]+ calcd: 544.9, found: 548.3.1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 7.77 (dd, J = 7.8, 2.0 Hz, 2H), 7.67 – 7.59 (m, 1H), 6.83 (d, J = 15.8 Hz, 1H), 6.59 (d, J = 29.4 Hz, 1H), 6.23 (s, 1H), 4.75 – 4.46 (m, 4H), 3.74 (d, J = 23.6 Hz, 3H).

[0359] Step 5: tert-butyl (2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)carbamate

[0360] To a flask containing 3-(5-amino-6-methoxyisoindoline-2-carbonyl)-6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)pyridin-2(1H)-one (30.00 mg, 0.05 mmol) was added THF (3.00 mL) followed by the addition of (2-methylprop-2- yl)oxidanecarboxylic anhydride (23.95 mg, 0.11 mmol) under N2at 0oC. The mixture was stirred at 65oC for 18hr. The system was adjusted to neutral by saturated sodium bicarbonate aqueous solution. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get tert-butyl (2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)carbamate (20.00 mg, 0.03 mmol, 56.35%) as a white solid. [M]+ calcd:645.0, found:646.0.1H NMR (400 MHz,DMSO) δ 12.84 (s, 1H), 7.93 (s, 1H), 7.77 (d, J = 1.4 Hz, 1H), 7.76 – 7.64 (m, 2H), 7.62 (d, J = 8.0 Hz, 1H), 7.07 (d, J = 11.0 Hz, 1H), 6.26 (s, 1H), 4.86 – 4.73 (m, 2H), 4.72 – 4.53 (m, 2H), 3.79 (d, J = 23.6 Hz, 3H), 1.45 (d, J = 9.6 Hz, 9H).

[0361] Example 23: Synthesis of methyl (2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)carbamate

[0362] Step 1: 5-methoxy-6-nitroisoindoline-1,3-dione

[0363] To a flask containing 5-methoxyisoindoline-1,3-dione (10.00 g, 56.44 mmol) was added H2SO4 (100 mL) followed by the addition of KNO3 (6.28 g, 62.09 mmol) at 0oC under N2. The mixture was stirred at 20oC for 2h. The reaction liquid is quenched with H2O. Extract three times with EA and H2O. Get 5-methoxy-6-nitroisoindoline-1,3-dione (9.00 g, 40.511 mmol, 71.77%) as a yellow solid. [M]+ calcd: 222.0, found: 223.0.1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 4.10 (s, 3H).

[0364] Step 2: 5-methoxy-6-nitroisoindoline

[0365] To a flask containing 5-methoxy-6-nitroisoindoline-1,3-dione (11.00 g, 49.51 mmol) was added THF (40 mL) followed by the addition of BH3(1mol / L) (495.13 mL, 495.13 mmol) at 0oC under N2. The mixture was stirred at 85oC for 18 h. The reaction liquid is quenched with MeOH. The mixture was stirred at 85oC for 1h. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 5-methoxy-6-nitroisoindoline (8.00 g, 41.19 mmol, 83.20%) as a yellow solid. [M]+ calcd: 194.0, found: 195.0.

[0366] Step 3: tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate

[0367] To a flask containing 5-methoxy-6-nitroisoindoline (3.00 g, 15.45 mmol) was added DCM (30.00 mL) followed by the addition of TEA (6.44 mL, 46.34 mmol) and (2- methylprop-2-yl) oxidanecarboxylic anhydride (4.05 g, 18.54 mmol) at 0oC under N2. The mixture was stirred at rt for 2h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-30%) to afford the product tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate (3.50 g, 11.89 mmol, 76.98%) as a yellow solid. [M]+ calcd: 294.1, found: 280.4.1H NMR (400 MHz, DMSO) δ 7.87 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 3.8 Hz, 1H), 4.63 (d, J = 10.4 Hz, 2H), 4.55 (d, J = 8.8 Hz, 2H), 3.90 (t, J = 4.6 Hz, 3H), 1.46 (s, 9H).

[0368] Step 4: tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate

[0369] To a flask containing tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate (1400.00 mg, 4.75 mmol) was added MeOH (15 mL) followed by the addition of Pd / C (140.00 mg, 1.31 mmol). The mixture was stirred at rt for 2h under H2. Filtrate is obtained after filtration. The organic system was concentrated under vacuum. The organic system wasconcentrated to give the residue which was purified by Flash chromatography (PE: EA = 0- 30%) to afford the product tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (1.00 g, 3.78 mmol, 79.53%) as a yellow solid. [M]+ calcd: 264.1, found: 250.0.1H NMR (400 MHz, DMSO) δ 6.75 (d, J = 6.7 Hz, 1H), 6.54 (d, J = 7.2 Hz, 1H), 4.69 (s, 2H), 4.41 (t, J = 10.4 Hz, 4H), 3.74 (d, J = 3.4 Hz, 3H), 1.45 (d, J = 6.5 Hz, 9H).

[0370] Step 5: tert-butyl 5-methoxy-6-((methoxycarbonyl)amino)isoindoline-2- carboxylate

[0371] To a flask containing tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (25.00 mg, 0.09 mmol) was added DMF (1.00 mL) followed by the addition of NaH (4.54 mg, 0.19 mmol) at 0oC. The mixture was stirred at room temperature for 1h. Added methyl carbochlorination (0.01 mL, 0.14 mmol) at room temperature. The mixture was stirred at 50oC for 18h. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give tert-butyl 5-methoxy-6- ((methoxycarbonyl)amino)isoindoline-2-carboxylate (20 mg, 0.06 mmol, 65.60%) as a white solid. [M]+ calcd:322.1, found:267.0.1H NMR (400 MHz, DMSO) δ 8.43 (s, 1H), 7.56 (d, J = 11.0 Hz, 1H), 7.00 (d, J = 5.7 Hz, 1H), 4.51 (t, J = 11.2 Hz, 4H), 3.78 (d, J = 3.6 Hz, 3H), 3.63 (s, 3H), 1.45 (s, 9H).

[0372] Step 6: methyl (6-methoxyisoindolin-5-yl)carbamate

[0373] To a flask containing tert-butyl 5-methoxy-6- ((methoxycarbonyl)amino)isoindoline-2-carboxylate (20.00 mg, 0.06 mmol) was added DCM (1.00 mL) followed by the addition of TFA (0.10 mL, 1.30 mmol) under N2 at 0oC. The mixture was stirred at rt for 2hr. The system was adjusted to neutral by saturated sodium bicarbonate aqueous solution. Extract three times with EA and H2O. The organic phaseconcentrates under vacuum. Get methyl (6-methoxyisoindolin-5-yl)carbamate (13.00 mg, 0.05 mmol, 94.28%) as a yellow oil. [M]+ calcd: 222.1, found: 223.0.

[0374] Step 7: methyl (2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)carbamate

[0375] To a flask containing 6-(chlorodifluoromethyl)-4-[(1,3-dichlorobenzen-2- yl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (18.00 mg, 0.04 mmol) was added ACN (5.0 mL) followed by the addition of 1-methylimidazole (12.91 mg, 0.15 mmol), methyl [(6- methoxy-2,3-dihydro-1H-isoindol-5-yl)amino]methanoate (9.99 mg, 0.04 mmol) at room temperature. The mixture was stirred at room temperature for 10 min. Added [chloro(dimethyl amino)methylidene]dimethylammonium hexafluoro-λ5-phosphanuide (182.10 mg, 0.65 mmol) at room temperature. The mixture was stirred at room temperature for 1h. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give methyl (2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)carbamate (10.00 mg, 0.01 mmol, 36.80%) as a white solid. [M]+ calcd: 603.0, found: 604.0.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 8.48 (d, J = 5.5 Hz, 1H), 7.76 (d, J = 7.9 Hz, 2H), 7.69 – 7.56 (m, 2H), 7.09 (d, J = 10.6 Hz, 1H), 6.26 (s, 1H), 4.86 – 4.74 (m, 2H), 4.72 – 4.54 (m, 2H), 3.78 (d, J = 23.9 Hz, 3H), 3.64 (d, J = 10.2 Hz, 3H).

[0376] Example 24: Synthesis of 3-(2-(4-((3-(aminomethyl)-2,6-dichlorophenyl)thio)- 6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0377] Step 1: 3-(2-(4-((3-(azidomethyl)-2,6-dichlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)-1,3-oxazinan-2-one

[0378] To a solution of 4-((3-(azidomethyl)-2,6-dichlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (100 mg, 0.22 mmol) in acetonitrile (10 mL) were added 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (81.56 mg, 0.33 mmol), TCFH (79.72 mg, 0.29 mmol) and NMI (113.00 mg, 1.31 mmol), the reaction was stirred at rt for 18 h and 40oC for 6 h. LCMS showed the reaction was completed. The solvent was removed in vacuo. The residue was purified by column chromatography on silica gel and Prep-HPLC to give 3-(2-(4-((3-(azidomethyl)-2,6- dichlorophenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (110 mg, 0.16 mmol, 73.07%) as a white solid. [M]+ calcd:685.91, found:686.90.1H NMR (400 MHz, DMSO) δ 7.80 (m, 2H), 7.26 (d, J = 27.2 Hz, 2H), 6.28 (s, 1H), 4.86 – 4.59 (m, 6H), 4.32 (s, 2H), 3.78 (dd, J = 24.3, 8.8 Hz, 3H), 3.46 (d, J = 9.3 Hz, 2H), 2.07 (d, J = 5.2 Hz, 2H).

[0379] Step 2: 3-(2-(4-((3-(aminomethyl)-2,6-dichlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)-1,3-oxazinan-2-one

[0380] To a solution of 3-(2-(4-((3-(azidomethyl)-2,6-dichlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one (100 mg, 0.15 mmol) in THF / H2O (5:1, 10 mL) was added Ph3P (45.89 mg, 0.18 mmol), the reaction was stirred at 50oC for 24 h. Then NH3H2O (0.2 mL) was added at rt for 5 hours. LCMS showed about 60 % of product was detected. The solvent was removed in vacuo and purified by Prep-HPLC to give 3-(2-(4-((3-(aminomethyl)-2,6- dichlorophenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (22.6 mg, 0.03 mmol, 23.27%) as a white solid. [M]+ calcd:659.91, found:661.00.1H NMR (400 MHz, DMSO) δ 7.78 (m, 2H), 7.21 (m, 2H), 6.12 (s, 1H), 4.79 (d, J = 27.4 Hz, 4H), 4.32 (d, J = 4.4 Hz, 2H), 4.04 (d, J = 7.2 Hz, 2H), 3.79 (d, J = 24.4 Hz, 3H), 3.49 – 3.42 (m, 2H), 2.07 (d, J = 6.8 Hz, 2H).19F NMR (377 MHz, DMSO) δ -54.82 (d, J = 73.3 Hz, 2F).

[0381] Example 25: Synthesis of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- ((methylamino)methyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one

[0382] To a mixture of 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5-carbaldehyde (60 mg, 0.10 mmol) and methanamine (0.1 mL, 0.2 mmol, 2 mol in MeOH) in MeOH (5 mL) were added AcOH (0.05 mL) at room temperature under N2 atmosphere and the mixture was stirred at room temperature for 30 min. After added NaBH3CN (18.9 mg, 0.3 mmol) and the mixture was stirred at room temperature for 4 hrs. The reaction was purified by Prep-HPLC to afford 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-((methylamino)methyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one (7.7 mg, 0.012 mmol, yield: 12%) as a white solid. [M+H]+calcd, 642; found, 642 (M+H)+.1H NMR (400 MHz, DMSO) δ 12.90 (s, 1H), 7.75 (t, J = 7.6 Hz, 2H), 7.64 – 7.42 (m, 3H), 7.13 (d, J = 12.4 Hz, 1H), 6.24 (s, 1H), 4.95 – 4.57 (m, 4H), 4.00 (s, 2H), 3.73 (d, J = 33.9 Hz, 1H), 3.42 – 3.32 (m, 4H), 2.60 (d, J = 9.6 Hz, 3H), 2.08 – 1.94 (m, 2H).19F NMR (377 MHz, DMSO) δ -55.19 (d, J = 37.1 Hz).

[0383] Example 26: Synthesis of 1-(6-((benzylamino)methyl)-2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3- carbonyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one

[0384] To a mixture of 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5- carbaldehyde (30 mg, 0.05 mmol) and phenylmethanamine (10.7 mg, 0.1 mmol) in MeOH (5 mL) were added AcOH (0.05 mL) at room temperature under N2 atmosphere and the mixture was stirred at room temperature for 30 min. After added NaBH3CN (10.0 mg, 0.15 mmol) and the mixture was stirred at room temperature for 4 hrs. The reaction was purified by Prep- HPLC to afford 1-(6-((benzylamino)methyl)-2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one (15 mg, 0.02 mmol, yield: 41.8%) as a white solid. [M+H]+calcd, 718; found, 718 (M+H)+.1H NMR (400 MHz, DMSO) δ 7.76 – 7.62 (m, 2H), 7.61 – 7.45 (m, 2H), 7.45 – 7.17 (m, 7H), 5.84 (d, J = 34.5 Hz, 1H), 4.74 (d, J = 54.9 Hz, 4H), 3.76 (t, J = 67.8 Hz, 4H), 3.16 (d, J = 45.7 Hz, 5H), 1.79 (d, J = 54.4 Hz, 2H).19F NMR (377 MHz, DMSO) δ -54.59 (s).

[0385] Example 27: Synthesis of 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5- methoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin- 4-yl)thio)benzamide

[0387] To a solution of 1,3-dichloro-2-nitrobenzene (20.00 g, 104.17 mmol) in H2SO4(120 mL) was added NBS (18.44 g, 104.17 mmol), the reaction was stirred at 60oC for 2 h. TLC showed the reaction was completed. The mixture was poured into ice water and extracted with EA. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Then the residue was purified by column chromatography on silica gel to give 1-bromo-2,4-dichloro-3-nitrobenzene (21.00 g, 69.77 mmol, 66.98%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 8.11 (d, J = 8.8 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H).

[0388] Step 2: 3-bromo-2,6-dichloroaniline

[0389] To a solution of 1-bromo-2,4-dichloro-3-nitrobenzene (5.00 g, 18.46 mmol) in ethanol / H2O (4:1, 50 mL) were added ammonium chloride (5.92 g, 110.75 mmol) and iron (0) (5.15 g, 92.29 mmol), the reaction was stirred at 80oC for 18 h. TLC showed the reaction was completed. The solvent was filtered while it was hot and removed in vacuo. The residue was purified by column chromatography on silica gel to give 3-bromo-2,6-dichloroaniline (2.80 g, 11.04 mmol, 59.82%) as a white solid.1H NMR (400 MHz, DMSO-d6) δ 7.19 (d, J = 8.5 Hz, 1H), 6.94 (d, J = 8.6 Hz, 1H), 5.85 (s, 2H).

[0390] Step 3: 3-bromo-2,6-dichlorobenzenethiol

[0391] To a solution of 3-bromo-2,6-dichloroaniline (2.00 g, 8.30 mmol) in 3 M HCl (50 mL) was added sodium nitrite (0.69 g, 9.96 mmol) in 20 mL water at -10oC, the reaction was stirred at -10oC for 1 h. Then the [(ethoxythioxomethyl)sulfanyl]potassium (2.26 g, 14.11 mmol) in 5 mL water was added at 0oC, the reaction was stirred at 60oC for 1 h. The residue was extracted with EA three times. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The potassium hydroxide (2.33 g, 41.51 mmol) in ethanol / H2O (5:1) (80 mL) was added to the organic phase, the reaction was stirred at 80oC for 2 h. TLC showed the reaction was completed. The residue was removed in vacuo and adjusted with 1 M HCl to pH~2. The resulting suspension was filtered to give 3-bromo-2,6- dichlorobenzenethiol (500.00 mg, 1.55 mmol, 46.70%) as a brown solid. The crude enamine was used directly in next step.1H NMR (400 MHz, DMSO) δ 7.88 (d, J = 8.7 Hz, 1H), 7.52 (d, J = 8.7 Hz, 1H).

[0392] Step 4: ethyl 4-((3-bromo-2,6-dichlorophenyl)thio)-6-(chlorodifluoromethyl)- 2-oxo-1,2-dihydropyridine-3-carboxylate

[0393] To a solution of 3-bromo-2,6-dichlorobenzenethiol (4.20 g, 13.77 mmol) in ethanol (20 mL) was added ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1,2- dihydropyridine-3-carboxylate (3.15 g, 11.02 mmol) and TEA (5.42 mL, 41.32 mmol), the reaction was stirred at 90oC for 24 h. LCMS showed the reaction was completed. The solvent was removed in vacuo. Then the residue was purified by prep-HPLC to give ethyl 4-((3- bromo-2,6-dichlorophenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3- carboxylate (4.10 g, 6.65 mmol, 48.31%) as a white solid. [M]+ calcd:507.55, found:507.70.1H NMR (400 MHz, DMSO) δ 8.15 (d, J = 8.5 Hz, 1H), 7.48 (d, J = 8.6 Hz, 1H), 6.06 (s, 1H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H).

[0394] Step 5: ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-cyanophenyl)thio)- 2-oxo-1,2-dihydropyridine-3-carboxylate

[0395] To a solution of ethyl 4-((3-bromo-2,6-dichlorophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.00 g, 1.97 mmol) in NMP (10 mL) was added CuCN (0.18 g, 1.97 mmol), the reaction was stirred at 170oC for 2 h under N2. LCMS showed about 30 % of product was detected. The residue was extracted with EA three times. The combined organic phase was dried over Na2SO4and concentrated in vacuo. Then the residue was purified by column chromatography on silica gel to give ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-cyanophenyl)thio)-2-oxo-1,2-dihydropyridine-3- carboxylate (300.00 mg, 0.63 mmol, 31.88%) as a white solid. [M]+ calcd:451.94, found:454.80.

[0396] Step 6: 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-cyanophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carboxylic acid

[0397] To a solution of ethyl 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- cyanophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylate (300.00 mg, 0.66 mmol) in THF / H2O (10 mL) was added lithium hydroxide (47.51 mg, 1.98 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The solvent was removed in vacuo. Then the residue was adjusted with 1 M HCl to pH~2 and extracted with EA three times. The combined organic phase was dried over Na2SO4and concentrated in vacuo. The residue was purified by beating with EA to give 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3- cyanophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (200.00 mg, 0.45 mmol, 67.51%) as a white solid. [M]+ calcd:423.91, found:426.90.

[0398] Step 7: 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5-methoxy-6-(2-oxo-1,3- oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4-yl)thio)benzonitrile

[0399] To a solution of 6-(chlorodifluoromethyl)-4-((2,6-dichloro-3-cyanophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (100.00 mg, 0.40 mmol) in acetonitrile (10 mL) were added 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (345.75 mg, 0.86 mmol), TCFH (209.44 mg, 0.75 mmol) and NMI (296.90 mg, 3.45 mmol), the reaction was stirred at rt for 48 h. LCMS showed the reaction was completed. The reaction was removed in vacuoand purified by Prep-HPLC to give 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5-methoxy- 6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4- yl)thio)benzonitrile (200.00 mg, 0.31 mmol, 36.36%) as a white solid. [M]+ calcd:654.01, found:656.90.1H NMR (400 MHz, DMSO) δ 8.15 (d, J = 8.5, 1.6 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 28.8 Hz, 2H), 7.16 (d, J = 9.9 Hz, 1H), 6.56 (d, J = 5.2 Hz, 1H), 4.76 (d, J = 28.9 Hz, 4H), 4.31 (s, 2H), 3.79 (d, J = 23.6 Hz, 3H), 3.44 (s, 2H), 2.06 (s, 2H).

[0400] Step 8: 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5-methoxy-6-(2-oxo-1,3- oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4-yl)thio)benzamide

[0401] To a solution of 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[5-methoxy-6-(2- oxo-1,3-oxazinan-3-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4- yl]sulfanyl}benzene-1-carbonitrile (20.00 mg, 0.03 mmol) in EtOH / H2O(1:1, 2 mL) was added potassium hydroxide (5.13 mg, 0.09 mmol), the reaction was stirred at 100oC for 3 h. LCMS showed the reaction was completed. The reaction was removed in vacuo and purified by Prep-HPLC to give 2,4-dichloro-3-((6-(chlorodifluoromethyl)-3-(5-methoxy-6-(2-oxo-1,3- oxazinan-3-yl)isoindoline-2-carbonyl)-2-oxo-1,2-dihydropyridin-4-yl)thio)benzamide (5.00 mg, 0.007 mmol, 23.11%) as a white solid. [M]+ calcd:672.02, found:674.80.1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 8.04 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.65 (dd, J = 8.3, 1.8 Hz, 1H), 7.26 (d, J = 28.8 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.31 (s, 1H), 4.83 (dd, J = 25.6, 11.2 Hz, 2H), 4.66 (t, J = 20.0 Hz, 2H), 4.31 (d, J = 5.7 Hz, 2H), 3.78 (d, J = 25.2 Hz, 3H), 3.45 (q, J = 7.5, 6.2 Hz, 2H), 2.06 (d, J = 6.3 Hz, 2H).19F NMR (377 MHz, DMSO-d6) δ - 55.15(s, 2F).

[0402] Example 28: Synthesis of N-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl) thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl) morpholine-4-carboxamide

[0403] Step 1: tert-butyl 5-(1H-imidazole-1-carboxamido)-6-methoxyisoindoline-2- carboxylate

[0404] To a solution of tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (100 mg, 0.37 mmol) in DCM (3 mL) was added CDI (61.35 mg, 0.37 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was monitored by MS and TLC, and products were generated after the raw material reaction was completed. [M+1] + calcd:358.16; LCMS: 359.05

[0405] Step 2: tert-butyl 5-methoxy-6-(morpholine-4-carboxamido) isoindoline-2- carboxylate

[0406] To a solution of tert-butyl 5-(1H-imidazole-1-carboxamido)-6- methoxyisoindoline-2-carboxylate (100 mg, 0.37 mmol) in DCM (3 mL) was added CDI (61.35 mg, 0.37 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography, then concentrated in vacuo, and dried to afford the title compound tert-butyl 5-methoxy-6-(morpholine-4-carboxamido) isoindoline-2-carboxylate (105 mg, 0.29 mmol, 77.44%) as a white solid. [M+1] + calcd:377.20; LCMS: 378.20

[0407] Step 3: N-(6-methoxyisoindolin-5-yl) morpholine-4-carboxamide

[0408] To a solution of tert-butyl 5-methoxy-6-(morpholine-4-carboxamido) isoindoline- 2-carboxylate (75 mg, 0.19 mmol) in DCM (1.5 mL) was added HCl / dioxane (1.5 mL) and the reaction was stirred at room temperature for 30 min. The reaction was directly concentrated in vacuo and dried to afford the title compound N-(6-methoxyisoindolin-5-yl) morpholine-4-carboxamide (65 mg, 0.19 mmol, 99.07%) as a light brown solid. [M+1] + calcd:277.14; LCMS: 278.10

[0409] Step 4: N-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl) thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl) morpholine-4-carboxamide

[0410] To a solution of N-(6-methoxyisoindolin-5-yl) morpholine-4-carboxamide (27.00 mg, 0.097 mmol) in ACN (3.5 mL) was added 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl) thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (30 mg, 0.075 mmol), TCFH (42.02 mg, 0.15 mmol), NMI (36.89 mg, 0.45 mmol), and the reaction was stirred at 40oC for 30 min. The residue was purified by prep-HPLC, concentrated in vacuo, and dried to afford the title compound N-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl) thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl) morpholine-4-carboxamide (30 mg, 0.045 mmol, 60.71%) as a white solid. [M+1] + calcd:658.04; LCMS:659.20.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 7.74 (dd, J = 15.7, 6.0 Hz, 3H), 7.67 – 7.57 (m, 1H), 7.07 (d, J = 12.0 Hz, 1H), 6.24 (s, 1H), 4.89 – 4.51 (m, 4H), 3.80 (d, J = 22.7 Hz, 3H), 3.60 (dd, J = 9.7, 5.2 Hz, 4H), 3.39 (dd, J = 4.7, 2.2 Hz, 4H). 19F NMR (377 MHz, DMSO) δ -55.08 (d, J = 72.2 Hz).

[0411] Example 29: Synthesis of N-(2-(6-(chlorotrifluoroethylene)-4-((2,6- dichlorophenyl) thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl) piperidine-1-carboxamide

[0412] Step 1: tert-butyl 5-(1H-imidazole-1-carboxamido)-6-methoxyisoindoline-2- carboxylate

[0413] To a solution of tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (100 mg, 0.38 mmol) in DCM (3 mL) was added CDI (61.35 mg, 0.38 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was monitored by MS and TLC, and products were generated after the raw material reaction was completed. [M+1] + calcd:358.16; LCMS:359.10

[0414] Step 2: tert-butyl 5-methoxy-6-(piperidine-1-carboxamido) isoindoline-2- carboxylate

[0415] To a solution of tert-butyl 5-(1H-imidazole-1-carboxamido)-6- methoxyisoindoline-2-carboxylate (100 mg, 0.38 mmol) in DCM (3 mL) was added CDI (61.35 mg, 0.38 mmol), and the reaction was stirred at room temperature for 30 min. The reaction was concentrated in vacuo. The residue was purified using silica gel column chromatography, then concentrated in vacuo, and dried to afford the title compound tert-butyl 5-methoxy-6-(piperidine-1-carboxamido) isoindoline-2-carboxylate (100 mg, 0.26 mmol, 79.54%) as a white solid. [M+1] + calcd:375.22; LCMS:376.20.1H NMR (400 MHz, DMSO) δ 7.62 (d, J = 13.6 Hz, 1H), 7.55 (s, 1H), 6.97 (d, J = 5.8 Hz, 1H), 4.50 (dd, J = 15.9, 10.3 Hz, 4H), 3.80 (d, J = 3.1 Hz, 3H), 3.37 (dd, J = 10.7, 6.1 Hz, 6H), 1.56 (s, 3H), 1.53 – 1.19 (m, 10H).

[0416] Step 3: N-(6-methoxyisoindolin-5-yl) piperidine-1-carboxamide

[0417] To a solution of tert-butyl 5-methoxy-6-(piperidine-1-carboxamido) isoindoline-2- carboxylate (100 mg, 0.26 mmol) in DCM (1.5 mL) was added HCl / dioxane (1.5 mL) and the reaction was stirred at room temperature for 30 min. The reaction was directly concentrated in vacuo and dried to afford the title compound N-(6-methoxyisoindolin-5-yl) piperidine-1-carboxamide (95 mg, 0.26 mmol, 98.46%) as a white solid. [M+1] + calcd:275.16; LCMS:276.10.

[0418] Step 4: N-(2-(6-(chlorotrifluoroethylene)-4-((2,6-dichlorophenyl) thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl) piperidine-1-carboxamide

[0419] To a solution of N-(6-methoxyisoindolin-5-yl) piperidine-1-carboxamide (30.93 mg, 0.112 mmol) in dioxo-λ6-sulfanecarbonitrile (3.5 mL) was added 6- (chlorotrifluoroethylene)-4-((2,6-dichlorophenyl) thio)-2-oxo-1,2-dihydropyridine-3- carboxylic acid (30 mg, 0.075 mmol), TCFH (42.09 mg, 0.15 mmol) and NMI (36.95 mg, 0.45 mmol), then the reaction was stirred at 40oC for 40 min. The residue was purified by prep-HPLC, and dried to afford the title compound N-(2-(6-(chlorotrifluoroethylene)-4-((2,6- dichlorophenyl) thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl) piperidine-1-carboxamide (30 mg, 0.046 mmol, 60.89%) as a white solid. [M+1]+calcd:656.06; LCMS:657.20.1H NMR (400 MHz, DMSO) δ 12.84 (s, 1H), 7.76 (q, J = 4.7 Hz, 3H), 7.61 (dd, J = 5.7, 3.0 Hz, 1H), 7.59 (s, 1H), 7.05 (d, J = 12.2 Hz, 1H), 6.25 (s, 1H), 4.86 – 4.72 (m, 2H), 4.62 (dd, J = 22.0, 9.6 Hz, 2H), 3.80 (d, J = 22.5 Hz, 3H), 3.44 – 3.36 (m, 4H), 1.52 (dd, J = 28.4, 4.9 Hz, 6H).19F NMR (377 MHz, DMSO) δ -51.20 – -59.79 (m).

[0420] Example 30: Synthesis of N-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)morpholine- 4-carboxamide

[0421] Step 1: tert-butyl 5-aminoisoindoline-2-carboxylate

[0422] To a solution of 2-methylpropan-2-yl 5-amino-2,3-dihydro-1H-isoindole-2- carboxylate (200 mg, 0.85 mmol) in DCM (3 mL) was added CDI (207.7 mg, 0.85 mmol) at rt. Then the mixture was stirred at rt for 1 hour. Concentrated and the residue of 2- methylpropan-2-yl 5-[(imidazol-1-ylcarbonyl)amino]-2,3-dihydro-1H-isoindole-2- carboxylate (200 mg, 0.61 mmol, 71.35%) was used for next step without further purification. [M]+ calcd:328, found:329.

[0423] Step 2: tert-butyl 5-(morpholine-4-carboxamido)isoindoline-2-carboxylate

[0424] To a solution of 2-methylpropan-2-yl 5-[(imidazol-1-ylcarbonyl)amino]-2,3- dihydro-1H-isoindole-2-carboxylate (200 mg, 0.61 mmol) in DCM (3 mL) was added 1,4- oxazinane (0.11 mL, 1.22 mmol) at rt. Then the mixture was stirred at rt for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by chromatography (silica gel, PE:EA=1:1) to give tert-butyl 5-(morpholine-4-carboxamido)isoindoline-2-carboxylate (217 mg, 0.63 mmol, purity : 90%) as a white solid. [M]+ calcd:347, found:348.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.49 – 7.41 (m, 1H), 7.31 (d, J = 8.2 Hz, 1H), 7.20 – 7.13 (m, 1H), 4.56 – 4.47 (m, 4H), 3.62 – 3.57 (m, 4H), 3.44 – 3.39 (m, 4H), 1.45 (s, 9H).

[0425] Step 3: of N-(isoindolin-5-yl)morpholine-4-carboxamide

[0426] To a solution of tert-butyl 5-(morpholine-4-carboxamido)isoindoline-2- carboxylate (217 mg, 0.63 mmol) in DCM (1 mL) was added HCl / dioxane (1 mL) at rt. Then the mixture was stirred at rt for 1 hour. The mixture was concentrated in vacuo to give N- (isoindolin-5-yl)morpholine-4-carboxamide (217 mg, 0.88 mmol, purity:80%) as a yellow solid. [M]+ calcd:247. found: 248.

[0427] Step 4: N-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)morpholine-4-carboxamide

[0428] To a solution of N-(2,3-dihydro-1H-isoindol-5-yl)-1,4-oxazinane-4-carboxamide (64 mg, 0.26 mmol) in ACN (3 mL) was added 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (50 mg, 0.13 mmol) and NMI (62 mg, 0.26 mmol), TCFH (84 mg, 0.26 mmol) at rt. Then the mixture was stirred at 35 ℃ for 30 minutes. The mixture was filtered and purified by pre-HPLC to give N-(2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3- carbonyl)isoindolin-5-yl)morpholine-4-carboxamide (65 mg, 0.10 mmol, 39.87%) as a white solid. [M]+ calcd:628, found:629.1H NMR (400 MHz, DMSO-d6) δ 12.83 (s, 1H), 8.60 (d, J = 6.8 Hz, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.62 (t, J = 8.0 Hz, 1H), 7.50 (d, J = 44.4 Hz, 1H), 7.36 (t, J = 9.2 Hz, 1H), 7.24 (dd, J = 23.8, 8.4 Hz, 1H), 6.26 (s, 1H), 4.79 (d, J = 11.6 Hz, 2H), 4.70 – 4.56 (m, 2H), 3.60 (dd, J = 9.4, 4.6 Hz, 4H), 3.42 (dd, J = 10.4, 6.0 Hz, 4H).

[0429] Example 31: Synthesis of tert-butyl (2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)carbamate

[0431] To a solution of tert-butyl 5-nitroisoindoline-2-carboxylate (500.0 mg, 1.89 mmol) in DCM (20 mL) was added HCl-dioxane (4 M / L, 10 mL) at room temperature. The reaction suspension was stirred at room temperature for 12 hours with monitoring by LCMS. The solvent was removed by rotary evaporator. Then the mixture was filtered and collected to obtain 5-nitroisoindoline (300 mg, 1.89 mmol, 96.59%) as a white solid (HCl salt). The product was used without further purification. [M]+calcd: 164.06, found: 165.00.1H NMR (400 MHz, DMSO) δ 10.21 (s, 2H), 8.31 (s, 1H), 8.23 (dt, J = 9.1, 4.6 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 4.61 (d, J = 6.4 Hz, 4H).

[0432] Step 2: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5- nitroisoindoline-2-carbonyl)pyridin-2(1H)-one

[0433] To a solution of 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylic acid (124.2 mg, 0.31 mmol), 5-nitroisoindoline (50.9 mg, 0.31 mmol) in CH3CN (10.0 mL) were added NMI (75.5 mg, 0.92 mmol), and the reaction was followed by the addition of TCFH (129.1 mg, 0.46 mmol) at 00C. The reaction mixture was stirred at 35 ℃ overnight. LCMS and TLC showed the reaction was completed, and then the reaction mixture was directly subjected to silica gel column chromatography (petroleum ether / ethyl acetate as eluent) and prep-HPLC to afford 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-nitroisoindoline-2-carbonyl)pyridin-2(1H)-one (120.0 mg, 0.31 mmol, 70.80%) as a white solid. [M]+calcd: 544.96, found: 546.25,548.25.

[0434] Step 3: 3-(5-aminoisoindoline-2-carbonyl)-6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)pyridin-2(1H)-one

[0435] To a solution of 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5- nitroisoindoline-2-carbonyl)pyridin-2(1H)-one (120.3 mg, 0.22 mmol) in EtOH (4.0 mL) and H2O (1.0 Ml) was added Fe (61.4 mg, 1.10 mmol) and NH4Cl (58.8 mg, 1.10 mmol). The suspension was degassed under vacuum and purged with N2 for 3 times. The mixture was stirred at 75oC for 2.0 hours. The reaction was complete determined by LCMS. The suspension was filtered and the filter cake was washed with EtOH (15.0 mL X 3). The combined filtrates were further purified by silica gel column chromatography (DCM / MeOH as eluent) to afford 3-(5-aminoisoindoline-2-carbonyl)-6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)pyridin-2(1H)-one (100.0 mg, 0.22 mmol, yield: 87.96%) as a white solid. [M]+calcd: 514.98, found:516.30,518.30.

[0436] Step 4: tert-butyl (2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)carbamate

[0437] To a solution of 3-(5-aminoisoindoline-2-carbonyl)-6-(chlorodifluoromethyl)-4- ((2,6-dichlorophenyl)thio)pyridin-2(1H)-one (39.8 mg, 0.077 mmol) in THF (5.0 mL) was added (Boc)2O (16.8 mg, 0.077 mmol) at 00C. The mixture was stirred at 500C overnight. LCMS and TLC showed the reaction was completed and then the reaction mixture was directly subjected to silica gel column chromatography (petroleum ether / ethyl acetate as eluent) and further purified with prep-HPLC to afford tert-butyl (2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3- carbonyl)isoindolin-5-yl)carbamate (15 mg, 0.077 mmol, 31.58%) as a white solid. [M]+calcd: 615.04, found:616.30,618.30.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 9.41 (d, J = 12.1 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.67 – 7.58 (m, 1.5H), 7.48 (s, 0.5H), 7.35 (d, J = 8.2 Hz, 0.5H), 7.28 (d, J = 5.6 Hz, 1.0H), 7.22 (d, J = 8.3 Hz, 0.5H), 6.25 (s, 1H), 4.79 (d, J = 15.3 Hz, 2H), 4.73 – 4.54 (m, 2H), 1.47 (d, J = 6.5 Hz, 9H).

[0438] Example 32: Synthesis of 4-{[3-(aminomethyl)-2,6-dichlorophenyl]sulfanyl}- 6-(chlorodifluoromethyl)-3-{[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one

[0439] Step 1: 2-methylpropan-2-yl 6-hydroxy-5-nitro-2,3-dihydro-1H-isoindole-2- carboxylate

[0440] To a solution of 2-methylpropan-2-yl 6-bromo-5-nitro-2,3-dihydro-1H-isoindole- 2-carboxylate (300.00 mg, 0.87 mmol) and t-Bu XPhos (90.43 mg, 0.21 mmol) in H2O (4 mL) and dioxane (20 mL) was added KOH (97.91 mg, 1.75 mmol), the reaction was stirred 100oC for 1 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel to 2- methylpropan-2-yl 6-hydroxy-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate (150.00 mg, 0.54 mmol, 61.22%) as a white solid. [M]+ calcd:280,found:281.

[0441] Step 2: 2-methylpropan-2-yl 6-methoxy-5-nitro-2,3-dihydro-1H-isoindole-2- carboxylate

[0442] To a solution of 2-methylpropan-2-yl 6-hydroxy-5-nitro-2,3-dihydro-1H- isoindole-2-carboxylate (400.00 mg, 1.43 mmol) and Cs2CO3 (325.49 mg, 1.00 mmol) in THF (5 mL) and MeOH (2.5 mL) was added MeI (0.09 mL, 1.43 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep-HPLC to give 2-methylpropan-2-yl 6-methoxy-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate (300.00 mg, 1.02 mmol, 71.43%) as a white solid. [M]+ calcd:294,found:295.

[0443] Step 3: 2-methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)- 2,3-dihydro-1H-isoindole-2-carboxylate

[0444] To a solution of 2-methylpropan-2-yl 6-methoxy-5-nitro-2,3-dihydro-1H- isoindole-2-carboxylate (400.00 mg, 1.36 mmol) in MeOH (20 mL) was added Pd / C 10% (288.13 mg, 0.27 mmol), the reaction was stirred at rt for 1 h under H2. LCMS showed the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give 2-methylpropan-2-yl 5-amino-6-methoxy-2,3-dihydro-1H-isoindole- 2-carboxylate (300.00 mg, 1.13 mmol, 83.51%) as a white solid. [M]+ calcd:264,found:265

[0445] Step 4: 2-methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)- 2,3-dihydro-1H-isoindole-2-carboxylate

[0446] To a solution of 2-methylpropan-2-yl 5-amino-6-methoxy-2,3-dihydro-1H- isoindole-2-carboxylate (150.00 mg, 0.57 mmol) in DCM (10 mL) was added N-(3-chloropropyl)-1-oxomethanimine (67.84 mg, 0.57 mmol) dropwise at 0oC under N2, stirred at rt for 18 h, then concentrated under reduced pressure and dissolved in THF (10 mL), the reaction was cooled to 0oC and added NaH (68.10 mg, 1.70 mmol) and stirred at rt for 1 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, the organic layer was concentrated under reduced pressure to give 2- methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole- 2-carboxylate (100.00 mg, 0.29 mmol, 50.72%) as a white solid. [M]+ calcd:347,found:348

[0447] Step 5: 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H- isoindole

[0448] A solution of 2-methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)- 2,3-dihydro-1H-isoindole-2-carboxylate (100.00 mg, 0.29 mmol) in TFA (1 mL) and DCM (3 mL) was stirred at rt for 1h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep-HPLC to give 6-methoxy-5-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (70.00 mg, 0.28 mmol, 98.34%) as a white solid. [M]+ calcd:247,found:248

[0449] Step 6: 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6-methoxy-5-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H- pyridin-4-yl]sulfanyl}benzene-1-carbonitrile

[0450] To a solution of 6-(chlorodifluoromethyl)-4-[(2,6-dichloro-3- cyanophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (100.00 mg, 0.24 mmol), 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (58.10 mg, 0.24 mmol) and NMI (115.60 mg, 1.41 mmol) in MeCN (5 mL) was added TCFH (85.52 mg, 0.31 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep- HPLC to give 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6-methoxy-5-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4- yl]sulfanyl}benzene-1-carbonitrile (70.00 mg, 0.11 mmol, 45.49%) as a white solid. [M]+ calcd:654,found:655

[0451] Step 7: 2-methylpropan-2-yl {[(2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3- {[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}- 2-oxo-1H-pyridin-4-yl]sulfanyl}phenyl)methyl]amino}methanoate

[0452] To a solution of 2,4-dichloro-3-{[6-(chlorodifluoromethyl)-3-{[6-methoxy-5-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-2-oxo-1H-pyridin-4- yl]sulfanyl}benzene-1-carbonitrile (40.00 mg, 0.06 mmol) in THF (4 mL)was added Raney- Ni (14.17 mg, 0.25 mmol), the reaction was stirred at rt for 18 h under H2. LCMS showed the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give 2-methylpropan-2-yl {[(2,4-dichloro-3-{[6-(chlorodifluoromethyl)- 3-{[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}- 2-oxo-1H-pyridin-4-yl]sulfanyl}phenyl)methyl]amino}methanoate (15.00 mg, 0.02 mmol, 32.35%) as a white solid. [M]+ calcd:759,found:759

[0453] Step 8: 4-{[3-(aminomethyl)-2,6-dichlorophenyl]sulfanyl}-6- (chlorodifluoromethyl)-3-{[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro- 1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one

[0454] A solution of 2-methylpropan-2-yl {[(2,4-dichloro-3-{[6-(chlorodifluoromethyl)- 3-{[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}- 2-oxo-1H-pyridin-4-yl]sulfanyl}phenyl)methyl]amino}methanoate (5.00 mg, 7.00 μmol) in TFA (1 mL) and DCM (3 mL) was stirred at rt for 1 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep- HPLC to give 4-{[3-(aminomethyl)-2,6-dichlorophenyl]sulfanyl}-6-(chlorodifluoromethyl)- 3-{[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}- 1,2-dihydropyridin-2-one (1.50 mg, 2.00 μmol, 34.56%) as a white solid. [M]+ calcd:658,found:659.1H NMR (400 MHz, DMSO) δ 7.73 (d, J = 3.0 Hz, 2H), 7.17 – 7.02 (m, 2H), 6.40 (d, J = 9.6 Hz, 1H), 5.89 (s, 1H), 4.73 (d, J = 32.9 Hz, 4H), 3.87 (s, 2H), 3.73 (s, 3H), 3.44 – 3.37 (m, 2H), 3.25 – 3.18 (m, 2H), 1.91 (n, J = 11.4, 5.6 Hz, 2H).19F NMR (377 MHz, DMSO) δ -54.52 (s). Example 33: Synthesis of 1-(2-(4-((2-chloro-6-ethylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one

[0455] Step 1: ethyl 4-((2-chloro-6-vinylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo- 1,2-dihydropyridine-3-carboxylate

[0456] To a solution of ethyl 4-((2-chloro-6-iodophenyl)thio)-6-(chlorodifluoromethyl)- 2-oxo-1,2-dihydropyridine-3-carboxylate (400 mg, 0.77 mmol) in dioxane - water (6 mL) were added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (177.68 mg, 1.15 mmol), Pd(dppf)Cl2(56.27 mg, 0.08 mmol) and Na2CO3(244.54 mg, 2.31 mmol) respectively. The resulting mixture was heated to 90oC under N2 for 8 h. After which the reaction mixture was concentrated under pressure and purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to obtain ethyl 4-((2-chloro-6-vinylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (150 mg, 0.34 mmol, 44.91%) as a brown solid. [M]+ calcd: 419, found: 420.

[0457] Step 2: ethyl ethyl 4-((2-chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)- 2-oxo-1,2-dihydropyridine-3-carboxylate

[0458] To the solution of ethyl 4-((2-chloro-6-vinylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (130 mg, 0.31 mmol) in EtOH (30 mL) was added 10% Pd / C (50 mg, 0.47 mmol), it was stirred at rt for 24 h. The reaction was filtered and concentrated under pressure, the residue was purified by prep-TLC (PE / EA = 10:1) to give ethyl 4-((2-chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylate (50 mg, 0.18 mmol, 41.00%) as a yellow oil. [M]+ calcd: 421, found: 422.1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 7.63 – 7.54 (m, 2H), 7.50 (dd, J = 7.5, 1.6 Hz, 1H), 6.11 (s, 1H), 4.35 (q, J = 7.1 Hz, 2H), 2.81 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.5 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.72 (s).

[0459] Step 3: 4-((2-chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2- dihydropyridine-3-carboxylic acid

[0460] To a solution of ethyl 4-((2-chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)- 2-oxo-1,2-dihydropyridine-3-carboxylate (50 mg, 0.12 mmol) in H2O (0.50 mL) and THF (2 mL) was added LiOH.H2O (24.84 mg, 0.59 mmol). The resulting mixture was heated to rt for 48 h. After which the reaction mixture was quenched by ice water, extracted with DCM. The aqueous was adjusted PH=2 with HCl (3 M), extracted with EA twice, the combined organiclayers were washed with brine, dried over Na2SO4, filtered and concentrated to give 4-((2- chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (40 mg, 0.10 mmol, 85.69%) as a white solid. [M]+ calcd: 393. found: 394.1H NMR (400 MHz, DMSO) δ 7.59 – 7.40 (m, 4H), 5.77 (s, 1H), 2.77 (dd, J = 15.0, 7.3 Hz, 2H), 1.07 (t, J = 7.5 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.31 (s).

[0461] Step 4: 1-(2-(4-((2-chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo- 1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one

[0462] To the solution of 4-((2-chloro-6-ethylphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (45 mg, 0.11 mmol) in MeCN (3 mL) were added 1-(isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (49.60 mg, 0.23 mmol), NMI (0.03 mL, 0.40 mmol) and TCFH (41.70 mg, 0.15 mmol) respectively, it was stirred at rt under N2for 18 h. After which the reaction mixture was quenched by ice water and extracted with EA twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by prep-HPLC to obtain 1-(2-(4-((2-chloro-6- ethylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3- carbonyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (24 mg, 0.04 mmol, 35.43%) as a white solid. [M]+ calcd: 592, found: 593.1H NMR (400 MHz, DMSO) δ 12.73 (s, 1H), 7.62 – 7.58 (m, 1H), 7.58 – 7.53 (m, 1H), 7.50 (dd, J = 7.5, 1.6 Hz, 1H), 7.35 – 7.32 (m, 1H), 7.31 – 7.26 (m, 1H), 7.26 – 7.19 (m, 1H), 6.61 – 6.55 (m, 1H), 6.18 (s, 1H), 4.90 – 4.78 (m, 2H), 4.74 – 4.57 (m, 2H), 3.64 – 3.56 (m, 2H), 3.25 – 3.20 (m, 2H), 2.87 – 2.79 (m, 2H), 1.94 (q, J = 11.6, 5.8 Hz, 2H), 1.11 – 1.06 (m, 3H).19F NMR (377 MHz, DMSO) δ -55.17 (d, J = 19.9 Hz), -55.26 (s).

[0463] Example 34: Synthesis of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- (hydroxymethyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one

[0464] Step 1: 6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5-carbaldehyde12

[0465] To a solution of tert-butyl 5-formyl-6-(2-oxotetrahydropyrimidin-1(2H)- yl)isoindoline-2-carboxylate (100 mg, 0.29 mmol) in DCM (10 mL) was added HCl-dioxane (1.5 mL) at 0oC and the resulting mixture was stirred at room temperature for 3 hrs. The solvent was removed by vacuum and used directly in the next step.

[0466] Step 2: 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5- carbaldehyde

[0467] To a mixture of 6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5-carbaldehyde (80 mg, 0.23 mmol) and 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carboxylic acid (74.5 mg, 0.25 mmol) in MeCN (10 mL) were added TCFH (105.4 mg, 0.38 mmol), NMI (123 mg, 1.5 mmol) at room temperature under N2 atmosphere and the mixture was stirred at room temperature for 16 hrs. The reaction was purified by Prep-HPLC to afford 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5- carbaldehyde (90 mg, 0.14 mmol, yield: 62.5%) as a white solid. [M+H]+calcd, 627; found, 627 (M+H)+.

[0468] Step 3: 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-(hydroxymethyl)isoindolin-5-yl)tetrahydropyrimidin- 2(1H)-one

[0469] To a mixture of 2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-5- carbaldehyde (90 mg, 0.14 mmol) in MeOH (10 mL) was added NaBH4(16 mg, 0.42 mmol) at 0oC under N2atmosphere and the mixture was stirred at room temperature for 30 min. The reaction was purified by Prep-HPLC to afford 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-(hydroxymethyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one (20.6 mg, 0.03 mmol, yield: 23.4%) as a white solid. [M+H]+calcd, 629; found, 629 (M+H)+.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 7.75 (d, J = 8.0 Hz, 2H), 7.67 – 7.57 (m, 1H), 7.46 (d, J = 27.1 Hz, 1H), 7.20 (d, J = 26.8 Hz, 1H), 6.57 (d, J = 6.2 Hz, 1H), 6.23 (s, 1H), 5.07 (dt, J = 23.3, 5.6 Hz, 1H), 4.91 – 4.56 (m, 4H), 4.48 – 4.30 (m, 2H), 3.63 – 3.49 (m, 1H), 3.28 – 3.21 (m, 2H), 2.00 – 1.89 (m, 2H).19F NMR (377 MHz, DMSO) δ -55.09 (d, J = 53.7 Hz).

[0470] Example 35: Synthesis of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- ((dimethylamino)methyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one

[0471] Step 1: 5-bromo-6-nitroisoindoline-1,3-dione

[0472] To a solution of 5-bromoisoindoline-1,3-dione (50.0 g, 0.22 mol) in H2SO4 (400 mL) was added HNO3 (11.1 mL) slowly, The mixture was stirred at 50oC for 16 hr. Pour the reaction mixture onto ice (1.5 Kg). Filter the precipitate. Wash the precipitate several times with water to afford the 5-bromo-6-nitroisoindoline-1,3-dione (41.0 g, 0.15 mol, 69%) as a white solid. LCMS (m / z): [M-H]- calcd, 269,271; found, 269,271 (M-H)-.

[0473] Step 2: 5-bromo-6-nitroisoindoline

[0474] To a solution of 5-bromo-6-nitroisoindoline-1,3-dione (41.0 g, 151.9 mmol) in THF (100 mL) was added BH3 (850 mL, 1M in THF). and the reaction was stirred at 80°C for 16 hr. The residue was diluted with H2O and extracted with EA , the aqueous phase was adjust pH to 7~8, and extracted with EA twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) to afford 5-bromo-6- nitroisoindoline (12.0 g, 49.5 mmol, 32.6%) as a yellow solid. LCMS (m / z): [M+H]+calcd, 243,245; found, 243,245 (M+H)+.

[0475] Step 3: tert-butyl 5-bromo-6-nitroisoindoline-2-carboxylate

[0476] To a solution of 5-bromo-6-nitroisoindoline (12.0 g, 49.5 mmol) in DCM (150 mL) were added TEA (20.2 mL, 148.5 mmol), (Boc)2O (16.2 g, 74.3 mmol) and DMAP (1.83 g, 14.9 mmol). and the reaction was stirred at room temperature for 5 hrs. The residue was diluted with H2O and extracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-50% EtOAc in PE) to afford tert-butyl 5-bromo-6- nitroisoindoline-2-carboxylate (12.0 g, 35.0 mmol, 70.7%) as a yellow solid.1H NMR (400 MHz, DMSO) δ 8.02 (d, J = 8.2 Hz, 1H), 7.89 (d, J = 6.8 Hz, 1H), 4.62 (dd, J = 15.4, 8.7 Hz, 4H), 1.46 (d, J = 6.0 Hz, 9H).

[0477] Step 4: tert-butyl 5-amino-6-bromoisoindoline-2-carboxylate

[0478] To a solution of tert-butyl 5-bromo-6-nitroisoindoline-2-carboxylate (3.0 g, 8.7 mmol) in EtOH (30 mL) and H2O (6 mL) were added Fe (2.4 g, 43.5 mmol), NH4Cl (4.7 g, 87.0 mmol). The reaction was stirred at 80oC for 3 hrs. The residue was diluted with H2O andextracted with EA, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-15% MeOH in DCM) to afford tert-butyl 5-amino-6-bromoisoindoline-2- carboxylate (2.2 g, 7.0 mmol, 80.5%) as a yellow solid. [M+H]+calcd, 313,315; found, 313,315 (M+H)+.

[0479] Step 5: tert-butyl 5-bromo-6-(2-oxotetrahydropyrimidin-1(2H)- yl)isoindoline-2-carboxylate

[0480] To a solution of 2-(4-bromophenyl)propan-2-amine (2.0 g, 6.4 mmol) in DCM (20 mL) was added 1-chloro-3-isocyanatopropane (914 mg, 7.7 mmol) and the reaction was stirred at room temperature for 16 hrs. The reaction was removed by vacuum and THF (25 mL) was added in the reaction, after NaH (768 mg, 19.2 mmol) was added and stirred at 50oC for 5 hrs. After MeOH was added, The reaction mixture was concentrated and the residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to afford tert-butyl 5- bromo-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-2-carboxylate (1.2 g, 3.03 mmol, yield: 47.3%) as a yellow solid. [M+H]+calcd, 396,398; found, 396,398 (M+H)+

[0481] Step 6: tert-butyl 5-(2-oxotetrahydropyrimidin-1(2H)-yl)-6-vinylisoindoline-2- carboxylate

[0482] To a mixture of tert-butyl 5-bromo-6-(2-oxotetrahydropyrimidin-1(2H)- yl)isoindoline-2-carboxylate (1.2 g, 3.04 mmol) and 4,4,5,5-tetramethyl-2-vinyl-1,3,2- dioxaborolane (935.7 mg, 6.08 mmol) in dioxane (10 mL) and H2O (2 mL) were added Pd(dppf)Cl2 (219.3 mg, 0.3 mmol), K2CO3 (1.26 g, 9.12 mmol) at room temperature under N2 atmosphere and the mixture was stirred at 90oC for 5 hrs. The reaction was quenched with water and extracted with EtOAc for three times. The combined organic layers were dried overanhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to afford tert-butyl 5-(2- oxotetrahydropyrimidin-1(2H)-yl)-6-vinylisoindoline-2-carboxylate (800 mg, 2.33 mmol, yield: 76.7%) as a yellow solid. [M+H]+calcd, 344; found, 344 (M+H)+.

[0483] Step 7: tert-butyl 5-formyl-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline- 2-carboxylate

[0484] To a mixture of tert-butyl 5-(2-oxotetrahydropyrimidin-1(2H)-yl)-6- vinylisoindoline-2-carboxylate (800 mg, 2.33 mmol) and in MeOH (10 mL) were added K2OsO4(110.4 mg, 0.3 mmol), NaIO4(3.0 g, 14.0 mmol) at room temperature under N2atmosphere and the mixture was stirred at room temperature for 2 hrs. The reaction was quenched with water and extracted with EtOAc for three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to afford tert-butyl 5- formyl-6-(2-oxotetrahydropyrimidin-1(2H)-yl)isoindoline-2-carboxylate (700 mg, 2.02 mmol, yield: 86.7%) as a white solid. [M+H]+calcd, 346; found, 346 (M+H)+.1H NMR (400 MHz, MeOD) δ 10.35 (s, 1H) 7.66 – 7.61 (m, 2H), 5.15 – 4.88 (m, 4H), 3.93 – 3.77 (m, 1H), 3.56 – 3.42 (m, 3H), 2.27 – 2.06 (m, 2H), 1.46 (d, J = 6.0 Hz, 9H).

[0485] Step 8: tert-butyl 5-((dimethylamino)methyl)-6-(2-oxotetrahydropyrimidin- 1(2H)-yl)isoindoline-2-carboxylate compound with 1-(6- ((dimethylamino)methyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (1:1)

[0486] To a mixture of tert-butyl 5-formyl-6-(2-oxotetrahydropyrimidin-1(2H)- yl)isoindoline-2-carboxylate (240 mg, 0.70 mmol) and dimethylamine (0.7 mL, 1.4 mmol, 2 mol in MeOH) in MeOH (10 mL) were added AcOH (0.05 mL) at room temperature underN2 atmosphere and the mixture was stirred at room temperature for 30 min. After was added NaBH3CN (132.3 mg, 2.1 mmol) and the mixture was stirred at room temperature for 4 hrs. The reaction was quenched with water and extracted with EtOAc for three times. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to dryness. The residue was purified by flash chromatography (silica gel, 0-10% MeOH in DCM) to afford tert-butyl 5-((dimethylamino)methyl)-6-(2-oxotetrahydropyrimidin-1(2H)- yl)isoindoline-2-carboxylate compound with 1-(6-((dimethylamino)methyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one (1:1) (80 mg, 0.21 mmol, yield: 30.6%) as a white solid. [M+H]+calcd, 375; found, 375 (M+H)+

[0487] Step 9: 1-(6-((dimethylamino)methyl)isoindolin-5-yl)tetrahydropyrimidin- 2(1H)-one

[0488] To a solution of tert-butyl 5-((dimethylamino)methyl)-6-(2- oxotetrahydropyrimidin-1(2H)-yl)isoindoline-2-carboxylate compound with 1-(6- ((dimethylamino)methyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (1:1) (80 mg, 0.21 mmol) in DCM (3 mL) was added HCl-dioxane (1 mL) at 0oC and the resulting mixture was stirred at room temperature for 3 hrs. The solvent was removed by vacuum and used directly in the next step.

[0489] Step 10: 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)-6-((dimethylamino)methyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one

[0490] To a mixture of 1-(6-((dimethylamino)methyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one (70 mg, 0.25 mmol) and 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (74.5 mg, 0.25 mmol) in MeCN (10 mL) were added TCFH (105.4 mg, 0.38 mmol), NMI (123 mg, 1.5 mmol) at room temperature under N2 atmosphere and the mixture was stirred at room temperature for 16 hrs. The reaction was purified by Prep-HPLC to afford 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6- ((dimethylamino)methyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (9.5 mg, 0.015 mmol, yield: 5.8%) as a white solid. [M+H]+calcd, 656; found, 656(M+H)+.1H NMR (400 MHz, CD3OD) δ 7.66 – 7.61 (m, 2.5H), 7.60 – 7.49 (m, 2H), 7.45 (s, 0.5H), 6.31 (d, J = 5.4 Hz, 1H), 5.15 – 4.88 (m, 4H), 4.43 (dd, J = 12.9, 5.9 Hz, 1H), 4.13 – 4.00 (m, 1H), 3.93 – 3.77 (m, 1H), 3.56 – 3.42 (m, 3H), 3.00 (d, J = 5.1 Hz, 3H), 2.78 (d, J = 15.9 Hz, 3H), 2.27 – 2.06 (m, 2H).19F NMR (377 MHz, CD3OD) δ -57.79 (s)

[0491] Example 36: Synthesis of N-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)piperidine- 1-carboxamide

[0492] Step 1: tert-butyl 5-(1H-imidazole-1-carboxamido)isoindoline-2-carboxylate

[0493] To a solution of 2-methylpropan-2-yl 5-amino-2,3-dihydro-1H-isoindole-2- carboxylate (200 mg, 0.85 mmol) in DCM (3 mL) was added CDI (207.7 mg, 0.85 mmol) at rt. Then the mixture was stirred at rt for 1 hour. Concentrated and the residue of 2- methylpropan-2-yl 5-[(imidazol-1-ylcarbonyl)amino]-2,3-dihydro-1H-isoindole-2- carboxylate (200 mg, 0.61 mmol, 71.35%) was used for next step without further purification. [M]+ calcd:328, found:329.

[0494] Step 2: tert-butyl 5-(piperidine-1-carboxamido)isoindoline-2-carboxylate

[0495] To a solution of 2-methylpropan-2-yl 5-[(imidazol-1-ylcarbonyl)amino]-2,3- dihydro-1H-isoindole-2-carboxylate (200 mg, 0.61 mmol) in DCM (3 mL) was added hexahydropyridine (0.12 mL, 1.21 mmol) at rt. Then the mixture was stirred at rt for 30 minutes. The mixture was concentrated in vacuo. The residue was purified by chromatography (silica gel, PE: EA=1:1) to give tert-butyl 5-(piperidine-1- carboxamido)isoindoline-2-carboxylate (219 mg, 0.63 mmol, purity:80%) as a white solid.δ 8.45 (s, 1H), 7.48 – 7.41 (m, 1H), 7.34 – 7.29 (m, 1H), 7.18 – 7.11 (m, 1H), 4.57 – 4.45 (m, 4H), 3.43 – 3.38 (m, 4H), 1.64 – 1.47 (m, 6H), 1.45 (s, 9H).

[0496] Step 3: N-(isoindolin-5-yl)piperidine-1-carboxamide

[0497] To a solution of tert-butyl 5-(piperidine-1-carboxamido)isoindoline-2-carboxylate (219 mg, 0.63 mmol) in DCM (1 mL) was added HCl / dioxane (1 mL,4 mol / L) at rt. Then the mixture was stirred at rt for 1 hour. LCMS showed the reaction was completed. The mixture was concentrated in vacuo to give N-(isoindolin-5-yl)piperidine-1-carboxamide (237 mg, 0.97 mmol, purity:80%) as a yellow solid. [M]+ calcd:245, found:246.

[0498] Step 4: N-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo- 1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)piperidine-1-carboxamide

[0499] To a solution of N-(isoindolin-5-yl)piperidine-1-carboxamide (68 mg, 0.28 mmol) in ACN (3 mL) was added 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo- 1H-pyridine-3-carboxylic acid (50 mg, 0.13 mmol) and NMI (62 mg, 0.28 mmol), TCFH (84 mg, 0.28 mmol) at rt. Then the mixture was stirred at 35 ℃ for 30 minutes. The mixture was filtered and purified by prep-HPLC to give N-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)piperidine-1- carboxamide (45 mg, 0.07 mmol, 25.86%) as a white solid. [M]+ calcd:626, found:627.1H NMR (400 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.50 (d, J = 7.3 Hz, 1H), 7.76 (d, J = 8.1 Hz, 2H), 7.62 (t, J = 8.1 Hz, 1H), 7.50 (d, J = 46.0 Hz, 1H), 7.35 (t, J = 8.4 Hz, 1H), 7.22 (dd, J =24.7, 8.3 Hz, 1H), 6.26 (s, 1H), 4.89 – 4.44 (m, 4H), 3.41 (dd, J = 11.0, 6.7 Hz, 5H), 1.71 – 1.36 (m, 6H).19F NMR (377 MHz, DMSO) δ -55.21 (s).

[0500] Example 37: Synthesis of 1-(2-(4-((2-chloro-6-cyclopropylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one

[0501] Step 1: 2-chloro-6-iodobenzenethiol

[0502] At -10oC, to the solution of 2-chloro-6-iodoaniline (506 mg, 1.99 mmol) in HCl (1.60 mL, 4.80 mmol) was added NaNO2 (165.27 mg, 2.39 mmol) with H2O (2 mL), the reaction mixture was stirred at rt for 1h. After that, potassium O-ethyl carbonodithioate (542.91 mg, 3.39 mmol) was added to the reaction mixture dropwise, it was stirred at 60oC for another 1h. After being cooled down to room temperature, the reaction mixture was quenched by ice water, extracted with DCM and saturated NaHCO3, the combined organic layers were washed with H2O, dried over Na2SO4, filtered and concentrated to give the crudeintermediate product. Then to the solution of KOH (559.98 mg, 9.98 mmol) in EtOH (11 mL) and H2O (2 mL) was added the intermediate product, the resulting mixture was heated to 80oC for 18 h. After being cooled down to room temperature, the reaction mixture was quenched by ice water and adjusted PH=2 with HCl (3 M), extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by column chromatography on silica gel (0~10% ethyl acetate in petroleum ether) to give 2-chloro-6-iodobenzenethiol (155 mg, 0.57 mmol, 28.70%) as a white solid.1H NMR (400 MHz, DMSO) δ 7.81 (d, J = 7.6 Hz, 1H), 7.58 – 7.48 (m, 1H), 6.91 (t, J = 7.4 Hz, 1H), 5.77 (s, 1H).

[0503] Step 2: ethyl 4-((2-chloro-6-iodophenyl)thio)-6-(chlorodifluoromethyl)-2-oxo- 1,2-dihydropyridine-3-carboxylate

[0504] To a solution of 2-chloro-6-iodobenzenethiol (1.00 g, 3.70 mmol) in EtOH (20 mL) were added ethyl 4-chloro-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3- carboxylate (1.01 g, 3.70 mmol) and TEA (1.54 mL, 11.09 mmol) respectively. The resulting mixture was heated to 80oC under N2 for 18 h. After which the reaction mixture was concentrated under pressure and purified by flash column chromatography (silica gel, 0~10%, ethyl acetate in petroleum ether) to obtain ethyl 4-((2-chloro-6-iodophenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (1.10 g, 2.17 mmol, 58.80%) as a white solid. [M]+ calcd: 519, found: 520.1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 8.12 (d, J = 7.8 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 6.18 (s, 1H), 4.40 – 4.35 (m, 2H), 1.34 (t, J = 7.1 Hz, 3H).

[0505] Step 3: ethyl 4-((2-chloro-6-cyclopropylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate

[0506] To a solution of ethyl 4-((2-chloro-6-iodophenyl)thio)-6-(chlorodifluoromethyl)- 2-oxo-1,2-dihydropyridine-3-carboxylate (400 mg, 0.77 mmol) in dioxane - water (6 mL) were added cyclopropylboronic acid (165.16 mg, 1.92 mmol), Pd(dppf)Cl2 (56.27 mg, 0.08 mmol) and Na2CO3(244.54 mg, 2.31 mmol) respectively. The resulting mixture was heated to 90oC under N2 for 12 h. After which the reaction mixture was concentrated under pressure and purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to obtain the crude product ethyl 4-((2-chloro-6-cyclopropylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (200 mg) as a white solid. [M]+ calcd: 433. found: 434.

[0507] Step 4: 4-((2-chloro-6-cyclopropylphenyl)thio)-6-(chlorodifluoromethyl)-2- oxo-1,2-dihydropyridine-3-carboxylic acid

[0508] To a solution of ethyl 4-((2-chloro-6-cyclopropylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (150 mg, 0.34 mmol) in H2O (1 mL) and THF (4 mL) was added LiOH.H2O (72.46 mg, 1.73 mmol). The resulting mixture was stirred at rt-40oC for 24 h. After which the reaction mixture was quenched by ice water, extracted with DCM. The aqueous phase was adjusted PH=2 with HCl (3 M) and extracted with EA twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by prep-HPLC to give 4-((2-chloro-6-cyclopropylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3- carboxylic acid (50 mg, 0.12 mmol, 35.64%) as a white solid. [M]+ calcd: 405, found: 406.1H NMR (400 MHz, DMSO) δ 7.58 – 7.46 (m, 2H), 7.08 (dd, J = 7.6, 1.3 Hz, 1H), 5.97 (s, 1H), 2.31 – 2.25 (m, 1H), 0.95 – 0.86 (m, 2H), 0.72 – 0.63 (m, 2H).19F NMR (377 MHz, DMSO) δ -55.73 (s).

[0509] Step 5: 1-(2-(4-((2-chloro-6-cyclopropylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5- yl)tetrahydropyrimidin-2(1H)-one

[0510] To the solution of 4-((2-chloro-6-cyclopropylphenyl)thio)-6- (chlorodifluoromethyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (50 mg, 0.12 mmol) in MeCN (3 mL) were added 1-(isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (32.09 mg, 0.15 mmol), NMI (0.03 mL, 0.43 mmol) and TCFH (44.96 mg, 0.16 mmol) respectively, it was stirred at rt under N2for 18 h. After which the reaction mixture was quenched by ice water and extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by prep-HPLC to obtain 1- (2-(4-((2-chloro-6-cyclopropylphenyl)thio)-6-(chlorodifluoromethyl)-2-oxo-1,2- dihydropyridine-3-carbonyl)isoindolin-5-yl)tetrahydropyrimidin-2(1H)-one (8.20 mg, 0.01 mmol, 11.00%) as a white solid. [M]+ calcd: 604, found: 605.1H NMR (400 MHz, DMSO) δ 12.70 (s, 1H), 7.58 – 7.48 (m, 2H), 7.34 (d, J = 6.5 Hz, 1H), 7.29 – 7.18 (m, 2H), 7.12 (d, J = 7.7 Hz, 1H), 6.58 (d, J = 8.7 Hz, 1H), 6.23 (s, 1H), 4.92 – 4.77 (m, 2H), 4.74 – 4.55 (m, 2H), 3.65 – 3.56 (m, 2H), 3.25 – 3.19 (m, 2H), 2.35 – 2.29 (m, 1H), 1.99 – 1.91 (m, 2H), 0.99 – 0.87 (m, 2H), 0.75 – 0.65 (m, 2H).19F NMR (377 MHz, DMSO) δ -54.84 – -55.44 (m).

[0511] Example 38: Synthesis of 2-(4-((2,6-dichlorophenyl)thio)-2-oxo-6- (trifluoromethyl)-1,2-dihydropyridine-3-carbonyl)isoindoline-5-carbonitrile

[0512] Step 1: tert-butyl 5-cyanoisoindoline-2-carboxylate

[0513] To a solution of tert-butyl 5-bromoisoindoline-2-carboxylate (1.2 g, 4.02 mmol) in DMF (10 mL), then was added Zn(CN)2(0.95 g, 8.05 mmol) and Pd(PPh3)4(0.5 g, 0.41 mmol), the reaction mixture was stirred at 80oC overnight under N2. Diluted with H2O (30 ml), extracted with EtOAc (50 ml x 3), the combined organic phase was washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by column chromatography on silica gel (DCM in MeOH =20% ~25%) to obtain the desired product tert-butyl 5-cyanoisoindoline-2-carboxylate (700 mg, 2.86 mmol, 71.20%) as a white solid. [M]+calcd: 244, found: 189.1H NMR (400 MHz, DMSO) δ 7.83 (d, J = 3.2 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.55 (dd, J = 7.8, 3.2 Hz, 1H), 4.64 (t, J = 11.8 Hz, 4H), 1.46 (s, 9H).

[0514] Step 2: isoindoline-5-carbonitrile

[0515] To a solution of tert-butyl 5-cyanoisoindoline-2-carboxylate (690 mg, 2.83 mmol) in DCM (7 mL), then was added TFA (2 mL, 26.12 mmol), the reaction mixture was stirred at 25oC for 1 hour. Filtered and concentrated in vacuo to give the crude product which was purified by column chromatography on silica gel (MeOH in DCM =15% ~ 20%) to obtain the desired product isoindoline-5-carbonitrile (350 mg, 2.43 mmol, 85.94%) as a yellow oil. [M]+calcd: 144, found: 145.

[0516] Step 3: 2-(4-((2,6-dichlorophenyl)thio)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carbonyl)isoindoline-5-carbonitrile

[0517] To a solution of isoindoline-5-carbonitrile (30 mg, 0.21 mmol) in acetonitrile (1 mL), then was added 4-((2,6-dichlorophenyl)thio)-2-oxo-6-(trifluoromethyl)-1,2- dihydropyridine-3-carboxylic acid (88 mg, 0.23 mmol), 1-methyl-1H-imidazole (60 mg, 0.73 mmol) and [chloro(dimethylamino)methylidene]dimethylammonium hexafluoro-λ5- phosphanuide (75.9 mg, 0.27 mmol). The reaction mixture was stirred at 25oC for 3 hours. Purified by prep-HPLC to obtain the desired product 2-(4-((2,6-dichlorophenyl)thio)-2-oxo- 6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonyl)isoindoline-5-carbonitrile (35 mg, 0.07 mmol, 32.96%) as a white solid. [M]+calcd: 509, found: 510.1H NMR (400 MHz, DMSO) δ 12.95 (s, 1H), 7.88 (d, J = 24.8 Hz, 1H), 7.81 (t, J = 9.2 Hz, 1H), 7.75 (dd, J = 8.0, 3.0 Hz, 2H), 7.66 – 7.58 (m, 2H), 6.35 (s, 1H), 4.92 (d, J = 15.6 Hz, 2H), 4.75 (dd, J = 26.6, 11.3 Hz, 2H).

[0518] Example 40: Synthesis of 4-((2-chlorophenyl)thio)-3-(5,6- dimethoxyisoindoline-2-carbonyl)-6-(trifluoromethyl)pyridin-2(1H)-one

[0519] To a flask containing 4-chloro-3-(5,6-dimethoxyisoindoline-2-carbonyl)-6- (trifluoromethyl)pyridin-2(1H)-one (100 mg, 0.24 mmol) was added EtOH (1.0 mL) followed by the addition of TEA (0.20 mL, 1.49 mmol) and 2-chlorobenzenethiol (35.91 mg, 0.24 mmol). The mixture was stirred at 80oC for 6 hr. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give 4-((2- chlorophenyl)thio)-3-(5,6-dimethoxyisoindoline-2-carbonyl)-6-(trifluoromethyl)pyridin- 2(1H)-one (25 mg, 0.04 mmol, 19.71%) as a white solid. [M]+ calcd: 510.0, found: 511.0.1H NMR (400 MHz, DMSO) δ 12.79 (s, 1H), 7.81 (dd, J = 7.8, 1.6 Hz, 1H), 7.74 (dd, J = 8.0, 1.2 Hz, 1H), 7.60 (td, J = 7.8, 1.8 Hz, 1H), 7.51 (td, J = 7.6, 1.2 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.43 (s, 1H), 4.76 (s, 2H), 4.58 (q, J = 13.4 Hz, 2H), 3.76 (s, 3H), 3.71 (s, 3H).

[0520] Example 42: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-(pyridazin-3-ylamino)isoindoline-2-carbonyl)pyridin-2(1H)- one

[0521] Step 1: tert-butyl 5-(pyridazin-3-ylamino)isoindoline-2-carboxylate.

[0522] To a solution of 2-methylpropan-2-yl 5-bromo-2,3-dihydro-1H-isoindole-2- carboxylate (200 mg, 0.67 mmol) and 1,2-diazin-3-amine (63.79 mg, 0.67 mmol) in toluene (3 ml) was added Cs2CO3 (655.88 mg, 2.01 mmol), Pd2(dba)3 (61.45 mg, 0.07 mmol) and XANT-PHOS (77.65 mg, 0.13 mmol), the resulting mixture was stirred at 100oC for 18 h under N2. The reaction mixture was cooled to rt, quenched with water (50 mL), extracted with EtOAc (100 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel (EtOAc in PE = 0 ~ 100%) to obtain the desired product 2-methylpropan-2-yl 5-(1,2-diazin-3-ylamino)-2,3-dihydro-1H-isoindole-2- carboxylate (60 mg, 0.19 mmol, 28.64%) as a light yellow solid. LC / MS (ESI) m / z: 313(M+H)+.

[0523] Step 2: N-(pyridazin-3-yl)isoindolin-5-amine.

[0524] To a solution of 2-methylpropan-2-yl 5-(1,2-diazin-3-ylamino)-2,3-dihydro-1H- isoindole-2-carboxylate (60 mg, 0.19 mmol) in DCM (5 ml) at 0oC was dropwise added HCl / dioxane (4M, 5 ml), the resulting mixture was stirred at rt for 1 h under N2. The reaction mixture was concentrated to give crude desired product N-(pyridazin-3-yl)isoindolin-5-amine as a grey solid, used directly next step. LC / MS (ESI) m / z: 213(M+H)+

[0525] Step 3: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5- (pyridazin-3-ylamino)isoindoline-2-carbonyl)pyridin-2(1H)-one.

[0526] To a solution of 5-(1,2-diazin-3-ylamino)-2,3-dihydro-1H-isoindole (20 mg, 0.09 mmol) in MeCN (1 mL) at 0oC was dropwise added 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (30.13 mg, 0.08 mmol), NMI (26.98 mg, 0.33 mmol) and TCFH (34.34 mg, 0.12 mmol), the reaction mixture was stirred at rt for 3 h. The reaction mixture was quenched with water (5 mL), extracted with EtOAc (10 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by prep- HPLC to obtain the desired product 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3- (5-(pyridazin-3-ylamino)isoindoline-2-carbonyl)pyridin-2(1H)-one (9 mg, 0.02 mmol, 22%) as a brown solid. LC / MS (ESI) m / z: 595 (M+H)+.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 9.33 (d, J = 10.4 Hz, 1H), 8.66 (dd, J = 6.6, 4.4 Hz, 1H), 8.13 (s, 1H), 7.88 (d, J = 65.3 Hz, 1H), 7.76 (dd, J = 7.9, 3.2 Hz, 2H), 7.61 (ddd, J = 31.8, 19.1, 5.2 Hz, 2H), 7.47 – 7.40 (m, 1H), 7.33 (dd, J = 23.1, 8.3 Hz, 1H), 7.13 (dd, J = 9.1, 1.6 Hz, 1H), 6.26 (s, 1H), 4.95 – 4.62 (m, 4H).

[0527] Example 43: Synthesis of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)piperazin-2-one

[0528] Step 1: tert-butyl 5-bromo-6-methoxyisoindoline-2-carboxylate

[0529] To a solution of tert-butyl 5-methoxyisoindoline-2-carboxylate (1.0 g, 4 mmol) in THF (10 mL) / ACN (10 mL) was added NBS (1.4 g, 8 mmol) slowly. After stirred rt overnight. the reaction mixture was acidified with NaHCO3to pH 7 ~ 8 and extracted with EA. Organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0 ~ 20%, ethyl acetate in petroleum ether) to afford tert-butyl 5-bromo-6-methoxyisoindoline-2-carboxylate (506 mg, 1.5 mmol, 37%) as a yellow solid. LCMS (m / z): [M+H]+calcd, 328; found, 313 (M-56+41)+.1H NMR (400 MHz, CDCl3) δ 7.41 (d, J = 24.9 Hz, 1H), 6.78 (d, J = 19.6 Hz, 1H), 4.60 (dd, J = 15.0, 10.0 Hz, 4H), 3.89 (d, J = 5.7 Hz, 3H), 1.51 (s, 9H).

[0530] Step 2: tert-butyl 5-methoxy-6-(4-(4-methoxybenzyl)-2-oxopiperazin-1- yl)isoindoline-2-carboxylate

[0531] To a solution of tert-butyl 5-bromo-6-methoxyisoindoline-2-carboxylate (200 mg, 0.6 mmol) and 4-(4-methoxybenzyl)piperazin-2-one (200 mg, 0.9 mmol) in dioxane (10 ml) was added Cs2CO3 (585 mg, 1.8 mmol), CuI (114 mg, 0.6 mmol) and trace- dimethylcyclohexane-1,2-diamine (86 mg, 0.6 mmol), The resulting mixture was heated to 120°C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 20~60%, MeOH in H2O) to afford tert-butyl 5-methoxy-6-(4-(4-methoxybenzyl)-2- oxopiperazin-1-yl)isoindoline-2-carboxylate (51 mg, 0.1 mmol, 17%) as a light yellow solid. LCMS (m / z): [M+H]+calcd, 468; found, 468 (M+H)+.

[0532] Step 3: 4-(4-methoxybenzyl)-1-(6-methoxyisoindolin-5-yl)piperazin-2-one

[0533] To a solution of tert-butyl 5-methoxy-6-(4-(4-methoxybenzyl)-2-oxopiperazin-1- yl)isoindoline-2-carboxylate (51 mg, 0.1 mmol) in DCM (3 mL) was added HCl (3 mL, 4 M in dioxane). After being stirred at rt for 2 hr, The reaction mixture was concentrated to afford 4-(4-methoxybenzyl)-1-(6-methoxyisoindolin-5-yl)piperazin-2-one as a brown solid which was used in the next step directly without further purification. LCMS (m / z): [M+H]+calcd, 368; found, 368 (M+H)+.

[0534] Step 4: 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-4-(4-methoxybenzyl)piperazin- 2-one

[0535] To a solution of 4-(4-methoxybenzyl)-1-(6-methoxyisoindolin-5-yl)piperazin-2- one (36 mg, 0.1 mmol) in ACN (5 ml) was added 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (48 mg, 0.12 mmol), NMI (28 mg, 0.35 mmol) and TCFH (42 mg, 0.15 mmol). The resulting mixture was stirred at room temperature for 16 hr. The residue was diluted with EtOAc, washed with NaHCO3(aq.), the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0 ~ 14%, MeOH in DCM) to afford 1-(2-(6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)- 6-methoxyisoindolin-5-yl)-4-(4-methoxybenzyl)piperazin-2-one (30 mg, 0.04 mmol, 40%) as a light yellow solid. LCMS (m / z): [M+H]+calcd, 749; found, 749 (M+H)+.

[0536] Step 5: 4-methoxynaphthalene-1,2-dicarboxylic acid

[0537] To a solution of 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-4-(4- methoxybenzyl)piperazin-2-one (30 mg, 0.04 mmol) in TFA (5 mL) was added TfOH (2 mL), and the reaction was stirred at 60°C for 16 hr. The solvent was removed and purified byprep-HPLC to give 1-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)piperazin-2-one (1.5 mg, 0.002 mmol, 5%) as a white solid. LCMS (m / z): [M-H] - calcd, 627; found, 627 (M-H) -.1H NMR (400 MHz, DMSO) δ 7.75 (d, J = 8.0 Hz, 2H), 7.65 – 7.57 (m, 1H), 7.17 (dd, J = 17.9, 8.6 Hz, 2H), 6.16 (s, 1H), 4.90 – 4.54 (m, 4H), 3.76 (d, J = 25.3 Hz, 3H), 3.48 – 3.36 (m, 4H), 3.09 – 2.94 (m, 2H).19F NMR (377 MHz, DMSO) δ -54.99 (d, J = 72.3 Hz).

[0538] Example 44: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)isoindolin-5-yl)pyrimidine- 2,4(1H,3H)-dione

[0539] Step 1: 1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione

[0540] To a solution of pyrimidine-2,4(1H,3H)-dione (3000 mg, 26.76 mmol) in DMF (5 mL) was added 1-[(4-methylphenyl)dioxo-λ6-sulfanyl]imidazole (7138.34 mg, 32.12 mmol),(4-methoxyphenyl)methanol (0.15 mL, 26.76 mmol),TEA (7.44 mL, 53.53 mmol) and potassium carbonate (3698.81 mg, 26.76 mmol)at 20oC. The reaction mixture was stirred at 120℃ for 20 hours. Dissolve the remaining foam in DCM (100 mL). Wash the solution with water (2×100 mL). Dry the organic layer over Na2SO4. Evaporate the organic layer. Purify the crude product by column chromatography on silica gel eluting with EtOAc / n-hexane (50:50). to give 1-[(4-methoxyphenyl)methyl]-1,2,3,4-tetrahydropyrimidine-2,4-dione (140 mg, 0.603 mmol, 2.25%) as a white solid. [M]+calcd,232; found, 233.1H NMR (400 MHz, DMSO) δ 11.29 (s, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.00 – 6.81 (m, 2H), 5.58 (dd, J = 7.8, 2.2 Hz, 1H), 4.79 (s, 2H), 3.74 (s, 4H).

[0541] Step 2: tert-butyl 5-(3-(4-methoxybenzyl)-2,6-dioxo-3,6-dihydropyrimidin- 1(2H)-yl)isoindoline-2-carboxylate

[0542] To a solution of 1-(4-methoxybenzyl)pyrimidine-2,4(1H,3H)-dione (140 mg, 0.47 mmol) in N,N-dimethylmethanamide (5 mL) was added 1-[(4-methoxyphenyl)methyl]- 1,2,3,4-tetrahydropyrimidine-2,4-dione (109.04 mg, 0.47 mmol), methyl[2- (methylamino)cyclohexyl]amine (13.36 mg, 0.09 mmol),K2CO3(129.77 mg, 0.94 mmol) and CuI (17.88 mg, 0.09 mmol) at 20oC under N2,. The reaction mixture was stirred at 120℃ for 18 hours. The reaction mixture was filtered and concentrated. The residue which was purified by Flash chromatography (PE: EA = 0-50%) to afford tert-butyl 5-(3-(4-methoxybenzyl)-2,6- dioxo-3,6-dihydropyrimidin-1(2H)-yl)isoindoline-2-carboxylate (120 mg, 0.267 mmol, 56.86%) as white solid. [M-56]+calcd,393; found, 394+.1H NMR (400 MHz, DMSO) δ 7.90 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.0, 4.3 Hz, 1H), 7.31 (d, J = 8.6 Hz, 2H), 7.21 – 7.07 (m, 2H), 6.98 – 6.86 (m, 2H), 5.82 (d, J = 7.9 Hz, 1H), 4.87 (s, 2H), 4.61 (t, J = 10.0 Hz, 4H), 3.74 (s, 3H), 1.46 (s, 10H).

[0543] Step 3: 3-(isoindolin-5-yl)pyrimidine-2,4(1H,3H)-dione

[0544] To a solution of tert-butyl 5-(3-(4-methoxybenzyl)-2,6-dioxo-3,6- dihydropyrimidin-1(2H)-yl)isoindoline-2-carboxylate (140 mg, 0.31 mmol) in TFA (1 mL, 13.06 mmol) was added TfOH (0.3 mL, 3.39 mmol) ,methyl[2- (methylamino)cyclohexyl]amine (3.82 mg, 0.03 mmol) at 20oC under N2. The reaction mixture was stirred at 30℃ for 2 hours. The reaction mixture was filtered and concentrated. The residue which was purified by perp-HPLC ((Column: YMC-C8-5um; Mobile phase: from 10% to 95% MECN with H2O(0.1%FA); flow rate: 30 mL / min; wave length: 220 nm / 254 nm；)) to give 3-(isoindolin-5-yl)pyrimidine-2,4(1H,3H)-dione (60 mg, 0.262 mmol, 84.04%) as a yellow oil. [M]+calcd, 229; found, 230.

[0545] Step 4: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)isoindolin-5-yl)pyrimidine-2,4(1H,3H)-dione

[0546] To a solution of 3-(isoindolin-5-yl)pyrimidine-2,4(1H,3H)-dione (50 mg, 0.22 mmol) in ACN (3 mL), then was added 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (87.38 mg, 0.22 mmol), NMI (89.43 mg, 1.09 mmol) and TCFH (122.14 mg, 0.44 mmol)at 30oC under N2. The reaction mixture was stirred at 40℃ for 1 hour. The mixture was purified by perp-HPLC ((Column: YMC-C8-5um; Mobile phase: from 10% to 95% MECN with H2O(0.1%FA); flow rate: 30 mL / min; wave length: 220 nm / 254 nm；)) to give3-(2-{[6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridin-3-yl]carbonyl}-2,3-dihydro-1H-isoindol-5-yl)- 1,2,3,4-tetrahydropyrimidine-2,4-dione (80 mg, 0.13 mmol, 59.95%) as a white solid. [M]+calcd, 610; found, 611.1H NMR (400 MHz, DMSO) δ 7.96 (d, J = 8.0 Hz, 1H), 7.46 (dd, J = 7.8, 4.6 Hz, 1H), 7.36 (t, J = 10.4 Hz, 2H), 7.24 (d, J = 7.8 Hz, 1H), 7.18 (dd, J = 8.0, 1.8 Hz, 1H), 6.99 (d, J = 8.8 Hz, 2H), 5.88 (d, J = 7.8 Hz, 1H), 4.93 (s, 2H), 4.67 (t, J = 9.8 Hz, 4H), 3.81 (s, 3H), 1.53 (s, 9H).19F NMR (377 MHz, DMSO) δ -51.26 – -58.56 (m).

[0547] Example 45: Synthesis of 3-(4-acetyl-2,3,4,6,7,8-hexahydro-[1,4]oxazino[2,3- f]isoindole-7-carbonyl)-6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)pyridin- 2(1H)-one

[0548] Step 1: 5-methoxy-6-nitroisoindoline-1,3-dione

[0549] To a flask containing 5-methoxyisoindoline-1,3-dione (10.00 g, 56.44 mmol) was added H2SO4 (100.00 mL) followed by the addition of KNO3 (6.28 g, 62.09 mmol) at 0oCunder N2. The mixture was stirred at 20oC for 2 h. The reaction liquid is quenched with H2O. Extract three times with EA and H2O. Get 5-methoxy-6-nitroisoindoline-1,3-dione (9 g, 40.51 mmol, 71.77%) as a yellow solid. [M]+ calcd: 222.0, found: 223.0.1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.30 (s, 1H), 7.77 (s, 1H), 4.10 (s, 3H).

[0550] Step 2: 5-methoxy-6-nitroisoindoline

[0551] To a flask containing 5-methoxy-6-nitroisoindoline-1,3-dione (11.00 g, 49.51 mmol) was added THF (40 mL) followed by the addition of BH3(1mol / L)(495.13 mL, 495.13 mmol) at 0oC under N2. The mixture was stirred at 85oC for 18 h. The reaction liquid is quenched with MeOH. The mixture was stirred at 85oC for 1h. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 5-methoxy-6-nitroisoindoline (8.00 g, 41.19 mmol, 83.20%) as a yellow solid. [M]+ calcd: 194.0, found: 195.0.

[0552] Step 3: 6-nitroisoindolin-5-ol

[0553] To a flask containing 5-methoxy-6-nitroisoindoline (1.50 g, 7.72 mmol) was added DCM (15.00 mL) followed by the addition of tribromo borane (7.74 g, 30.89 mmol) at 0oC under N2. The mixture was stirred at 0oC for 2h. The reaction liquid is quenched with MeOH at 0oC. The organic phase concentrates under vacuum. Get 6-nitroisoindolin-5-ol (1.00 g, 5.55 mmol, 71.86%) as a yellow solid. [M]+ calcd: 180.0, found: 181.0.1H NMR (400 MHz, DMSO) δ 7.76 (s, 1H), 7.29 (s, 1H), 4.10 (s, 2H), 4.03 (s, 2H), 3.89 (s, 3H).

[0554] Step 4: tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate

[0555] To a flask containing 6-nitroisoindolin-5-ol (1.40 g, 7.77 mmol) was added THF (15 mL) followed by the addition of TEA (3.24 mL, 23.31 mmol) and (2-methylprop-2-yl) oxidanecarboxylic anhydride (2.04 g, 9.32 mmol) under N2. The mixture was stirred at rt for 0.5h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-20%) to afford the product tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate (1.20 g, 4.28 mmol, 55.10%) as a yellow solid. [M]+ calcd: 280.1, found: 266.3.

[0556] Step 5: tert-butyl 5-amino-6-hydroxyisoindoline-2-carboxylate

[0557] To a flask containing tert-butyl 5-hydroxy-6-nitroisoindoline-2-carboxylate (100.00 mg, 0.35 mmol) was added MeOH (2.00 mL) followed by the addition of Pd / C (10.00 mg, 0.09 mmol) and H2(5.00 L, 0.14 mmol). The mixture was stirred at rt for 1h under H2. Filtrate is obtained after filtration. The organic system was concentrated under vacuum. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-30%) to afford the product tert-butyl 5-amino-6- hydroxyisoindoline-2-carboxylate (50.00 mg, 0.20 mmol, 55.99%) as a yellow solid. [M]+ calcd:250.1, found:251.1.1H NMR (400 MHz, DMSO) δ 9.05 (s, 1H), 6.56 (d, J = 3.0 Hz, 1H), 6.48 (d, J = 7.3 Hz, 1H), 4.50 (s, 2H), 4.36 (d, J = 9.3 Hz, 4H), 1.43 (s, 9H).

[0558] Step 6: tert-butyl 3,4,6,8-tetrahydro-[1,4] oxazino[2,3-f]isoindole-7(2H)- carboxylate

[0559] To a flask containing tert-butyl 5-amino-6-hydroxyisoindoline-2-carboxylate (70.00 mg, 0.28 mmol) was added DMF (3.0 ml) followed by the addition of K2CO3 (193.25 mg, 1.39 mmol) and 1,2-dibromoethane (0.03 mL, 0.41 mmol).The mixture was stirred at 120oC for 18hr. Filtrate is obtained after filtration. The organic system was concentrated to give the residue which was purified by Flash chromatography (DCM: MeOH = 0-10%) to afford the product tert-butyl 3,4,6,8-tetrahydro-[1,4] oxazino[2,3-f]isoindole-7(2H)- carboxylate (20.00 mg, 0.07 mmol, 25.88%) as a yellow solid. [M]+ calcd: 276.1, found: 277.2.1H NMR (400 MHz, DMSO) δ 6.58 (d, J = 3.4 Hz, 1H), 6.46 (d, J = 5.3 Hz, 1H), 5.75 (s, 1H), 4.38 (d, J = 9.1 Hz, 4H), 4.12 – 4.04 (m, 2H), 3.25 (s, 2H), 1.43 (s, 8H).

[0560] Step 7: tert-butyl 4-acetyl-3,4,6,8-tetrahydro-[1,4]oxazino[2,3-f]isoindole- 7(2H)-carboxylate

[0561] To a flask containing tert-butyl 3,4,6,8-tetrahydro-[1,4]oxazino[2,3-f]isoindole- 7(2H)-carboxylate (15.00 mg, 0.05 mmol) was added DCM (1 mL) followed by the addition of TEA (0.02 mL, 0.16 mmol) and acetic anhydride (0.006 mL, 0.06 mmol). The mixture was stirred at room temperature for 6h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-40%) to afford the product tert-butyl 4-acetyl-3,4,6,8-tetrahydro-[1,4]oxazino[2,3- f]isoindole-7(2H)-carboxylate (15.00 mg, 0.05 mmol, 86.80%) as a yellow solid. [M]+ calcd: 318.1, found: 263.1.

[0562] Step 7: 1-(2,3,7,8-tetrahydro-[1,4]oxazino[2,3-f]isoindol-4(6H)-yl)ethan-1-one

[0563] To a flask containing tert-butyl 4-acetyl-3,4,6,8-tetrahydro-[1,4]oxazino[2,3- f]isoindole-7(2H)-carboxylate (8.50 mg, 0.02 mmol) was added DCM (2 mL) followed by the addition of TFA (0.2 mL, 2.61 mmol) under N2 at 0oC. The mixture was stirred at rt for2hr. The system was adjusted to neutral by saturated sodium bicarbonate aqueous solution. Extract three times with EA and H2O. The organic phase concentrates under vacuum. Get 1- (2,3,7,8-tetrahydro-[1,4]oxazino[2,3-f]isoindol-4(6H)-yl)ethan-1-one (5.50 mg, 0.02 mmol, 92.60%) as a yellow oil. [M]+ calcd: 218.1, found: 219.0.

[0564] Step 8: 3-(4-acetyl-2,3,4,6,7,8-hexahydro-[1,4]oxazino[2,3-f]isoindole-7- carbonyl)-6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)pyridin-2(1H)-one

[0565] To a flask containing 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]- 2-oxo-1H-pyridine-3-carboxylic acid (7.60 mg, 0.02 mmol) was added ACN (2.0 mL) followed by the addition of 1-methylimidazole (5.45 mg, 0.06 mmol), 1-(2,3,7,8-tetrahydro- [1,4]oxazino[2,3-f]isoindol-4(6H)-yl)ethan-1-one (4.97 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature for 10 min. Added [chloro(dimethyl amino)methylidene]dimethylammonium hexafluoro-λ5-phosphanuide (6.92 mg, 0.02 mmol) at room temperature. The mixture was stirred at room temperature for 1h. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give 3-(4-acetyl-2,3,4,6,7,8-hexahydro-[1,4]oxazino[2,3-f]isoindole-7- carbonyl)-6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)pyridin-2(1H)-one (8.00 mg, 0.01 mmol, 70.18%) as a white solid. [M]+ calcd: 599.0, found: 600.1.1H NMR (400 MHz, DMSO) δ 12.85 (s, 1H), 7.83 – 7.75 (m, 2H), 7.65 (s, 1H), 7.62 (d, J = 7.8 Hz, 1H), 6.93 (d, J = 8.7 Hz, 1H), 6.24 (s, 1H), 4.77 (d, J = 6.3 Hz, 2H), 4.61 (d, J = 21.9 Hz, 2H), 4.25 (d, J = 4.2 Hz, 2H), 3.94 – 3.71 (m, 2H), 2.24 (d, J = 16.2 Hz, 3H).

[0566] Example 46: Synthesis of 4-((2,6-dichlorophenyl)thio)-3-(5-(5-methyl-2- oxoimidazolidin-1-yl)isoindoline-2-carbonyl)-6-(trifluoromethyl)pyridin-2(1H)-one

[0567] Step 1: 3-(4-methoxybenzyl)-5-methylimidazolidine-2,4-dione

[0568] To a mixture of 5-methyl-2-oxotetrahydro-1H-imidazol-4-one (400 mg, 3.51 mmol) and potassium carbonate (629 mg, 4.56 mmol) in N,N-dimethylmethanamide (8 mL) was added 4-(chloromethyl)-1-methoxybenzene (658.8 mg, 4.21 mmol) at rt, the mixture was stirred under N2atmosphere at 80 °C for 16 hrs. The reaction was diluted with water and extracted with EA (50 mL X 2), the combined organic layer was washed with water and saturated brine, dried over Na2SO4, filtered and concentrated, purified by flash chromatography and eluted with 0-5 % MeOH in DCM to give 3-[(4- methoxyphenyl)methyl]-5-methyl-2-oxotetrahydro-1H-imidazol-4-one(500 mg, 2.13 mmol, 60.89 %) as a white solid. LC-MS (ESI): mass calcd. for C12H14N2O3, 234.10; m / z found, 235 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 8.25 (s, 1H), 7.19 (d, J = 8.6 Hz, 2H), 6.89 (d, J = 8.7 Hz, 2H), 4.54 – 4.31 (m, 2H), 4.17 – 4.10 (m, 1H), 3.73 (s, 3H), 1.24 (d, J = 6.9 Hz, 3H).

[0569] Step 2: 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one

[0570] To a mixture of sodium boranuide (161.5 mg, 4.27 mmol) in THF (20 mL) was added ethoxyethane trifluoroborane (757.3 mg, 5.34 mmol) at 0 °C. The mixture was stirred under N2atmosphere at 0 °C for 30 mins. A solution of 3-(4-methoxybenzyl)-5- methylimidazolidine-2,4-dione (500 mg, 2.13 mmol) in THF (20 mL) was added drop-wise to the mixture, the reaction was quenched with MeOH and 1N HCl, stirred at rt overnight, extracted with EA (100 mL X 2), washed with saturated brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash chromatography and eluted with 0-15 % MeOH in DCM to give 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (200 mg, 0.91 mmol, 42.55 %) as a white solid. LC-MS (ESI): mass calcd. for C12H16N2O2, 220.12; m / z found, 221 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 7.14 (t, J = 5.7 Hz, 2H), 6.93 – 6.85 (m, 2H), 6.52 (s, 1H), 4.14 (s, 2H), 3.73 (s, 3H), 3.59 (ddd, J = 14.1, 6.3, 1.0 Hz, 1H), 3.27 (t, J = 8.4 Hz, 1H), 2.68 (dd, J = 8.6, 6.5 Hz, 1H), 1.06 (d, J = 6.1 Hz, 3H).

[0571] Step 3: tert-butyl 5-(3-(4-methoxybenzyl)-5-methyl-2-oxoimidazolidin-1- yl)isoindoline-2-carboxylate

[0572] To a mixture of 2-methylpropan-2-yl 5-bromo-2,3-dihydro-1H-isoindole-2- carboxylate (161 mg, 0.54 mmol), 3-[(4-methoxyphenyl)methyl]-5-methyl-2-oxotetrahydro- 1H-imidazole (10 mg, 0.05 mmol), bis[caesium(1+)] carbonate (527.7 mg, 1.62 mmol) and [5-(diphenylphosphanyl)-9,9-dimethyl-9H-xanthen-4-yl]diphenylphosphane(62.5 mg, 0.11 mmol) in dioxane (8 mL) was added tris(1,5-diphenylpenta-1,4-dien-3-one) palladium(0) (87.4 mg, 0.11 mmol) at rt, the mixture was stirred under N2 atmosphere at 100 °C for 16 hours. The mixture was concentrated under reduced pressure, purified by silica gel chromatography and eluted with 60 % EA in PE to give 2-methylpropan-2-yl 5-{3-[(4- methoxyphenyl)methyl]-5-methyl-2-oxotetrahydro-1H-imidazol-1-yl}-2,3-dihydro-1H- isoindole-2-carboxylate (180 mg, 0.41 mmol, 76.19 %) as a white solid. LC-MS (ESI): mass calcd. for C25H31N3O4, 437.23; m / z found, 438 [M+H]+ 1H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 14.6 Hz, 1H), 7.38 (dd, J = 14.8, 6.0 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.22 (d, J = 8.6 Hz, 2H), 6.96 – 6.88 (m, 2H), 4.55 (t, J = 11.0 Hz, 4H), 4.45 – 4.34 (m, 1H), 4.30 (d, J =2.9 Hz, 2H), 3.74 (s, 3H), 3.46 (t, J = 8.7 Hz, 1H), 2.88 (dd, J = 8.8, 5.3 Hz, 1H), 1.46 (s, 9H), 1.13 (d, J = 6.0 Hz, 3H).

[0573] Step 4: 1-(isoindolin-5-yl)-5-methylimidazolidin-2-one

[0574] To a mixture of tert-butyl5-(3-(4-methoxybenzyl)-5-methyl-2-oxoimidazolidin-1- yl)isoindoline-2-carboxylate (150 mg, 0.34 mmol) in 2,2,2-trifluoroaceticacid (0.5 mL, 6.53 mmol) was added trifluoromethanesulfonic acid (0.1 mL, 1.13 mmol) at rt, the mixture was stirred under N2 atmosphere at rt for 30 mins. The mixture was concentrated under reduced pressure, diluted with an aqueous Na2CO3solution to adjust pH = 9, diluted with MeOH and DMF, purified by C18 chromatography and eluted with 60 % MeOH in H2O to give 5-(5- methyl-2-oxotetrahydro-1H-imidazol-1-yl)-2,3-dihydro-1H-isoindole (70 mg, 0.32 mmol, 93.98 %) as a brown solid. LC-MS (ESI): mass calcd. for C12H15N3O, 217.12; m / z found, 218 [M+H]+.

[0575] Step 5: 4-((2,6-dichlorophenyl)thio)-3-(5-(5-methyl-2-oxoimidazolidin-1- yl)isoindoline-2-carbonyl)-6-(trifluoromethyl)pyridin-2(1H)-one

[0576] To a mixture of 5-(5-methyl-2-oxotetrahydro-1H-imidazol-1-yl)-2,3-dihydro-1H- isoindole (20 mg, 0.10 mmol), 4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-6-(trifluoromethyl)- 1H-pyridine-3-carboxylic acid (42.4 mg, 0.11 mmol) and 1-methylimidazole (60.4 mg, 0.74 mmol) in acetonitrile (1 mL) was added [chloro(dimethylamino)methylidene]dimethylammoniumhexafluoro-λ5-phosphanuide (51.6mg, 0.18 mmol) at rt, the mixture was stirred under N2 atmosphere at rt for 16 hrs. The reaction mixture was concentrated and purified by prep-HPLC to give 4-[(2,6- dichlorophenyl)sulfanyl]-3-{[5-(5-methyl-2-oxotetrahydro-1H-imidazol-1-yl)-2,3-dihydro- 1H-isoindol-2-yl]carbonyl}-6-(trifluoromethyl)-1,2-dihydropyridin-2-one (10 mg, 0.02 mmol, 18.62 %) as a white solid. LC-MS (ESI): mass calcd. for C25H19Cl2F3N4O3S, 582.05; m / z found, 583 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 8.0 Hz, 1H), 7.57 – 7.26 (m, 3H), 6.88 (d, J = 9.8 Hz, 1H), 6.32 (s, 1H), 4.83 (d, J = 8.5 Hz, 2H), 4.67 (dd, J = 19.3, 12.0Hz, 2H), 4.53 – 4.35 (m, 1H), 3.67 – 3.52 (m, 1H), 2.99 (d, J = 6.9 Hz, 1H), 1.19 (t, J = 5.9 Hz, 3H).19F NMR (377 MHz, DMSO-d6) δ - 67.35 (s).

[0577] Example 47: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(2-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6- carbonyl)pyridin-2(1H)-one

[0578] Step 1: 2,3-bis(methoxycarbonyl)pyridine 1-oxide

[0579] To a flask containing methyl dimethyl pyridine-2,3-dicarboxylate (8.00 g, 40.99 mmol) was added ACN (80.00 mL) followed by the addition of TFAA (17.22 g, 81.98 mmol) and dioxidane oxomethanediamine (7.71 g, 81.98 mmol) at 0oC. The mixture was stirred at room temperature for 4h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (DCM: MeOH = 0-10%) to afford the product 2,3-bis(methoxycarbonyl)pyridine 1-oxide (7.00 g, 33.14 mmol, 80.87%) as a yellow oil. [M]+ calcd: 211.0, found: 232.5.

[0580] Step 2: dimethyl 6-chloropyridine-2,3-dicarboxylate

[0581] To a flask containing 2,3-bis(methoxycarbonyl)pyridine 1-oxide (7.00 g, 33.14 mmol) was added POCl3(50.00 mL) under N2at 0oC. The mixture was stirred at 105oC for 4h. The system is modulated neutral. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-40%) to afford the product dimethyl 6-chloropyridine-2,3-dicarboxylate (2.50 g, 10.88 mmol, 32.84%) as a yellow oil. [M]+ calcd: 229.0, found: 230.0.

[0582] Step 2: [6-chloro-2-(hydroxymethyl)pyridin-3-yl]methanol

[0583] To a solution of methyl 6-chloro-2-(methoxycarbonyl)pyridine-3-carboxylate (1.00 g, 15.24 mmol) in THF (40.00 mL) and MeOH(1.50 ml) at 0oC was dropwise added LiBH4 (1.01 g, 45.72 mmol), the resulting mixture was stirred at rt for 3 h under N2. The reaction mixture was quenched with sat. NH4Cl solution (50.00 mL), extracted with EtOAc (50.00 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product [6-chloro-2- (hydroxymethyl)pyridin-3-yl]methanol as a brown solid, used directly next step. [M]+ calcd:174, found:174.

[0584] Step3: 6-chloro-2,3-bis(chloromethyl)pyridine

[0585] To a solution of crude [6-chloro-2-(hydroxymethyl)pyridin-3-yl]methanol in SOCl2 (10.00 mL) mmol) at 0oC, the resulting mixture was stirred at 35oC for 18 h under N2.The reaction mixture was quenched with iced-water (50.00 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 10%) to obtain the desired product 6-chloro-2,3-bis(chloromethyl)pyridine(450.00 mg, 2.15 mmol) as a brown solid,[M]+ calcd:210, found:210.

[0586] Step 4: 2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine

[0587] To a flask containing 6-chloro-2,3-bis(chloromethyl)pyridine (1.30 g, 6.176 mmol) was added DMF (10.00 mL) followed by the addition of (2,4-dimethoxyphenyl) methanamine (2.07 g, 12.35 mmol) under N2. The mixture was stirred at 0oC for 10 min. Added DIEA (3.19 g, 24.70 mmol) at 0oC. The mixture was stirred at rt for 18h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-30%) to afford the product 2-chloro-6-(2,4- dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (700.00 mg, 2.29 mmol, 37.23%) as a yellow solid. [M]+ calcd:304.1, found:305.3.1H NMR (400 MHz, DMSO) δ 7.69 (d, J = 7.9 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.2, 2.4 Hz, 1H), 3.85 (s, 4H), 3.79 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H).

[0588] Step 5: 6-(2,4-dimethoxybenzyl)-2-methoxy-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine

[0589] To a flask containing 2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine (230 mg, 0.75 mmol) was added MeOH (3.0 mL)followed by the addition of sodium methanolate (203.84 mg, 3.77 mmol). The mixture was stirred at 80oC for 6h. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (DCM: MeOH= 0-10%) to afford the product 6-(2,4-dimethoxybenzyl)-2-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (120 mg, 0.40 mmol, 52.94%) as a yellow solid. [M]+ calcd: 300.1, found: 301.3.1H NMR (400 MHz, DMSO) δ 7.69 (d, J = 7.8 Hz, 1H), 7.30 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 8.2 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.2, 2.4 Hz, 1H), 3.85 (s, 4H), 3.79 (s, 2H), 3.78 (s, 3H), 3.76 (s, 3H).

[0590] Step 6: 2-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine

[0591] To a flask containing 6-(2,4-dimethoxybenzyl)-2-methoxy-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine (110.00 mg, 0.36 mmol) was added DCM (4.00 mL) followed by the addition of 1-chloroethyl carbonochloridate (157.07 mg, 1.09 mmol) under N2 at 0oC. The mixture was stirred at 40oC for 1h. Concentrate under vacuum. Added MeOH (4.00 mL). The mixture was stirred at 80oC for 1h. Concentrate under vacuum. Extract three times with EA and H2O. The organic system was concentrated to give the residue which was purified by Flash chromatography (ACN: H2O = 0-100%) to afford the product 2-methoxy-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridine (50.00 mg, 0.33 mmol, 90.91%) as a yellow solid. [M]+ calcd: 150.0, found: 151.3.

[0592] Step 7: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(2-methoxy- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2(1H)-one

[0593] To a flask containing 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]- 2-oxo-1H-pyridine-3-carboxylic acid (50.00 mg, 0.12 mmol) was added ACN (2.0 mL) followed by the addition of 1-methylimidazole (35.87 mg, 0.43 mmol), 2-methoxy-6,7- dihydro-5H-pyrrolo[3,4-b]pyridine (22.49 mg, 0.15 mmol) at room temperature. The mixture was stirred at room temperature for 10 min. Added [chloro(dimethylamino)methylidene]dimethylammonium hexafluoro-λ5-phosphanuide (45.53 mg, 0.16 mmol) at room temperature. The mixture was stirred at room temperature for 1 h. The system is concentrated under vacuum. Extract three times with EA and H2O. Which was purified by silica gel cliunm to give 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3- (2-methoxy-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2(1H)-one (15.00 mg, 0.03 mmol, 22.56%) as a white solid. [M]+ calcd: 530.9, found: 532.0.1H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 7.79 – 7.69 (m, 3H), 7.66 – 7.59 (m, 1H), 6.79 (dd, J = 11.8, 8.4 Hz, 1H), 6.27 (s, 1H), 4.70 (dd, J = 51.8, 21.4 Hz, 4H), 3.84 (d, J = 22.0 Hz, 3H).

[0594] Example 48: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-(5-methyl-2-oxoimidazolidin-1-yl)isoindoline-2- carbonyl)pyridin-2(1H)-one

[0595] 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5-(5-methyl-2- oxoimidazolidin-1-yl)isoindoline-2-carbonyl)pyridin-2(1H)-one

[0596] To a mixture of 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo- 1H-pyridine-3-carboxylic acid (73.7 mg, 0.18 mmol), 5-(5-methyl-2-oxotetrahydro-1H- imidazol-1-yl)-2,3-dihydro-1H-isoindole (48 mg, 0.22 mmol) and 1-methylimidazole (120.9 mg, 1.47 mmol) in acetonitrile (2 mL) was added [chloro(dimethylamino)methylidene]dimethylammoniumhexafluoro-λ5-phosphanuide (103.3 mg, 0.37 mmol) at rt. The mixture was stirred under N2atmosphere at rt for 12 hrs, purified by prep-HPLC to get 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-{[5-(5- methyl-2-oxotetrahydro-1H-imidazol-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2- dihydropyridin-2-one (30 mg, 0.05 mmol, 27.16 %) as a white solid. LC-MS (ESI): mass calcd. for C25H19Cl3F2N4O3S, 598.02; m / z found, 599[M+H]+.19F NMR (377 MHz, DMSO- d6) δ -55.17 (d, J = 33.6 Hz), -55.35 (s).1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.63 (t, J = 8.1 Hz, 1H), 7.58 – 7.26 (m, 3H), 6.87 (d, J = 9.9 Hz, 1H), 6.27 (s, 1H), 4.93 – 4.75 (m, 2H), 4.67 (dd, J = 21.1, 12.1Hz, 2H), 4.52 – 4.32 (m, 1H), 3.58 (dd, J = 8.7, 5.7 Hz, 1H), 3.04 – 2.90 (m, 1H), 1.18 (t, J = 6.0 Hz, 3H).

[0597] Example 49: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(5-methoxy-2,3-dihydro-1H-benzo[e]isoindole-2- carbonyl)pyridin-2(1H)-one

[0598] Step 1: methyl 4-hydroxy-2-naphthoate

[0599] To a solution of benzaldehyde (5.0 g, 47 mmol) and dimethyl succinate (7.5 g, 51.7 mmol) in MeOH (80 mL) was added MeONa (10 g, 185 mmol) slowly, The resulting mixture was heated to 75℃ overnight. When the reaction was completed, the reaction mixture was acidified with 3M HCl to pH 1 and extracted with dichloromethane. Organic layer was dried over Na2SO4 and concentrated under reduced pressure to give crude product (3a). Crude product (3a) was dissolved in THF (80 ml), to which trifluoroacetic anhydride (9.8 g, 47 mmol) was then slowly added with stirring at room temperature, and resultingmixture was stirred under reflux. When the reaction was completed, the reaction mixture was cooled to room temperature and neutralized with aq. NaHCO3 at 0°C. The reaction mixture was extracted with ethyl acetate, and organic layer was dried over Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, 0~13%, ethyl acetate in petroleum ether) to afford methyl 4-hydroxy-2-naphthoate (4.08 g, 20 mmol, 43%) as a yellow solid. LCMS (m / z): [M+H]+calcd, 203; found, 203 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.27 – 8.18 (m, 2H), 7.93 – 7.90 (m, 1H), 7.67 – 7.49 (m, 3H), 3.97 (s, 3H).

[0600] Step 2: methyl 4-methoxy-2-naphthoate

[0601] To a solution of methyl 4-hydroxy-2-naphthoate (3.8 g, 18.8 mmol) in DMF (50 mL) was added MeI (5 mL, 56.4 mmol) and K2CO3(7.7 g, 56.4 mmol). The reaction was stirred at rt for 16 hours. The reaction mixture was quenched with water, extracted with EA. The combined organic layer was dried, filtered and concentrated to give the residue which was purified by Flash chromatography (PE: EA = 0-15%) to afford the methyl 4-methoxy-2- naphthoate (1.3 g, 6 mmol, 32%) as a yellow oil. LCMS (m / z): [M+H]+calcd, 217; found, 217 (M+H)+

[0602] Step 3: methyl 1-bromo-4-methoxy-2-naphthoate

[0603] To a solution of methyl 4-methoxy-2-naphthoate (1.3 g, 6 mmol) in ACN (10 ml) was added NBS (1.1 g, 6.6 mmol), The resulting mixture was stirred at 90°C for 16 hr. The residue was diluted with EtOAc, washed with NaHCO3(aq.), the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 0~8%, ethyl acetate in petroleum ether) to afford methyl 1-bromo-4-methoxy-2- naphthoate (1.7 g, 5.7 mmol, 95%) as a yellow solid. LCMS (m / z): [M+H]+calcd, 296;found, 296 (M+H) +.1H NMR (400 MHz, CDCl3) δ 8.43 – 8.38 (m, 1H), 8.31 – 8.25 (m, 1H), 7.66 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.59 (ddd, J = 8.1, 5.7, 1.2 Hz, 1H), 7.03 (s, 1H), 4.03 (s, 3H), 4.01 (s, 3H).

[0604] Step 4: dimethyl 4-methoxynaphthalene-1,2-dicarboxylate

[0605] At CO atmosphere, to a solution of methyl 1-bromo-4-methoxy-2-naphthoate (1.7 g, 5.7 mmol) in MeOH (20 ml) was added Pd(dppf)Cl2(833 mg, 1.1 mmol) and TEA (1.4 g, 11.4 mmol), The resulting mixture was stirred at 70°C for 16 hr. The solvent was removed and purified by flash column chromatography (silica gel, 0~20%, ethyl acetate in petroleum ether) to afford dimethyl 4-methoxynaphthalene-1,2-dicarboxylate (688 mg, 2.5 mmol, 44%) as a white solid. LCMS (m / z): [M+H]+calcd, 275; found, 275 (M+H)+.

[0606] Step 5: 4-methoxynaphthalene-1,2-dicarboxylic acid

[0607] To a solution of dimethyl 4-methoxynaphthalene-1,2-dicarboxylate (680 mg, 2.5 mmol) in MeOH (8 mL) / H2O (2 mL) was added NaOH (300 mg, 7.5 mmol) .and the reaction was stirred at 60°C for 16 hr. The solvent was removed to afford 4- methoxynaphthalene-1,2-dicarboxylic acid as a light yellow solid was used in the next step directly. LCMS (m / z): [M+H]+calcd, 247; found, 247 (M+H)+.

[0608] Step 6: 5-methoxy-1H-benzo[e]isoindole-1,3(2H)-dione

[0609] To a solution of 4-methoxynaphthalene-1,2-dicarboxylic acid (615 mg, 2.5 mmol) in HOAc (10 mL) was added NH4OAc (385 mg, 5 mmol). and the reaction was stirred at 140°C for 6 hr. After removal of solvent, the residue was diluted with DCM, washed with NaHCO3 (aq.), the organic layer was extracted with DCM twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 5-methoxy- 1H-benzo[e]isoindole-1,3(2H)-dione (392 mg, 1.7 mmol, 68%) as a yellow solid was used in the next step directly. LCMS (m / z): [M+H]+calcd, 228; found, 228 (M+H)+.1H NMR (400 MHz, DMSO) δ 11.11 (s, 1H), 8.72 (d, J = 8.3 Hz, 1H), 8.29 (d, J = 8.5 Hz, 1H), 7.85 – 7.78 (m, 1H), 7.71 (ddd, J = 8.3, 6.9, 1.2 Hz, 1H), 7.26 (s, 1H), 4.15 (s, 3H).

[0610] Step 7: 5-methoxy-2,3-dihydro-1H-benzo[e]isoindole

[0611] To a solution of 5-methoxy-1H-benzo[e]isoindole-1,3(2H)-dione (392 mg, 1.7 mmol) in THF (4 mL) was added BH3 (17 mL, 1M in THF). and the reaction was stirred at 80°C for 16 hr. The residue was diluted with H2O and extracted with EA , the aqueous phase was adjust pH to 7~8, and extracted with EA twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to afford 5-methoxy-2,3-dihydro- 1H-benzo[e]isoindole (227 mg, 1.1 mmol, 64%) as a reddish brown solid was used in the next step directly. LCMS (m / z): [M+H]+calcd, 200; found, 200 (M+H)+.1H NMR (400 MHz, CDCl3) δ 8.27 (d, J = 8.3 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.55 – 7.41 (m, 2H), 6.75 (s, 1H), 4.60 – 4.38 (m, 4H), 4.00 (s, 3H)

[0612] Step 8: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5-methoxy- 2,3-dihydro-1H-benzo[e]isoindole-2-carbonyl)pyridin-2(1H)-one

[0613] To a solution of 5-methoxy-2,3-dihydro-1H-benzo[e]isoindole (50 mg, 0.25 mmol) in ACN (5 ml) was added 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2- oxo-1,2-dihydropyridine-3-carboxylic acid (115 mg, 0.30 mmol), NMI (71 mg, 0.87 mmol) and TCFH (103 mg, 0.37 mmol). The resulting mixture was stirred at room temperature for 16 hr. The residue was diluted with EtOAc, washed with NaHCO3 (aq.), the aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified by prep-HPLC to give 6- (chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(5-methoxy-2,3-dihydro-1H- benzo[e]isoindole-2-carbonyl)pyridin-2(1H)-one (34.8 mg, 0.06 mmol, 24%) as a white solid. LCMS (m / z): [M+H]+calcd, 583; found, 583 (M+H)+.1H NMR (400 MHz, DMSO) δ 12.86 (s, 1H), 8.20 (d, J = 7.9 Hz, 1H), 7.82 – 7.49 (m, 6H), 7.07 (d, J = 8.5 Hz, 1H), 6.28 (s, 1H), 5.17 – 4.76 (m, 4H), 3.97 (d, J = 26.1 Hz, 3H).19F NMR (377 MHz, DMSO) δ -55.16 (s).

[0614] Example 50: Synthesis of 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)- 1,3-oxazinan-2-one

[0615] Step1: tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate

[0616] To a solution of 5-methoxy-6-nitro-2,3-dihydro-1H-isoindole (500.00 mg, 2.58 mmol) in DCM (8 mL) were added (Boc)2O (842.92 mg, 3.86 mmol) and 2-[ethyl(2- hydroxyethyl)amino]ethan-1-ol (0.68 mL, 5.15 mmol), the reaction was stirred at rt for 1 h. LCMS showed the reaction was completed. The solvent was removed in vacuo. Then the residue was purified by column chromatography on silica gel to give tert-butyl 5-methoxy-6- nitroisoindoline-2-carboxylate (370.00 mg, 1.13 mmol, 43.94%) as a white solid. [M]+ calcd:294.12, found:239.00.

[0617] Step 2: tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate

[0618] To a solution of tert-butyl 5-methoxy-6-nitroisoindoline-2-carboxylate (370.00 mg, 1.28 mmol) in methanol (10 mL) was added 10% Pd / C (66.89 mg, 0.63 mmol), the reaction was stirred at rt for 3 h under H2. LCMS showed the reaction was completed. Thesolvent was removed in vacuo. Then the residue was purified by column chromatography on silica gel to give tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (320.00 mg, 0.97 mmol, 77.04%) as a white solid. [M]+ calcd:264.15, found:265.00.1H NMR (400 MHz, DMSO) δ 6.75 (d, J = 6.4 Hz, 1H), 6.53 (d, J = 7.1 Hz, 1H), 4.41 (t, J = 10.5 Hz, 4H), 3.74 (d, J = 3.6 Hz, 3H), 1.44 (s, 9H).

[0619] Step 3: tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6- methoxyisoindoline-2-carboxylate

[0620] To a solution of tert-butyl 5-amino-6-methoxyisoindoline-2-carboxylate (150.00 mg, 0.57 mmol) in Tol (5 mL) was added 3-chloropropyl chloromethanoate (89.09 mg, 0.57 mmol), the reaction was stirred at 70oC for 2 h under N2. LCMS showed about 85% of product was detected. The solvent was removed in vacuo. The crude enamine was used directly in next step. [M]+ calcd:384.15. found:769.10.

[0621] Step 4: tert-butyl 5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2- carboxylate

[0622] To a solution of tert-butyl 5-(((3-chloropropoxy)carbonyl)amino)-6- methoxyisoindoline-2-carboxylate (130.00 mg, 0.34 mmol) in acetonitrile (6 mL) was added potassium carbonate (93.36 mg, 0.68 mmol), the reaction was stirred at 70oC for 18 h under N2. LCMS showed the reaction was completed. The reaction was removed in vacuo and purified by column chromatography on silica gel to give tert-butyl 5-methoxy-6-(2-oxo-1,3- oxazinan-3-yl)isoindoline-2-carboxylate (100.00 mg, 0.20 mmol, 59.48%) as a white solid. [M]+ calcd:348.17, found:349.00.1H NMR (400 MHz, DMSO) δ 8.46 (s, 1H), 7.01 (d, J = 5.7 Hz, 1H), 4.51 (t, J = 11.3 Hz, 4H), 4.16 (t, J = 6.1 Hz, 2H), 3.79 (d, J = 3.7 Hz, 2H), 3.71 (m, 3H), 2.07 – 2.03 (m, 2H), 1.45 (s, 9H).

[0623] Step 5: 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0624] To a solution of tert-butyl 5-methoxy-6-(2-oxo-1,3-oxazinan-3-yl)isoindoline-2- carboxylate (100.00 mg, 0.29 mmol) in DCM (3 mL) was added TFA (1 mL), the reaction was stirred at rt for 2 h. LCMS showed the reaction was completed. The reaction was removed in vacuo and purified by prep-HPLC to give 3-(6-methoxyisoindolin-5-yl)-1,3- oxazinan-2-one (10.00 mg, 0.04 mmol, 13.33%) as a white solid. [M]+ calcd:248.28, found:249.00.

[0625] Step 6: 3-(2-(6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-2-oxo-1,2- dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one

[0626] To a solution of 3-(6-methoxyisoindolin-5-yl)-1,3-oxazinan-2-one (20.00 mg, 0.08 mmol) in acetonitrile (1 mL) were added 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-2-oxo-1H-pyridine-3-carboxylic acid (46.10 mg, 0.12 mmol), TCFH (41.89 mg, 0.15 mmol) and NMI (59.38 mg, 0.69 mmol), the reaction was stirred at rt for 48 h under N2. LCMS showed the reaction was completed. The reaction was removed in vacuo and purified by prep-HPLC to give 3-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5-yl)-1,3- oxazinan-2-one (15.80 mg, 0.03 mmol, 21.55%) as a white solid. [M]+ calcd:630.87, found:632.20.1H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1H), 7.76 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.9 Hz, 1H), 7.26 (d, J = 29.4 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.27 (s, 1H), 4.90 – 4.76 (m, 2H), 4.65 (t, J = 21.4 Hz, 2H), 4.31 (d, J = 5.8 Hz, 2H), 3.78 (d, J = 25.7 Hz, 3H), 3.45 (dt, J = 11.6, 6.0 Hz, 2H), 2.09 – 2.02 (m, 2H).19F NMR (377 MHz, DMSO-d6) δ -55.24 (s, 2F).

[0627] Example 51: Synthesis of 6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-3-(2-(2-oxoimidazolidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine-6-carbonyl)pyridin-2(1H)-one

[0628] Step 1: (6-chloropyridine-2,3-diyl)dimethanol.

[0629] To a solution of methyl 6-chloro-2-(methoxycarbonyl)pyridine-3-carboxylate (1 g, 15.24 mmol) in THF (40 mL) and MeOH(1.5 ml) at 0℃ was dropwise added LiBH4 (1.01 g, 45.72 mmol), the resulting mixture was stirred at rt for 3 h under N2. The reaction mixture was quenched with sat. NH4Cl solution (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product [6-chloro-2-(hydroxymethyl)pyridin-3- yl]methanol as a brown solid, used directly next step. [M]+ calcd:173, found:174.

[0630] Step 2: 6-chloro-2,3-bis(chloromethyl)pyridine.

[0631] To a solution of crude [6-chloro-2-(hydroxymethyl)pyridin-3-yl]methanol in SOCl2 (10 mL) mmol) at 0oC, the resulting mixture was stirred at 35oC for 18 h under N2.The reaction mixture was quenched with iced-water (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 10%) to obtain the desired product 6- chloro-2,3-bis(chloromethyl)pyridine(450 mg, 2.15 mmol) as a brown solid,[M]+ calcd:209, found:210.

[0632] Step 3: 2-chloro-6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridine.

[0633] To a solution of 6-chloro-2,3-bis(chloromethyl)pyridine(450 mg, 2.15 mmol) in DMF (6 mL) was added DIEA (832 mg, 6.45 mmol) and (2,4- dimethoxyphenyl)methanamine (359 mg, 2.15 mmol) at rt. The resulting mixture was stirred at rt for 18h under N2.The reaction mixture was filtered and concentrated to give the crude product which was purified by prep-HPLC to obtain the desired product 2-chloro-6-(2,4- dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine (250 mg, 0.82 mmol, 38.24%) as a yellow solid. [M]+ calcd:304, found:305.1H NMR (400 MHz, CDCl3) δ 7.33 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 6.43 – 6.39 (m, 2H), 3.94 (s, 2H), 3.89 (s, 2H), 3.82 (s, 2H), 3.75 (d, J = 3.9 Hz, 6H).

[0634] Step 4: 1-(6-(2,4-dimethoxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2- yl)imidazolidin-2-one.

[0635] To a solution of 2-chloro-6-[(2,4-dimethoxyphenyl)methyl]-6,7-dihydro-5H- pyrrolo[4,3-b]pyridine (100 mg, 0.33 mmol) and 2-oxotetrahydro-1H-imidazole (33.90 mg, 0.39 mmol) in toluene (5 mL) was added Cs2CO3(320.90 mg, 0.98 mmol), xant phos(11.58 mg, 0.02 mmol) and Pd2(dba)3 (30.09 mg, 0.03 mmol), the resulting mixture was stirred at 100oC for 3h under N2. The reaction mixture was cooled to rt, quenched with water (50 mL), extracted with EtOAc (30 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by column chromatography on silica gel ( EtOAc in PE = 0 ~ 50%) to obtain the desired product 6-[(2,4-dimethoxyphenyl)methyl]-2-(2-oxotetrahydro-1H- imidazol-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine (80 mg, 0.23 mmol, 68.79%) as a yellow solid. [M]+ calcd:354, found:355

[0636] Step 5: 1-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)imidazolidin-2-one.

[0637] To a solution of 6-[(2,4-dimethoxyphenyl)methyl]-2-(2-oxotetrahydro-1H- imidazol-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine (60 mg, 0.16 mmol) in DCM (3 mL) at 0℃ was dropwise added 1-chloroethyl chloromethanoate (72.61 mg, 0.51 mmol), the resulting mixture was stirred at 40℃ for 1 h under N2, and the reaction mixture was concentrated and the residue was added MeOH (3 ml) at rt, the reaction mixture was stirred at 70oC for another 1 h. The reaction mixture was concentrated to give the crude product 2-(2- oxotetrahydro-1H-imidazol-1-yl)-6,7-dihydro-5H-pyrrolo[4,3-b]pyridine (20 mg, 0.10 mmol, 57.84%) as a brown solid. [M]+ calcd:204, found:205.

[0638] Step 6: 6-(chlorodifluoromethyl)-4-((2,6-dichlorophenyl)thio)-3-(2-(2- oxoimidazolidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-6-carbonyl)pyridin-2(1H)- one.

[0639] To a solution of 4-[(2,6-dichloro-3-cyanophenyl)sulfanyl]-2-oxo-6- (trifluoromethyl)-1H-pyridine-3-carboxylic acid (20 mg, 0.10 mmol) in MeCN (2 mL) at 0℃ was dropwise added 5,6-dimethoxy-2,3-dihydro-1H-isoindole (32 mg, 0.08 mmol), NMI (28.7 mg, 0.35 mmol) and TCFH (36.58 mg, 0.13 mmol) the resulting mixture was stirred at rt for 18 h under N2. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL x 3), the combined organic layer was washed by water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product which was purified by prep-HPLC to obtain the desired product 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-3-{[2-(2-oxotetrahydro-1H-imidazol-1-yl)-6,7-dihydro-5H- pyrrolo[4,3-b]pyridin-6-yl]carbonyl}-1,2-dihydropyridin-2-one (4.8 mg, 0.01 mmol) as a white solid. [M]+ calcd:570, found:571.1H NMR (400 MHz, DMSO) δ 12.88 (s, 1H), 8.16 (dd, J = 14.9, 8.7 Hz, 1H), 7.79 – 7.67 (m, 3H), 7.65 – 7.58 (m, 1H), 7.25 (s, 1H), 6.25 (s, 1H), 4.72 (dd, J = 44.3, 26.7 Hz, 4H), 3.97 (dt, J = 31.5, 8.0 Hz, 2H), 3.44 – 3.37 (m, 2H).

[0640] Example 52: Synthesis of 3-(4-((1H-tetrazol-5-yl)methyl)isoindoline-2- carbonyl)-4-((2,6-dichlorophenyl)thio)-6-(trifluoromethyl)pyridin-2(1H)-one

[0641] Step 1: tert-butyl 4-formylisoindoline-2-carboxylate

[0642] To a solution of 2-methylpropan-2-yl 4-bromo-2,3-dihydro-1H-isoindole-2- carboxylate (1 g, 3.35 mmol) in DMF (20 mL) and MeOH (20 mL), Pd(dppf)Cl2 (0.25 g, 0.34 mmol) and TEA (0.47 mL, 3.35 mmol) was stirred 16 h at 90 ℃ and TM was detected. The mixture was cooled to rt and the residue was diluted with water and extracted with EA. The organic layer was dried, concentrated and purified by chromatography (silica gel, PE: EA=1:1) to give methyl 2-{[(2-methylprop-2-yl)oxy]carbonyl}-2,3-dihydro-1H-isoindole-4- carboxylate (500 mg, 1.80 mmol, 53.76 %) as oil.[M]+calcd:277.13, found:278.2.1H NMR (400 MHz, CDCl3) δ 7.89 (dd, J = 12.8, 8.0 Hz, 1H), 7.89 (dd, J = 12.8, 8.0 Hz, 2H), 7.33 (dt, J = 20.4, 7.4 Hz, 2H), 4.90 (d, J = 10.4 Hz, 2H), 4.63 (d, J = 13.8 Hz, 3H), 3.86 (t, J = 7.4 Hz, 3H), 1.52 – 1.40 (m, 9H).

[0643] Step 2: tert-butyl 4-(hydroxymethyl)isoindoline-2-carboxylate

[0644] To a solution of methyl 2-{[(2-methylprop-2-yl)oxy]carbonyl}-2,3-dihydro-1H- isoindole-4-carboxylate (770 mg, 2.78 mmol) in THF (4 mL) , LiAlH4(158.06 mg, 4.17 mmol) was added at 0 ℃, then was stirred at rt 16 h , TM was detected. The mixture was cooled to rt and the residue was diluted with water and extracted with EA. The organic layer was dried, concentrated and purified by chromatography (silica gel, PE: EA=1:1) to give 2- methylpropan-2-yl 4-(hydroxymethyl)-2,3-dihydro-1H-isoindole-2-carboxylate (250 mg, 1.003 mmol, 36.12 %) as oil. [M]+calcd:249,found:250

[0645] Step 3: tert-butyl 4-(((methylsulfonyl)oxy)methyl)isoindoline-2-carboxylate

[0646] To a solution of 2-methylpropan-2-yl 4-(hydroxymethyl)-2,3-dihydro-1H- isoindole-2-carboxylate (785 mg, 3.15 mmol) in DCM (15 mL), TEA (2.63 mL, 18.89 mmol)was added at 0℃ 15 min, after MsCl (1081.95 mg, 9.45 mmol) was added at 0 ℃, the mixture was stirred 3 hours at rt. The reaction was diluted with DCM and water. The organic layer was separated, washed with NaCl and NaHCO3solution, and concentrated in vacuo. Then the residue to give 2-(2-{[(2-methylprop-2-yl)oxy]carbonyl}-2,3-dihydro-1H-isoindol- 4-yl)ethane-1-sulfonic acid (800 mg, 2.44 mmol) as crude.[M]+calcd:327,found:328

[0647] Step 4: tert-butyl 4-(cyanomethyl)isoindoline-2-carboxylate

[0648] To a solution of 2-(2-{[(2-methylprop-2-yl)oxy]carbonyl}-2,3-dihydro-1H- isoindol-4-yl)ethane-1-sulfonic acid (750 mg, 2.29 mmol) in DMF (5 mL) , KCN (745.90 mg, 11.45 mmol), the mixture was stirred 16 hours at rt, TM was detected. The mixture was cooled to rt and the residue was diluted with water and extracted with EA. The organic layer was dried, concentrated and purified by chromatography (silica gel, PE: EA=1:1) to give 2- methylpropan-2-yl 4-(cyanomethyl)-2,3-dihydro-1H-isoindole-2-carboxylate (400 mg, 1.55 mmol, 67.59 %) as oil. [M]+calcd:258,found:259.1H NMR (400 MHz, CDCl3) δ 7.39 – 7.01 (m, 3H), 4.82 – 4.47 (m, 4H), 3.58 (d, J = 4.0 Hz, 2H), 1.45 (d, J = 3.4 Hz, 9H).

[0649] Step 5: tert-butyl 4-((1H-tetrazol-5-yl)methyl)isoindoline-2-carboxylate

[0650] To a solution of 2-methylpropan-2-yl 4-(cyanomethyl)-2,3-dihydro-1H-isoindole- 2-carboxylate (35 mg, 0.14 mmol) in DMF (dry, 4 mL) was added sodium diazoazanide (132.035 mg, 2.031 mmol) and CAN (26.94 mg, 0.068 mmol). The mixture was stirred at 110oC for overnight. The mixture was cooled to rt and diluted with water. The mixture was acidified by 1 M HCl aq. and then the mixture was extracted with EA. The organic layer was dried and concentrated and purified by prep-HPLC to give 2-methylpropan-2-yl 4-(4H- 1,2,3,4-tetraazol-5-ylmethyl)-2,3-dihydro-1H-isoindole-2-carboxylate (7 mg, 0.023 mmol, 17.14 %). [M]+calcd: 301, found: 302.1H NMR (400 MHz, DMSO) δ 7.45 – 7.02 (m, 3H), 4.66 – 4.42 (m, 4H), 4.25 (d, J = 4.8 Hz, 2H), 1.46 (d, J = 2.4 Hz, 9H).

[0651] Step 6: 4-((1H-tetrazol-5-yl)methyl)isoindoline

[0652] To a solution of 2-methylpropan-2-yl 4-(4H-1,2,3,4-tetraazol-5-ylmethyl)-2,3- dihydro-1H-isoindole-2-carboxylate (7 mg, 0.023 mmol) in DCM (1 ml) was added HCl / dioxane (0.5 ml). The mixture was stirred at rt for 2 hours. The mixture was concentrated to give 4-(4H-1,2,3,4-tetraazol-5-ylmethyl)-2,3-dihydro-1H-isoindole (5 mg) as a crude. [M]+calcd: 201, found: 202.

[0653] Step 7: 3-(4-((1H-tetrazol-5-yl)methyl)isoindoline-2-carbonyl)-4-((2,6- dichlorophenyl)thio)-6-(trifluoromethyl)pyridin-2(1H)-one

[0654] To a solution of 4-(4H-1,2,3,4-tetraazol-5-ylmethyl)-2,3-dihydro-1H-isoindole (28.09 mg, 0.14 mmol) in ACN (3 mL) was added 4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo-6- (trifluoromethyl)-1H-pyridine-3-carboxylic acid (48.25 mg, 0.13 mmol) and NMI (70 mg, 0.85 mmol) and TCFH (50.92 mg, 0.18 mmol).The mixture was stirred at rt for overnight. The mixture was filtered and purified by prep-HPLC to give 4-[(2,6- dichlorophenyl)sulfanyl]-3-{[4-(4H-1,2,3,4-tetraazol-5-ylmethyl)-2,3-dihydro-1H-isoindol-2- yl]carbonyl}-6-(trifluoromethyl)-1,2-dihydropyridin-2-one (2.6 mg, 0.005 mmol, 3.28 %). [M]+calcd: 566, found:568.1H NMR (400 MHz, DMSO) δ 7.74 (dt, J = 12.0, 5.8 Hz, 2H), 7.62 (dd, J = 14.4, 6.8 Hz, 1H), 7.48 – 7.25 (m, 2H), 7.18 (s, 1H), 6.40 – 6.20 (m, 1H), 4.92 – 4.63 (m, 4H), 4.35 – 4.16 (m, 2H).

[0655] Example 53: Synthesis of 6-(chlorodifluoromethyl)-4-[(2,6- dichlorophenyl)sulfanyl]-3-{[6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2-one

[0656] Step 1: 2-methylpropan-2-yl 6-methoxy-5-nitro-2,3-dihydro-1H-isoindole-2- carboxylate

[0657] To a solution of 6-methoxy-5-nitro-2,3-dihydro-1H-isoindole (1.00 g, 5.15 mmol) and (BOC)2O (1.69 g, 7.72 mmol) in DCM (10 mL) was added TEA (1.43 mL, 10.30 mmol), the reaction was stirred at rt for 4 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by column chromatography on silica gel to give 2-methylpropan-2-yl 6-methoxy-5-nitro-2,3-dihydro-1H-isoindole-2-carboxylate (500.00 mg, 1.70 mmol, 32.99%) as a white solid. [M]+ calcd:238,found:239.

[0658] Step 2: 2-methylpropan-2-yl 5-amino-6-methoxy-2,3-dihydro-1H-isoindole-2- carboxylate

[0659] To a solution of 2-methylpropan-2-yl 6-methoxy-5-nitro-2,3-dihydro-1H- isoindole-2-carboxylate (0.50 g, 1.70 mmol) in MeOH (20 mL) was added Pd / C 10% (0.18 g,0.17 mmol), the reaction was stirred at rt for 3 h under H2. LCMS showed the reaction was completed. The reaction was filtered and the filtrate was concentrated under reduced pressure to give 2-methylpropan-2-yl 5-amino-6-methoxy-2,3-dihydro-1H-isoindole-2-carboxylate (200.00 mg, 0.76 mmol, 44.54%) as a colorless oil. [M]+ calcd:264,found:265.

[0660] Step 3: 2-methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)- 2,3-dihydro-1H-isoindole-2-carboxylate0oC~rt 3 4

[0661] To a solution of 2-methylpropan-2-yl 5-amino-6-methoxy-2,3-dihydro-1H- isoindole-2-carboxylate (180.00 mg, 0.68 mmol) in DCM (10 mL) was added N-(3- chloropropyl)-1-oxomethanimine (81.41 mg, 0.68 mmol) dropwise at 0oC under N2, stirred at rt for 18 h, then concentrated under reduced pressure and dissolved in THF (10 mL), the reaction was cooled to 0oC and added NaH (81.72 mg, 2.04 mmol) and stirred at rt for 1 h. LCMS showed the reaction was completed. The reaction was quenched with H2O and extracted with EA, the organic layer was concentrated under reduced pressure to give 2- methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole- 2-carboxylate (150.00 mg, 0.43 mmol, 63.40%) as a white solid. [M]+ calcd:347,found:3481H NMR (400 MHz, DMSO) δ 7.08 (d, J = 7.6 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.39 (s, 1H), 4.56 (d, J = 9.7 Hz, 2H), 4.49 (d, J = 8.1 Hz, 2H), 3.77 (t, J = 6.5 Hz, 3H), 3.39 (d, J = 3.3 Hz, 2H), 3.25 – 3.20 (m, 2H), 1.94 – 1.82 (m, 2H), 1.47 (s, 9H).

[0662] Step 4: 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H- isoindole

[0663] A solution of 2-methylpropan-2-yl 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)- 2,3-dihydro-1H-isoindole-2-carboxylate (100.00 mg, 0.29 mmol) in TFA (1 mL) and DCM(2 mL) was stirred at rt for 1 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and the residue was dissolved in DCM, the solution was adjusted with aq.NaHCO3to pH~6, the organic layer was concentrated under reduced pressure to give 6-methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (60.00 mg, 0.24 mmol, 84.29%) as a white solid. [M]+ calcd:247,found:248

[0664] Step 5: 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-{[6- methoxy-5-(2-oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2- dihydropyridin-2-one

[0665] To a solution of 6-(chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-2-oxo- 1H-pyridine-3-carboxylic acid (60.00 mg, 0.15 mmol), 6-methoxy-5-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindole (37.04 mg, 0.15 mmol) and NMI (73.69 mg, 0.90 mmol) in MeCN (5 mL) was added TCFH (54.52 mg, 0.19 mmol), the reaction was stirred at rt for 18 h. LCMS showed the reaction was completed. The reaction was concentrated under reduced pressure and purified by prep-HPLC to give 6- (chlorodifluoromethyl)-4-[(2,6-dichlorophenyl)sulfanyl]-3-{[6-methoxy-5-(2- oxohexahydropyrimidin-1-yl)-2,3-dihydro-1H-isoindol-2-yl]carbonyl}-1,2-dihydropyridin-2- one (10.50 mg, 0.02 mmol, 11.13%) as a white solid. [M]+ calcd:629,found:6301H NMR (400 MHz, DMSO) δ 12.89 (s, 1H), 7.73 (d, J = 8.1 Hz, 2H), 7.59 (t, J = 7.6 Hz, 1H), 7.11 (m, J = 17.4, 13.3 Hz, 2H), 6.40 (d, J = 7.8 Hz, 1H), 6.01 (s, 1H), 4.87 – 4.42 (m, 4H), 3.76 (d, J = 23.8 Hz, 3H), 3.38 (d, J = 3.8 Hz, 2H), 3.22 (d, J = 4.0 Hz, 2H), 1.91 (m, J = 11.5, 5.7 Hz, 2H).19F NMR (377 MHz, DMSO) δ -54.77 (s).

[0666] Example 54: Synthesis of 4-(2-(6-(chlorodifluoromethyl)-4-((2,6- dichlorophenyl)thio)-2-oxo-1,2-dihydropyridine-3-carbonyl)-6-methoxyisoindolin-5- yl)morpholin-3-one

[0667] Step 1: tert-butyl 5-methoxy-6-(3-oxomorpholino)isoindoline-2-carboxylate

[0668] To a solution of tert-butyl 5-bromo-6-methoxyisoindoline-2-carboxylate (200 mg, 0.6 mmol) and morpholin-3-one (96 mg, 0.9 mmol) in dioxane (10 mL) was added Cs2CO3 (342 mg, 1.8 mmol), trace-dimethylcyclohexane-1,2-diamine (17 mg, 0.12 mmol) and CuI (83 mg, 0.6 mmol), The resulting mixture was heated to 120°C overnight. After being cooled down to room temperature, the reaction was partitioned between EtOAc and water, organic layer was separated, aqueous layer was extracted with EtOAc twice, the combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated, the residue was purified by flash column chromatography (silica gel, 0~100%, ethyl acetate in petroleum ether) to afford tert-butyl 5-methoxy-6-(3-oxomorpholino)isoindoline-2-carboxylate (56 mg, 0.16 mmol, 26%) as a white solid. LCMS (m / z): [M+H]+calcd, 349; found, 349 (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.09 (d, J = 25.9 Hz, 1H), 6.87 (d, J = 20.2 Hz, 1H), 4.69 – 4.56 (m, 4H), 4.35 (s, 2H), 4.02 (t, J = 4.9 Hz, 2H), 3.84 (d, J = 5.1 Hz, 3H), 3.63 (s, 2H), 1.51 (s, 9H).

[0669] Step 2: 4-(6-methoxyisoindolin-5-yl)morpholin-3-one

[0670] To a solution of tert-butyl 5-methoxy-6-(3-oxomorpholino)isoindoline-2- carboxylate (56 mg, 0.16 mmol) in DCM (3 mL) was added HCl (3 mL, 4 M in dioxane). After being stirred at rt for 3 hr, The reaction mixture was concentrated to afford the 4-(6- methoxyisoindolin-5-yl)morpholin-3-one as a white solid which was used in the next step directly without further purification. LCMS (m...

Claims

Listing of Claims:

1. A compound having the structural formula I:or a pharmaceutically acceptable salt thereof, wherein Y is C(O) or CRx1Ry1; Y1is C(O) or CRxRy; Y2is C(O) or CRx2Ry2; X, X1, X2, and X3are each independently is N or CH; R1is phenyl, carbocyclyl, heterocyclyl, or heteroaryl, each of which are substituted with 1 to 4 groups selected from Ra; R2is (C1-C4)alkyl or halo(C1-C4)alkyl; R3is hydrogen, halo, (C1-C4)alkyl, -(C1-C4)alkylcycloalkyl, cycloalkyl, -(C1-C4)alkyl heterocyclyl, and heterocyclyl, wherein each heterocyclyl and cycloalkyl alone, or as connected to (C1-C4)alkyl, are optionally substituted with one or more groups selected from halo, oxo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; each R4is independently selected from halo, (C1-C4)alkyl, (C2-C4)alkynyl, (C2- C4)alkenyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkoxyNRcRd, -(C1-C4)alkylC(O)ORc, -(C1- C4)alkoxyC(O)ORc, -(C1-C4)alkylC(O)Rc, -(C1-C4)alkoxyC(O)Rc, -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkoxyheterocyclyl, -(C1-C4)alkoxyheteroaryl, -(C1- C4)alkylcycloalkyl, -(C1-C4)alkoxycycloalkyl, -NRc(C1-C4)alkylheteroaryl, -NRc(C1- C4)alkylheterocyclyl, -NRc(C1-C4)alkylcycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, - NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -(C1- C4)alkylNRcC(O)Rd, -(C1-C4)alkylNRcC(O)ORd, -(C1-C4)alkylNRc(C1-C4)alkylC(O)NRdRe, - (C1-C4)alkylNRcC(O)NRdRe, -(C1-C4)alkoxyNRcC(O)Rd, -(C1-C4)alkoxyNRcC(O)ORd, -(C1- C4)alkoxyNRc(C1-C4)alkylC(O)NRdRe, -(C1-C4)alkoxyNRcC(O)NRdRe, -S(C1-C4)alkyl, - O(heteroaryl), -O(heterocyclyl), -O(cycloalkyl), -C(O)NRcRd, -(C1-C4)alkylC(O)NRcRd, - (C1-C4)alkoxyC(O)NRcRd, C(O)Rc, and -C(O)ORc, wherein each heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb;each Rais independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, cyano(C2-C4)alkynyl, -(C2- C4)alkynyl heterocyclyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, cyano, -(C1- C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylNRc1Rd1, -(C1-C4)alkoxyNRc1Rd1, -(C1- C4)alkylC(O)ORc1, -(C1-C4)alkoxyC(O)ORc1, -(C1-C4)alkylC(O)Rc1, -(C1-C4)alkoxyC(O)Rc1, -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkoxy heterocyclyl, -(C1- C4)alkoxyheteroaryl, -(C1-C4)alkylcycloalkyl, -(C1-C4)alkoxycycloalkyl, -NRc(C1- C4)alkylheteroaryl, -NRc1(C1-C4)alkylheterocyclyl, -NRc1(C1-C4)alkylcycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, -NRc1Rd1, -NRc1C(O)Rd1, -NRc1C(O)ORd1, -NRc1(C1- C4)alkylC(O)NRd1Re1, -NRc1C(O)NRd1Re1, -(C1-C4)alkylNRc1C(O)Rd1, -(C1- C4)alkylNRc1C(O)ORd1, -(C1-C4)alkylNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1- C4)alkylNRc1C(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)Rd1, -(C1-C4)alkoxyNRc1C(O)ORd1, - (C1-C4)alkoxyNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)NRd1Re1, -S(C1- C4)alkyl, -C(O)NRc1Rd1, -(C1-C4)alkylC(O)NRc1Rd1, -(C1-C4)alkoxyC(O)NRc1Rd1, -C(O)Rc1, and -C(O)ORc1, wherein each heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb1; Rx, Ry, Rx1, Ry1, Rx2, and Ry2are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkylaryl, (C1-C4)alkylheterocyclyl, (C1-C4)alkyl(C3- C6)cycloalkyl, -(C2-C4)alkynylC(O)Rd3, cyano(C2-C4)alkynyl, hydroxy(C1-C4)alkyl, -(C1- C4)alkyl(C1-C4)alkoxy, hydroxy(C2-C4)alkynyl, -(C1-C4)alkylS(O)2(C1-C4)alkyl, -(C1- C4)alkylS(O)(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, cyano(C1-C4)alkyl, - (C1-C4)alkylNRc3Rd3, -(C1-C4)alkoxyNRc3Rd3, -(C1-C4)alkylC(O)ORc3, -(C1- C4)alkoxyC(O)ORc3, -(C1-C4)alkylC(O)Rc3, -(C1-C4)alkoxyC(O)Rc3, -(C1- C4)alkylNRc3C(O)Rd3, -(C1-C4)alkylNRc3C(O)ORd3, -(C1-C4)alkylNRc3(C1- C4)alkylC(O)NRd3Re3, -(C1-C4)alkylNRc3C(O)NRd3Re3, -(C1-C4)alkoxyNRc3C(O)Rd3, -(C1- C4)alkoxyNRc3C(O)ORd3, -(C1-C4)alkoxyNRc3(C1-C4)alkylC(O)NRd3Re3, -(C1- C4)alkoxyNRc3C(O)NRd3Re3, -C(O)NRc3Rd3, -(C1-C4)alkylC(O)NRc3Rd3, -C(O)Rc3, - C(O)ORc3, aryl, and heteroaryl; or Rxand Ry, Rx1and Ry1, and / or Rx1and Ry1are taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl or heterocyclyl, each optionally substituted with one or more groups selected from halo, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; Rb, Rb1, Rb2, and Rb3are each independently selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, hydroxy, phenyl, heteroaryl, heterocyclyl, cycloalkyl, -(C1-C4)alkylheteroaryl, -(C1-C4)alkylheterocyclyl, -(C1-C4)alkylphenyl, -(C1-C4)alkylcycloalkyl, -NRc2Rd2, -NRc2C(O)Rd2, -NRc2C(O)ORd2, -C(O)NRc2Rd2, -C(O)ORc2, - C(O)Rc2, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylNRc2Rd2, -(C1-C4)alkylNRc2C(O)Rd2, - (C1-C4)alkylNRc2C(O)ORd2, -(C1-C4)alkylC(O)NRc2Rd2, -(C1-C4)alkylC(O)ORc2, and -(C1- C4)alkylC(O)Rc2, wherein each phenyl, heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more groups selected from (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, (C1-C4)alkenyl, halo(C1- C4)alkenyl, -S(O)2(C1-C4)alkyl, -S(O)2(C1-C4)alkenyl, cyano, phenyl, benzyl, 4- to 6- membered heterocyclyl, and 5- to 7-membered heteroaryl; Rc, Rd, Re, Rc1, Rd1, Rc2, Rd2, Re1, Rc3, Rd3, Re3, and Rf3are each independently selected from hydrogen, (C1-C4)alkyl, halo(C1-C4)alkyl, phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl; p is 1, 2, 3 or 4; and when p is 2 or 3 or 4, two R4groups on adjacent carbon atoms may be taken together to form a 6-membered heterocyclyl or a phenyl, each of which may be optionally substituted with one or more groups selected from Rb2; provided the compound is not 4-((2,6-dichlorophenyl)thio)-3-(5,6- dimethoxyisoindoline-2-carbonyl)-6-(trifluoromethyl)pyridin-2(1H)-one or 2-(4-((2,6- dichlorophenyl)thio)-2-oxo-6-(trifluoromethyl)-1,2-dihydropyridine-3-carbonyl)isoindoline- 4-carbonitrile; or a salt thereof.

2. The compound of Claim 1, or a pharmaceutically acceptable salt thereof, wherein Rx, Ry, Rx1, Ry1, Rx2, and Ry2are each independently selected from hydrogen, (C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkylaryl, (C1-C4)alkylheterocyclyl, (C1-C4)alkyl(C3- C6)cycloalkyl, -(C2-C4)alkynylC(O)Rd3, cyano(C2-C4)alkynyl, hydroxy(C2-C4)alkynyl, -(C1- C4)alkylS(O)2(C1-C4)alkyl, -(C1-C4)alkylS(O)(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1- C4)alkoxy, cyano, cyano(C1-C4)alkyl, -(C1-C4)alkylNRc3Rd3, -(C1-C4)alkoxyNRc3Rd3, -(C1- C4)alkylC(O)ORc3, -(C1-C4)alkoxyC(O)ORc3, -(C1-C4)alkylC(O)Rc3, -(C1-C4)alkoxyC(O)Rc3, -(C1-C4)alkylNRc3C(O)Rd3, -(C1-C4)alkylNRc3C(O)ORd3, -(C1-C4)alkylNRc3(C1- C4)alkylC(O)NRd3Re3, -(C1-C4)alkylNRc3C(O)NRd3Re3, -(C1-C4)alkoxyNRc3C(O)Rd3, -(C1- C4)alkoxyNRc3C(O)ORd3, -(C1-C4)alkoxyNRc3(C1-C4)alkylC(O)NRd3Re3, -(C1- C4)alkoxyNRc3C(O)NRd3Re3, -C(O)NRc3Rd3, -(C1-C4)alkylC(O)NRc3Rd3, -C(O)Rc3, - C(O)ORc3, aryl, and heteroaryl; or Rxand Ry, Rx1and Ry1, and / or Rx1and Ry1are taken together with the carbon atom to which they are attached to form a (C3-C6)cycloalkyl or (C3-C6)alkylheterocyclyl, each optionally substituted with one or more groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy; and Rb, Rb1, Rb2, and Rb3are each independently selected from (C1-C4)alkyl, halo(C1- C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, oxo, hydroxy, phenyl, -NRc2Rd2, -NRc2C(O)Rd2, -NRc2C(O)ORd2, -C(O)NRc2Rd2, -C(O)ORc2, -C(O)Rc2, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1- C4)alkylNRc2Rd2, -(C1-C4)alkylNRc2C(O)Rd2, -(C1-C4)alkylNRc2C(O)ORd2, -(C1- C4)alkylC(O)NRc2Rd2, -(C1-C4)alkylC(O)ORc2, and -(C1-C4)alkylC(O)Rc2.

3. The compound of Claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, hydroxy(C1- C4)alkyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, cyano(C2-C4)alkynyl, -(C2- C4)alkynylheterocyclyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy, cyano, -(C1- C4)alkylNRc1Rd1, -(C1-C4)alkoxyNRc1Rd1, -(C1-C4)alkylC(O)ORc1, -(C1-C4)alkoxyC(O)ORc1, -(C1-C4)alkylC(O)Rc1, -(C1-C4)alkoxyC(O)Rc1, -(C1-C4)alkylheterocyclyl, -(C1- C4)alkylheteroaryl, -(C1-C4)alkoxy heterocyclyl, -(C1-C4)alkoxyheteroaryl, -(C1- C4)alkylcycloalkyl, -(C1-C4)alkoxycycloalkyl, -NRc(C1-C4)alkylheteroaryl, -NRc1(C1- C4)alkylheterocyclyl, -NRc1(C1-C4)alkylcycloalkyl, cycloalkyl, heteroaryl, heterocyclyl, - NRc1Rd1, -NRc1C(O)Rd1, -NRc1C(O)ORd1, -NRc1(C1-C4)alkylC(O)NRd1Re1, - NRc1C(O)NRd1Re1, -(C1-C4)alkylNRc1C(O)Rd1, -(C1-C4)alkylNRc1C(O)ORd1, -(C1- C4)alkylNRc1(C1-C4)alkylC(O)NRd1Re1, -(C1-C4)alkylNRc1C(O)NRd1Re1, -(C1- C4)alkoxyNRc1C(O)Rd1, -(C1-C4)alkoxyNRc1C(O)ORd1, -(C1-C4)alkoxyNRc1(C1- C4)alkylC(O)NRd1Re1, -(C1-C4)alkoxyNRc1C(O)NRd1Re1, -S(C1-C4)alkyl, -C(O)NRc1Rd1, - (C1-C4)alkylC(O)NRc1Rd1, -(C1-C4)alkoxyC(O)NRc1Rd1, -C(O)Rc1, and -C(O)ORc1, wherein each heteroaryl, heterocyclyl, and cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb1.

4. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Y is CRx1Ry1.

5. The compound of any one of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Rx1and Ry1are each independently selected from hydrogen, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, -(C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkylC(O)ORc3, -(C1- C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl.

6. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Rx1and Ry1are each independently selected from hydrogen, (C1-C4)alkyl, - (C1-C4)alkylC(O)ORc3, -(C1-C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl.

7. The compound of any one of Claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein Rx1and Ry1are each independently selected from hydrogen, -(C1- C4)alkylNRc3Rd3, and cyano(C1-C4)alkyl.

8. The compound of any one of Claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein Rx1and Ry1are each independently selected from hydrogen, CH3, CH2C(O)NH2, CH2C(O)OH, CH2C(O)OCH3, CH2OCH3, CH2OH, CH2NH2, CH2NHCH3, and CH2CN.

9. The compound of any one of Claims 1 to 8, or a pharmaceutically acceptable salt thereof, wherein Rx1and Ry1are each independently selected from hydrogen, CH3, CH2C(O)NH2, CH2C(O)OH, CH2C(O)OCH3, and CH2CN.

10. The compound of any one of Claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein Rx1and Ry1are each independently selected from hydrogen, CH2C(O)NH2, and CH2CN.

11. The compound of any one of Claims 1 to 10, or a pharmaceutically acceptable salt thereof, wherein Y is CH2.

12. The compound of any one of Claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein Y2is CRx2Ry2.

13. The compound of any one of Claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein Y2is CH2.

14. The compound of any one of Claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein X, X1, X2, and X3are each CH.

15. The compound of any one of Claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen or CH3.

16. The compound of any one of Claims 1 to 15, or a pharmaceutically acceptable salt thereof, wherein R3is hydrogen.

17. The compound of any one of Claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R2is halo(C1-C4)alkyl.

18. The compound of any one of Claims 1 to 17, or a pharmaceutically acceptable salt thereof, wherein R2is CF2Cl, CF3, or CF2CH3.

19. The compound of any one of Claims 1 to 18, or a pharmaceutically acceptable salt thereof, wherein R2is CF2Cl.

20. The compound of any one of Claims 1 to 19, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl or heteroaryl, each of which are substituted with 1 to 4 groups selected from Ra.

21. The compound of any one of Claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl or 5- to 7-membered heteroaryl, each of which are substituted with 1 to 4 groups selected from Ra.

22. The compound of any one of Claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R1is phenyl, oxazolyl, or thiazolyl, each of which are substituted with 1 to 4 groups selected from Ra.

23. The compound of any one of Claims 1 to 22, or a pharmaceutically acceptable salt.

24. The compound of any one of Claims 1 to 23, or a pharmaceutically acceptable saltthereof, wherein R1 is selected from25. The compound of any one of Claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein26. The compound of any one of Claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, (C1-C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl[5- to 7- membered heterocyclyl], 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, (C1- C4)alkylNRc1Rd1, hydroxy, cyano, (C3-C6)cycloalkyl, -C(O)NRc1Rd1, and -C(O)ORc1.

27. The compound of any one of Claims 1 to 26, or a pharmaceutically acceptable salt thereof, wherein each Rais independently selected from halo, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano(C1-C4)alkyl, -(C1-C4)alkyl[5- to 7-membered heterocyclyl], 5- to 7-membered heteroaryl, 5- to 7-membered heterocyclyl, (C1-C4)alkylNRc1Rd1, hydroxy, cyano, (C3-C6)cycloalkyl, -C(O)NRc1Rd1, and -C(O)ORc1.

28. The compound of any one of Claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein Rc1and Rd1are each independently selected from hydrogen and (C1- C4)alkyl.

29. The compound of any one of Claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R1is selected from, , ,30. The compound of any one of Claims 1 to 29, or a pharmaceutically acceptable salt ,31. The compound of any one of Claims 1 to 30, or a pharmaceutically acceptable salt thereof, wherein32. The compound of any one of Claims 1 to 31, or a pharmaceutically acceptable salt thereof, wherein Y1is C(O).

33. The compound of any one of Claims 1 to 32, or a pharmaceutically acceptable salt thereof, wherein p is 1 or 2.

34. The compound of any one of Claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein two R4groups on adjacent carbon atoms are taken together to form 1,4- dioxanyl, 1,3-dioxolanyl, morpholinyl, or a phenyl, each of which may be optionally substituted with one or more groups selected from Rb2.

35. The compound of any one of Claims 1 to 34, or a pharmaceutically acceptable salt thereof, wherein Rb2is (C1-C4)alkyl, C(O)Rc2, or (C1-C4)alkylC(O)ORc2.

36. The compound of any one of Claims 1 to 35, or a pharmaceutically acceptable salt thereof, wherein Rb2is C(O)CH3, CH2C(O)OCH2CH3, or CH3.

37. The compound of any one of Claims 1 to 36, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, (C1-C4)alkyl, hydroxy(C1- C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, (C2-C4)alkynyl, hydroxy, cyano, -(C1- C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1-C4)alkoxyC(O)ORc, -(C1-C4)alkyl[5- to 9- membered heteroaryl], -O[5- to 9-membered heteroaryl], (C3-C6)cycloalkyl, 5- to 9- membered heteroaryl, 4- to 9-membered heterocyclyl, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, - NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each 5- to 7-membered heteroaryl, 4- to 9-membered heterocyclyl, and (C3- C6)cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb.

38. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, (C1-C4)alkyl, hydroxy(C1- C4)alkyl, (C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1- C4)alkoxyC(O)ORc, -(C1-C4)alkyl[5- to 7-membered heteroaryl], -O[5- to 7-membered heteroaryl], (C3-C6)cycloalkyl, 5- to 7-membered heteroaryl, 4- to 9-membered heterocyclyl, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, -NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1- C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each 5- to 7-membered heteroaryl, 4- to 9- membered heterocyclyl, and (C3-C6)cycloalkyl alone, or as connected to another group, are optionally substituted with one or more Rb.

39. The compound of any one of Claims 1 to 38, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, (C1-C4)alkyl, hydroxy(C1- C4)alkyl, (C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1- C4)alkoxyC(O)ORc, -(C1-C4)alkyltetrazolyl, -O(pyrimidinyl), pyrimidinyl, oxazolidinyl, cylopropyl, pyrazolyl, imidazolyl, thiophenyl, 1,2,3-triazolyl, tetrazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H- imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, 5,6,7,8- tetrahydroimidazo[1,2-a]pyrimidinyl, imidazolidinyl, 5-azaspiro[2.5]octanyl, 2,3-dihydro- 1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, -NRcRd, - NRcC(O)Rd, -NRcC(O)ORd, -NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each, tetrazolyl, pyrimidinyl, pyrazolyl, imidazolyl, thiopheneyl, 1,2,3-triazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, oxazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, imidazolidinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, and cyclopropyl alone, or as connected to another group, are optionally substituted with one or more Rb.

40. The compound of any one of Claims 1 to 39, or a pharmaceutically acceptable salt thereof, wherein each R4is independently selected from halo, (C1-C4)alkyl, hydroxy(C1- C4)alkyl, (C1-C4)alkoxy, hydroxy, cyano, -(C1-C4)alkylNRcRd, -(C1-C4)alkylC(O)ORc, -(C1- C4)alkoxyC(O)ORc, -(C1-C4)alkyltetrazolyl, -O(pyrimidinyl), pyrimidinyl, oxazolidinyl, cylopropyl, pyrazolyl, imidazolyl, thiophenyl, 1,2,3-triazolyl, tetrazolyl, 1,3-oxazinanyl, piperidinyl, hexahydropyrimidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H- imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, 1,2,3,6-tetrahydropyridinyl, 5,6,7,8- tetrahydroimidazo[1,2-a]pyrimidinyl, imidazolidinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4-diazepanyl, -NRcRd, -NRcC(O)Rd, -NRcC(O)ORd, - NRc(C1-C4)alkylC(O)NRdRe, -NRcC(O)NRdRe, -S(C1-C4)alkyl, -C(O)NRcRd, and C(O)ORc, wherein each, tetrazolyl, pyrimidinyl, pyrazolyl, imidazolyl, thiopheneyl, 1,2,3-triazolyl, 1,3- oxazinanyl, piperidinyl, hexahydropyrimidinyl, oxazolidinyl, pyrrolidinyl, piperazinyl, morpholinyl, 2,3-dihydro-1H-imidazo[4,5-c]pyridinyl, 1,2,3,4-tetrahydropyrimidinyl, imidazolidinyl, 2,3-dihydro-1H-benzo[d]imidazolyl, 1,3-diazocanyl, 1,3-diazepanyl, 1,4- diazepanyl, and cyclopropyl alone, or as connected to another group, are optionally substituted with one or more Rb.

41. The compound of any one of Claims 1 to 40, or a pharmaceutically acceptable salt thereof, wherein Rbis selected from (C1-C4)alkyl, oxo, hydroxy, hydroxy(C1-C4)alkyl, (C1- C4)alkyl(C1-C4)alkoxy, -(C1-C4)alkyl(C3-C6)cycloalkyl, (C3-C6)cycloalkyl, and phenyl.

42. The compound of any one of Claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein Rbis selected from (C1-C4)alkyl, oxo, hydroxy, hydroxy(C1-C4)alkyl, (C1- C4)alkyl(C1-C4)alkoxy, and phenyl.

43. The compound of any one of Claims 1 to 42, or a pharmaceutically acceptable salt thereof, wherein Rc, Rd, and Reare each independently selected from hydrogen, (C1-C4)alkyl, phenyl, benzyl, 4- to 6-membered heterocyclyl, and 5- to 7-membered heteroaryl.

44. The compound of any one of 1 to 43, or a pharmaceutically acceptable salt thereof, wherein Rc, Rd, and Reare each independently selected from hydrogen, (C1-C4)alkyl, phenyl, benzyl, morpholinyl, piperidinyl, pyrrolidinyl, pyridazinyl, and pyridinyl.

45. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt46. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt47. The compound of any one of Claims 1 to 37, or a pharmaceutically acceptable salt48. The compound of any one of Claims 1 to 47, or a pharmaceutically acceptable salt thereof, wherein X1is CH.

49. The compound of Claim 1, wherein the compound is selected from any one of compounds 1-514; or a pharmaceutically acceptable salt thereof.

50. A pharmaceutical composition comprising a compound of any one of Claims 1 to 49, or a pharmaceutically acceptable salt.

51. A method of treating a condition associated with increased protein levels of NRF2 and / or β-catenin in a subject comprising administering to a subject the therapeutically effective amount of a compound of any one of Claims 1 to 49, or a pharmaceutically acceptable salt; or the composition of Claim 50.

52. The method of Claim 51, wherein the condition is selected from lung cancer, non- small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, cholangiocarcinoma, hepatocellular carcinoma, uterine endometrial carcinoma, head and neck squamous cell carcinoma,esophageal adenocarcinoma, bladder urothelial carcinoma, cervical squamous carcinoma, biliary tract cancers, adenoid cystic carcinoma, colon cancer, rectal cancer, renal clear cell carcinoma, angiosarcoma, breast cancer, melanoma, cutaneous squamous cell carcinoma, meningioma, renal papillary cell carcinoma,gastric cancer, prostate adenocarcinoma, pancreatic cancer, ovarian cancer, lymphocytic leukemia, myeloid leukemia, basal cell carcinoma, and ampullary carcinoma.

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