NAMPT modulators, preparations and uses thereof

Abstract

The present disclosure provides compounds of formula 1 or 8, compositions containing same, and methods of using same, including use in modulating NAMPT and treating various diseases and conditions responsive to NAMPT activation. JPEG2025532674000852.jpg45150

Description

[Technical Field]

[0001] Related Applications This application claims priority to International Application No. PCT / CN2022 / 120763, filed September 23, 2022, and International Application No. PCT / CN2023 / 075667, filed February 13, 2023, the contents of both applications being incorporated by reference in their entirety.

[0002] The present disclosure relates to compounds that modulate nicotinamide phosphoribosyltransferase (NAMPT), compositions containing the compounds, methods for preparing the compounds, and methods of using the compounds to treat various diseases or conditions that benefit from NAMPT activation. [Background technology]

[0003] Nicotinamide phosphoribosyltransferase (NAMPT) is a dimeric type II phosphoribosyltransferase and the major nicotinamide adenine dinucleotide (NAD) transporter in humans. + NAMPT is a key enzyme in the nicotinamide-phosphoribosyl pyrophosphate (NAMPT) metabolic pathway. Specifically, NAMPT catalyzes the rate-limiting reaction in this pathway, converting nicotinamide and phosphoribosyl pyrophosphate to the intermediate nicotinamide mononucleotide (NMN), which is then converted to NAD. + NAD is important for serving as an electron-carrying coenzyme for oxidoreductases that play a key role in cellular energy-generating pathways, including the tricarboxylic acid cycle (TCA). + NAD also serves as an ADP donor for other enzymes, such as sirtuins (SIRTs) and poly(ADP-ribose) polymerases (PARPs), which have important functions in energy homeostasis, cell signaling and division, and DNA repair. + NAD due to its function in relation to the prominence of SIRT and PARP in particular +Deficiency of ATP has been shown to cause a wide range of diseases, including cardiac disease, renal disease, hyperproliferative diseases or conditions, cancer, chemotherapy-induced tissue damage, renal disease, metabolic diseases, muscle diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by stem cell dysfunction, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, diabetes-related complications, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve damage, (poliomyelitis), and spinal cord injury.

[0004] NAD as a potential target for therapeutic drugs + There is a great interest in NAD + Various strategies have been proposed to increase NAD levels. One approach is to increase NAD levels by supplementing its biosynthetic precursors, including nicotinic acid (NA) and nicotinamide mononucleotide (NAM). + One approach is to directly increase the level of NAD+, and another approach is to inhibit NAD+ consumption, such as by prescribing PARP inhibitors. However, these efforts have not achieved the desired results due to issues in pharmacological efficacy and safety. For example, NA supplements can cause skin flushing through GPR109A activation, and PARP inhibitors can cause side effects as a result of underlying toxicity.

[0005] Recently, NAMPT activation has been shown to be associated with NAD + It has emerged as an alternative therapeutic approach that promises to safely and effectively raise NAD levels. + Several small molecule activators have been discovered that have demonstrated efficacy in boosting NAD levels. For example, a series of aminopropylcarbazole derivatives designated P7C3 have been shown to increase NAD levels in human cell lines. +Additionally, other candidate NAMPT activators have been identified, including a series of urea-containing small molecules, SBI-797812 and DS68702229, with varying degrees of efficacy and pharmacokinetic profiles.

[0006] Certain NAMPT activators are disclosed in WO 2020 / 010252, WO 2017161261, WO 2018132372, WO 2021159015, WO 2021226276 and WO 2022109311. Background information on NAMPT and specific NAMPT activators is provided by Colon, et al., Biochemical Pharmacology 198(2022)114946; Verdin, Science,VOL 350,ISSUE 6265,1208; Wang et al., European Journal of Medicinal Chemistry 236(2022)114260; Wang et al., Cell,158,1324-1334; Gardell et al., NATURE COMMUNICATIONS |(2019)10:3241 | https: / / doi.org / 10.1038 / s41467-019-11078-z; Akiu, et al., Chem.Pharm.Bull.69,1110-1122(2021).

[0007] Further research in this field is needed to identify new candidates for NAMPT activation. Small molecule activators of NAMPT and the use of such activators to treat or prevent diseases or conditions responsive to increased NAMPT activity are described herein. [Prior art documents] [Patent documents]

[0008] [Patent Document 1] International Publication No. 2020 / 010252 [Patent Document 2] International Publication No. 2017161261 [Patent Document 3] International Publication No. 2018132372 [Patent Document 4] International Publication No. 2021159015 [Patent Document 5] International Publication No. 2021226276 [Patent Document 6] International Publication No. 2022109311 [Non-patent literature]

[0009] [Non-Patent Document 1] Colon, et al.,Biochemical Pharmacology 198(2022)114946 [Non-patent document 2] Verdin,Science,VOL 350,ISSUE 6265,1208;Wang et al.,European Journal of Medicinal Chemistry 236(2022)114260 [Non-patent document 3] Wang et al.,Cell,158,1324-1334;Gardell et al.,NATURE COMMUNICATIONS|(2019)10:3241|https: / / doi.org / 10.1038 / s41467-019-11078-z;Akiu,et al.,Chem.Pharm.Bull.69,1110-1122(2021) Summary of the Invention

[0010] One aspect of the present disclosure provides a compound selected from compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, which can be used to treat various diseases or conditions, such as diseases or conditions that benefit from NAMPT activation. For example, a compound of the following structural formula 1 [ka] Disclosed herein are tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, X1 is C or S, provided that when X1 is C, W is absent, and when X1 is S, W is O or absent; U is selected from O and S, provided that X1 is S and U cannot be S; X2 is C, N, or absent, X3 is C or N, and X4 is C, N, or absent; Ring B is a 5- to 6-membered heterocyclic group, and Ring B contains 0 or 1 heteroatom at a position other than X1, X2, X3, and X4; Ring C is phenyl, a 9- to 10-membered aryl, a 5- to 6-membered heteroaryl, a 9- to 10-membered heteroaryl, a 3- to 6-membered carbocyclyl, or a 4- to 12-membered heterocyclic group; L is [ka] Selected from R L is, for each occurrence, independently selected from H, halogen, deuterium, and C1-C3 alkyl optionally substituted with 1-3 groups selected from halogen; R b1 and R b2 are attached to two adjacent positions of ring B, and R b1 and R b2are bonded to form ring A, where ring A is phenyl or a 5- to 6-membered heteroaryl group, and where ring A is R a is substituted with a z group of R a is, for each occurrence, independently selected from halogen, CN, C1-C4 alkyl, -NR p R q , -NR p C(=O)R s , -NR p S(=O)2R q , OR s , -C(=O)NR p R q , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; During the ceremony, R a C1-C4 alkyl is -NR p R q , -C(=O)NR p R q , phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halogen, and OR s and optionally substituted with 1 to 3 groups selected from R a wherein the 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is optionally substituted by 1 to 2 groups selected from C1-C4 alkyl, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, and —NH(C1-C4 alkyl); R x is H, ═O, CN, C3-C6 carbocyclyl, C1-C4 alkyl, [ka] is selected from During the ceremony, R x wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, and OH; where R xThe 6-membered aryl or 5-6-membered heteroaryl of the C1-C4 alkyl is halogen, OR s , CN, C(=O)NR p R q , N.R. p R q , C1-C6 alkyl (which may be halogen, OR z , OR s and 4-6 membered heterocyclyl optionally substituted with C1-C2 alkyl), C1-C6 alkenyl, C1-C6 alkynyl, 3-6 membered carbocyclyl, and 4-7 membered heterocyclyl (which is optionally substituted with C1-C4 alkyl, halogen, and OR s optionally substituted with 1 to 3 groups selected from where R x The C1-C4 alkyl 5-9 membered heterocyclyl is optionally substituted with 1-2 groups selected from C1-C6 alkyl, ═O and halogen; R z is selected from H, 6-membered aryl and 5-6-membered heteroaryl; where R z wherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; R y is selected from H, C1-C2 alkyl, and absent; R c For each occurrence, deuterium, halogen, C1-C4 alkyl, =O, =S, OR s , -NHC(=O)R s , -NHC(=O)OR s , N.R. p R q , -NHC(=O)NR p R q , CN, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, and —C(═O)NR p R q are independently selected from During the ceremony, Rc The C1-C4 alkyl is halogen and OR s and optionally substituted with 1 to 3 groups selected from During the ceremony, R p is, for each occurrence, independently selected from H and C1-C6 alkyl; R q is, for each occurrence, independently selected from H, C1-C6 alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; or R p and R q are bonded to form a 3- to 6-membered carbocyclyl, R s represents, for each occurrence, independently, H, C1-C6 alkyl (which includes halogen, deuterium, O(C1-C4 alkyl), and NR p R q ), phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R q and R s is, independently, for each occurrence, optionally substituted with 1 to 2 groups selected from C1-C4 alkyl and —O(C1-C4 alkyl), and During the ceremony, m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, and 3; z is an integer selected from 0, 1, 2, 3, and 4; and The sum of p and q is an integer less than or equal to 5.

[0011] As another example, a compound of the following structural formula 8 [ka] Disclosed herein are tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, wherein R b3and R b4 are independently selected from H and C1-C3 alkyl, or R b3 and R b4 is linked to form a 3- to 4-membered carbocyclyl, and all other variables not specifically defined herein are defined in the preceding embodiment.

[0012] In one aspect of the disclosure, the compound of the formula disclosed herein is selected from compounds 1-645 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing.

[0013] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition can comprise a compound selected from compounds 1-645 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and a pharmaceutically acceptable carrier. These compositions may further comprise an additional active pharmaceutical agent.

[0014] Another aspect of the present disclosure provides a method of treating a disease or condition, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt. , wherein the disease or condition is selected from cardiac disease, kidney disease, hyperproliferative diseases or conditions, cancer, chemotherapy-induced tissue damage, renal disease, metabolic diseases, muscle diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by stem cell dysfunction, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, complications associated with diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

[0015] A further aspect of the present disclosure provides a method of treating a disease or condition that benefits from NAMPT activation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0016] In some embodiments, the method of treatment comprises administering to a subject in need thereof a compound selected from compounds 1-645 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer and pharmaceutically acceptable salt.

[0017] In some embodiments, the method of treatment comprises administering to a subject in need thereof an additional active pharmaceutical agent either in the same pharmaceutical composition, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), or a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a separate composition. In some embodiments, the method of treatment comprises administering a compound selected from compounds 1-645 shown in Table 1, a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, together with the additional active pharmaceutical agent, either in the same pharmaceutical composition or a separate composition. When administered as a separate composition, the additional therapeutic agent may be administered prior to, concurrently with, or following administration of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt disclosed herein.

[0018] Also disclosed herein are methods of modulating, e.g., activating, NAMPT in a subject in need thereof, comprising contacting the subject with a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h (e.g., compounds 1 through 645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt. In some embodiments, a method of modulating, e.g., activating, NAMPT in a subject in need thereof comprises contacting the subject with a compound selected from compounds 1-645 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0019] Also disclosed herein are methods of increasing NAD+ levels in a subject in need thereof, comprising contacting the subject with a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt. In some embodiments, a method of increasing NAMPT-mediated NAD+ levels in a subject in need thereof comprises contacting the subject with a compound selected from compounds 1-645 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt. DETAILED DESCRIPTION OF THE INVENTION

[0020] I. Definition: As used herein, the terms "a" or "an" when referring to a noun encompass the phrase "at least one," and thus encompass both the singular and plural units of the noun. For example, "an additional pharmaceutical agent" means one or more than one additional pharmaceutical agent.

[0021] The term "alkyl" refers to a hydrocarbon group selected from straight-chain and branched saturated hydrocarbon groups containing 1 to 20, e.g., 1 to 18, 1 to 12, 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Alkyl groups include, for example, methyl, ethyl, 1-propyl or n-propyl ("n-Pr"), 2-propyl or isopropyl ("i-Pr"), 1-butyl or n-butyl ("n-Bu"), 2-methyl-1-propyl or isobutyl ("i-Bu"), 1-methylpropyl or s-butyl ("s-Bu"), 1,1-dimethylethyl or t-butyl ("t-Bu"). Other examples of alkyl groups include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl- Examples of lower alkyl include 2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, and 3,3-dimethyl-2-butyl groups. The lower alkyl contains 1 to 8, preferably 1 to 6, more preferably 1 to 4, and more preferably 1 to 3 carbon atoms.

[0022] The term "alkenyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C=C double bond and 2 to 20, e.g., 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Alkenyl groups include ethenyl or vinyl, prop-1-enyl, prop-2-enyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-dienyl, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, hexa-1,3-dienyl, and the like. Lower alkenyl contains 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms.

[0023] The term "alkynyl" refers to a hydrocarbon group selected from straight-chain and branched hydrocarbon groups containing at least one C≡C triple bond and 2 to 20, e.g., 2 to 18, 2 to 12, 2 to 10, 2 to 8, 2 to 6, or 2 to 4 carbon atoms. Examples of alkynyl groups include ethynyl, 1-propynyl, 2-propynyl (propargyl), 1-butynyl, 2-butynyl, 3-butynyl, and the like. Lower alkynyl groups contain 2 to 8, preferably 2 to 6, and more preferably 2 to 4 carbon atoms.

[0024] The term "heteroalkyl" refers to an alkyl group, as defined herein, in which one or more of its constituent carbon atoms has been replaced with a heteroatom, such as nitrogen, oxygen, or sulfur, for example, CH3CH2OH, CH3CH2OC2H5, CH3CH2SH, CH3CH2SC2H5, CH3CH2NH2, CH3CH2NHC2H5, etc. In some embodiments, in addition to replacement of one or more of its constituent carbon atoms with nitrogen, oxygen, or sulfur, a heteroalkyl group is optionally further substituted as defined herein.

[0025] The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, such as monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, a cycloalkyl group can have 3 to 12, 3 to 10, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Further, for example, a cycloalkyl group can be a monocyclic group of 3 to 12, 3 to 8, 3 to 6, 3 to 4, or 5 to 6 carbon atoms. Monocyclic cycloalkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, etc. Bicyclic cycloalkyl groups include those having 7 to 12 ring atoms arranged as a bicycle selected from [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems, or as a bridged bicycle selected from bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, and bicyclo[3.2.2]nonane. The ring may be saturated or may have at least one double bond (i.e., be partially unsaturated), but is not fully conjugated and is not aromatic, as "aromatic ring" is defined herein.

[0026] The terms "heterocyclic" or "heterocycle" or "heterocyclyl" refer to a ring selected from 3-12 membered, e.g., 3-6 membered, 3-5 membered, 4-5 membered, or 5-6 membered, monocyclic, bicyclic, and tricyclic saturated and partially unsaturated rings containing at least one carbon atom in addition to 1, 2, 3, or 4 heteroatoms selected from, e.g., oxygen, sulfur, nitrogen, and silicon. "Heterocycle" also refers to a 5- to 7-membered heterocycle containing at least one heteroatom selected from N, O, and S fused to a 5-, 6-, and / or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that when the heterocyclic ring is fused to the carbocyclic aromatic or heteroaromatic ring, the point of attachment is on the heterocycle, and when the heterocyclic ring is fused to the cycloalkyl, the point of attachment can be on the cycloalkyl or heterocycle.

[0027] "Heterocycle" also refers to an aliphatic spirocycle containing at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocycle. The ring may be saturated or have at least one double bond (i.e., partially unsaturated). The heterocycle is optionally substituted with oxo. The point of attachment can be a carbon or heteroatom within the heterocycle. A heterocycle is not a heteroaryl as defined herein.

[0028] Examples of heterocycles include, but are not limited to, (as numbered from the attachment position designated as priority 1) 1-pyrrolidinyl, 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 2,5-piperazinyl, pyranyl, 2-morpholinyl, 3-morpholinyl, oxiranyl, aziridinyl, Thiiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, dihydropyridinyl, tetrahydropyridinyl, thiomorpholinyl, thiooxanyl, piperidinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1,4-oxathianyl, 1,4-dioxepanyl, 1,4-oxathiepanyl, 1,4-oxazepanyl, 1,4- Dithiepanyl, 1,4-thiazepanyl, 1,4-diazepanyl, 1,4-dithianyl, 1,4-azathianyl, oxazepinyl, diazepinyl, thiazepinyl, dihydrothienyl, dihydropyranyl, dihydrofuranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, Examples of heterocyclic rings include 2H-pyranyl, 4H-pyranyl, 1,4-dioxanyl, 1,3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1,1-dioxo-thiomorpholinyl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, and azabicyclo[2.2.2]hexanyl. Substituted heterocycles also include ring systems substituted with one or more oxo moieties, such as piperidinyl N-oxide, morpholinyl N-oxide, 1-oxo-1-thiomorpholinyl, and 1,1-dioxo-1-thiomorpholinyl.

[0029] The term "fused ring" as used herein refers to a polycyclic ring system, such as a bicyclic or tricyclic ring system, in which two rings share only two ring atoms and one bond in common. Examples of fused rings can include fused bicyclic cycloalkyl rings, such as those having 7 to 12 ring atoms arranged as a bicyclic ring selected from the above-mentioned [4,4], [4,5], [5,5], [5,6], and [6,6] ring systems; fused bicyclic aryl rings, such as the above-mentioned 7- to 12-membered bicyclic aryl ring systems; fused tricyclic aryl rings, such as the above-mentioned 10- to 15-membered tricyclic aryl ring systems; fused bicyclic heteroaryl rings, such as the above-mentioned 8- to 12-membered bicyclic heteroaryl rings; fused tricyclic heteroaryl rings, such as the above-mentioned 11- to 14-membered tricyclic heteroaryl rings; and fused bicyclic or tricyclic heterocyclyl rings.

[0030] The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus, and silicon, including any oxidized form of nitrogen or sulfur, a quaternized form of any basic or substitutable nitrogen in a heterocyclic ring, e.g., N (such as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR + where R is, for example, an optionally substituted alkyl group (as in N-substituted pyrrolidinyl).

[0031] As used herein, the term "unsaturated" means that a moiety has one or more units or degrees of unsaturation. Unsaturation is a situation in which not all of the available valence bonds in a compound are filled by substituents, and the compound therefore contains one or more double or triple bonds. A double bond can be: [ka] (two solid lines). As used herein, [ka] The depictions (solid and dashed lines) indicate bonds that may be double or single bonds.

[0032] The term "alkoxy," as used herein, refers to an alkyl group, as defined above, in which one carbon of the alkyl group has been replaced with an oxygen atom, provided that the oxygen atom is linked between two carbon atoms.

[0033] The term "halogen" includes F, Cl, Br, and I, ie, fluoro, chloro, bromo, and iodo, respectively.

[0034] As used herein, a "CN," "cyano," or "nitrile" group refers to --C.ident.N.

[0035] As used herein, "aromatic ring" refers to a carbocyclic or heterocyclic ring comprising a conjugated planar ring system having a delocalized pi orbital composed of [4n+2]p orbitals, where n is an integer from 0 to 6. A "non-aromatic" ring refers to a carbocyclic or heterocyclic ring that does not meet the requirements set forth above for an aromatic ring, and can be fully or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings, as further defined below. An "aromatic ring" refers to a ring having conjugated double bonds, e.g., [ka] as, or a ring with an inner circle, e.g. [ka] It can be shown as:

[0036] The term "aryl" as used herein refers to groups selected from monocyclic carbocyclic aromatic rings, such as phenyl; 7- to 12-membered, such as 9- to 10-membered, bicyclic ring systems in which at least one ring is carbocyclic and aromatic, for example selected from naphthalene, indane, and 1,2,3,4-tetrahydroquinoline; and tricyclic ring systems, for example 10- to 15-membered tricyclic ring systems in which at least one ring is carbocyclic and aromatic, for example fluorene.

[0037] For example, an aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocyclic ring optionally containing at least one heteroatom selected from N, O, and S, provided that when the carbocyclic aromatic ring is fused to the heterocyclic ring and the point of attachment is on the carbocyclic aromatic ring and when the carbocyclic aromatic ring is fused to the cycloalkyl group, the point of attachment can be on the carbocyclic aromatic ring or the cycloalkyl group. Divalent radicals formed from substituted benzene derivatives and having free valences on ring atoms are called substituted phenylene radicals. Divalent groups derived from monovalent polycyclic hydrocarbon groups named ending in "-yl" by removing one hydrogen atom from the free valence carbon atom are named by adding "-ydene" to the name of the corresponding monovalent group; for example, a naphthyl group with two points of attachment is called a naphthylidene.

[0038] The term "heteroaryl" refers to a group selected from 5- to 7-membered, e.g., 5- to 6-membered, aromatic monocyclic rings containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; 8- to 12-membered bicyclic rings containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being in the aromatic ring; and 11- to 14-membered tricyclic rings containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, at least one ring being aromatic, and at least one heteroatom being in the aromatic ring.

[0039] For example, a heteroaryl group can be a 5- to 7-membered heteroaromatic ring fused to a 5- to 7-membered cycloalkyl ring. For such fused bicyclic heteroaryl ring systems in which only one of the rings contains at least one heteroatom, the point of attachment can be at the heteroaromatic ring or the cycloalkyl ring.

[0040] When the total number of S and O atoms in the heteroaryl group exceeds 1, then these heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is 2 or less. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is 1 or less.

[0041] Heteroaryl groups include (as numbered from the attachment position designated as priority 1) for example, pyridyl (e.g., 2-pyridyl, 3-pyridyl, or 4-pyridyl), cinnolinyl, pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,4-imidazolyl, imidazopyridinyl, isoxazolyl, oxazolyl, thiazolyl, isothiazolyl, thiadiazolyl, tetrazolyl, thienyl, triazinyl, benzothienyl, furyl, benzofuryl, benzimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (e.g., 1H-pyrrolo[2,3-b]pyridin-5-yl), pyrazolopyridinyl (e.g., 1H-pyrazolo[3,4 [-b]pyridin-5-yl), benzoxazolyl (e.g., benzo[d]oxazol-6-yl), pteridinyl, purinyl, 1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl, 1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridinyl, benzothiazolyl (e.g., benzo[d]thiazol-6-yl), indazolyl (e.g., 1H-indazol-5-yl), and 5,6,7,8-tetrahydroisoquinolinyl.

[0042] The term "acyl" refers to a substituent where the point of attachment to the substituent is a carbonyl. Exemplary acyl groups include, but are not limited to, -C(=O)R', -C(=O)NR'R'', or -C(=O)OR', where R' and R'' are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, any of which is further optionally substituted with one or more substituents.

[0043] Some compounds may exist with different points of attachment of hydrogen, called "tautomers." For example, a compound containing a carbonyl -CHC(O)- group (keto form) may undergo tautomerism to form a hydroxyl -CH=C(OH)- group (enol form). Both the keto and enol forms, individually and mixtures thereof, are intended to be included where applicable.

[0044] The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the present disclosure may contain asymmetric centers and therefore exist as enantiomers. For example, when a compound has two or more asymmetric centers, it may further exist as diastereoisomers. Enantiomers and diastereoisomers are included in the broader class of stereoisomers. All possible stereoisomers, including substantially pure resolved enantiomers, their racemic mixtures, and mixtures of diastereoisomers, are intended to be included in the present disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless otherwise specified, a reference to one isomer applies to any possible isomer. Whenever an isomeric composition is not specified, all possible isomers are included.

[0045] Diastereomeric mixtures can be separated into their individual diastereoisomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. Enantiomers can also be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., a chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereoisomers, and converting the individual diastereoisomers into the corresponding pure enantiomers (e.g., by hydrolysis). Enantiomers can also be separated using a chiral HPLC column.

[0046] Single stereoisomers, e.g., substantially pure enantiomers, can be obtained by resolution of racemic mixtures using methods such as the formation of diastereoisomers with optically active resolving agents. Racemic mixtures of chiral compounds of the present disclosure can be separated and isolated by any suitable method, including (1) formation of ionic diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods, (2) formation of diastereomeric compounds with chiral derivatizing agents, separation of diastereoisomers, and conversion to pure stereoisomers, and (3) direct separation of substantially pure or enriched stereoisomers under chiral conditions.

[0047] The term "substantially pure" in the context of stereoisomers means that the target stereoisomer contains no more than 35% by weight of any other stereoisomer, such as no more than 30%, or even no more than 25%, or even no more than 20%, etc. In some embodiments, the term "substantially pure" means that the target stereoisomer contains no more than 10%, such as no more than 5%, or no more than 1%, by weight of any other stereoisomer.

[0048] Unless otherwise indicated, structures depicted herein are meant to include all isomeric forms of the structure, such as racemic mixtures, cis / trans isomers, geometric (or conformational) isomers, such as (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Thus, geometric and conformational mixtures of the compounds disclosed herein are within the scope of the disclosure. Unless otherwise specified, all tautomeric forms of the compounds of the disclosure are within the scope of the disclosure.

[0049] The present disclosure provides pharmaceutically acceptable salts of the disclosed compounds, tautomers, solvates, and stereoisomers. A salt of a compound is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group.

[0050] As used herein, the term "pharmaceutically acceptable" refers to a component that is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and other mammals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio. A "pharmaceutically acceptable salt" means any non-toxic salt that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of the present disclosure.

[0051] "Pharmaceutically acceptable salts" include, but are not limited to, salts with inorganic acids selected from hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, and nitrate. Also included are salts with organic acids selected from malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, alkanoate, such as acetate, and salts with HOOC-(CH)-COOH, where n is selected from 0 to 4. Similarly, examples of pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, magnesium, aluminum, lithium, and ammonium. Suitable pharmaceutically acceptable salts are disclosed, for example, in S. M. Berge, et al., J. Pharmaceutical Sciences, 1977, 66, pp. 1-19.

[0052] Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, benzenesulfonic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Accordingly, such pharmaceutically acceptable salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate), caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyrate-1,4-dioate, hexylate-1,4-dioate, hexylate-2,4-dioate, hexylate-3,4-dioate, hexylate-4,4-dioate, hexylate-5,5-dioate, hexylate-6,5-dioate, hexylate-7,5-dioate, hexylate-8,5-dioate, hexylate-9,5-dioate, hexylate-10,5-dioate, hexylate-11,5-dioate, hexylate-12,5-dioate, hexylate-13,5-dioate, hexylate-14,5-dioate, hexylate-15,5-dioate, hexylate-16,5-dioate, hexylate-17,5-dioate, hexylate-18,5-dioate, hexylate-19 ... , 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, sulfonate, xyleneate, xyleneate, phenylpropionate, phenylpropionate, phenylpropionate, citrate, citrate, methanesulfonate, including propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and other salts. In some embodiments, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and those formed with organic acids such as maleic acid.

[0053] Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1~4Suitable salts include ammonium, quaternary ammonium, and amine cation salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Suitable salts include ammonium, quaternary ammonium, and amine cation salts formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates. Suitable salts include besylate and glucosamine salts.

[0054] If a compound is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid addition salt. Conversely, if the product is a free base, an addition salt, such as a pharmaceutically acceptable addition salt, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, following conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that can be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

[0055] The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the present disclosure may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, -CD3, -CD2-, -CDH-, -CD2H, or -CDH2 may contain one or more deuterium atoms in place of hydrogen. For example, the compounds may contain, for example, tritium ( 3 H), iodine-125( 125 I) or carbon-14( 14 C). All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.

[0056] As used herein, "optionally substituted" is interchangeable with the phrase "substituted or unsubstituted." In general, the term "substituted" refers to the replacement of a hydrogen radical in a given structure with the radical of a specified substituent. Unless otherwise specified, an "optionally substituted" group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. [ka] When attached to a ring structure without a specific position, such as R c When m is a positive integer, R may be attached to any chemically feasible position of ring C, regardless of whether ring C is a monocyclic or polycyclic structure. For example, unless otherwise specified, when m' is a positive integer, R c teeth, [ka] As shown in the following formula, R may be bonded to any chemically feasible position of the four-membered ring structure of ring C or any chemically feasible position (e.g., C or N) of the five-membered ring structure of ring C. c teeth, [ka] As shown in Figure 1, as designated, it may be attached to any chemically feasible position on the six-membered ring structure of ring C (when m' is a positive integer) and to a fixed position on the five-membered ring structure of ring C.

[0057] Combinations of chemical moieties, eg, substituents, ring structures, linkers, and / or heteroatoms, envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

[0058] In some embodiments, the substituents (e.g., in the situation where a group is optionally substituted with one or more substituents, e.g., optionally substituted phenyl) are independently selected from an optionally substituted heteroatom and an optionally substituted, optionally hetero, optionally cyclic C-C 18 hydrocarbyl, in particular optionally substituted, optionally hetero, optionally cyclic C-C 18 The hydrocarbyl is an optionally substituted, optionally hetero, optionally cyclic alkyl, alkenyl or alkynyl, or an optionally substituted, optionally hetero, aryl, and / or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (alkoxy, aryloxy, etc.), optionally substituted acyl (e.g., formyl, alkanoyl, carbamoyl, carboxyl, amido), optionally substituted amino (e.g., amino, alkylamino, dialkylamino, amido, sulfamidyl), optionally substituted thiol (mercapto, alkylthiol, arylthiol, etc.), optionally substituted sulfinyl or sulfonyl (e.g., alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl), nitro, or cyano.

[0059] In some embodiments, substituents are independently selected from halogen, —R′, —OR′, ═O, ═NR′, ═N—OR′, —NR′R″, —SR′, —SiR′R″R′″, —OC(═O)R′, —C(═O)R′, —COR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR′—C(═O)NR″R′″, —NR′—SONR″R′″, —NR′CO Particularly preferred are groups having zero, one, or two substituents selected from 2R', -NH-C(NH2)=NH, -NR'C(NH2)=NH, -NH-C(NH2)=NR', -S(O)R', -S02R', -S02NR'R'', -NR''S02R', -CN, -NO2, -N3, -CH(Ph)2, perfluoro(C1-C4)alkoxy, and perfluoro(C1-C4)alkyl. R', R'' and R''' each independently represent hydrogen, unsubstituted C1-C8 alkyl and heteroalkyl, C1-C8 alkyl and heteroalkyl substituted with one to three halogens, unsubstituted aryl, aryl substituted with one to three halogens, unsubstituted alkyl, alkoxy, or thioalkoxy, or aryl-(C1-C4)alkyl. When R' and R'' are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 5-, 6-, or 7-membered ring. Thus, -NR'R'' includes 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1,2,3,4-tetrahydronaphthalenyl, it is optionally substituted with a substituted or unsubstituted C3-C7 spirocycloalkyl group. The C3-C7 spirocycloalkyl group is optionally substituted in the same manner as defined herein for "cycloalkyl."

[0060] In some embodiments, the substituents are selected from halogen, —R′, —OR′, ═O, —NR′R″, —SR′, —SiR′R′R′″, —OC(═O)R′, —C(═O)R′, —COR′, —C(═O)NR′R″, —OC(═O)NR′R″, —NR″C(═O)R′, —NR″COR′, —NR′-SONR″R′″, —S(═O)R′, —SOR′, —SONR′R″, —NR″SOR′, —CN, —NO, perfluoroC1-C4 alkoxy, and perfluoroC1-C4 alkyl, where R′ and R″ are as defined above.

[0061] In some embodiments, the substituents are independently a substituted or unsubstituted heteroatom, a substituted or unsubstituted C1-C6 alkyl containing 0-3 heteroatoms (e.g., C1-C3 alkyl or C1-C2 alkyl), a substituted or unsubstituted C2-C6 alkenyl containing 0-3 heteroatoms (e.g., C2-C4 alkenyl), a substituted or unsubstituted C2-C6 alkynyl containing 0-3 heteroatoms (e.g., C2-C4 alkynyl), or a substituted or unsubstituted C5-C6 alkyl containing 0-3 heteroatoms. 14 aryl (eg, C5-C6 aryl), where each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

[0062] In some embodiments, the substituents are independently selected from aldehyde, aldimine, alkanoyloxy, alkoxy, alkoxycarbonyl, alkyloxy, alkyl, alkenyl, alkynyl, amine, azo, halogen, carbamoyl, carbonyl, carboxamide, carboxyl, cyanyl, ester, haloformyl, hydroperoxyl, hydroxyl, imine, isocyanide, isocyanate, N-tert-butoxycarbonyl, nitrate, nitrite, nitro, nitroso, phosphate, phosphono, sulfide, sulfonyl, sulfo, sulfhydryl, thiol, thiocyanyl, trifluoromethyl, and trifluoromethyl ether (OCF3) groups.

[0063] Preferred substituents are disclosed herein and are illustrated in the tables, structures, examples, and claims, and may apply across different compounds of the disclosure, e.g., substituents of a given compound may be used in combination with other compounds.

[0064] It may be advantageous to separate reaction products from one another and / or from starting materials. The desired products of each step or series of steps are separated and / or purified (hereinafter "separated") to the desired degree of homogeneity by techniques common in the art. Typically, such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can include any number of methods, including, for example, reverse-phase and normal-phase; size exclusion; ion exchange; high-, medium-, and low-pressure liquid chromatography methods and apparatus; small-scale analytical; simulated moving bed ("SMB") and preparative thin- or thick-layer chromatography, and small-scale thin-layer and flash chromatography techniques. Those skilled in the art will be able to apply such techniques to achieve the desired separation.

[0065] Non-limiting examples of suitable solvents that can be used in the present disclosure include water, methanol (MeOH), ethanol (EtOH), dichloromethane or methylene chloride (CHCl), toluene, acetonitrile (MeCN), dimethylformamide (DMF), dimethyl sulfoxide (DMSO), methyl acetate (MeOAc), ethyl acetate (EtOAc), heptane, isopropyl acetate (IPAc), tert-butyl acetate (t-BuOAc), isopropyl alcohol (IPA), tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-MeTHF), methyl ethyl ketone (MEK), tert-butanol, diethyl ether (EtO), methyl tert-butyl ether (MTBE), 1,4-dioxane, and N-methylpyrrolidone (NMP).

[0066] Non-limiting examples of suitable bases that can be used in the present disclosure include 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), potassium tert-butoxide (KOtBu), potassium carbonate (KCO), N-methylmorpholine (NMM), triethylamine (EtN; TEA), diisopropylethylamine (i-PrEtN; DIPEA), pyridine, potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), and sodium methoxide (NaOMe; NaOCH).

[0067] The term "subject" refers to animals, including humans.

[0068] The term "therapeutically effective amount" refers to the amount of compound for which it is administered that produces the desired effect (e.g., amelioration of a disease or condition, reduction in the severity of a disease or condition, and / or reduction in the progression of a disease or condition, e.g., a disease or condition that can benefit from NAMPT activation). The exact amount of a therapeutically effective amount will depend on the purpose of the treatment and can be ascertained by one skilled in the art using known techniques (see, e.g., Lloyd (1999), The Art, Science and Technology of Pharmaceutical Compounding).

[0069] As used herein, the term "treatment" and its cognates refer to slowing or halting disease progression. As used herein, "treatment" and its cognates include, but are not limited to, complete or partial remission, cure of a disease or condition or symptoms thereof, and reduction in the risk of a disease or condition, e.g., a disease or condition that may benefit from NAMPT activation. Improvement or reduction in severity of any of these symptoms can be assessed according to methods and techniques known in the art.

[0070] The terms "about" and "approximately," when used in connection with a number such as a percentage, include the specified number as well as a range of numbers recognized by one of ordinary skill in the art (e.g., a percentage range, e.g., a range of ±10% relative to a particular point value).

[0071] II. Compounds and Compositions In a first embodiment, the compound of the present disclosure is a compound of the following structural formula 1: [ka] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; X1 is C or S, provided that when X1 is C, W is absent, and when X1 is S, W is O or absent; U is selected from O and S, provided that X1 is S and U cannot be S; X2 is C, N, or absent, X3 is C or N, and X4 is C, N, or absent; Ring B is a 5- to 6-membered heterocyclic group, and Ring B contains 0 or 1 heteroatom at a position other than X1, X2, X3, and X4; Ring C is phenyl, a 9- to 10-membered aryl, a 5- to 6-membered heteroaryl, a 9- to 10-membered heteroaryl, a 3- to 6-membered carbocyclyl (e.g., a 3-, 4-, 5-, or 6-membered carbocyclyl group), or a 4- to 12-membered heterocyclic group (e.g., a 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered heterocyclic group); L is [ka] Selected from R L is, for each occurrence, independently selected from H, deuterium, halogen (e.g., F, Cl, or Br), and C1-C3 alkyl optionally substituted with 1-3 groups selected from halogen (e.g., C1 alkyl, C2 alkyl, C3 alkyl, or CF3); R b1 and R b2 are attached to two adjacent positions of ring B, and Rb1 and R b2 are bonded to form ring A, where ring A is phenyl or a 5- to 6-membered heteroaryl group, where ring A is R a is substituted with a z group; R a is, for each occurrence, independently selected from halogen (e.g., F, Cl, or Br), CN, C1-C4 alkyl (e.g., C1, C2, C3, or C4 alkyl), -NR p R q , -NR p C(=O)R s , -NR p S(=O)2R q , OR s , -C(=O)NR p R q , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl (e.g., 3-, 4-, 5-, 6-, or 7-membered carbocyclyl), and 3- to 7-membered heterocyclyl (e.g., 3-, 4-, 5-, 6-, or 7-membered heterocyclyl); During the ceremony, R a C1-C4 alkyl is -NR p R q , -C(=O)NR p R q , phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halogen, and OR s and optionally substituted with 1 to 3 groups selected from R a wherein the 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is optionally substituted by 1 to 2 groups selected from C1-C4 alkyl, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, and —NH(C1-C4 alkyl); R x is H, ═O, CN, C3-C6 carbocyclyl, C1-C4 alkyl, [ka] Selected from During the ceremony, R xwherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl (e.g., 5-, 6-, 7-, 8-, or 9-membered heterocyclyl), 6-membered aryl, 5- to 6-membered heteroaryl, and OH; where R x The 6-membered aryl or 5-6-membered heteroaryl of the C1-C4 alkyl is halogen, OR s , CN, C(=O)NR p R q , N.R. p R q , C1-C6 alkyl (which may be halogen, OR z , OR s and 4-6 membered heterocyclyl optionally substituted with C1-C2 alkyl), C1-C6 alkenyl (e.g., C1, C2, C3, C4, C5 or C6 alkenyl), C1-C6 alkynyl (e.g., C1, C2, C3, C4, C5 or C6 alkynyl), 3-6 membered carbocyclyl (e.g., 3, 4, 5 or 6 membered carbocyclyl), and 4-7 membered heterocyclyl (e.g., 4, 5, 6 or 7 membered heterocyclyl) (which is optionally substituted with C1-C4 alkyl, halogen, and OR s optionally substituted with 1 to 3 groups selected from where R x the C1-C4 alkyl 5-9 membered heterocyclyl is optionally substituted with 1-2 groups selected from C1-C6 alkyl (e.g., C1, C2, C3, C4, C5 or C6 alkyl), ═O and halogen; R z is selected from H, 6-membered aryl and 5-6-membered heteroaryl; where R z wherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; R y is selected from H, C1-C2 alkyl, and absent; R cFor each occurrence, deuterium, halogen, C1-C4 alkyl, =O, =S, OR s , -NHC(=O)R s , -NHC(=O)OR s , N.R. p R q , -NHC(=O)NR p R q , CN, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, and —C(═O)NR p R q are independently selected from During the ceremony, R c The C1-C4 alkyl is halogen and OR s and optionally substituted with 1 to 3 groups selected from During the ceremony, R p is, for each occurrence, independently selected from H and C1-C6 alkyl; R q is, for each occurrence, independently selected from H, C1-C6 alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; or R p and R q are bonded to form a 3- to 6-membered carbocyclyl, R s represents, for each occurrence, independently, H, C1-C6 alkyl (which includes halogen, deuterium, O(C1-C4 alkyl), and NR p R q ), phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R q and R s is, independently, for each occurrence, optionally substituted with 1 to 2 groups selected from C1-C4 alkyl and —O(C1-C4 alkyl), and During the ceremony, m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, and 3; z is an integer selected from 0, 1, 2, 3, and 4; and The sum of p and q is an integer less than or equal to 5 (for example, the sum of p and q is 0, 1, 2, 3, or 4).

[0072] Combinations of substituents disclosed herein are those that result in the formation of stable or chemically feasible compounds. Due to abbreviations or common practice, specific hydrogen atoms bonded to specific atoms (e.g., carbon atoms C or nitrogen atoms N) are not specifically depicted in chemical structures, formulas, or notations. Hydrogen atoms are considered to be present to the extent that the valence of a specific atom (e.g., C or N) is completed.

[0073] In a second embodiment, the compound of the present disclosure is a compound of the following structural formula 2a or 2a′: [Table 1] and tautomers, solvates or stereoisomers of the compounds or tautomers thereof, or pharmaceutically acceptable salts of the foregoing, wherein Y1, Y2, Y3, and Y4 are independently selected from C and N, and all other variables not specifically defined herein are as defined in the preceding embodiments. For example, one of Y1, Y2, Y3, and Y4 is N, and the remaining are C. In another example, two of Y1, Y2, Y3, and Y4 are N, and the remaining are C. In another example, three of Y1, Y2, Y3, and Y4 are N, and the other is C. In another example, all four of Y1, Y2, Y3, and Y4 are N. In another example, all four of Y1, Y2, Y3, and Y4 are C.

[0074] In a third embodiment, the compound of the present disclosure has the following structural formula 2b: [ka] and a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y1, Y2, Y3, and Y4 are independently selected from C and N, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. For example, one of Y1, Y2, Y3, and Y4 is N, and the remaining are C. In another example, two of Y1, Y2, Y3, and Y4 are N, and the remaining are C. In another example, three of Y1, Y2, Y3, and Y4 are N, and the other is C. In another example, all four of Y1, Y2, Y3, and Y4 are N. In another example, all four of Y1, Y2, Y3, and Y4 are C.

[0075] In a fourth embodiment, the compound of the present disclosure is a compound of the following structural formula 2c, 2c-1, or 2c-2: [Table 2] a tautomer, solvate or stereoisomer of the compound or tautomer thereof, or a pharmaceutically acceptable salt of the foregoing, wherein Y1, Y2, Y3, and Y4 are independently selected from C and N, Y5, Y6, and Y7 are independently selected from N, S, O, and C, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. For example, one of Y1, Y2, Y3, and Y4 is N, and the remaining are C. In another example, two of Y1, Y2, Y3, and Y4 are N, and the remaining are C. In another example, three of Y1, Y2, Y3, and Y4 are N, and the other is C. In another example, all four of Y1, Y2, Y3, and Y4 are N. In another example, all four of Y1, Y2, Y3, and Y4 are C.

[0076] In a fifth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 2d-2i: [Table 3] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein all other variables not specifically defined herein are as defined in any one of the preceding embodiments as appropriate.

[0077] In a sixth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 3a and 3a-1 to 3a-16: [Table 4-1] [Table 4-2] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Z1 and Z2 are independently selected from C and N, Z3 is selected from C, N, S and O, and R c’ is O or S, m' for each occurrence is independently selected from 0, 1, and 2, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. For example, one of Z1 and Z2 is N and the other is C. In another example, both Z1 and Z2 are N. In another example, both Z1 and Z2 are C.

[0078] In a seventh embodiment, the compound of the present disclosure is a compound of the following structural formulas 3b-3c: [Table 5] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein m' is selected from 0 and 1, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0079] In an eighth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 3d to 3e: [Table 6] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein m' is independently selected for each occurrence from 0 and 1, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0080] In a ninth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 3f-3h: [Table 7] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein m′, for each occurrence, is independently selected from 0, 1, and 2; m″, for each occurrence, is independently selected from 0 and 1; R L is selected from H and F, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0081] In a tenth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 4a-4h: [Table 8] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein m′, for each occurrence, is independently selected from 0, 1, and 2; m″, for each occurrence, is independently selected from 0 and 1; R L is selected from H and F, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0082] In an eleventh embodiment, the compounds of the present disclosure are compounds of the following structural formulas 5a-5e: [Table 9] a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein R c is deuterium, m' is selected from 0, 1, and 2, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0083] In a twelfth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 6a-6d: [Table 10] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein V, V, V, and V are independently selected from C and N; L is selected from H and F, and R c is deuterium, and R d is independently for each occurrence selected from halogen, CN, OCH3, C1-C4 alkyl, C1-C4 alkenyl, C1-C4 alkynyl, 3- to 6-membered carbocyclyl, and 3- to 6-membered heterocyclyl; m' is selected from 0, 1, and 2; and n is selected from 0, 1, 2, and 3; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. For example, one of V1, V2, V3, and V4 is N, and the remainder are C. In another example, two of V1, V2, V3, and V4 are N, and the remainder are C. In another example, three of V1, V2, V3, and V4 are N, and the other is C. In another example, all four of V1, V2, V3, and V4 are N. In another example, all four of V1, V2, V3, and V4 are C.

[0084] In a thirteenth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 6e-6h: [Table 11] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein V1, V2, V3 and V4 are independently selected from C, O, S and N, and R L is selected from H and F, and R c is deuterium, R d and m' is selected from 0, 1, and 2, and n is selected from 0, 1, 2, and 3 for each occurrence; and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. For example, one of V1, V2, V3, and V4 is N, and the remainder are C. As another example, two of V1, V2, V3, and V4 are N, and the remainder are C. As another example, three of V1, V2, V3, and V4 are N, and the other is C. As another example, all four of V1, V2, V3, and V4 are N. As another example, one of V1, V2, V3, and V4 is O, another one of V1, V2, V3, and V4 is N, and the remainder are C. As another example, one of V1, V2, V3, and V4 is S, another one of V1, V2, V3, and V4 is N, and the remainder are C. As another example, another one of V1, V2, V3, and V4 is O, another one of V1, V2, V3, and V4 is C, and the remainder are N; as another example, one of V1, V2, V3, and V4 is S, another one of V1, V2, V3, and V4 is C, and the remainder are N.

[0085] In a fourteenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, ring A is selected from phenyl, pyridyl, and 5-membered heteroaryl containing 1-2 heteroatoms selected from N, S, and O, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0086] In a fifteenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, X1 is C, X2 is not present, X3 is C or N, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments. In one embodiment, X4 is not present. In another embodiment, X4 is present.

[0087] In a sixteenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, ring C is [ka] and ring C is selected from m R c All other variables substituted with groups and not specifically defined herein are as defined in any one of the appropriate preceding embodiments, for example, Ring C is substituted with a group selected from halogen, methyl, trifluoromethyl, OH, NH, ═O, ═S, and C(═O)NH.

[0088] In a seventeenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R a is halogen, CN, C1-C3 alkyl, -NR p R q , -NR p C(=O)R s , -NR p S(=O)2R q, OR s , -C(=O)NR p R q , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; During the ceremony, R a C1-C3 alkyl is -NR p R q , -C(=O)NR p R q , phenyl, 4- to 7-membered heterocyclyl, halogen and OR s and optionally substituted with 1 to 2 groups selected from R a wherein the 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is optionally substituted with one group selected from C1-C3 alkyl, —O(C1-C3 alkyl), —N(C1-C3 alkyl)2, and —NH(C1-C3 alkyl), and During the ceremony, R p is, for each occurrence, independently selected from H and C1-C3 alkyl; R q is, for each occurrence, independently selected from H, C1-C3 alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocyclyl; R s is, for each occurrence, independently selected from H, C1-C3 alkyl (optionally substituted with 1-2 groups selected from halogen), phenyl, and 4-7 membered heterocyclyl; During the ceremony, R q and R s and wherein, for each occurrence, the 4- to 7-membered heterocyclyl is optionally substituted with one group independently selected from C1-C3 alkyl and —O(C1-C3 alkyl); and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0089] In an eighteenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R a are Br, Cl, CN, methyl, ethyl, -C(CH3)3, -CH(CH3)2, CH2N(CH3)2, CH2CH2C(=O)NH2, [ka] NH2, -N(CH3)2, [ka] -NHC(=O)CH3, -NHS(=O)2CH3, [ka] OH, OCH3, [ka] -C(=O)NH2, -C(=O)NHCH3, [ka] CH2NHCH3, CH2OCH3, -CHF2, [ka] and OCHF2 and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0090] In a nineteenth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R a is selected from F, Br, Cl, CN, OH, 5- to 6-membered heteroaryl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, and methyl optionally substituted with 3- to 6-membered heterocyclyl, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0091] In a twentieth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R x H, ═O, CN, 3-6 carbocyclyl, C1-C2 alkyl, [ka] is selected from During the ceremony, R x wherein the C1-C2 alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, and OH; where R x The 6-membered aryl or 5-6-membered heteroaryl of the C1-C2 alkyl is halogen, OR s , CN, CONH2, NH2, C1-C4 alkyl (which is halogen, OR z , OR s and 4- to 6-membered heterocyclyl optionally substituted with C1-C2 alkyl), C1-C3 alkenyl, C1-C3 alkynyl, 3- to 4-membered carbocyclyl, and 4- to 7-membered heterocyclyl (optionally substituted with 1 to 3 groups selected from C1-C2 alkyl, halogen, and OR s and In the formula, R x The C1-C2 alkyl 5-9 membered heterocyclyl is optionally substituted with 1-2 groups selected from C1-C2 alkyl, ═O and halogen, wherein R s is selected from H and C1-C2 alkyl optionally substituted with 1 to 3 groups selected from halogen, O(C1-C2 alkyl), —N(C1-C2 alkyl)(C1-C2 alkyl), and R z is selected from H, 6-membered aryl and 5-6-membered heteroaryl; In the formula, R zwherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0092] In a twenty-first embodiment, in a compound, tautomer, solvate or stereoisomer of a compound, or tautomer, or pharmaceutically acceptable salt of the present disclosure, R x is selected from C1-C2 alkyl, and R x wherein the C1-C2 alkyl is substituted with a 6-membered aryl or a 5- to 6-membered heteroaryl, and R x The 6-membered aryl or 5-6-membered heteroaryl of the C1-C2 alkyl is selected from halogen, OCH3, CN, CONH2, NH2, C1-C2 alkyl (halogen and OR z O(C-C alkyl) (optionally substituted with 1-3 groups selected from halogen), 3- to 4-membered carbocyclyl, and 4- to 7-membered heterocyclyl, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0093] In a twenty-second embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R x is H, =O, CN, methyl, ethyl, propyl, CH2CN, [ka] [ka] [ka] phenyl, [ka] [ka] and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0094] In a twenty-third embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R c may, for each occurrence, independently represent deuterium, halogen, methyl (optionally OR s substituted with), trifluoromethyl, =O, =S, OR s , -NHC(=O)R s , -NHC(=O)OR s , N.R. p R q , -NHC(=O)NR p R q , CN, -C(=O)NR p R q , optionally substituted 5- to 6-membered heteroaryl and optionally substituted 5- to 6-membered heterocyclyl; R p is, for each occurrence, independently selected from H and C1-C2 alkyl; R q is, for each occurrence, independently selected from H, C1-C2 alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; R s is, for each occurrence, independently selected from H, C1-C2 alkyl (optionally substituted with 1-3 groups selected from halogen and deuterium), phenyl, and 4-7 membered heterocyclyl; During the ceremony, R q and R s is optionally substituted, for each occurrence, with one group selected from C1-C2 alkyl and —O(C1-C2 alkyl); and m is selected from 0, 1, 2, and 3; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0095] In a twenty-fourth embodiment, in a compound, tautomer, solvate or stereoisomer of a compound, or tautomer, or pharmaceutically acceptable salt of the present disclosure, R c For each occurrence, deuterium, F, CH3, CF3, OH, =O, =S, OCH3, NH2, -NHC(=O)CH3, -NHC(=O)NHCH3, -NHC(=O)NH2, -NHC(=O)OCH3, [ka] CN, CH2OH, -C(=O)NH2, Cl, -NHCN, OCHF2, [ka] All other variables independently selected from -SCH3, OCD3, and -C(=O)CH3 and not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0096] In a twenty-fifth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, m is 0, and all other variables not specifically defined herein are as defined in any one of the appropriate preceding embodiments.

[0097] In a twenty-sixth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R L is H and R y is H or deuterium, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0098] In a twenty-seventh embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, In Eq. [ka] teeth, [ka] and In Eq. [ka] teeth, [ka] is selected from L is -CH2-, -CD2-, [ka] is selected from R x teeth, [ka] is selected from U is O or S; V1, V2, V3, and V4 are selected from C and N; R L is, for each occurrence, independently selected from H, deuterium, F, and CH; R a is, for each occurrence, selected from CN, halogen, optionally substituted 3- to 4-membered carbocyclyl, optionally substituted 4- to 5-membered heterocyclyl, and optionally substituted O(C1-C3 alkyl); R c is, for each occurrence, independently selected from deuterium, halogen, OH, C1-C3 alkyl, O(C1-C3 alkyl), and 5-6 membered heteroaryl, where R c O(C1-C3 alkyl) is optionally substituted with 1 to 3 deuterium atoms; R d is, for each occurrence, independently selected from halogen, CN, C1-C3 alkyl, and O(C1-C3 alkyl); z, for each occurrence, is an integer independently selected from 0, 1, 2, and 3; m' for each occurrence is an integer independently selected from 0, 1, and 2; m″, for each occurrence, is an integer independently selected from 0 and 1; n, for each occurrence, is an integer independently selected from 0, 1, 2, and 3; and n', for each occurrence, is an integer independently selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0099] In a twenty-eighth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, In Eq. [ka] teeth, [ka] is selected from L is -CH2-, -CD2-, [ka] is selected from R x teeth [ka] is selected from R d is, for each occurrence, independently selected from halogen, CN, C1-C3 alkyl, and O(C1-C3 alkyl); m' for each occurrence is an integer independently selected from 0, 1, and 2; m″, for each occurrence, is an integer independently selected from 0 and 1; and n, for each occurrence, is an integer independently selected from 0, 1, 2, and 3, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0100] In a twenty-ninth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, In Eq. [ka] teeth, [ka] is selected from L is -CH2-, -CD2-, [ka] is selected from R x teeth [ka] is selected from R d is, for each occurrence, independently selected from halogen, CN, C1-C3 alkyl, and O(C1-C3 alkyl); m', for each occurrence, is an integer independently selected from 0, 1, and 2; and n, for each occurrence, is an integer independently selected from 0, 1, 2, and 3, and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0101] In a thirtieth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, U is O, V1, V2, V3, and V4 are selected from C and N, and no more than two of V1, V2, V3, and V4 are N; R L is H or deuterium, R a is, for each occurrence, independently selected from CN, F, Cl, Br, 3-membered carbocyclyl, 4- to 5-membered heterocyclyl optionally substituted with —N(C1-C2 alkyl)(C1-C2 alkyl), and OCHF2; R c For each occurrence, deuterium, F, OH, CH3, OCH3, OCD3 and [ka] are independently selected from R d is, for each occurrence, independently selected from F, Cl, Br, CH3, CH2CH3, CN, and OCH3; z, for each occurrence, is an integer independently selected from 0, 1, and 2; m' for each occurrence is an integer independently selected from 0, 1, and 2; n, for each occurrence, is an integer independently selected from 0, 1, 2, and 3; and n', for each occurrence, is an integer independently selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0102] In a thirty-first embodiment, the compounds of the present disclosure are compounds of the following structural formulas 7a-7e: [Table 12] a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein L is -CH2-, -CD2-, [ka] wherein m' is selected from 0, 1, and 2; z is selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0103] In a thirty-second embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is selected from -CH2- and -CD2-; R a is, for each occurrence, independently selected from C1-C3 alkyl, halogen, and O(C1-C3 alkyl) optionally substituted with 1-3 groups selected from halogen; R c is, for each occurrence, independently selected from deuterium, halogen, OH, CH3, OCH3, and OCD3; R d is, for each occurrence, independently selected from halogen, CN, OCH3, and C1-C4 alkyl; R x teeth, [ka] wherein K is selected from -CH2- and -CD2-; and n, for each occurrence, is an integer independently selected from 0, 1, 2, and 3; and All other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0104] In a thirty-third embodiment, the compound of the present disclosure is a compound of the following structural formula 8: [ka] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; X1 is C, X2 is C, N, or absent, X3 is C or N, and X4 is C, N, or absent; Ring B is a 5- to 6-membered heterocyclic group, and Ring B contains 0 or 1 heteroatom at a position other than X1, X2, X3, and X4; Ring C is phenyl, a 9- to 10-membered aryl, a 5- to 6-membered heteroaryl, a 9- to 10-membered heteroaryl, a 3- to 6-membered carbocyclyl, or a 4- to 12-membered heterocyclic group; L is [ka] Selected from R L is, for each occurrence, independently selected from H, deuterium, halogen, and C1-C3 alkyl optionally substituted with 1-3 groups selected from halogen; R b1 and R b2 are attached to two adjacent positions of ring B, and R b1 and R b2 are bonded to form ring A, where ring A is phenyl or a 5- to 6-membered heteroaryl group, and where ring A is R a is substituted with a z group of R b3 and R b4 are independently selected from H and C1-C3 alkyl, or R b3 and R b4 are bonded to form a 3- or 4-membered carbocyclyl, R a is, for each occurrence, independently selected from halogen, CN, C1-C4 alkyl, -NR p R q , -NR p C(=O)R s , -NR p S(=O)2R q , OR s , -C(=O)NR p R q , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; During the ceremony, R a C1-C4 alkyl is -NR p Rq , -C(=O)NR p R q , phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halogen, and OR s and optionally substituted with 1 to 3 groups selected from R a wherein the 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is optionally substituted by 1 to 2 groups selected from C1-C4 alkyl, —O(C1-C4 alkyl), —N(C1-C4 alkyl)2, and —NH(C1-C4 alkyl); R x is H, ═O, CN, C3-C6 carbocyclyl, C1-C4 alkyl, [ka] is selected from During the ceremony, R x wherein the C1-C4 alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, and OH; where R x The 6-membered aryl or 5-6-membered heteroaryl of the C1-C4 alkyl is halogen, OR s , CN, C(=O)NR p R q , N.R. p R q , C1-C6 alkyl (which may be halogen, OR z , OR s and 4-6 membered heterocyclyl optionally substituted with C1-C2 alkyl), C1-C6 alkenyl, C1-C6 alkynyl, 3-6 membered carbocyclyl, and 4-7 membered heterocyclyl (which is optionally substituted with C1-C4 alkyl, halogen, and OR s optionally substituted with 1 to 3 groups selected from where R xThe C1-C4 alkyl 5-9 membered heterocyclyl is optionally substituted with 1-2 groups selected from C1-C6 alkyl, ═O and halogen; R z is selected from H, 6-membered aryl and 5-6-membered heteroaryl; where R z wherein the 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; R y is selected from H, C1-C2 alkyl, and absent; R c For each occurrence, deuterium, halogen, C1-C4 alkyl, =O, =S, OR s , -NHC(=O)R s , -NHC(=O)OR s , N.R. p R q , -NHC(=O)NR p R q , CN, optionally substituted 5- to 6-membered heteroaryl or optionally substituted 5- to 6-membered heterocyclyl and —C(═O)NR p R q are independently selected from During the ceremony, R c The C1-C4 alkyl is halogen and OR s and optionally substituted with 1 to 3 groups selected from During the ceremony, R p is, for each occurrence, independently selected from H and C1-C6 alkyl; R q is, for each occurrence, independently selected from H, C1-C6 alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; or R p and R q are bonded to form a 3- to 6-membered carbocyclyl, R s represents, for each occurrence, independently, H, C1-C6 alkyl (which includes deuterium, halogen, O(C1-C4 alkyl), and NR p R q), phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R q and R s is optionally substituted with 1 to 2 groups selected from C1-C4 alkyl and —O(C1-C4 alkyl), for each occurrence; During the ceremony, m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, and 3; z is an integer selected from 0, 1, 2, 3, and 4; The sum of p and q is an integer less than or equal to 5, and All other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0105] In a thirty-fourth embodiment, the compounds of the present disclosure are compounds of the following structural formulas 9a-9h: [Table 13] a tautomer, solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing; L is -CH2-, -CD2-, [ka] wherein m', for each occurrence, is independently an integer selected from 0, 1, and 2; m'', for each occurrence, is independently an integer selected from 0, 1, and 2; z, for each occurrence, is independently an integer selected from 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0106] In a thirty-fifth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, L is -CH2-, -CD2-, and [ka] is selected from R a is selected from C1-C3 alkyl, CN, and halogen; R x teeth [ka] and K is selected from -CH2- and -CD2-; R c is, for each occurrence, independently selected from deuterium, C1-C3 alkyl, halogen, 5-6 membered heteroaryl optionally substituted with 1-3 groups selected from halogen and deuterium, OH, and O(C1-C3 alkyl); R d is, for each occurrence, independently selected from halogen, CN, OCH, —C(═O)NH, and C-C alkyl; and n, for each occurrence, is an integer independently selected from 0, 1, 2, and 3; All other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0107] In a thirty-sixth embodiment, in a compound, tautomer, solvate or stereoisomer of the compound or tautomer, or pharmaceutically acceptable salt of the present disclosure, R a is selected from F and Cl; R x teeth, [ka] is selected from R cis, for each occurrence, independently selected from deuterium, F, OH, OCH, OCD, and C(=O)NH; m, for each occurrence, is independently 0, 1, or 2; m', for each occurrence, is independently 0, 1, or 2; z, for each occurrence, is independently 0, 1, or 2; All other variables not specifically defined herein are as defined in any one of the preceding embodiments, as appropriate.

[0108] In certain embodiments, the compound of the present disclosure is selected from compounds 1-645 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing. [Table 14-1] [Table 14-2] [Table 14-3] [Table 14-4] [Table 14-5] [Table 14-6] [Table 14-7] [Table 14-8] [Table 14-9] [Table 14-10]

Table 14-11

Table 14-12

Table 14-13

Table 14-14

Table 14-15

Table 14-16

Table 14-17

Table 14-18

Table 14-19

Table 14-20

Table 14-21

Table 14-22

Table 14-23

Table 14-24

Table 14-25

Table 14-26

Table 14-27

[0109] The notation "or 1" used in chemical structures herein means that the configuration of the chiral center indicated by the "or 1" is not determined. For example, compound 185 has an "or 1" located above a stereocenter bonded to a methyl group and a hydrogen atom. This means that the configuration of the chiral carbon labeled with "or 1" is either R or S.

[0110] Another aspect of the present disclosure provides pharmaceutical compositions comprising at least one compound selected from compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, and at least one pharmaceutically acceptable carrier.

[0111] In some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable vehicle and a pharmaceutically acceptable adjuvant, hi some embodiments, the pharmaceutically acceptable carrier is selected from a pharmaceutically acceptable filler, disintegrant, surfactant, binder, and lubricant.

[0112] It is also understood that the pharmaceutical compositions of the present disclosure can be used in combination therapy. That is, the pharmaceutical compositions described herein can further comprise an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from the compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, can be administered as a separate composition simultaneously with, before, or after a composition comprising an additional active pharmaceutical agent.

[0113] In some embodiments, pharmaceutically acceptable carriers can be selected from adjuvants and vehicles. Pharmaceutically acceptable carriers used herein can be selected from, for example, any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surfactants, isotonicity agents, thickeners, emulsifiers, preservatives, solid binders, and lubricants suitable for the desired specific dosage form. Remington: The Science and Practice of Pharmacy, 21st edition, 2005, ed. D.B. Troy, Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 1988 to 1999, Marcel Dekker, New York, disclose various carriers used in the formulation of pharmaceutical compositions and known techniques for their preparation. Except insofar as any conventional carrier is incompatible with the compounds of the present disclosure, such as by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other components of the pharmaceutical composition, its use is contemplated within the scope of the present disclosure.Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphates, glycine, sorbic acid, and potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts and electrolytes (protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, etc.), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), cellulose and its derivatives (carboxymethylcellulose, etc.), and the like. Examples of suitable additives include cellulose acetate, cellulose acetate sodium, ethylcellulose, and cellulose acetate), powdered tragacanth, malt, gelatin, talc, excipients (e.g., cocoa butter and suppository wax), oils (peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, soybean oil, and the like), glycols (e.g., propylene glycol and polyethylene glycol), esters (e.g., ethyl oleate and ethyl laurate), agar, buffers (e.g., magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solution, non-toxic compatible lubricants (e.g., sodium lauryl sulfate, magnesium stearate, and the like), coloring agents, release agents, coating agents, sweeteners, flavorings, fragrances, preservatives, antioxidants, and the like.

[0114] A compound selected from the compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 to 3a-16, 3b to 3h, 4a to 4h, 5a to 5e, 6a to 6h, 7a to 7e, 8, and 9a to 9h disclosed herein (e.g., compounds 1 to 645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions disclosed herein, can be administered orally in solid dosage forms such as capsules, tablets, troches, dragees, granules, and powders, or in liquid dosage forms such as elixirs, syrups, emulsions, dispersions, and suspensions. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can also be administered parenterally in sterile liquid dosage forms (e.g., dispersions, suspensions, or solutions). Other dosage forms can also be used to administer the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein as ointments, creams, drops, transdermal patches, or powders for topical administration, eye drops or suspension-forming agents, such as eye drops, for ophthalmic administration, as aerosol sprays or powder compositions for inhalation or intranasal administration, or as creams, ointments, sprays, or suppositories for rectal or vaginal administration.

[0115] Gelatin capsules containing a compound disclosed herein, its tautomer, a solvate or stereoisomer of the compound or tautomer, and / or a pharmaceutically acceptable salt thereof, and a powdered carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, etc., can also be used. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be manufactured as sustained-release products to provide continuous release of the drug over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric-coated for selective disintegration in the gastrointestinal tract.

[0116] Liquid dosage forms for oral administration may further comprise at least one agent selected from coloring and flavoring agents to enhance patient acceptance.

[0117] In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may contain a water-soluble salt of at least one compound described herein, at least one suitable stabilizer, and, if necessary, at least one buffer substance. Antioxidants such as sodium bisulfite, sodium sulfite, or ascorbic acid, alone or in combination, are examples of suitable stabilizers. Citric acid and its salts and sodium EDTA are also examples of suitable stabilizers. Furthermore, parenteral solutions may further contain at least one preservative selected from, for example, benzalkonium chloride, methyl- and propylparaben, and chlorobutanol.

[0118] Pharmaceutically acceptable carriers are selected from carriers that are compatible with the active ingredients of the composition (and, in some embodiments, can stabilize the active ingredients) and are not harmful to the subject being treated. For example, solubilizers such as cyclodextrins (which can form specific, more soluble complexes with at least one compound and / or at least one pharmaceutically acceptable salt disclosed herein) can be used as pharmaceutical excipients for delivering the active ingredients. Other examples of carriers include colloidal silicon dioxide, magnesium stearate, cellulose, sodium lauryl sulfate, and pigments such as D&C Yellow #10. Suitable pharmaceutically acceptable carriers are described in Remington's Pharmaceutical Sciences, A. Osol.

[0119] For administration by inhalation, the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can be conveniently delivered in the form of an aerosol spray from a pressurized pack or nebulizer. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein can be delivered as powders that can be formulated, and the powder compositions can be inhaled using an insufflation powder inhaler. One exemplary delivery system for inhalation can be a metered dose inhalation (MDI) aerosol, which can be formulated as a suspension or solution of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein in at least one suitable propellant selected, for example, from fluorocarbons and hydrocarbons.

[0120] For ocular administration, ophthalmic preparations can be formulated with an appropriate weight percent solution or suspension of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in a suitable ophthalmic vehicle such that the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is maintained in contact with the ocular surface for a period of time sufficient to allow the compound to penetrate the cornea and interior regions of the eye.

[0121] Useful pharmaceutical dosage forms for administering the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injections, and oral suspensions. In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of controlled-release or sustained-release compositions known in the art.

[0122] The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined amount of active agent calculated to produce the desired therapeutic effect in combination with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes of liquid compositions, or pills, tablets, capsules, lozenges, and the like in the case of solid compositions. In such compositions, the active agent typically ranges from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight, with the remainder being various vehicles or carriers and processing aids useful for forming the desired dosage form. Unit dosage formulations are preferably about 5, 10, 25, 50, 100, 250, 500, or 1,000 mg per unit. In certain embodiments, unit dosage forms are packaged in multipacks adapted for sequential use, such as blister packs containing at least 6, 9, or 12 sheets of unit dosage forms.

[0123] In some embodiments, a unit capsule can be prepared by filling a standard two-piece hard gelatin capsule with, for example, 100 milligrams of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in powder form, 150 milligrams of lactose, 50 milligrams of cellulose, and 6 milligrams of magnesium stearate.

[0124] In some embodiments, a mixture of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein with a digestible oil such as soybean oil, cottonseed oil, or olive oil can be prepared and injected into gelatin using a positive displacement pump to form a soft gelatin capsule containing 100 milligrams of the active ingredient. The capsule is washed and dried.

[0125] In some embodiments, tablets can be prepared by conventional procedures so that the dosage unit contains, for example, 100 milligrams of the compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, 0.2 milligrams of colloidal silicon dioxide, 5 milligrams of magnesium stearate, 275 milligrams of microcrystalline cellulose, 11 milligrams of starch, and 98.8 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.

[0126] In some embodiments, a parenteral composition suitable for administration by injection can be prepared by stirring 1.5% by weight of a compound disclosed herein and / or at least an enantiomer, diastereoisomer, or pharmaceutically acceptable salt thereof in 10% by volume of propylene glycol. The solution is made up to the expected volume with water for injection and sterilized.

[0127] In some embodiments, an aqueous suspension can be prepared for oral administration. For example, 5 milliliters of an aqueous suspension can be used, each containing 100 milligrams of finely divided compound, its stereoisomer, or a pharmaceutically acceptable salt thereof, 100 milligrams of sodium carboxymethylcellulose, 5 milligrams of sodium benzoate, 1.0 gram of sorbitol solution, USP, and 0.025 milliliters of vanillin.

[0128] When the compounds, tautomers, solvates, stereoisomers or pharmaceutically acceptable salts described herein are administered stepwise or in combination with at least one other therapeutic agent, the same dosage form can generally be used.When drugs are administered in physical combination, the dosage form and administration route should be selected according to the compatibility of the combined drugs.Therefore, the term "co-administration" is understood to include the simultaneous or sequential administration of at least two active ingredients, or the administration of at least two drugs as a fixed-dose combination.

[0129] The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts disclosed herein can be administered as the sole active ingredient or in combination with at least one second active ingredient.

[0130] The compounds, tautomers, solvates, or stereoisomers described herein can be used in the form described above or in the form of a pharmaceutically acceptable salt, such as a hydrochloride, hydrobromide, acetate, sulfate, citrate, carbonate, or trifluoroacetate. When the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein contain a relatively acidic functional group, the salt can be obtained by adding a desired base either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts. When the compounds, tautomers, solvates, or stereoisomers described herein contain a relatively basic functional group, the salt can be obtained by adding a desired acid either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, monohydrogencarbonic acid, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, monohydrogensulfuric acid, hydroiodic acid, or phosphorous acid, as well as salts derived from relatively non-toxic organic acids such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-tolylsulfonic acid, citric acid, tartaric acid, methanesulfonic acid, etc. Also included are salts of amino acids such as alginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, e.g., Berge et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 1977, 66, 1-19).

[0131] The neutral forms of the pharmaceutically acceptable salts described herein can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.

[0132] The present disclosure provides prodrugs. Prodrugs of the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein readily undergo chemical changes under physiological conditions to provide the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure. Furthermore, prodrugs can be converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. For example, they may be more bioavailable by oral administration than the parent drug. Prodrugs may also have improved solubility in pharmacological compositions compared to the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. A non-limiting example of a prodrug would be a compound of the present disclosure that is administered as an ester (the "prodrug"), but is subsequently metabolically hydrolyzed to the carboxylic acid, i.e., the active entity.

[0133] Certain compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts of the present disclosure can exist in unsolvated forms as well as solvated forms, including hydrated forms. Certain compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts of the present disclosure can exist in multiple crystalline or amorphous forms.

[0134] Certain compounds, tautomers, solvates, or pharmaceutically acceptable salts in the present disclosure may have asymmetric carbon atoms (optical centers) or double bonds; the racemates, enantiomers, diastereoisomers, geometric isomers, and individual isomers are all intended to be encompassed within the scope of the present disclosure.

[0135] III. Treatment Methods and Uses The present disclosure provides methods of treatment and uses utilizing the compounds described in any one of the various embodiments in Section II (Compounds and Compositions) and Table 1, e.g., compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h, as well as compounds 1 through 645 of Table 1, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing compounds, or pharmaceutical compositions comprising any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts thereof.

[0136] One aspect of the present disclosure provides a method of treating a disease or condition, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt, wherein The diseases or conditions include, but are not limited to, cardiac disease, renal disease, hyperproliferative diseases or conditions, cancer, chemotherapy-induced tissue damage, kidney disease, metabolic diseases, muscle diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by stem cell dysfunction, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, diabetes-related complications, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury. In some embodiments, the disease or condition may benefit from NAMPT activation.

[0137] In another aspect, disclosed herein are compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h (e.g., compounds 1 through 645 in Table 1), tautomers, solvates or stereoisomers thereof, or pharmaceutically acceptable salts of the foregoing, or compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, including any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, for use as a pharmaceutical.

[0138] In another aspect, to treat diseases or conditions including, but not limited to, cardiac disease, kidney disease, hyperproliferative diseases or conditions, cancer, chemotherapy-induced tissue damage, kidney disease, metabolic diseases, muscle diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by stem cell dysfunction, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, complications associated with diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury. Disclosed herein is the use of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a compound, tautomer, solvate, stereoisomer, stereoisomer, or pharmaceutically acceptable salt described herein, including any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, for the manufacture of a medicament of the invention. In some embodiments, the disease or condition can benefit from NAMPT activation.

[0139] In a further aspect of the disclosure, the compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h (e.g., compounds 1 through 645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts described herein, including any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, are useful in treating cardiac disease, renal disease, hyperproliferative disorders, or other conditions. are for use in the treatment of disease states including, but not limited to, cancer, chemotherapy-induced tissue damage, kidney disease, metabolic disease, muscular disease, neurological disease and injury, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by stem cell dysfunction, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, diabetes-related complications, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury. In some embodiments, the disease or condition may benefit from NAMPT activation.

[0140] Another aspect of the present disclosure provides a method of increasing NAD+ levels, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the compound, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt.

[0141] In another aspect, disclosed herein is the use of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), a tautomer, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein, including any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, for the manufacture of a medicament for increasing NAD+ levels.

[0142] In a further aspect of the present disclosure, the compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), tautomers, solvates or stereoisomers thereof, or pharmaceutically acceptable salts of the foregoing, or compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein, including any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, are for use in increasing NAD+ levels.

[0143] Another aspect of the present disclosure provides a method of modulating, e.g., activating, NAMPT in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition comprising any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts thereof.

[0144] In another aspect, disclosed herein is a compound of Formula 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, or the use of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein, including any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts thereof, for modulating, e.g., activating, NAMPT in a subject in need thereof.

[0145] In another aspect of the present disclosure, a pharmaceutical composition comprising any of the compounds, tautomers, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts described herein, including compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1-3a-16, 3b-3h, 4a-4h, 5a-5e, 6a-6h, 7a-7e, 8, and 9a-9h disclosed herein (e.g., compounds 1-645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, is for use in modulating, e.g., activating, NAMPT in a subject in need thereof by contacting the subject with the compound, tautomer, solvate or stereoisomer of the compound, or tautomer, pharmaceutically acceptable salt, or pharmaceutical composition.

[0146] Compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions comprising any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, can be used to treat, for example, but not limited to, heart disease, kidney disease, hyperproliferative diseases or conditions, cancer, chemotherapy-induced tissue damage, and the like. It may be administered once daily, twice daily, or three times daily to treat diseases or conditions, including: neurodegenerative disorders, kidney disease, metabolic disorders, muscle diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by stem cell dysfunction, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, diabetes-related complications, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, Down syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury. In some embodiments, the disease or condition may benefit from NAMPT activation.

[0147] Compounds of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 through 3a-16, 3b through 3h, 4a through 4h, 5a through 5e, 6a through 6h, 7a through 7e, 8, and 9a through 9h disclosed herein (e.g., compounds 1 through 645 in Table 1), tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, or pharmaceutical compositions comprising any of the compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts, can be administered in a variety of ways, for example, orally, topically, rectally, parenterally, by inhalation spray, or via an implanted reservoir, although the most suitable route in any given case will depend on the particular host and the nature and severity of the condition for which the active ingredient is being administered. The term "parenteral" as used herein includes subcutaneous, intradermal, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial injection or infusion techniques. The compositions disclosed herein are conveniently provided in unit dosage form and can be prepared by any of the methods well known in the art. Parenteral administration can be by continuous infusion over a selected period of time. Other modes of administration contemplated in the present disclosure are as described in WO 2013 / 075083, WO 2013 / 075084, WO 2013 / 078320, WO 2013 / 120104, WO 2014 / 124418, WO 2014 / 151142, and WO 2015 / 023915.

[0148] Contacting is generally achieved by administering to the subject an effective amount of one or more compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts disclosed herein. Generally, administration is adjusted to achieve a therapeutic dose of about 0.1-50 mg / kg, preferably 0.5-10 mg / kg, and more preferably 1-10 mg / kg, although optimal dosages are compound-specific and generally determined empirically for each compound.

[0149] The dosage administered will depend on factors such as the recipient's age, health, and weight, the extent of the disease, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. In general, the daily dosage of the active ingredient can vary, for example, from 0.1 to 2,000 milligrams per day. For example, 10 to 500 milligrams, administered one or more times daily, can be effective to obtain the desired results.

[0150] In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formulas 1, 2a, 2a', 2b, 2c, 2c-1, 2c-2, 2d-2i, 3a, 3a-1 to 3a-16, 3b to 3h, 4a to 4h, 5a to 5e, 6a to 6h, 7a to 7e, 8, and 9a to 9h disclosed herein (e.g., compounds 1 to 645 in Table 1), a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing compounds, or a pharmaceutical composition comprising any of the compound, tautomer, solvate, stereoisomer, and pharmaceutically acceptable salt is administered once daily, twice daily, or three times daily. The compounds, tautomers, solvates, stereoisomers, or pharmaceutically acceptable salts described herein are administered for morning / afternoon dosing with an evening rest period.

[0151] IV. Working Examples In order that the disclosure set forth herein may be more fully understood, the following examples are set forth herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting the disclosure in any way.

[0152] Example I. Synthesis of Exemplary Compounds Compounds of the present disclosure selected from compounds of the formulae set forth herein, tautomers thereof, solvates or stereoisomers of the compounds or tautomers, or pharmaceutically acceptable salts of the foregoing, can be made according to standard chemical practices or as illustrated herein, including the following general synthetic procedures and specific synthetic schemes for compounds 1-645 as representative examples of Formula 1. Intermediates: Preparation of 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int1) [ka] Step 1. 6-Methylbenzo[d]oxazol-2(3H)-one (Int1-2) To a solution of 2-amino-5-methylphenol (20 g, 162 mmol) in ACN (acetonitrile) (200 mL) was added CDI (N,N'-carbonyldiimidazole) (52.67 g, 325 mmol) at room temperature. The mixture was stirred at 80 °C for 14 hours. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo to give 6-methylbenzo[d]oxazol-2(3H)-one (22 g) as a pale yellow solid, which was used in the next step without further purification. MS (ESI) m / z 150 [M+H] + . Step 2. 6-Methyl-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int1-3) To a solution of 6-methylbenzo[d]oxazol-2(3H)-one (22 g, 148 mmol) in DMF (220 mL) was added NaH (3.89 g, 162 mmol) under N at 0°C. The mixture was stirred for 30 min. SEM-Cl (24.59 g, 148 mmol) was added and the reaction was warmed to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0°C and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated to give 6-methyl-3-(2-trimethylsilylethoxymethyl)-1,3-benzoxazol-2-one (35 g) as a yellow semi-solid, which was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 7.29-7.19(m,2H),7.19-7.08(m,1H),5.28(s,2H),3.66(t,J=7.9Hz,2H),2.40(s,3H),0.92(t,J=7.9Hz,2H),0.06(s,9H). Step 3. 6-(Bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int1) To a solution of 6-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (3 g, 10.7 mmol) in CCl4 (30 mL) was added NBS (2.29 g, 12.9 mmol) and AIBN (176 mg, 1.07 mmol) at room temperature. The mixture was stirred at 80 °C for 14 h. After the reaction was completed, the solid was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 10 / 1) to give 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (1.66 g, 43.2%) as a yellow semisolid. 1 H NMR(400MHz,CDCl3)δ 7.31-7.25(m,2H),7.17-7.08(m,1H),5.28(s,2H),4.56(s,2H),3.65(t,J=7.9Hz,2H),0.95(t,J=7.9Hz,2H),0.06(s,9H). 6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int2) and 6-((5-bromo-1-methyl-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int3) [ka] Step 1. Mixture of 5-bromo-3-hydroxy-3-methylisoindolin-1-one (Int2-1) and 6-bromo-3-hydroxy-3-methylisoindolin-1-one (Int3-1) To a solution of 5-bromoisoindoline-1,3-dione (15 g, 66.36 mmol) in DCM (300 mL) was added methylmagnesium bromide (1 M in THF, 200 mL) dropwise under N at 0 °C. After the addition, the mixture was stirred at 0 °C for 3 h before being quenched with saturated NH Cl (aq). After extraction with DCM, the organic layer was washed with brine, dried over anhydrous Na SO , filtered, and concentrated in vacuo to give the crude product containing a mixture of 5-bromo-3-hydroxy-3-methylisoindolin-1-one and 6-bromo-3-hydroxy-3-methylisoindolin-1-one (16 g) as a white solid, which was used in the next step without further purification. MS (ESI) m / z 242 [M+H] + . Step 2. Mixture of 5-bromo-3-methylisoindolin-1-one (Int2-2) and 6-bromo-3-methylisoindolin-1-one (Int3-2) Under N protection, triethylsilane (30 g, 264 mmol) and boron trifluoride diethyl etherate (37.5 g, 264 mmol) were added successively to a mixture of 5-bromo-3-hydroxy-3-methylisoindolin-1-one and 6-bromo-3-hydroxy-3-methylisoindolin-1-one (16 g, 66 mmol) in dry DCM (160 mL) at −15° C. The reaction mixture was then stirred at room temperature for 2 hours, and saturated NaHCO (aq) (100 mL) was added. The mixture was then extracted with DCM, and the organic layer was washed with brine, dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 2 / 3) to give a mixture of 5-bromo-3-methylisoindolin-1-one and 6-bromo-3-methylisoindolin-1-one (11.5 g, 76%) as a white solid. MS (ESI) m / z 226 [M+H] + . Step 3. Mixture of 6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int2) and 6-((5-bromo-1-methyl-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int3) To a solution of a mixture of 5-bromo-3-methylisoindolin-1-one and 6-bromo-3-methylisoindolin-1-one (8 g, 35.3 mmol) in DMF (60 mL) was added NaH (934 mg, 38.9 mmol) under N at 0° C. The mixture was stirred for 30 min. 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (15.2 g, 42.4 mmol) was added and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0° C. and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 3 / 1) to give a mixture of 6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one and 6-((5-bromo-1-methyl-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (11 g, 21%) as a yellow semi-solid. MS(ESI) m / z 503 [M+H] + . 5-(Bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (Int4) [ka] Step 1. 5-Methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (Int4-2) To a solution of 5-methyl-1H-benzo[d][1,2,3]triazole (40 g, 300 mmol) in DMF (400 mL) was added NaH (13.23 g, 330 mmol) in portions at 0 °C under N. The mixture was stirred for 30 min. (2-(chloromethoxy)ethyl)trimethylsilane (52.4 g, 315 mmol) was added, and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0 °C, and the mixture was then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated to give 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (80 g) as a yellow oil, which was used in the next step without further purification. MS (ESI) m / z 264 [M+H] + . Step 2. 5-(Bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (Int4) To a solution of 5-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (80 g, 304 mmol) in CCl4 (800 mL) was added NBS (59 g, 334 mmol) and AIBN (4.9 g, 30 mmol) at room temperature. The mixture was stirred at 80 °C for 14 h. After the reaction was completed, the solid was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 10 / 1) to give 5-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (24 g, 23%) as a brown oil. MS (ESI) m / z 342 [M+H] + . 2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoindolin-1-one (Int5) [ka] To a solution of isoindolin-1-one (7 g, 52 mmol) in DMF (70 mL) was added NaH (2.3 g, 57 mmol) at 0° C. under N. The mixture was stirred for 30 min. 5-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (24 g, 70 mmol) was added and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0° C., and the mixture was then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc=3 / 2) to give 2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoindolin-1-one (10 g, 48%) as a brown oil. MS(ESI) m / z 395 [M+H] + . 6-((1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int6), 6-((5-bromo-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int7) and 5-bromo-2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoindolin-1-one (Int8). [ka] Int6, Int7 and Int8 were prepared according to the procedure described for Int5. 6-(Bromomethyl)-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (Int9) [ka] Step 1. 3-(4-Methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one (Int9-1) To a solution of 6-methylbenzo[d]oxazol-2(3H)-one (4 g, 26.8 mmol) in DMF (40 mL) was added CsCO (17.49 g, 53.6 mmol) and 1-(chloromethyl)-4-methoxybenzene (4.2 g, 26.8 mmol) at room temperature. The mixture was stirred at 60 °C for 2 h. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo to give 3-(4-methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one (6.5 g) as a yellow solid, which was used in the next step without further purification. MS (ESI) m / z 270 [M+H] + . Step 2. 6-(Bromomethyl)-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (Int9) To a solution of 3-(4-methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one (600 mg, 2.23 mmol) in CCl4 (10 mL) was added NBS (436 mg, 2.45 mmol) and AIBN (37 mg, 0.22 mmol) at room temperature. The mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the solid was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 1 / 5) to give 6-(bromomethyl)-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (300 mg, 38.6%) as an off-white solid. MS (ESI) m / z 348 [M+H] + . (R)-6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int10) and (S)-6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (Int11) [ka] Chiral separation of Int2 by chiral SFC (CHIRALPAK AD-H column; column dimensions: 5 cm x 25 cm, 5 μm; mobile phase A: CO2; mobile phase B: MeOH (0.5% 2 mM NH3-MeOH), flow rate: 200 g / min, wavelength: 220 nm) afforded two enantiomers: Int10 and Int11. One of the two enantiomers was a pale yellow solid with a RT of 1.728 min (column: Chiral ND(2) 3.0*100 mm, 3 μm; cosolvent: MeOH (0.1% DEA), flow rate: 2 ml / min; gradient: 10% to 50% in 2.0 min, hold at 50% for 1.0 min; detector: 220 nm). MS(ESI) m / z 503 / 505 [M+H] + The other of the two enantiomers was a pale yellow solid with a RT of 1.969 min (column: Chiral ND(2) 3.0*100 mm, 3 μm; cosolvent: MeOH (0.1% DEA); flow rate: 2 ml / min; gradient: 10% to 50% in 2.0 min, hold at 50% for 1.0 min; detector: 220 nm), MS(ESI) m / z 503 / 505 [M+H] + . Intermediate Int2-2 was prepared as follows: [ka] Step 1. 4-Bromo-2-ethylbenzoic acid (Int2-4) THF (2.5 L) and Int2-3 (500 g, 2.28 mol) were charged into a 20 L reactor under N2 protection. 2 M ethylmagnesium bromide in THF (2.5 L, 6.16 mol) was added to the above solution at 0 °C. The mixture was stirred at room temperature overnight. IPC using TLC showed that Int2-3 was not detected. The mixture was poured into MeOH (1 L) below 10 °C. The mixture was concentrated. EA (5 L) and water (2.5 L) were poured into the mixture. 2 M HCl (3.15 L) was added to the above solution at 15-30 °C. After separation, the aqueous phase was extracted with EA (2.5 L). The organic layers were combined, and the mixture was poured into 5% Na2CO3 (5 L) below 30 °C, and then separated. The aqueous phase and EA (5000 mL) were charged into a 20 L reactor. To the above solution was added 2M HCl (2.9 L) at 15-30°C, and then the layers were separated. The organic phase was washed with 20% NaCl (2.5 L) and then dried over NaSO. After filtration, the filtrate was concentrated to give the title compound as a white solid (231.3 g, 44%). Step 2. Methyl 4-bromo-2-ethylbenzoate (Int2-5) MeOH (2 L) and Int2-4 (200 g, 0.87 mol) were charged into a 2 L flask. SOCl2 (249.3 g, 2.10 mol) was added to the above solution below 40 °C. The mixture was stirred at 50-60 °C overnight. IPC using TLC showed that Int2-4 was not detected. The mixture was concentrated. EA (2 L) and water (2 L) were charged to the mixture. The mixture was poured into 5% Na2CO3 (100 mL) below 30 °C and then separated. The organic phase was washed with 20% NaCl (1 L) and then dried over Na2SO4. After filtration, the filtrate was concentrated to give the title compound as a white solid (214 g, 100%). Step 3: 5-Bromo-3-methylisoindolin-1-one (Int2-2) CCl4 (1 L), Int2-5 (100 g, 0.41 mol), AIBN (13.5 g, 0.08 mol), and NBS (73 g, 0.41 mol) were charged into a 3 L flask at 15-30°C. The reactor was heated to 70-80°C and then stirred for 2 hours. IPC using TLC showed that Int2-5 was not detected. The mixture was filtered, and the filtrate was collected and concentrated under vacuum. Heptane (1 L) was then charged into the reactor and stirred for 15 minutes at 15-30°C. After filtration, the filtrate was concentrated. A 2 M solution of ammonia in MeOH (1.32 L, 9.25 mol) was added to the above solution at 15-30°C. The mixture was heated to 30-35°C and then stirred overnight and concentrated under vacuum. Then, EA (1 L) and PE (1 L) were charged into the reactor and stirred for 15 minutes at 15-30° C. After filtering and drying at 40-50° C. for about 2 hours, the title compound was obtained as a pale yellow solid (117.2 g, 67%). 3-((3-Bromopyridin-2-yl)methyl)isoindolin-1-one (Int12) [ka] Step 1. tert-Butyl 1-oxoisoindoline-2-carboxylate (Int12-1) To a solution of isoindolin-1-one (20 g, 150 mmol), (Boc)O (39.3 g, 180 mmol), and EtN (45.5 g, 451 mmol) in THF (600 mL) was added DMAP (1.84 g, 15.0 mmol) at room temperature under N. After the addition, the mixture was stirred at 25 °C for 1 h. LC-MS showed that the starting material was mostly converted to the product. Water (200 mL) was then added and extracted with EtOAc (100 mL x 3). The organics were then combined and dried (NaSO) before being concentrated to dryness. The crude product was purified by flash (PE / EtOAc = 10:1) to give the product tert-butyl 1-oxoisoindoline-2-carboxylate (25 g, 71.4%) as a white solid. MS (ESI) m / z 234 [M+H] + . Step 2. tert-Butyl 1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindoline-2-carboxylate (12-2) LiHMDS (99.6 ml, 99.6 mmol) was added to a solution of tert-butyl 1-oxoisoindoline-2-carboxylate (23.24 g, 99.6 mmol) in THF (100 mL) at −78° C. After the solution was stirred at −78° C. for 1 h, 3-bromo-2-(bromomethyl)pyridine (25.0 g, 99.6 mmol) in THF (100 mL) was added, followed by stirring at −78° C. for 1.5 h. LC-MS showed that the starting material was mostly converted to product. The reaction mixture was extracted with saturated NaCl (aq.) and then EtOAc, and the combined organic layers were washed with saturated NaCl (aq.). The organic phase was dried over NaSO, and the solvent was evaporated. The residue was purified by flash chromatography on silica gel using 25-40% EtOAc in hexane to give the product tert-butyl 1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindoline-2-carboxylate (15 g, 37.3%) as a white solid. MS (ESI) m / z 403 [M+H] + . Step 3. 3-((3-Bromopyridin-2-yl)methyl)isoindolin-1-one (Int12) To a solution of tert-butyl 1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindoline-2-carboxylate (15.0 g, 37.2 mmol) in DCM (16 mL) was added TFA (4 mL) and the mixture was stirred at room temperature for 2 h. The reaction progress was monitored by LC-MS. Upon completion, the mixture was diluted with DCM (40 mL) and washed with saturated NaHCO3 solution. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was obtained as a black solid (15 g, 80.4%). MS (ESI) m / z 303 [M+H] + . HPLC conditions for the final product: (Column: XBridge® BEH Shield RP18; Column size: 4.6*50mm, 2.5μm; Mobile phase A: water containing 0.1% FA, Mobile phase B: ACN containing 0.05% FA; Flow rate: 1.5mL / min; Gradient: 5% B to 95% B in 10 min). The final product yield was the yield of the last step. General Synthetic Procedure A: 2-(4-hydroxybenzyl)isoquinolin-1(2H)-one (1) [ka] Step 1. 2-(4-(benzyloxy)benzyl)isoquinolin-1(2H)-one (1-3) To a solution of isoquinolin-1(2H)-one (150 mg, 1.03 mmol) in DMF (1.5 mL) was added NaH (25 mg, 1.03 mmol) under N at 0°C. The mixture was stirred for 30 min. 1-(benzyloxy)-4-(chloromethyl)benzene (265 mg, 1.14 mmol) was added, and the reaction was warmed to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0°C, and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc = 1.5 / 1) to give 2-(4-(benzyloxy)benzyl)isoquinolin-1(2H)-one (300 mg, 85%) as a white solid. MS (ESI) m / z 342 [M+H] + . Step 2. 2-(4-hydroxybenzyl)isoquinolin-1(2H)-one (1) To a solution of 2-(4-(benzyloxy)benzyl)isoquinolin-1(2H)-one (300 mg, 0.88 mmol) in methanol (10 mL) in a 100 mL round-bottom flask equipped with a magnetic stir bar and nitrogen inlet was added Pd / C (10 mg). The flask was evacuated and purged with nitrogen three times, and then evacuated and placed under hydrogen (1 atm). The mixture was stirred overnight at room temperature, filtered through a pad of Celite, and the filter cake was washed with methanol. The filtrate was concentrated and purified by preparative HPLC to give 2-(4-hydroxybenzyl)isoquinolin-1(2H)-one (49 mg, 22%) as an off-white solid. MS (ESI) m / z 252 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),8.23(d,J=8.0Hz,1H),7.73-7.66(m,1H),7.64(d,J=7.8Hz,1H),7.55-7.46 (m,2H),7.18(d,J=8.3Hz,2H),6.71(d,J=8.3Hz,2H),6.62(d,J=7.3Hz,1H),5.05(s,2H). Step B: 6-((1-oxoisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (4) [ka] Step 1. 3-(4-Methoxybenzyl)-6-((1-oxoisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (4-1) To a solution of isoquinolin-1(2H)-one (63 mg, 0.43 mmol) in DMF (1 mL) was added NaH (10 mg, 0.43 mmol) under N at 0°C. The mixture was stirred for 30 min. 6-(Bromomethyl)-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (151 mg, 0.43 mmol) was added, and the reaction was warmed to room temperature. The suspension was stirred for an additional 2 h. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc = 1 / 1) to give 3-(4-methoxybenzyl)-6-((1-oxoisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (50 mg, 28%) as a yellow solid. MS(ESI) m / z 413[M+H] + . Step 2. 6-((1-oxoisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (4) TfOH (0.10 mL) was added to a stirred solution of 3-(4-methoxybenzyl)-6-((1-oxoisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (50 mg, 0.12 mmol) in TFA (1 mL). The mixture was stirred at 70° C. for 0.5 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 6-((1-oxoisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (12 mg, 34%) as a white solid. MS (ESI) m / z 293 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.23(d,J=8.0Hz,1H),7.75-7.68(m,1H),7.65(d,J=7.8Hz,1H),7.59(d,J=7.4Hz,1H),7.51(t ,J=7.5Hz,1H),7.33(s,1H),7.16(d,J=8.0Hz,1H),7.04(d,J=8.0Hz,1H),6.65(d,J=7.4Hz,1H),5.17(s,2H). Step C: 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoquinolin-1(2H)-one (7) [ka] Step 1. 2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoquinolin-1(2H)-one (7-1) To a solution of isoquinolin-1(2H)-one (50 mg, 0.34 mmol) in DMF (1 mL) was added NaH (8 mg, 0.34 mmol) under N at 0°C. The mixture was stirred for 30 min. 5-(bromomethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazole (118 mg, 0.34 mmol) was added and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0°C and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc=1.5 / 1) to give 2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoquinolin-1(2H)-one (50 mg, 35%) as a yellow solid. MS(ESI) m / z 407 [M+H] + . Step 2. 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoquinolin-1(2H)-one (7) TFA (1 mL) was added to a stirred solution of 2-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoquinolin-1(2H)-one (50 mg, 0.12 mmol) in DCM (1 mL). The mixture was stirred for 5 h. The mixture was concentrated in vacuo and purified by C18 column (ACN=45%) to give 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)isoquinolin-1(2H)-one (20 mg, 58%) as a white solid. MS (ESI) m / z 277 [M+H] + .1 H NMR(400MHz,DMSO-d6)δ 15.58(s,1H),8.25(d,J=8.0Hz,1H),7.89(d,J=8.6Hz,1H),7.81(s,1H),7.74-7.63(m ,3H),7.52(t,J=7.5Hz,1H),7.45(d,J=8.6Hz,1H),6.68(d,J=7.3Hz,1H),5.36(s,2H). Step D: 2-(4-hydroxybenzyl)-5-methylisoindoline-1,3-dione (14) [ka] Step 1. 2-(4-Methoxybenzyl)-5-methylisoindoline-1,3-dione (14-3) To a stirred solution of 5-methylisoindoline-1,3-dione (100 mg, 0.62 mmol) in DMF (5 mL) was added 1-(chloromethyl)-4-methoxybenzene (98 mg, 0.62 mmol) and K2CO3 (171 mg, 1.24 mmol). The reaction mixture was stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with EA (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4, and concentrated to give the title compound (174 mg, crude) as a pale yellow solid. MS (ESI) m / z 282 [M+H] + . Step 2. 2-(4-Hydroxybenzyl)-5-methylisoindoline-1,3-dione (14) To a solution of 2-(4-methoxybenzyl)-5-methylisoindoline-1,3-dione (174 mg, 0.62 mmol) in DCM (5 mL) was added BBr (466 mg, 1.86 mmol) at 0 °C for 2 h, and then quenched with water and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)-5-methylisoindoline-1,3-dione (90 mg, 54.3%) as a white solid. MS (ESI) m / z 268 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),7.61(d,J=7.4Hz,1H),7.53-7.48(m,1H),7.43(t,J=7.2Hz,1H),7.28-7.18(m,2H),7.17(s,1H),7.11-6.97(m,5H),5. 18(d,J=15.2Hz,1H),4.71(dd,J=6.4,4.4Hz,1H),4.44(d,J=15.2Hz,1H),3.45(dd,J=14.0,4.4Hz,1H),3.14(dd,J=14.0,6.4Hz,1H). Step E: 6-((1-(2-fluorobenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (146) [ka] Step 1. 6-((1-(2-Fluorobenzyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (146-1) To a solution of 6-((1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (200 mg, 0.48 mmol) in THF (5 mL) was added LiHMDS (0.53 mL, 0.53 mmol) at −78° C. under N. The mixture was stirred for 30 min. Then, 1-(bromomethyl)-2-fluorobenzene (92 mg, 0.48 mmol) was added. The suspension was stirred for another 1 h. NH.sub.4Cl (aq) was added and then extracted with EtOAc. The organic layer was separated, dried over anhydrous Na.sub.2SO.sub.4, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=25 / 1) to give the title compound (150 mg, 59%) as a yellow solid. MS(ESI)m / z 519[M+H] + . Step 2. 6-((1-(2-fluorobenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (146) To a solution of 6-((1-(2-fluorobenzyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (150 mg, 0.28 mmol) in DCM (3 mL) was added TFA (3 mL). The mixture was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and ammonium hydroxide (1 mL) was added at 0° C. The suspension was stirred for a further 1 h. The mixture was concentrated and purified by preparative HPLC to give the title compound (33 mg, 28%) as a white solid. MS (ESI) m / z 389 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.58(dd,J=4.8,1.6Hz,1H),7.92(dd,J=6.4,2.4Hz,1H),7.88(dd,J=8.0,1.6Hz,1H),7.59(s,1H),7.53-7.47(m,2H),7.35(s,1H),7.24-7. 14(m,2H),5.30(t,J=6.4Hz,1H),5.11(d,J=15.6Hz,1H),4.43(d,J=15.6Hz,1H),3.47(dd,J=15.4,7.2Hz,1H),3.35(dd,J=15.4,5.6Hz,1H). General Procedure F 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)oxazole[4,5-b]pyridin-2(3H)-one (222) [ka] Step 1. 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)oxazole[4,5-b]pyridin-2(3H)-one (222-2) To a solution of 3-((3-bromopyridin-2-yl)methyl)isoindolin-1-one (17 mg, 0.06 mmol) in DMF (1 mL) was added NaH (3 mg, 0.07 mmol) under N at 0° C. After the addition, the mixture was stirred at 0° C. for 1 h. Then, 6-(bromomethyl)-3-(2-trimethylsilylethoxymethyl)oxazolo[4,5-b]pyridin-2-one (20 mg, 0.06 mmol) was added under N at 0° C. After the addition, the mixture was stirred at 25° C. for 1 h. LC-MS showed that the starting material was mostly converted to the product. Then, water (10 mL) was added and extracted with EtOAc (10 mL×3). The organics were then combined and dried (NaSO) before being concentrated to dryness. The crude product was purified by flash (PE / EtOAc=1:1) to give 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (25 mg, 77.2%) as a white solid. MS(ESI) m / z 581 [M+H] + . Step 2. 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)oxazole[4,5-b]pyridin-2(3H)-one (222) To a solution of 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (20 mg, 0.03 mmol) in DCM (1 mL) was added TFA (1 mL). The mixture was stirred for 1 hour and then concentrated in vacuo. The residue was dissolved in DCM (1 mL) and ammonium hydroxide (1 mL) was added at 0° C. The suspension was stirred for an additional 1 hour. The mixture was concentrated and purified by preparative HPLC to give 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (4 mg, 24.5%) as a white solid. MS(ESI) m / z 451[M+H]+ . 1 H NMR(400MHz,CDCl3)δ 8.58(dd,J=4.8,1.6Hz,1H),7.92(dd,J=6.4,2.4Hz,1H),7.88(dd,J=8.0,1.6Hz,1H),7.59(s,1H),7.53-7.47(m,2H),7.35(s,1H),7.24-7. 14(m,2H),5.30(t,J=6.4Hz,1H),5.11(d,J=15.6Hz,1H),4.43(d,J=15.6Hz,1H),3.47(dd,J=15.4,7.2Hz,1H),3.35(dd,J=15.4,5.6Hz,1H). Intermediate 222-1 was prepared as follows: [ka] Step 1. 6-Bromo-3-((2-(trimethylsilyl)ethoxy)methyl)oxazole[4,5-b]pyridin-2(3H)-one (222-4) To a solution of 6-bromo-3H-oxazolo[4,5-b]pyridin-2-one (4.3 g, 20 mmol) in DMF (40 mL) was added NaH (959 mg, 24 mmol) under N at 0 °C. After the addition, the mixture was stirred at 0 °C for 1 h. Then, SEMCl (3.67 g, 22 mmol) was added, and the mixture was stirred at 0 °C for 1 h. LC-MS showed that the starting material was mostly converted to the product. Then, water (100 mL) was added, and extracted with EtOAc (50 mL × 3). The organics were combined and dried (Na SO ), then concentrated to dryness. The crude product was purified by flash (PE / EtOAc=5:1) to give 6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (5 g, 68.9%) as a yellow oil. MS(ESI) m / z 345 [M+H] + . Step 2. 6-Methyl-3-((2-(trimethylsilyl)ethoxy)methyl)oxazole[4,5-b]pyridin-2(3H)-one (222-5) To a solution of 6-bromo-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (100 mg, 0.29 mmol) in DMF (10 ml) was added bis(triphenylphosphine)palladium(II) chloride (41 mg, 0.06 mmol) and tetramethyltin (104 mg, 0.6 mmol) at room temperature under N. After the addition, the mixture was stirred at 160 °C for 30 min using a microwave. LC-MS showed that the starting material was mostly converted to the product. Water (10 mL) was then added and extracted with EtOAc (10 mL x 3). The organics were then combined and dried (NaSO) before being concentrated to dryness. The crude product was purified by flash (PE / EtOAc=5:1) to give the product 6-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (60 mg, 73.9%) as a yellow oil. MS(ESI) m / z 281 [M+H] + . Step 3. 6-(Bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)oxazole[4,5-b]pyridin-2(3H)-one (222-1) To a solution of 6-methyl-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (500 mg, 1.78 mmol) and NBS (349 mg, 1.96 mmol) in CCl (5.0 mL) was added AIBN (29 mg, 0.18 mmol) at room temperature under N. After the addition, the mixture was stirred with microwave at 90 °C for 1 h. LC-MS showed that the starting material was mostly converted to product. Water (10 mL) was then added and extracted with EtOAc (10 mL x 3). The organics were then combined and dried (NaSO) before being concentrated to dryness. The crude product was purified by flash (PE / EtOAc=10:1) to give 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)oxazolo[4,5-b]pyridin-2(3H)-one (160 mg, 25%) as a yellow oil. MS(ESI) m / z 359 [M+H] + . Synthesis of compounds 2-537: 2-(4-hydroxybenzyl)-3,4-dihydroisoquinolin-1(2H)-one (2) [ka] The title compound 2 was prepared according to general procedure A as a white solid (6 mg, 2.2%). MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.34(s,1H),7.91(d,J=7.6Hz,1H),7.51-7.42(m,1H),7.35(t,J=7.5Hz,1H),7.27(d,J=7.5Hz,1H),7 .12(d,J=8.2Hz,2H),6.72(d,J=8.3Hz,2H),4.58(s,2H),3.43(t,J=6.6Hz,2H),2.92(t,J=6.6Hz,2H). 1-(4-hydroxybenzyl)-3,4-dihydroquinolin-2(1H)-one (3) [ka] The title compound 3 was prepared according to general procedure A as a white solid (39 mg, 18%). MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.27(s,1H),7.20(d,J=7.2Hz,1H),7.11(t,J=7.6Hz,1H),7.02(d,J=8.4Hz,2H),6.94(d,J= 8.0Hz,2H),6.67(d,J=8.4Hz,2H),5.01(s,2H),2.91(t,J=7.2Hz,2H),2.66(t,J=7.2Hz,2H). 1-(4-hydroxybenzyl)quinolin-2(1H)-one (5) [ka] The title compound 5 was prepared according to general procedure A as a white solid (60 mg, 54%). MS (ESI) m / z 252 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.34(s,1H),7.96(d,J=9.2Hz,1H),7.72(d,J=8.0Hz,1H),7.51(t,J=7.6Hz,1H),7.43(d,J= 8.8Hz,1H),7.22(t,J=7.6Hz,1H),7.05(d,J=8.4Hz,2H),6.70(t,J=8.4Hz,3H),5.39(s,2H). 4-(4-hydroxybenzyl)-2H-benzo[b][1,4]oxazin-3(4H)-one (6) [ka] The title compound 6 was prepared according to general procedure A as a white solid (93 mg, 42%). MS (ESI) m / z 256 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.33(s,1H),7.09(d,J=8.4Hz,2H),7.07-7.04(m,1H),6.98-6.94(m,3H),6.70(d,J=8.4Hz,2H),5.03(s,2H),4.75(s,2H). 6-((1-oxo-3,4-dihydroisoquinolin-2(1H)-yl)methyl)benzo[d]oxazol-2(3H)-one (8) [ka] The title compound 8 was prepared according to general procedure B as a white solid (20 mg, 46%). MS (ESI) m / z 295 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.92(dd,J=7.6,1.6Hz,1H),7.52-7.43(m,1H),7.41-7.33(m,1H),7.33-7.22(m,2H),7.13 (dd,J=8.0,1.6Hz,1H),7.05(d,J=8.0Hz,1H),4.70(s,2H),3.49(t,J=6.6Hz,2H),2.94(t,J=6.6Hz,2H). 6-((1,1-dioxidobenzo[d]isothiazol-2(3H)-yl)methyl)benzo[d]oxazol-2(3H)-one (9) [ka] The title compound 9 was prepared according to general procedure B as a white solid (48 mg, 59%). MS (ESI) m / z 317 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),7.90(d,J=7.6Hz,1H),7.75-7.66(m,1H),7.63-7.59(m,1H),7.57-7.52(m,1H),7. 34(d,J=1.5Hz,1H),7.22(dd,J=8.0,1.6Hz,1H),7.10(d,J=7.9Hz,1H),4.41(s,2H),4.32(s,2H). 2-(4-hydroxybenzyl)-1,4-dihydroisoquinolin-3(2H)-one (10) [ka] Step 1: Methyl 2-(2-(((4-(benzyloxy)benzyl)amino)methyl)phenyl)acetate (10-3) (4-(benzyloxy)phenyl)methanamine (772 mg, 3.62 mmol) was added to a solution of methyl 2-(2-formylphenyl)acetate (500 mg, 2.8 mmol) in absolute ethanol (10 mL) under N2. The redissolved mixture was stirred at room temperature for 16 hours, and the mixture was cooled to 0 °C. NaBH3CN (354 mg, 5.62 mmol) was added in portions until the intermediate imine disappeared. The reaction mixture was poured into ice water (50 mL) and extracted with EA (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to give the crude product (400 mg, 38%) as a yellow oil. Mass (m / z): 376 [M+H] + . Step 2: 2-(4-(benzyloxy)benzyl)-1,4-dihydroisoquinolin-3(2H)-one (10-4) A mixture of methyl 2-(2-(((4-(benzyloxy)benzyl)amino)methyl)phenyl)acetate (380 mg, 1.01 mmol) in MeOH (10 mL). The reaction mixture was heated to 40° C. for 12 h, and LC-MS showed the reaction was complete. The solvent was removed in vacuo and purified by column chromatography on silica gel (MeOH in DCM=0% to 10%) to give 2-(4-(benzyloxy)benzyl)-1,4-dihydroisoquinolin-3(2H)-one (140 mg, 40%) as a yellow oil. Mass (m / z): 344 [M+H] + . Step 3: 2-(4-hydroxybenzyl)-1,4-dihydroisoquinolin-3(2H)-one (10) To a solution of 2-(4-(benzyloxy)benzyl)-1,4-dihydroisoquinolin-3(2H)-one (120 mg, 0.35 mmol) in DCM (10 mL) was added BBr3 (95 mg, 0.38 mmol) at −78° C. The mixture was stirred under N2 at −78° C. for 2 h. The organic layer was separated and concentrated in vacuo and purified by preparative HPLC to give 2-(4-hydroxybenzyl)-1,4-dihydroisoquinolin-3(2H)-one (28 mg, 32%) as a white solid. MS (ESI) m / z: 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.34(s,1H),7.32(m,4H),7.05(d,J=8.4Hz,2H),6.71(d,J=8.8Hz,2H),4.52(s,2H),4.38(s,2H),3.60(s,2H). 2-(4-hydroxybenzyl)isoindoline-1,3-dione (11) [ka] Step 1. 2-(4-(benzyloxy)benzyl)isoindoline-1,3-dione (11-2) To a mixture of potassium 1,3-dioxoisoindolin-2-ide (1 g, 4.3 mmol) in DMF (10 mL) was added 1-(benzyloxy)-4-(chloromethyl)benzene (836 mg, 4.51 mmol). The resulting mixture was stirred at reflux for 3 hours. The reaction mixture was cooled to ambient temperature. The insoluble solid was collected by filtration and washed with water (100 ml). The collected solid was dried in an oven to give the title compound (1.39 g, 94.2%) as a white solid. MS (ESI) m / z 344 [M+H] + . Step 2. 2-(4-Hydroxybenzyl)isoindoline-1,3-dione (11) Pd / C (50 mg, 0.15 mmol) was added to a stirred mixture of 2-(4-(benzyloxy)benzyl)isoindoline-1,3-dione (500 mg, 1.46 mmol) in methanol (10 mL). The mixture was evacuated and filled with hydrogen three times. The resulting mixture was stirred under a hydrogen atmosphere at room temperature overnight. The reaction mixture was filtered and washed with methanol (20 mL). The collected filtrate was concentrated in vacuo. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)isoindoline-1,3-dione (168 mg, 45.6%) as a white solid. MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),7.93-7.80(m,4H),7.12(d,J=8.4Hz,2H),6.70(d,J=8.4Hz,2H),4.64(s,2H). 2-(4-hydroxybenzyl)isoindolin-1-one (12) [ka] Step 1. 2-(4-Methoxybenzyl)isoindolin-1-one (12-1) To a stirred solution of isoindolin-1-one (200 mg, 1.5 mmol) in THF (10 mL) was added NaH (60%, 72 mg, 1.8 mmol) at 0° C. for 10 min. Then, 1-(chloromethyl)-4-methoxybenzene (283 mg, 1.8 mmol) was added. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water and extracted with EA (3×50 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated to give the title compound (379 mg, crude) as a pale yellow solid. MS (ESI) m / z 254 [M+H] + . Step 2. 2-(4-Hydroxybenzyl)isoindolin-1-one (12) To a solution of 2-(4-methoxybenzyl)isoindolin-1-one (379 mg, 1.5 mmol) in DCM (5 mL) was added BBr (1.13 g, 4.5 mmol) at 0 °C and stirred for 2 h, and then quenched with water and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)isoindolin-1-one (86 mg, 24%) as a white solid. MS (ESI) m / z 240 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.35(s,1H),7.70(d,J=7.5Hz,1H),7.60-7.52(m,2H),7.48(t,J=7.2Hz,1 H),7.09(d,J=8.0Hz,2H),6.72(d,J=8.4Hz,2H),4.60(s,2H),4.31(s,2H). 1-(4-hydroxybenzyl)-1,2-dihydro-3H-indazol-3-one (13) [ka] The title compound 13 was prepared as a white solid (32 mg, 13.3%) following the procedure described for compound 12. MS (ESI) m / z 241 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 10.63(s,1H),9.31(s,1H),7.59(d,J=8.0Hz,1H),7.50(d,J=8.5Hz,1H),7.30(t,J=7.7H z,1H),7.04(d,J=8.4Hz,2H),6.97(t,J=7.4Hz,1H),6.66(d,J=8.4Hz,2H),5.20(s,2H). 2-(4-hydroxybenzyl)-5-(phenylamino)isoindoline-1,3-dione (15) [ka] Step 1. 5-Bromo-2-(4-methoxybenzyl)isoindoline-1,3-dione (15-1) To a stirred solution of 5-bromoisoindoline-1,3-dione (300 mg, 1.33 mmol) in DMF (8 mL) was added 1-(chloromethyl)-4-methoxybenzene (230 mg, 1.46 mmol), K2CO3 (367 mg, 2.66 mmol), and stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated to give the title compound (450 mg, crude) as a pale yellow solid. MS (ESI) m / z 346 / 348 [M+H] + . Step 2. 2-(4-Methoxybenzyl)-5-(phenylamino)isoindoline-1,3-dione (15-3) To a solution of 5-bromo-2-(4-methoxybenzyl)isoindoline-1,3-dione (100 mg, 0.29 mmol) in dioxane (5 mL) was added aniline (27 mg, 0.29 mmol), Pd(dba) (13 mg, 0.015 mmol), X-Phos (14 mg, 0.03 mmol), and CsCO (190 mg, 0.58 mmol) at room temperature under N. The resulting mixture was stirred at 90 °C for 12 h. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 3) to give the title compound (65 mg, 63% yield) as a yellow oil. MS (ESI) m / z 359 [M+H] + . Step 3. 2-(4-Hydroxybenzyl)-5-(phenylamino)isoindoline-1,3-dione (15) To a solution of 2-(4-methoxybenzyl)-5-(phenylamino)isoindoline-1,3-dione (65 mg, 0.18 mmol) in DCM (5 mL) was added BBr (136 mg, 0.54 mmol) at 0 °C and stirred for 2 h, and then quenched with water and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)-5-(phenylamino)isoindoline-1,3-dione (23 mg, 37%) as a white solid. MS (ESI) m / z 345 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.36(s,1H),9.14(s,1H),7.66(d,J=8.3Hz,1H),7.38(t,J=7.7Hz,2H),7 .32-7.18(m,4H),7.12-7.04(m,3H),6.66(d,J=8.4Hz,2H),4.58(s,2H). 5-Bromo-2-(4-hydroxybenzyl)isoindoline-1,3-dione (16) [ka] The title compound 16 was prepared according to general procedure D as a white solid (26 mg, 34%). MS (ESI) m / z 332 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),8.12-7.98(m,2H),7.81(d,J=7.9Hz,1H),7.12(d,J=8.4Hz,2H),6.69(d,J=8.4Hz,2H),4.63(s,2H). 2-(4-hydroxybenzyl)-4-(phenylamino)isoindoline-1,3-dione (17) [ka] The title compound 17 was prepared as a white solid (27 mg, 31%) following the procedure described for compound 15. MS (ESI) m / z 345 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),8.41(s,1H),7.58(t,J=7.8Hz,1H),7.43-7.37(m,3H),7.32(d,J=7.9H) z,2H),7.21(d,J=7.1Hz,1H),7.18-7.09(m,3H),6.71(d,J=8.4Hz,2H),4.62(s,2H). 5-(tert-butyl)-2-(4-hydroxybenzyl)isoindoline-1,3-dione (18) [ka] The title compound 18 was prepared according to general procedure D as a white solid (58 mg, 35%). MS (ESI) m / z 310 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.39(s,1H),7.90-7.78(m,3H),7.11(d,J=8.4Hz,2H),6.69(d,J=7.6Hz,2H),4.63(s,2H),1.34(s,9H). 6-Bromo-2-(4-hydroxybenzyl)isoindolin-1-one (19) [ka] The title compound 19 was prepared according to general procedure A as a yellow solid (7 mg, 24%). MS (ESI) m / z 318 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.91(s,1H),7.72(d,J=8.1Hz,1H),7.44(dd,J=8.0,2.4Hz,1H),7.15(dd,J=8.4,2.5Hz,2H),6.76(dd,J=8.5,2.7Hz,2H),4.69(s,2H),4.31(s,2H). 5-Bromo-2-(4-hydroxybenzyl)isoindolin-1-one (20) [ka] The title compound 20 was prepared according to general procedure A as a white solid (8 mg, 17%). MS (ESI) m / z 318 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),7.81(s,1H),7.69-7.63(m,2H),7.09(d,J=8.3Hz,2H),6.73(d,J=8.3Hz,2H),4.59(s,2H),4.31(s,2H). 4-Bromo-2-(4-hydroxybenzyl)isoindolin-1-one (21) [ka] The title compound 21 was prepared according to general procedure A as a white solid (3 mg, 26%). MS (ESI) m / z 318 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.79(d,J=7.6Hz,1H),7.74(d,J=8.0Hz,1H),7.45(t,J=7.7Hz,1H),7.17(d,J=8.3Hz,2H),6.78(d,J=8.3Hz,2H),4.72(s,2H),4.26(s,2H). 2-(4-hydroxybenzyl)-5-phenoxyisoindoline-1,3-dione (22) [ka] Step 1. 2-(4-(benzyloxy)benzyl)-5-bromoisoindoline-1,3-dione (22-1) To a stirred solution of 5-bromoisoindoline-1,3-dione (1.5 g, 6.64 mmol) in DMF (15 mL) was added 1-(benzyloxy)-4-(chloromethyl)benzene (1.55 g, 6.64 mmol), K2CO3 (1.83 g, 13.3 mmol) and stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous N2SO4 and concentrated to give the title compound (2.7 g, crude) as a pale yellow solid. MS (ESI) m / z 422 / 424 [M+H] + . Step 2. 2-(4-(benzyloxy)benzyl)-5-phenoxyisoindoline-1,3-dione (22-3) To a solution of 2-(4-(benzyloxy)benzyl)-5-bromoisoindoline-1,3-dione (100 mg, 0.24 mmol) in DMF (3 mL) was added CuI (2 mg, 0.012 mmol) and CsCO (155 mg, 0.48 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 15 h. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 3) to give the title compound (20 mg, 19.3%) as a yellow oil. MS (ESI) m / z 436.1 [M+H] + . Step 3. 2-(4-Hydroxybenzyl)-5-phenoxyisoindoline-1,3-dione (22) To a solution of 2-(4-(benzyloxy)benzyl)-5-phenoxyisoindoline-1,3-dione (20 mg, 0.046 mmol) in EtOH (5 mL) was added Pd / C (5 mg). The mixture was evacuated and filled with hydrogen three times. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC to give the title compound as a white solid (1 mg, 6.3%). MS (ESI) m / z 346 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.38(s,1H),7.88(d,J=8.2Hz,1H),7.50(t,J=7.8Hz,2H),7.39-7.25(m,3H),7 .18(d,J=8.0Hz,2H),7.10(d,J=8.3Hz,2H),6.69(d,J=8.3Hz,2H),4.62(s,2H). 2-(4-Hydroxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (23) [ka] Step 1. tert-Butyl 3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (23-2) To a stirred solution of 1,2-dihydro-3H-indazol-3-one (500 mg, 3.73 mmol) in DCM (20 mL), (Boc)2O (813 mg, 3.73 mmol), DMAP (45 mg, 0.37 mmol) were added and stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with DCM (3 x 50 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 3) to give the title compound (800 mg, 91.7%) as a yellow solid. MS (ESI) m / z 235 [M+H] + . Step 2. tert-Butyl 2-(4-methoxybenzyl)-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (23-3) To a stirred solution of tert-butyl 3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (300 mg, 1.28 mmol) in DMF (10 mL) was added 1-(chloromethyl)-4-methoxybenzene (201 mg, 1.28 mmol), K2CO3 (354 mg, 2.56 mmol) and stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (450 mg, 99.3%) as a yellow oil. MS (ESI) m / z 355 [M+H] + . Step 3. 2-(4-Methoxybenzyl)-1,2-dihydro-3H-indazol-3-one (23-4) To a stirred solution of tert-butyl 2-(4-methoxybenzyl)-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (450 mg, 1.27 mmol) in DCM (10 mL) was added TFA (5 mL) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and quenched with NaHCO (aq.) and extracted with DCM (3 x 50 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated to give the title compound (320 mg, crude) as a yellow oil. MS (ESI) m / z 255 [M+H] + . Step 4. 2-(4-Methoxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (23-5) To a stirred solution of 2-(4-methoxybenzyl)-1,2-dihydro-3H-indazol-3-one (66 mg, 0.26 mmol) in DMF (5 mL) was added iodomethane (37 mg, 0.26 mmol), K2CO3 (72 mg, 0.52 mmol) and stirred at 50 °C overnight. The reaction mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous Na2SO4 and concentrated to give the title compound (50 mg, 71.8%) as a yellow oil. MS (ESI) m / z 269 [M+H] + . Step 5. 2-(4-Hydroxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (23) To a solution of 2-(4-methoxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one (50 mg, 0.19 mmol) in DCM (5 mL) was added BBr (140 mg, 0.56 mmol) at 0 °C and reacted for 2 hours, and then quenched with water and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)-1-methyl-1,2-dihydro-3H-indazol-3-one as a white solid (9 mg, 19%). MS (ESI) m / z 255 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.36(s,1H),7.69(d,J=7.8Hz,1H),7.57(t,J=7.7Hz,1H),7.44(d,J=8.3Hz,1H),7.16( t,J=7.4Hz,1H),7.06(d,J=8.1Hz,2H),6.67(d,J=8.1Hz,2H),4.94(s,2H),3.24(s,3H). 1-Ethyl-2-(4-hydroxybenzyl)-1,2-dihydro-3H-indazol-3-one (24) [ka] The title compound 24 was prepared as a white solid (10 mg, 20%) following the procedure described for compound 23. MS (ESI) m / z 269 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.35(s,1H),7.69(d,J=7.8Hz,1H),7.56(t,J=7.7Hz,1H),7.43(d,J=8.3Hz,1H),7.14(t,J=7.4Hz,1H), 7.07(d,J=8.2Hz,2H),6.66(d,J=8.2Hz,2H),4.91(s,2H),3.90(q,J=6.9Hz,2H),0.67(t,J=6.9Hz,3H). 2-(4-Hydroxybenzyl)-1-propyl-1,2-dihydro-3H-indazol-3-one (25) [ka] The title compound 25 was prepared as a white solid (10 mg, 19.8%) according to the procedure described for compound 23. MS (ESI) m / z 283 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.35(s,1H),7.68(d,J=7.8Hz,1H),7.54(t,J=8.0Hz,1H),7.44(d,J=8.3Hz,1H),7.11(t,J=7.4Hz,1H),7.07(d,J =8.0Hz,2H),6.66(d,J=8.4Hz,2H),4.92(s,2H),3.80(t,J=7.6Hz,2H),1.19-1.06(m,2H),0.67(t,J=7.4Hz,3H). 2-(4-hydroxybenzyl)-5-isopropylisoindoline-1,3-dione (26) [ka] Step 1. 2-(4-(benzyloxy)benzyl)-5-(prop-1-en-2-yl)isoindoline-1,3-dione (26-1) To a solution of 2-(4-(benzyloxy)benzyl)-5-bromoisoindoline-1,3-dione (100 mg, 0.24 mmol) in 1-4, dioxane (3 mL), and water (1 mL) was added Pd(dppf)Cl (10 mg, 0.012 mmol) and KCO (65 mg, 0.47 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 3 h. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NSO, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 3) to give the title compound (60 mg, 65.8%) as a yellow oil. MS (ESI) m / z 384 [M+H] + . Step 2. 2-(4-Hydroxybenzyl)-5-isopropylisoindoline-1,3-dione (26) To a solution of 2-(4-(benzyloxy)benzyl)-5-(prop-1-en-2-yl)isoindoline-1,3-dione (60 mg, 0.16 mmol) in MeOH (5 mL) was added Pd / C (6 mg). The mixture was evacuated and filled with hydrogen three times. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered off, and the filtrate was concentrated. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)-5-isopropylisoindoline-1,3-dione (14 mg, 30.2%) as a white solid. MS (ESI) m / z 296 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),7.85-7.62(m,3H),7.11(d,J=8.3Hz,2H),6.69(d,J=8.3Hz,2H),4.63(s,2H),3.15-3.05(m,1H),1.25(d,J=6.9Hz,6H). 2-(2-(4-hydroxybenzyl)-3-oxoisoindolin-1-yl)acetonitrile (27) [ka] Step 1. (Z)-3-(2-iodophenyl)acrylonitrile (27-3) To a solution of 2-iodobenzaldehyde (500 mg, 2.15 mmol) and (cyanomethyl)triphenylphosphonium chloride (728 mg, 2.15 mmol) in DCM (5 mL) was added NaOH (95 mg, 2.37 mmol) in water (2 mL). The mixture was stirred for 1 h, diluted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EA=3 / 1) to give (Z)-3-(2-iodophenyl)acrylonitrile (300 mg, 54%) as a yellow oil. MS (ESI) m / z 256 [M+H] + . Step 2. 2-(2-(4-hydroxybenzyl)-3-oxoisoindolin-1-yl)acetonitrile (27) To a solution of (Z)-3-(2-iodophenyl)acrylonitrile (100 mg, 0.39 mmol), 4-(aminomethyl)phenol (53 mg, 0.43 mmol), CsCO (256 mg, 0.78 mmol), PPh (103 mg, 0.39 mmol), and Pd(OAc) (18 mg, 0.07 mmol) in toluene (2 mL) was added to a 50 mL round-bottom flask equipped with a magnetic stir bar and nitrogen inlet. The flask was evacuated and purged with nitrogen three times, and then evacuated and placed under CO (1 atm). The mixture was stirred at 90 °C overnight. The solution was concentrated and purified by preparative HPLC to give 2-(2-(4-hydroxybenzyl)-3-oxoisoindolin-1-yl)acetonitrile (4 mg, 3%) as a white solid. MS (ESI) m / z 279 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),7.76(d,J=7.5Hz,1H),7.70-7.65(m,2H),7.62-7.52(m,1H),7.14(d,J=8.2Hz,2H),6.71(d,J =8.3Hz,2H),4.97(d,J=15.0Hz,1H),4.64(t,J=4.2Hz,1H),4.30(d,J=15.0Hz,1H),3.41(d,J=4.1Hz,2H). 2-(4-Hydroxybenzyl)-3-oxoisoindoline-1-carbonitrile (28) [ka] Methyl 2-formylbenzoate (164 mg, 1 mmol), 4-(aminomethyl)phenol (123 mg, 1 mmol), trimethylsilanecarbonitrile (198 mg, 2 mmol), and scandium trifluoromethanesulfonate (123 mg, 0.25 mmol) were dissolved in EtOH (2 mL), and the solution was stirred at room temperature for 7 hours. After the reaction was complete, the mixture was concentrated in vacuo, and the crude product was purified by preparative HPLC to give 2-(4-hydroxybenzyl)-3-oxoisoindoline-1-carbonitrile (50 mg, 19%) as a white solid. MS (ESI) m / z 265 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 7.93(d,J=7.4Hz,1H),7.70-7.55(m,3H),7.24(d,J=8.0Hz,2H),6.83(d,J =8.0Hz,2H),5.42(d,J=14.9Hz,1H),5.08(s,1H),4.25(d,J=14.9Hz,1H). 7-Bromo-2-(4-hydroxybenzyl)isoindolin-1-one (29) [ka] The title compound 29 was prepared according to general procedure A as a yellow solid (6 mg, 9%). MS (ESI) m / z 318 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.62(d,J=7.6Hz,1H),7.48-7.41(m,2H),7.15(d,J=8.4Hz,2H),6.76(d,J=8.4Hz,2H),4.67(s,2H),4.29(s,2H). 2-(4-hydroxybenzyl)-5-methoxyisoindoline-1,3-dione (30) [ka] The title compound 30 was prepared according to general procedure D as a white solid (48 mg, 42%). MS (ESI) m / z 284 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),7.80(d,J=8.3Hz,1H),7.39(s,1H),7.31(dd,J=8.3,1.6Hz,1 H),7.11(d,J=8.3Hz,2H),6.69(d,J=8.3Hz,2H),4.61(s,2H),3.92(s,3H). 2-(4-hydroxybenzyl)-3-methylisoindolin-1-one (31) [ka] The title compound 31 was prepared according to general procedure A as a white solid (30 mg, 39%). MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.35(s,1H),7.70(d,J=7.5Hz,1H),7.62-7.56(m,2H),7.53-7.45(m,1H),7.10(d,J=8.1Hz,2H),6.70(d,J =8.1Hz,2H),4.94(d,J=15.0Hz,1H),4.37(q,J=6.7Hz,1H),4.24(d,J=15.0Hz,1H),1.37(d,J=6.7Hz,3H). 2-(4-hydroxybenzyl)-6-methylisoindolin-1-one (32) [ka] The title compound 32 was prepared according to general procedure A as a white solid (32 mg, 42%). MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),7.51(s,1H),7.43-7.37(m,2H),7.08(d,J=8.0Hz,2H),6.72(d,J=8.1Hz,2H),4.58(s,2H),4.25(s,2H),2.39(s,3H). 6-((1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (33) [ka] The title compound 33 was prepared according to general procedure B as an off-white solid (11 mg, 77%). MS (ESI) m / z 281 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.72(d,J=7.5Hz,1H),7.61-7.54(m,2H),7.50(t,J=7.3Hz,1H),7.23(s,1H),7.12-7.02(m,2H),4.73(s,2H),4.37(s,2H). 2-(4-hydroxybenzyl)-4-methylisoindolin-1-one (34) [ka] The title compound 34 was prepared according to general procedure A as a white solid (22 mg, 29%). MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),7.52(dd,J=6.5,1.9Hz,1H),7.42-7.36(m,2H),7.10(d,J=8 .2Hz,2H),6.73(d,J=8.2Hz,2H),4.60(s,2H),4.27(s,2H),2.27(s,3H). 2-(4-Hydroxybenzyl)-5-methoxyisoindolin-1-one (35) [ka] The title compound 35 was prepared according to general procedure A as an off-white solid (20 mg, 17%). MS (ESI) m / z 270 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.43(s,1H),7.60(d,J=8.4Hz,1H),7.13-6.99(m,4H),6.72(d,J=8.2Hz,2H),4.56(s,2H),4.24(s,2H),3.81(s,3H). 2-(4-Hydroxybenzyl)-5-(pyrrolidin-1-yl)isoindoline-1,3-dione (36) [ka] The title compound 36 was prepared as a white solid (3 mg, 6.1%) according to the procedure described for compound 15. MS (ESI) m / z 323 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.34(s,1H),7.60(d,J=8.4Hz,1H),7.08(d,J=8.3Hz,2H),6.88(d,J=2.2Hz,1H),6.77(dd,J =8.3,2.3Hz,1H),6.68(d,J=8.4Hz,2H),4.57(s,2H),3.42-3.36(m,4H),2.03-1.95(m,4H). 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-5-methylisoindoline-1,3-dione (37) [ka] Step 1. tert-Butyl 5-methyl-1H-benzo[d][1,2,3]triazole-1-carboxylate (37-1) To a stirred solution of 5-methyl-1H-benzo[d][1,2,3]triazole (500 mg, 3.76 mmol) in DCM (20 mL) was added (Boc)O (901 mg, 4.14 mmol), TEA (760 mg, 7.52 mmol), and stirred at room temperature overnight. The reaction mixture was quenched with water and extracted with DCM (3 x 50 mL). The organic layer was separated and dried over anhydrous NaSO and concentrated in vacuo to give the title compound (800 mg, crude) as a yellow solid. MS (ESI) m / z 234 [M+H] + . Step 2. tert-Butyl 5-(bromomethyl)-1H-benzo[d][1,2,3]triazole-1-carboxylate (37-2) To a stirred solution of tert-butyl 5-methyl-1H-benzo[d][1,2,3]triazole-1-carboxylate (200 mg, 0.86 mmol) in CCl (10 mL), NBS (183 mg, 1.03 mmol), AIBN (20 mg, 0.09 mmol) were added and reacted at 60 °C for 5 h. The reaction mixture was quenched with water and extracted with EA (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated to give the title compound (65 mg, 24.3%) as a yellow oil. MS (ESI) m / z 312 / 314 [M+H] + . Step 3. 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-5-methylisoindoline-1,3-dione (37) To a solution of tert-butyl 5-(bromomethyl)-1H-benzo[d][1,2,3]triazole-1-carboxylate (65 mg, 0.31 mmol) in DMF (5 mL) was added 5-methylisoindoline-1,3-dione (50 mg, 0.31 mmol) CsCO (202 mg, 0.62 mmol) and stirred at 50 °C overnight. The reaction was then quenched with water and extracted with EA (3 × 50 mL). The combined organic phases were washed with brine, dried over anhydrous NaSO, and concentrated. The residue was purified by preparative HPLC to give 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-5-methylisoindoline-1,3-dione (6 mg, 6.7%) as a white solid. MS (ESI) m / z 293 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 15.55(s,1H),7.87(d,J=8.6Hz,1H),7.82-7.76(m,2H),7.74(s,1H),7.66(d,J=7.7Hz,1H),7.37(d,J=8.6Hz,1H),4.92(s,2H),2.48(s,3H). 2-(4-Hydroxybenzyl)-1,3-dioxoisoindoline-5-carboxamide (38) [ka] Step 1. 2-(4-Hydroxybenzyl)-1,3-dioxoisoindoline-5-carboxylic acid (38-2) To a solution of 1,3-dioxo-1,3-dihydroisobenzofuran-5-carboxylic acid (384 mg, 2 mmol) and 4-(aminomethyl)phenol (246 mg, 2 mmol) in DMSO (3 mL) was added. The mixture was irradiated in a microwave oven at 150 °C for 10 minutes, and then the mixture was diluted with water and extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated to give 2-(4-hydroxybenzyl)-1,3-dioxoisoindoline-5-carboxylic acid (400 mg) as an off-white solid, which was used in the next step without further purification. MS (ESI) m / z 298 [M+H] + . Step 2. 2-(4-Hydroxybenzyl)-1,3-dioxoisoindoline-5-carboxamide (38) A solution of 2-(4-hydroxybenzyl)-1,3-dioxoisoindoline-5-carboxylic acid (200 mg, 0.67 mmol) in SOCl (2.0 mL) was stirred at 80° C. under N for 2 h. The mixture was concentrated in vacuo, the crude product was diluted with DCM (2 mL), and then added to ammonium hydroxide (1 mL) and stirred for 2 h. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give 2-(4-hydroxybenzyl)-1,3-dioxoisoindoline-5-carboxamide (13 mg, 6%) as a white solid. MS (ESI) m / z 297 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.39(s,1H),8.32(s,2H),8.30(d,J=7.7Hz,1H),7.96(d,J=7.7Hz,1H),7.72(s,1H),7.13(d,J=8.2Hz,2H),6.70(d,J=8.2Hz,2H),4.66(s,2H). 6-(4-Hydroxybenzyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (39) [ka] The title compound 39 was prepared according to general procedure A as an off-white solid (13 mg, 18.0%). MS (ESI) m / z 241 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),8.74(d,J=4.9Hz,1H),8.11(d,J=7.7Hz,1H),7.52(dd,J=7.5,5.1 Hz,1H),7.12(d,J=8.2Hz,2H),6.73(d,J=8.2Hz,2H),4.63(s,2H),4.38(s,2H). 6-(4-Hydroxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (40) [ka] The title compound 40 was prepared according to general procedure A as a yellow solid (12 mg, 8.5%). MS (ESI) m / z 241 [M+H] + . 1 H NMR(400MHz,CDCl3)δ 8.79(d,J=4.6Hz,1H),7.76(d,J=7.7Hz,1H),7.41(dd,J=7.5,4.9Hz,1H),7.19(d,J=8.2Hz,2H),6.83(d,J=8.2Hz,2H),4.78(s,2H),4.26(s,2H). 5-Ethyl-2-(4-hydroxybenzyl)isoindoline-1,3-dione (41) [ka] The title compound 41 was prepared as a yellow solid (8 mg, 8.2%) as a white solid following the procedure described for compound 26. MS (ESI) m / z 282 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.37(s,1H),7.79(d,J=7.6Hz,1H),7.74(s,1H),7.68(d,J=7.6Hz,1H),7.11(d,J=8.2H z,2H),6.69(d,J=8.3Hz,2H),4.62(s,2H),2.78(q,J=7.6Hz,2H),1.22(t,J=7.5Hz,3H). 2-(4-Hydroxybenzyl)-1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one (42) [ka] The title compound 42 was prepared according to general procedure A as a yellow solid (11 mg, 12.8%). MS (ESI) m / z 241 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 8.96(s,1H),8.70(d,J=4.4Hz,1H),7.63(d,J=4.8Hz,1H),7.17(d,J=8.2Hz,2H),6.77(d,J=8.1Hz,2H),4.71(s,2H),4.45(s,2H). 2-(4-Hydroxybenzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (43) [ka] The title compound 43 was prepared according to general procedure A as a yellow solid (11 mg, 21.5%). MS (ESI) m / z 241 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),8.92(s,1H),8.73(d,J=5.0Hz,1H),7.63(d,J=5.0Hz,1H),7.10(d,J=8.2Hz,2H),6.73(d,J=8.2Hz,2H),4.60(s,2H),4.40(s,2H). 2-((1H-benzo[d][1,2,3]triazol-5-yl)methyl)-3-methylisoindolin-1-one (44) [ka] The title compound 44 was prepared according to general procedure C as a white solid (8 mg, 28%). MS (ESI) m / z 279 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 15.63(s,1H),7.92-7.80(m,2H),7.75(d,J=7.5Hz,1H),7.66-7.55(m,2H),7.51(t,J=7.2Hz,1H),7.36(d, J=8.6Hz,1H),5.17(d,J=15.3Hz,1H),4.62(d,J=15.3Hz,1H),4.48(q,J=6.7Hz,1H),1.41(d,J=6.6Hz,3H). 2-(1-(4-hydroxyphenyl)ethyl)isoindolin-1-one (45) [ka] Step 1. (Z)-1-(4-hydroxyphenyl)ethan-1-one oxime (45-2) To a solution of 1-(4-hydroxyphenyl)ethan-1-one (3.5 g, 0.026 mol) in 50 mL of EtOH:HO (4:1), NaOAc (4.22 g, 0.05 mol) and hydroxylamine hydrochloride (2.86 g, 0.41 mol) were added. The reaction mixture was stirred at room temperature for 16 hours. Water was added, and the mixture was then extracted with EtOAc. The organic layer was collected. The crude product was then purified on a silica gel column (1:3 EtOAc:PE) to give (Z)-1-(4-hydroxyphenyl)ethan-1-one oxime (3 g, 77.2%) as a white solid. MS (ESI) m / z 152 [M+H] + . Step 2. 4-(1-aminoethyl)phenol (45-3) To a solution of (Z)-1-(4-hydroxyphenyl)ethan-1-one oxime (500 mg, 3.3 mmol) in MeOH (10 mL) was added Pd / C (2.5 g, 6.6 mmol) under hydrogen flow at room temperature for 16 hours. After the reaction was complete, the reaction mixture was filtered and the filtrate was collected. The solvent was removed in vacuo to give 4-(1-aminoethyl)phenol (400 mg, 88.8%) as a gray solid. MS (ESI) m / z 138 [M+H] + . Step 3. 2-(1-(4-hydroxyphenyl)ethyl)isoindolin-1-one (45) To a solution of 4-(1-aminoethyl)phenol (80 mg, 0.6 mmol) in DCE (5 mL) was added methyl 2-formylbenzoate (670 mg, 4.1 mmol), DIPEA (151 mg, 1.7 mmol), and sodium triacetoxyborohydride (618 mg, 2.9 mmol). The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was removed in vacuo, and the crude product was purified by preparative HPLC to give 2-(1-(4-hydroxyphenyl)ethyl)isoindolin-1-one (41 mg, 27.6%) as a white solid. MS (ESI) m / z 254 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.40(s,1H),7.69(d,J=7.5Hz,1H),7.59-7.52(m,2H),7.48(t,J=7.2Hz,1H),7.14(d,J=8.4Hz,2H),6.73(d ,J=8.4Hz,2H),5.45(q,J=7.1Hz,1H),4.47(d,J=17.7Hz,1H),4.01(d,J=17.7Hz,1H),1.58(d,J=7.1Hz,3H). 6-((1-methyl-3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (46) [ka] Step 1. tert-Butyl 2-((3-(4-methoxybenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (46-1) To a solution of tert-butyl 3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (81 mg, 0.34 mmol) in DMF (1 mL) was added NaH (8 mg, 0.34 mmol) under N at 0°C. The mixture was stirred for 30 min. 6-(bromomethyl)-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (120 mg, 0.34 mmol) was added, and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0°C, and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc = 1.5 / 1) to give tert-butyl 2-((3-(4-methoxybenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (80 mg, 46%) as a yellow solid. MS (ESI) m / z 502 [M+H] + . Step 2. 3-(4-Methoxybenzyl)-6-((3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (46-2) TFA (1 mL) was added to a stirred solution of tert-butyl 2-((3-(4-methoxybenzyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)-3-oxo-2,3-dihydro-1H-indazole-1-carboxylate (80 mg, 0.16 mmol) in DCM (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was concentrated in vacuo to give 3-(4-methoxybenzyl)-6-((3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 93%) as a white solid. MS (ESI) m / z 402 [M+H] + . Step 3. 3-(4-Methoxybenzyl)-6-((1-methyl-3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (46-3) To a solution of 3-(4-methoxybenzyl)-6-((3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 0.14 mmol) in DMF (1 mL) was added NaH (4 mg, 0.14 mmol) at 0° C. under N. The mixture was stirred for 30 min. Iodomethane (21 mg, 0.14 mmol) was added and the reaction was warmed to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0° C. and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc=1 / 1) to give 3-(4-methoxybenzyl)-6-((1-methyl-3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (40 mg, 64%) as a yellow solid. MS(ESI) m / z 416 [M+H] + . Step 4. 6-((1-methyl-3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (46) TfOH (0.1 mL) was added to a stirred solution of 3-(4-methoxybenzyl)-6-((1-methyl-3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (40 mg, 0.09 mmol) in TFA (1 mL). The mixture was stirred at 70° C. for 0.5 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 6-((1-methyl-3-oxo-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (7 mg, 22%) as a white solid. MS (ESI) m / z 296 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),7.72(d,J=7.8Hz,1H),7.58(t,J=7.7Hz,1H),7.46(d,J=8. 3Hz,1H),7.23-7.14(m,2H),7.09-6.98(m,2H),5.07(s,2H),3.26(s,3H). 6-((5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (47) [ka] Intermediate 47-1 was prepared according to the procedure described for Int7. Step 1. 3-(4-Methoxybenzyl)-6-((5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (47-2) To a solution of 6-((5-bromo-1-oxoisoindolin-2-yl)methyl)-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (150 mg, 0.31 mmol) in 1,4-dioxane (2.5 mL) was added morpholine (41 mg, 0.46 mmol), CsCO (204 mg, 0.62 mmol), Xphos (30 mg, 0.06 mmol), and Pd(dba) (57 mg, 0.06 mmol) under N. The mixture was stirred at 100 °C for 14 h. The mixture was purified by preparative TLC (DCM / MeOH=35 / 1) to give 3-(4-methoxybenzyl)-6-((5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (47 mg, 30%) as a yellow solid. MS(ESI) m / z 486 [M+H] + . Step 2. 6-((5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (47) TfOH (0.1 mL) was added to a stirred solution of 3-(4-methoxybenzyl)-6-((5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (47 mg, 0.09 mmol) in TFA (1 mL). The mixture was stirred at 70° C. for 0.5 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 6-((5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (3 mg, 6%) as a white solid. MS (ESI) m / z 366 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.53(d,J=8.3Hz,1H),7.18(s,1H),7.06-7.02(m,4H),4.66(s,2H),4.25(s,2H),3.73(t,J=4.8Hz,4H),3.21(t,J=4.9Hz,4H). 6-((5-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (48) [ka] Step 1. 6-((5-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (48-2) To a solution of 5-methylisoindolin-1-one (33 mg, 0.22 mmol) in DMF (1 mL) was added NaH (8 mg, 0.34 mmol) under N at 0° C. The mixture was stirred for 30 min. 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (80 mg, 0.22 mmol) was added and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0° C. and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc=1.5 / 1) to give 6-((5-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 63%) as a yellow solid. MS(ESI) m / z 425 [M+H] + . Step 2. 6-((5-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (48) To a solution of 6-((5-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 0.14 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and ammonium hydroxide (1 mL) was added at 0° C. The suspension was stirred for an additional 1 h. The mixture was concentrated and purified by preparative HPLC to give 6-((5-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (11 mg, 24%) as a white solid. MS (ESI) m / z 295 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.60(d,J=7.7Hz,1H),7.35(s,1H),7.31(d,J=8.3Hz,1H) ,7.21(s,1H),7.08-7.04(m,2H),4.70(s,2H),4.31(s,2H),2.40(s,3H). 6-((5-Methoxy-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (49) [ka] The title compound 49 was prepared as a white solid (22 mg, 61%) following the procedure described for compound 48. MS (ESI) m / z 311 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.62(d,J=8.4Hz,1H),7.20(s,1H),7.11(d,J=2.2Hz,1H),7.07-7.01(m,3H),4.68(s,2H),4.30(s,2H),3.81(s,3H). 6-((1-methyl-3-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (50) and 6-((3-methyl-1-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (51) [ka] Step 1. Mixture of 6-((1-methyl-3-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (50-1) and 6-((3-methyl-1-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (51-1) To a solution of a mixture of Int3 and Int2 (400 mg, 0.79 mmol) in DMF (6 mL) was added Pd2(dba)3 (36 mg, 0.04 mmol), X-phos (38 mg, 0.08 mmol), Cs2CO3 (518 mg, 1.59 mmol), and pyrrolidine (169 mg, 2.38 mmol) at room temperature under N2. The resulting mixture was stirred at 100 °C for 15 h. The mixture was diluted with EtOAc (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 1 / 3) to give the title compound mixture (80 mg, 20.4%) as a yellow oil. MS (ESI) m / z 494 [M+H] + . Step 2. 6-((1-methyl-3-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (50) and 6-((3-methyl-1-oxo-5-(pyrrolidin-1-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (51) To a solution of a mixture of 50-1 and 51-1 (80 mg, 0.16 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (2 mL) and NH4OH (1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give two compounds, Compound 50 and Compound 51. One of these two compounds was a white solid (3 mg, 10.2%) with a RT of 5.19 minutes (HPLC). MS (ESI) m / z 363 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.32 (d, J = 8.4 Hz, 1H), 7.16 (s, 1H), 7.05-6.99 (m, 2H), 6.78-6.73 (m, 2H), 4.99 (d, J = 15.2 Hz, 1H), 4.34 (d, J = 15.2 Hz, 1H), 4.23 (q, J = 6.4 Hz, 1H), 3.28-3.25 (m, 4H), 2.01-1.96 (m, 2H), 1.30 (d, J = 6.4 Hz, 3H). The other of the two compounds was a white solid (3 mg, 10.2%) with a RT = 5.41 min (HPLC). MS (ESI) m / z 363 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.46(d,J=9.2Hz,1H),7.16(s,1H),7.05-7.00(m,2H),6.58-6.51(m,2H),4.93(d,J=15.2Hz,1H),4.30 (d,J=15.2Hz,1H),4.22(q,J=6.4Hz,1H),3.31-3.24(m,4H),1.99-1.93(m,4H),1.32(d,J=6.4Hz,3H). 6-((1,1-dimethyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (52) [ka] The title compound 52 was prepared according to general procedure B as an off-white solid (58 mg, 42.2%). MS (ESI) m / z 309 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),7.72(d,J=7.6Hz,1H),7.67-7.60(m,2H),7.49(t,J=7.2Hz,1H),7.31( s,1H),7.19(dd,J=8.0,1.3Hz,1H),7.02(d,J=8.0Hz,1H),4.69(s,2H),1.36(s,6H). 6-((1-ethyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (53) [ka] The title compound 53 was prepared according to general procedure B as an off-white solid (20 mg, 14%). MS (ESI) m / z 309 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.72(d,J=7.5Hz,1H),7.63-7.48(m,3H),7.26(s,1H),7.11(dd,J=8.0,1.2Hz,1H),7.04(d,J=8.0Hz, 1H),5.06(d,J=15.1Hz,1H),4.51(t,J=4.0Hz,1H),4.29(d,J=15.1Hz,1H),2.05-1.99(m,2H),0.36(t,J=7.3Hz,3H). 6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (54) [ka] The title compound 54 was prepared according to general procedure B as a white solid (8 mg, 21%). MS (ESI) m / z 295 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.29(s,1H),7.72(d,J=7.5Hz,1H),7.65-7.55(m,2H),7.50(t,J=7.2Hz,1H),7.24(s,1H),7.09(d,J =8.0Hz,1H),7.04(d,J=7.9Hz,1H),5.01(d,J=15.2Hz,1H),4.49-4.38(m,2H),1.39(d,J=6.7Hz,3H). (R)-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (55) [ka] The title compound 55 was prepared according to general procedure B using (R)-3-methylisoindolin-1-one as the starting material to give a white solid (52 mg, 28%). MS (ESI) m / z 295 [M+H] + .1 H NMR(400MHz,CD3OD)δ 7.81(d,J=7.5Hz,1H),7.61(t,J=7.4Hz,1H),7.56-7.47(m,2H),7.21(s,1H),7.16(d,J=8.0Hz,1H),7.04(d ,J=8.0Hz,1H),5.16(d,J=15.1Hz,1H),4.54-4.46(m,2H),1.46(d,J=6.8Hz,3H).Chiral HPLC:(Column:CHIRALPAK IA-3; Column size: 4.6*50mm, 3μm; Mobile phase: MTBE(0.1%DEA):(MeOH:DCM=1:1)=85:15;Flow rate: 1.0mL / min) RT=1.704 min. (S)-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (56) [ka] Chiral separation of compound 54 by chiral preparative HPLC (column: CHIRALPAK IA; column size: 2 cm x 25 cm, 5 μm; mobile phase A: MTBE; mobile phase B: MeOH:DCM) gave two enantiomers: compounds 55 and 56. Compound 56 was an off-white solid with a RT of 2.104 min (chiral HPLC, column: CHIRALPAK IA-3; column size: 4.6 x 50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH:DCM = 1:1) = 85:15; flow rate: 1.0 mL / min). MS (ESI) m / z 295 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.81(d,J=7.6Hz,1H),7.61(t,J=7.5Hz,1H),7.56-7.47(m,2H),7.21(s,1H),7.16(d,J=8.0Hz ,1H),7.04(d,J=8.1Hz,1H),5.16(d,J=15.2Hz,1H),4.54-4.46(m,2H),1.46(d,J=6.8Hz,3H). 6-((3-methyl-1-oxo-5-(1H-pyrazol-4-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (57) and 6-((1-methyl-3-oxo-5-(1H-pyrazol-4-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (58) [ka] The title compounds 57 and 58 were prepared according to the procedure described for compounds 50 and 51. After preparative HPLC separation, two compounds were obtained: compound 57 and compound 58. One of the two compounds was a white solid (13 mg, 15.3%) with a RT of 2.98 min (HPLC). MS (ESI) m / z 361 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 13.03 (s, 1H), 11.68 (s, 1H), 8.16 (bs, 2H), 7.83 (s, 1H), 7.75 (dd, J = 8.0, 1.2 Hz, 1H), 7.67 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.09 (dd, J = 8.0, 2.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 4.99 (d, J = 15.3 Hz, 1H), 4.48-4.37 (m, 2H), 1.43 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (16 mg, 18.8%), RT = 3.27 min (HPLC). MS(ESI) m / z 361[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.91(s,1H),11.74(s,1H),8.18(bs,2H),7.93(s,1H),7.85(dd,J=7.9,1.6Hz,1H),7.55(d,J=7.9Hz,1H),7.25(s, 1H),7.09(d,J=8.0Hz,1H),7.04(d,J=8.0Hz,1H),5.03(d,J=15.2Hz,1H),4.50-4.35(m,2H),1.40(d,J=6.7Hz,3H). 6-((5-(3-methoxypyrrolidin-1-yl)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (59) and 6-((5-(3-methoxypyrrolidin-1-yl)-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (60) [ka] The title compounds 59 and 60 were prepared according to the procedure described for compounds 50 and 51. After preparative HPLC separation, two compounds were obtained: compound 59 and compound 60. One of the two compounds was a white solid (5 mg, 7.4%) with a RT of 4.21 min (HPLC). MS (ESI) m / z 394 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.47 (d, J = 9.0 Hz, 1H), 7.16 (s, 1H), 7.06-6.96 (m, 2H), 6.62-6.57 (m, 2H), 4.94 (d, J = 15.2 Hz, 1H), 4.32 (d, J = 15.2 Hz, 1H), 4.26 (q, J = 6.4 Hz, 1H), 4.11-4.07 (m, 1H), 3.49-3.27 (m, 7H), 2.12-2.03 (m, 2H), 1.35 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (4 mg, 6%) with a RT = 4.34 min (HPLC). MS (ESI) m / z 394 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.33(d,J=8.2Hz,1H),7.18(s,1H),7.08-6.98(m,2H),6.81-6.72(m,2H),4.99(d,J=15.2Hz,1H),4.36(d,J=15.2Hz,1 H),4.29(q,J=6.4Hz,1H),4.13-4.05(m,1H),3.48-3.29(m,4H),3.27(s,3H),2.14-2.02(m,2H),1.32(d,J=6.6Hz,3H). Mixture of 6-((3-methyl-5-(oxazol-5-yl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (61) and 6-((1-methyl-5-(oxazol-5-yl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (62) [ka] A mixture of compounds 61 and 62 was prepared as a white solid (3 mg, 5.5%) according to the procedure described for compounds 50 and 51. MS (ESI) m / z 362 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.52(s,0.5 H),8.49(s,0.5 H),8.04(s,1H),7.90-7.95(m,1H),7.88-7.80(m,2H),7.70(d,J=8.0Hz,1H),7.26(s,1H),7.13-7.09(m,1H),7.05(d,J=8.0Hz ,1H),5.04(d,J=15.2Hz,0.5H),5.00(d,J=15.2Hz,0.5H),4.58-4.38(m,2H),1.44(d,J=6.4Hz,1.5H),1.42(d,J=6.4Hz,1.5H). 6-((3-methyl-5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (63) and 6-((1-methyl-5-morpholino-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (64) [ka] The title compounds 63 and 64 were prepared according to the procedure described for compounds 50 and 51. After preparative HPLC separation, two compounds were obtained: compound 63 and compound 64. One of the two compounds was a white solid (8 mg, 7.9%) with a RT of 3.54 min (HPLC). MS (ESI) m / z 380 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.58 (s, 1H), 7.52 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H), 7.08-6.99 (m, 4H), 4.95 (d, J = 15.2 Hz, 1H), 4.35 (d, J = 15.2 Hz, 1H), 4.30 (q, J = 6.4 Hz, 1H), 3.73 (t, J = 4.9 Hz, 4H), 3.25-3.19 (m, 4H), 1.36 (d, J = 6.6 Hz, 3H). The other of the two compounds was a white solid (9 mg, 8.9%) with a RT = 3.59 min (HPLC). MS (ESI) m / z 380 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.72(s,1H),7.41(d,J=8.4Hz,1H),7.24-7.16(m,3H),7.11-6.98(m,2H),5.00(d,J=15.2Hz,1H),4.37(d ,J=15.2Hz,1H),4.32(q,J=6.4Hz,1H),3.75(t,J=4.8Hz,4H),3.16(t,J=4.9Hz,4H),1.34(d,J=6.8Hz,3H). 6-((3-methyl-1-oxo-5-(pyridin-3-ylamino)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (65) and 6-((1-methyl-3-oxo-5-(pyridin-3-ylamino)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (66) [ka] The title compounds 65 and 66 were prepared according to the procedure described for compounds 50 and 51. After preparative HPLC separation, two compounds were obtained: compound 65 and compound 66. One of the two compounds was a white solid (15 mg, 11%) with a RT of 2.09 min (HPLC). MS (ESI) m / z 387 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.82 (s, 1H), 8.42 (d, J = 2.7 Hz, 1H), 8.13 (dd, J = 4.7, 1.4 Hz, 1H), 7.62-7.51 (m, 2H), 7.29 (dd, J = 8.3, 4.6 Hz, 1H), 7.21 (s, 1H), 7.19 (d, J = 2.0 Hz, 1H), 7.14-7.02 (m, 3H), 4.98 (d, J = 15.2 Hz, 1H), 4.39-4.31 (m, 2H), 1.36 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (12 mg, 8.8%) with a RT = 2.21 min (HPLC). MS (ESI) m / z 387 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 8.59(s,1H),8.38(d,J=2.7Hz,1H),8.09(d,J=3.6Hz,1H),7.61-7.48(m,1H),7.45(d,J=8.1Hz,1H),7.34(d,J=2.1Hz,1 H),7.31-7.26(m,2H),7.22(s,1H),7.14-7.01(m,2H),4.99(d,J=15.2Hz,1H),4.43-4.30(m,2H),1.37(d,J=6.6Hz,3H). 6-((1-oxo-3-phenylisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (67) [ka] The title compound 67 was prepared as a white solid (21 mg, 21.8%) according to the procedure described for compound 48. MS (ESI) m / z 357 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),7.84-7.75(m,1H),7.57-7.47(m,2H),7.41-7.29(m,3H),7.26-7.17(m,1H),7.17-7.09(m,2H) ,7.01-6.98(m,2H),6.90(dd,J=8.0,1.6Hz,1H),5.53(s,1H),5.07(d,J=15.1Hz,1H),3.87(d,J=15.1Hz,1H). Intermediate 67-3 was prepared as follows: [ka] Step 1. 3-Hydroxy-3-phenylisoindolin-1-one (67-2) To a solution of isoindoline-1,3-dione (2 g, 13.6 mmol) in THF (20 mL) was added phenylmagnesium bromide (27.2 mL, 27.2 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h, diluted with EtOAc (30 mL), and washed with water (3×20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo to give the title compound (3.06 g, crude) as a yellow solid. MS (ESI) m / z 226 [M+H] + . Step 2. 3-Phenylisoindolin-1-one (67-3) To a solution of 3-hydroxy-3-phenylisoindolin-1-one (3.06 g, 13.6 mmol) in DCM (10 mL) was added triethylsilane (7.9 g, 68 mmol) and boron trifluoride diethyl etherate (3.9 g, 27.2 mmol). The resulting mixture was stirred at room temperature for 3 hours, diluted with EtOAc (30 mL), and washed with water (3 x 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by TLC (PE / EA = 1 / 3) to give the title compound (1.8 g, 63.3%) as a yellow solid. MS (ESI) m / z 210 [M+H] + . N-(3-methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (68) and N-(1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (69) [ka] Step 1. Mixture of tert-butyl (3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)carbamate (68-1) and tert-butyl (1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)carbamate (69-1) To a solution of a mixture of Int2 and Int3 (300 mg, 0.59 mmol) in 1,4-dioxane (10 mL) was added tert-butyl carbamate (600 mg, 1.19 mmol), Xantphos (69 mg, 0.12 mmol), Pd(OAc)2 (27 mg, 0.12 mmol) and Cs2CO3 (777 mg, 2.38 mmol) under N2. The mixture was purified by silica gel flash column chromatography (PE / EA=1.5 / 1) to give a mixture of tert-butyl (3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)carbamate and tert-butyl (1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)carbamate (500 mg, 77%) as a brown solid. MS(ESI) m / z 540 [M+H] + . Step 2. Mixture of 6-((5-amino-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (68-2) and 6-((5-amino-1-methyl-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (69-2) To a solution of a mixture of 68-1 and 69-1 (500 mg, 0.93 mmol) in DCM (3 mL) was added 4 M HCl in 1,4-dioxane (3 mL) and stirred for 2 h. The mixture was concentrated in vacuo to give a mixture of 6-((5-amino-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one and 6-((5-amino-1-methyl-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (400 mg, crude) as a brown solid, which was used in the next step without further purification. MS (ESI) m / z 440 [M+H] + . Step 3. Mixture of N-(3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (68-3) and N-(1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (69-3) To a solution of a mixture of 68-2 and 69-2 (400 mg, 0.44 mmol) in DCM (4 mL) was added DIEA (0.32 mL, 1.82 mmol) and acetyl chloride (78 mg, 1 mmol) under N2. The mixture was stirred for 2 hours and purified by preparative TLC (DCM / MeOH=40 / 1) to give a mixture of N-(3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide and N-(1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (240 mg, 54%) as a brown solid. MS(ESI) m / z 482 [M+H] + . Step 4. N-(3-methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (68) and N-(1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acetamide (69) To a solution of a mixture of 68-3 and 69-3 (240 mg, 0.50 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in DCM (6 mL) and ammonium hydroxide (2 mL) was added at 0° C. The suspension was stirred for another 1 h. The mixture was concentrated and purified by preparative HPLC to give two compounds: Compound 68 and Compound 69. One of these two compounds was a white solid (7 mg, 8%) with a RT of 2.69 min (HPLC). MS (ESI) m / z 352 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 10.23 (s, 1H), 7.86 (s, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.57 (dd, J = 8.3, 1.8 Hz, 1H), 7.21 (s, 1H), 7.11-6.99 (m, 2H), 4.97 (d, J = 15.2 Hz, 1H), 4.44-4.37 (m, 2H), 2.07 (s, 3H), 1.35 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (6 mg, 6.9%) with a RT = 2.83 min (HPLC). MS (ESI) m / z 352 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),10.15(s,1H),8.05(d,J=2.0Hz,1H),7.66(dd,J=8.2,2.0Hz,1H),7.48(d,J=8.2Hz,1H),7.21(s,1H),7.07(d d,J=8.0,2.0Hz,1H),7.02(d,J=8.0Hz,1H),4.99(d,J=15.2Hz,1H),4.43-4.33(m,2H),2.07(s,3H),1.36(d,J=6.6Hz,3H). N-(3-methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)methanesulfonamide (70) and N-(1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)methanesulfonamide (71). [ka] The title compounds 70 and 71 were prepared according to the procedure described for compounds 68 and 69. After preparative HPLC separation, two compounds were obtained: compound 70 and compound 71. One of these two compounds was a white solid (3 mg, 5%) with a RT of 2.85 min (HPLC). MS (ESI) m / z 388 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.06 (s, 1H), 8.37 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.28 (s, 1H), 7.26-7.17 (m, 2H), 7.09-6.99 (m, 2H), 4.97 (d, J = 15.2 Hz, 1H), 4.42-4.33 (m, 2H), 3.01 (s, 3H), 1.36 (d, J = 6.6 Hz, 3H). The other of the two compounds was a white solid (1 mg, 2%) with a RT = 3.02 min (HPLC). MS (ESI) m / z 388 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 10.76(s,1H),8.42(s,1H),7.55-7.49(m,2H),7.39(dd,J=8.2,2.0Hz,1H),7.18(s,1H),7.08 -6.97(m,2H),4.99(d,J=15.2Hz,1H),4.41-4.36(m,2H),2.99(s,3H),1.37(d,J=6.7Hz,3H). 6-((1-cyclopropyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (72) [ka] The title compound 72 was prepared as a white solid (16 mg, 19.2%) according to the procedure described for compound 67. MS (ESI) m / z 321 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.75(d,J=7.5Hz,1H),7.69-7.58(m,2H),7.55-7.51(m,1H),7.17(s,1H),7.09-6.99(m,2H), 5.04(d,J=15.4Hz,1H),4.60(d,J=15.4Hz,1H),3.71(d,J=8.0Hz,1H),0.68-0.52(m,4H),0.49-0.41(m,1H). (R)-6-((1-cyclopropyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (73) and (S)-6-((1-cyclopropyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (74) [ka] Chiral separation of compound 72 by chiral preparative HPLC (column: CHIRALPAK IG; column size: 2 cm x 25 cm, 5 μm; mobile phase A: MTBE; mobile phase B: MeOH:DCM) gave two enantiomers: compounds 73 and 74. One of these two enantiomers was a white solid with a RT of 4.563 min (chiral HPLC, column: CHIRALPAK IG-3; column size: 4.6 x 50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH:DCM = 1:1) = 95:5; flow rate: 1.0 mL / min). MS (ESI) m / z 321 [M+H] + The other of the two enantiomers was a white solid, RT = 3.760 min (chiral HPLC, column: CHIRALPAK IG-3; column size: 4.6*50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH: DCM = 1:1) = 95:5; flow rate: 1.0 mL / min): MS(ESI) m / z 321 [M+H] + . 6-((5-amino-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (75) and 6-((5-amino-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (76) [ka] To a solution of a mixture of 68-1 and 69-1 (200 mg, 0.37 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and ammonium hydroxide (1 mL) was added at 0° C. The suspension was stirred for another 1 h. The mixture was concentrated and purified by preparative HPLC to give two compounds, Compound 75 and Compound 76. One of the two compounds was a white solid (12 mg, 21%) with a RT of 2.25 min (HPLC). MS (ESI) m / z 310 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.38-7.30 (m, 1H), 7.21 (s, 1H), 7.10-6.99 (m, 4H), 4.97 (d, J = 15.2 Hz, 1H), 4.38 (d, J = 15.2 Hz, 1H), 4.32 (q, J = 6.4 Hz, 1H), 1.33 (d, J = 6.6 Hz, 3H). The other of the two compounds was a white solid (26 mg, 45%), RT = 2.45 min (HPLC). MS (ESI) m / z 310 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.57(s,1H),7.34(d,J=8.2Hz,1H),7.18(s,1H),7.09-6.99(m,2H),6.61(dd,J=8.0,2.0Hz,1H),6.5 7(s,1H),4.92(d,J=15.2Hz,1H),4.31(d,J=15.3Hz,1H),4.22(q,J=6.6Hz,1H),1.30(d,J=6.6Hz,3H). N-(3-methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)benzenesulfonamide (77) and N-(1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)benzenesulfonamide (78) [ka] The title compounds 77 and 78 were prepared according to the procedure described for compounds 68 and 69. After preparative HPLC separation, two compounds were obtained: compound 77 and compound 78. One of the two compounds was a white solid (26 mg, 51%) with a RT of 3.95 min (HPLC). MS (ESI) m / z 450 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.96 (bs, 2H), 7.84-7.77 (m, 2H), 7.64-7.57 (m, 1H), 7.57-7.49 (m, 3H), 7.25 (d, J = 1.9 Hz, 1H), 7.25 (d, J = 2.0 Hz, 1H), 7.16 (dd, J = 8.4, 2.0 Hz, 1H), 7.09-6.98 (m, 2H), 4.92 (d, J = 15.2 Hz, 1H), 4.40-4.31 (m, 2H), 1.28 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (20 mg, 39%) with a RT = 4.10 min (HPLC). MS (ESI) m / z 450 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.14(bs,2H),7.82-7.74(m,2H),7.65-7.51(m,3H),7.42(d,J=8.2Hz,1H),7.38(d,J=2.0Hz,1H),7.29(dd,J=8.2,2 .1Hz,1H),7.20(d,J=1.6Hz,1H),7.11-6.98(m,2H),4.93(d,J=15.2Hz,1H),4.40-4.29(m,2H),1.30(d,J=6.7Hz,3H). 6-((5-((2-azaspiro[3.3]heptan-6-yl)amino)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (79) [ka] The title compound 79 was prepared according to the procedure described for compound 47 using tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate as the starting material to give a white solid (9 mg, 21%). MS (ESI) m / z 405 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.53(bs,2H),7.39(d,J=8.3Hz,1H),7.18(s,1H),7.09-6.99(m,2H),6.60-6.52(m,2H),6.49(s,1H),4.93(d,J=15.3Hz,1H),4.32(d,J=15) .3Hz,1H),4.24(q,J=6.6Hz,1H),4.02(s,2H),3.92(s,2H),3.80-3.71(m,1H),2.71-2.64(m,2H),2.08-1.97(m,2H),1.32(d,J=6.6Hz,3H). Mixture of (E)-6-((1-benzylidene-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (80-1) and (Z)-6-((1-benzylidene-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (80-2) [ka] A mixture of compounds 80-1 and 80-2 was prepared as a white solid (42 mg, 33%) according to general procedure F. MS (ESI) m / z 369 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.83(d,J=7.6Hz,1H),7.57-7.53(m,1H),7.49-7.36(m,6H),7.31-7.28 (m,2H),7.13(dd,J=8.0,1.6Hz,1H),7.06(d,J=8.0Hz,1H),6.78(s,1H),5.11(s,2H). A mixture of intermediates 80-4 and 80-5 was prepared as follows: [ka] Step 1. 3-Benzyl-3-hydroxyisoindolin-1-one (80-3) To a solution of isoindoline-1,3-dione (2 g, 13.6 mmol) in THF (20 mL) was added benzylmagnesium bromide (40.8 mL, 40.8 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 h and diluted with EA (30 mL) and washed with water (3×20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo to give the title compound (3.25 g, crude) as a yellow solid. MS (ESI) m / z 240 [M+H] + . Step 2. Mixture of (Z)-3-benzylideneisoindolin-1-one (80-4) and (E)-3-benzylideneisoindolin-1-one (80-5) To a solution of 3-benzyl-3-hydroxyisoindolin-1-one (3.25 g, 13.6 mmol) in DCM (10 mL) was added triethylsilane (7.9 g, 68 mmol) and boron trifluoride diethyl etherate (3.9 g, 27.2 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 hours, diluted with EA (30 mL), and washed with water (3 x 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by TLC (PE / EA = 1 / 3) to give the title compound (1.5 g, 49.9%) as a yellow solid. MS (ESI) m / z 222 [M+H] + . 6-((5-(cyclopentylamino)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (81) [ka] The title compound 81 was prepared as a white solid (3 mg, 5%) following the procedure described for compound 47. MS (ESI) m / z 378 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),7.36(d,J=8.3Hz,1H),7.17(s,1H),7.07-6.98(m,2H),6.62(dd,J=8 .3,2.0Hz,1H),6.57(d,J=2.0Hz,1H),6.29(d,J=6.5Hz,1H),4.93(d,J=15.2Hz,1H) ,4.30(d,J=15.2Hz,1H),4.22(q,J=6.6Hz,1H),3.79-3.68(m,1H),1.99-1.86(m,2 H),1.71-1.63(m,2H),1.67-1.49(m,2H),1.49-1.39(m,2H),1.32(d,J=6.7Hz,3H). N-(4-((1-methyl-3-oxoisoindolin-2-yl)methyl)phenyl)acetamide (82) [ka] Step 1. 3-Methyl-2-(4-nitrobenzyl)isoindolin-1-one (82-3) To a solution of 3-methylisoindolin-1-one (500 mg, 3.4 mmol) in DMF (20 mL) was added NaH (150 mg, 60% in mineral oil, 3.7 mmol) under N at 0 °C. The mixture was stirred at 0 °C for 10 min. 1-(Bromomethyl)-4-nitrobenzene (808 mg, 3.7 mmol) was added at 0 °C. The mixture was stirred at room temperature for 4 h. Water (50 mL) was added to the solution, and the resulting mixture was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with water (50 mL × 2) and brine (50 mL), dried over anhydrous NaSO, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (PE / EtOAc = 1 / 1) to give 3-methyl-2-(4-nitrobenzyl)isoindolin-1-one (210 mg, 38%) as a yellow solid. MS(ESI)m / z 283[M+H] + . Step 2. 2-(4-aminobenzyl)-3-methylisoindolin-1-one (82-4) To a solution of 3-methyl-2-(4-nitrobenzyl)isoindolin-1-one (210 mg, 0.7 mmol) in EtOH (20 mL) was added Pd / C (30 mg) at room temperature. The mixture was stirred at room temperature under a hydrogen balloon for 4 hours. The reaction was filtered, and the filtrate was concentrated. The residue was purified by silica gel flash column chromatography (PE / EtOAc = 1 / 2) to give 2-(4-aminobenzyl)-3-methylisoindolin-1-one (130 mg, 69%) as a yellow solid. MS (ESI) m / z 253 [M+H] + . Step 3. N-(4-((1-methyl-3-oxoisoindolin-2-yl)methyl)phenyl)acetamide (82) To a solution of 2-(4-aminobenzyl)-3-methylisoindolin-1-one (40 mg, 0.2 mmol) in DCM (5 mL) was added DIEA (41 mg, 0.3 mmol) and AcCl (12 mg, 0.2 mmol) in an ice bath. The mixture was stirred at room temperature for 2 hours. Water (5 mL) was added, and the mixture was extracted with DCM (10 mL x 2). The combined organic layers were washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give N-(4-((1-methyl-3-oxoisoindolin-2-yl)methyl)phenyl)acetamide (34 mg, 72%) as a white solid. MS (ESI) m / z 295 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.91(s,1H),7.71(d,J=7.6Hz,1H),7.60-7.57(m,2H),7.53-7.47(m,3H),7.21(d,J=8.4Hz,2H),4.96 (d,J=15.2Hz,1H),4.41(q,J=6.4Hz,1H),4.34(d,J=15.6Hz,1H),2.01(s,3H),1.37(d,J=6.8Hz,3H). Mixture of 6-((3-methyl-1-oxo-5-(pyridin-3-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (83) and 6-((1-methyl-3-oxo-5-(pyridin-3-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (84) [ka] A mixture of compounds 83 and 84 was prepared as a white solid (17 mg, 11.5%) according to the procedure described for compounds 50 and 51. MS (ESI) m / z 372 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.95(d,J=2.3Hz,1H),8.63-8.59(m,1H),8.18-8.09(m,1H),8.02-7.94(m,1H),7.88-7.68(m,2H),7.54-7.48(m,1H),7 .27(d,J=1.6Hz,1H),7.14-7.01(m,2H),5.05(d,J=14.9Hz,1H),4.55-4.40(m,2H),1.47(d,J=6.8Hz,1.5H),1.44(d,J=6.8Hz,1.5H). Mixture of 6-((5-(cyclopent-1-en-1-yl)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (85) and 6-((5-(cyclopent-1-en-1-yl)-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (86) [ka] A mixture of compounds 85 and 86 was prepared as a white solid (19 mg, 9.8%) according to the procedure described for compounds 50 and 51. MS (ESI) m / z 361 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.85-7.46(m,3H),7.23(d,J=1.5Hz,1H),7.14-6.97(m,2H),6.46-6.37(m,1H),5.01(d,J=15.2Hz,0.5H), 4.99(d,J=15.2Hz,0.5H),4.50-4.34(m,2H),2.77-2.63(m,2H),2.55-2.52(m,2H),2.04-1.90(m,2H),1.42-1.37(m,3H). Mixture of 6-((5-cyclopentyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (87) and 6-((5-cyclopentyl-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (88) [ka] A mixture of compounds 87 and 88 was prepared as a white solid (14 mg, 9.6%) according to the procedure described for compounds 50 and 51. MS (ESI) m / z 363 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.64-7.54(m,1H),7.51-7.35(m,2H),7.23-7.20(m,1H),7.09-6.98(m,2H),5.01(d,J=15.2Hz,0.5H),5. 00(d,J=15.2Hz,0.5H),4.46-4.27(m,2H),3.14-2.98(m,1H),2.10-1.97(m,2H),1.85-1.49(m,6H),1.40-1.35(m,3H). 4-Fluoro-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (89) [ka] Step 1. 1-(Benzyloxy)-3-fluoro-5-methyl-2-nitrobenzene (89-2) To a solution of BnOH (2.7 g, 25 mmol) in DMF (100 mL) was added NaH (1 g, 60% in mineral oil, 25 mmol) at 0 °C. The mixture was stirred at 0 °C for 30 min. Then, 1,3-difluoro-5-methyl-2-nitrobenzene (4 g, 23.1 mmol) was added at 0 °C. The reaction was stirred at room temperature for 1 h. HO (50 mL) was added slowly, and the resulting mixture was extracted with EA (50 mL × 2). The combined organic layers were washed with HO (100 mL × 2) and brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by FCC (PE / EA = 10 / 1) to give 1-(benzyloxy)-3-fluoro-5-methyl-2-nitrobenzene (2.3 g, 38%) as a yellow solid. MS (ESI) m / z 262 [M+H] + . Step 2. 2-Amino-3-fluoro-5-methylphenol (89-3) A mixture of 1-(benzyloxy)-3-fluoro-5-methyl-2-nitrobenzene (2.3 g, 8.8 mmol) and Pd / C (690 mg, 5%) in MeOH (40 mL) was stirred overnight at room temperature under 1 atm of H. The mixture was filtered and concentrated. The residue was then washed with PE (5 mL) to give 2-amino-3-fluoro-5-methylphenol (1.1 g, 89%) as a brown solid. MS (ESI) m / z 141 [M+H] + . Step 3. 4-Fluoro-6-methylbenzo[d]oxazol-2(3H)-one (89-4) A mixture of 2-amino-3-fluoro-5-methylphenol (1.2 g, 7.1 mmol) and CDI (2.3 g, 14.2 mmol) in ACN (35 mL) was stirred at 80 °C overnight. The mixture was poured into ice water (50 mL) and extracted with EA (50 mL x 2). The combined organic layer was washed with HO (100 mL x 2) and brine (50 mL) and dried over NaSO. The residue was purified by trituration with PE to give 4-fluoro-6-methylbenzo[d]oxazol-2(3H)-one (1.1 g, 92%) as a white solid. MS (ESI) m / z 168 [M+H] + . Step 4. 4-Fluoro-3-(4-methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one (89-5) To a suspension of 4-fluoro-6-methylbenzo[d]oxazol-2(3H)-one (1.1 g, 6.5 mmol) and CsCO (4.3 g, 13.2 mmol) in DMF (50 mL) was added PMBCl (1.1 g, 6.5 mmol) at room temperature. The reaction was stirred at 60 °C overnight. The mixture was poured into ice water (100 mL) and extracted with EA (100 mL × 2). The combined organic layers were washed with HO (100 mL × 2) and brine (100 mL) and dried over NaSO. The residue was then purified by FCC (PE:EA = 5:1) to give 4-fluoro-3-(4-methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one (1.4 g, 73%) as a white solid. MS (ESI) m / z 288 [M+H] + . Step 5. 6-(Bromomethyl)-4-fluoro-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (89-6) A solution of 4-fluoro-3-(4-methoxybenzyl)-6-methylbenzo[d]oxazol-2(3H)-one (200 mg, 0.35 mmol), NBS (150 mg, 0.84 mmol), and AIBN (12 mg, 0.07 mmol) in CCl4 (5 mL) was stirred at 80 °C overnight. The mixture was concentrated and purified by FCC (PE:EA = 5:1) to give 6-(bromomethyl)-4-fluoro-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (80 mg, 32%) as a yellow solid. MS (ESI) m / z 366 [M+H] + . Step 6. 4-Fluoro-3-(4-methoxybenzyl)-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (89-7) To a solution of 3-methylisoindolin-1-one (32 mg, 0.22 mmol) in DMF (100 mL) was added NaH (10 mg, 60% in mineral oil, 0.23 mmol) at 0° C. The reaction was stirred at 0° C. for 30 min. Then, 6-(bromomethyl)-4-fluoro-3-(4-methoxybenzyl)benzo[d]oxazol-2(3H)-one (80 mg, 0.22 mmol) was added at 0° C. The reaction was stirred at room temperature for 1 h. HO (50 mL) was added and the mixture was extracted with EA (50 mL×2). The combined organic layers were washed with HO (100 mL×2) and brine (50 mL), dried over NaSO, filtered, and concentrated. The residue was purified by (PE / EA=5 / 1) to give 4-fluoro-3-(4-methoxybenzyl)-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (38 mg, 40%) as a white solid. MS(ESI) m / z 433 [M+H] + . Step 7. 4-Fluoro-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (89) TfOH (0.23 mL) was added to a stirred solution of 4-fluoro-3-(4-methoxybenzyl)-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (38 mg, 0.30 mmol) and SiHEt (19 mg, 0.17 mmol) in TFA (1.2 mL) at room temperature. The mixture was stirred at room temperature for 2 hours. The mixture was diluted with ice water (10 mL). NaCO (aq) was then added until pH 9. The mixture was extracted with DCM (10 mL × 2). The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 4-fluoro-6-((1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (16 mg, 58%) as a white solid. MS(ESI) m / z 313[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.72(d,J=7.2Hz,1H),7.63-7.57(m,2H),7.50(td,J=7.6,1.6Hz,1H),7.06(s,1H),7.00(d,J=10.8H z,1H),4.98(d,J=15.6Hz,1H),4.48(q,J=6.8Hz,1H),4.42(d,J=15.2Hz,1H),1.40(d,J=6.8Hz,3H). 3-Methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (90) and 1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (91) [ka] Step 1. Mixture of 3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxylic acid (90-1) and 1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxylic acid (91-1) To a solution of a mixture of Int2 and Int3 (750 mg, 1.49 mmol) in NMP (15 mL) was added Pd(OAc)2 (33 mg, 0.14 mmol), DPPP (61 mg, 0.14 mmol), K2CO3 (617 mg, 4.47 mmol), and water (1.5 mL) under N2, and then the mixture was evacuated and placed under CO (4 atm). The mixture was stirred at 100 °C for 14 h. The mixture was purified by C18 column to give a mixture of 3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxylic acid and 1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxylic acid (500 mg, 71%) as a brown solid. MS(ESI) m / z 469 [M+H] + . Step 2. Mixture of 3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (90-2) and 1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (91-2) To a solution of a mixture of 90-1 and 91-1 (200 mg, 0.42 mmol) in DMF (4 mL) was added HATU (486 mg, 1.28 mmol), ammonium hydroxide (1 mL, 25.96 mmol), and DIEA (0.30 mL, 1.70 mmol) under N. The mixture was stirred for 1 h, diluted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=30 / 1) to give a mixture of 3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide and 1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (110 mg, 55%) as a brown solid. MS(ESI) m / z 468 [M+H] + . Step 3. 3-Methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (90) and 1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (91) To a solution of a mixture of 90-2 and 91-2 (110 mg, 0.22 mmol) in DCM (6 mL) was added TFA (2 mL). The mixture was stirred for 3 hours and then concentrated in vacuo. The residue was dissolved in DCM (6 mL) and ammonium hydroxide (2 mL) was added at 0° C. The suspension was stirred for another hour. The mixture was concentrated and purified by preparative HPLC to give two compounds: Compound 90 and Compound 91. One of the two compounds was a white solid (11 mg, 27.7%) with a RT of 2.29 minutes (HPLC). MS (ESI) m / z 338 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.65 (s, 1H), 8.09 (s, 1H), 8.06 (s, 1H), 7.98 (dd, J = 7.9, 1.7 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.51 (s, 1H), 7.25 (d, J = 1.5 Hz, 1H), 7.10 (dd, J = 8.0, 1.6 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 5.02 (d, J = 15.1 Hz, 1H), 4.50 (q, J = 6.7 Hz, 1H), 4.43 (d, J = 15.2 Hz, 1H), 1.41 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (9 mg, 22.7%) at RT = 2.45 min (HPLC). MS(ESI)m / z 338[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),8.25(d,J=1.6Hz,1H),8.15(s,1H),8.11(dd,J=7.9,1.7Hz,1H),7.66(d,J=7.9Hz,1H),7.46(s,1H),7.24(d,J=1.5Hz,1H),7.0 9(dd,J=8.0,1.6Hz,1H),7.03(d,J=7.9Hz,1H),5.02(d,J=15.1Hz,1H),4.50(q,J=6.7Hz,1H),4.43(d,J=15.2Hz,1H),1.41(d,J=6.7Hz,3H). N,3-Dimethyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carboxamide (92) [ka] The title compound 92 was prepared as a white solid (21 mg, 42%) following the procedures described for compounds 90 and 91. MS (ESI) m / z 352 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),8.57(q,J=4.5Hz,1H),8.01(d,J=1.3Hz,1H),7.93(dd,J=7.9 ,1.4Hz,1H),7.78(d,J=7.9Hz,1H),7.24(d,J=1.4Hz,1H),7.09(dd,J=8.0, 1.6Hz,1H),7.03(d,J=7.9Hz,1H),5.01(d,J=15.2Hz,1H),4.51(q,J=6.7Hz ,1H),4.44(d,J=15.2Hz,1H),2.80(d,J=4.5Hz,3H),1.42(d,J=6.7Hz,3H). 3-(1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propenamide (93) and 3-(3-methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propenamide (94) [ka] Step 1. Mixture of (E)-3-(1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acrylic acid (93-1) and (E)-3-(3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)acrylic acid (94-1) To a solution of a mixture of Int2 and Int3 (200 mg, 0.4 mmol) in DMF (3 mL) was added Pd(OAc) (9 mg, 0.04 mmol), dppf (33 mg, 0.08 mmol), TEA (120 mg, 1.2 mmol), and acrylic acid (52 mg, 0.6 mmol) at room temperature under N. The resulting mixture was stirred at 70 °C for 3 h. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 3) to give a mixture of compounds 93-1 and 94-1 (150 mg, 75.9%) as a yellow oil. MS (ESI) m / z 495 [M+H] + . Step 2. Mixture of 3-(1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propanoic acid (93-2) and 3-(3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propanoic acid (94-2) To a solution of a mixture of 93-1 and 94-1 (150 mg, 0.30 mmol) in EtOH (5 mL) was added Pd / C (15 mg). The mixture was evacuated and filled with hydrogen three times. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated to give a mixture of 93-2 and 94-2 (120 mg, 79.6%) as a yellow oil. MS (ESI) m / z 497 [M+H] + . Step 3. Mixture of 3-(1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propenamide (93-3) and 3-(3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propenamide (94-3) To a solution of a mixture of 93-2 and 94-2 (120 mg, 0.24 mmol) in DMF (5 mL), HATU (110 mg, 0.29 mmol), NH4Cl (26 mg, 0.48 mmol), and DIPEA (62 mg, 0.48 mmol) were added at room temperature for 3 h, and then quenched with water and extracted with EA (3 x 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give a mixture of 93-3 and 94-3 (80 mg, 66.8%) as a yellow oil. MS (ESI) m / z 496 [M+H] + . Step 4. 3-(1-methyl-3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propenamide (93) and 3-(3-methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)propenamide (94) To a solution of a mixture of 93-3 and 94-3 (80 mg, 0.162 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (2 mL) and NH4OH (1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give two compounds, Compound 93 and Compound 94. One of the two compounds was a white solid (7 mg, 23.7%) with a RT of 2.56 minutes (HPLC). MS (ESI) m / z 366 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.15 (s, 1H), 7.65-7.61 (m, 3H), 7.25 (dd, J = 7.8, 1.5 Hz, 1H), 7.02-6.96 (m, 2H), 6.93-6.86 (m, 2H), 5.10 (d, J = 15.2 Hz, 1H), 4.32-4.21 (m, 2H), 2.93 (t, J = 7.5 Hz, 2H), 2.39 (t, J = 7.6 Hz, 2H), 1.37 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (8 mg, 27%), RT = 2.80 min (HPLC). MS (ESI) m / z 366 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),7.55(d,J=1.4Hz,1H),7.48-7.42(m,2H),7.29(s,1H),7.23(d,J=1.5Hz,1H),7.09-7.02(m,2H),6.77( s,1H),5.01(d,J=15.2Hz,1H),4.45-4.33(m,2H),2.90(t,J=7.5Hz,2H),2.39(t,J=7.6Hz,2H),1.37(d,J=6.7Hz,3H). 6-((3-methyl-1-oxo-5-((tetrahydro-2H-pyran-4-yl)amino)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (95) [ka] The title compound 95 was prepared as a white solid (23 mg, 13.5%) according to the procedure described for compound 47. MS (ESI) m / z 394 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.37(d,J=8.2Hz,1H),7.18(s,1H),7.06-7.01(m,2H),6.70-6.62(m,2H),4.93(d,J=15.3Hz,1H),4.31(d,J=15.3Hz,1H),4. 23(q,J=6.6Hz,1H),3.90-3.81(m,2H),3.57-3.46(m,1H),3.46-3.35(m,2H),1.91-1.82(m,2H),1.47-1.34(m,2H),1.32(d,J=6.7Hz,3H). 6-((3-methyl-1-oxo-5-(pyrrolidin-1-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (96) [ka] Step 1. 6-((3-methyl-1-oxo-5-(pyrrolidin-1-ylmethyl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (96-2) To a solution of 6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (250 mg, 0.49 mmol) in 1,4-dioxane (2 mL) was added potassium trifluoro(pyrrolidin-1-ylmethyl)borate (228 mg, 1.19 mmol), SPhos (82 mg, 0.19 mmol), Pd(OAc) (45 mg, 0.19 mmol), KPO (421 mg, 1.99 mmol), and water (0.5 mL) under N. The mixture was stirred at 100 °C for 14 h. The mixture was diluted with EtOAc and washed with water. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=25 / 1) to give 6-((3-methyl-1-oxo-5-(pyrrolidin-1-ylmethyl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (85 mg, 33%) as a brown solid. MS(ESI) m / z 508 [M+H] + . Step 2. 6-((3-methyl-1-oxo-5-(pyrrolidin-1-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (96) To a solution of 6-((3-methyl-1-oxo-5-(pyrrolidin-1-ylmethyl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (85 mg, 0.16 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and ammonium hydroxide (1 mL) was added at 0° C. The suspension was stirred for an additional 1 h. The mixture was concentrated and purified by preparative HPLC to give 6-((3-methyl-1-oxo-5-(pyrrolidin-1-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (18 mg, 27%) as a white solid. MS (ESI) m / z 378 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.72(d,J=7.7Hz,1H),7.60(s,1H),7.52(dd,J=7.8,1.4Hz,1H),7.24(d,J=1.5Hz,1H),7.10(dd,J=8.1,1.5Hz,1H),7.05( d,J=8.0Hz,1H),5.02(d,J=15.2Hz,1H),4.50-4.38(m,2H),4.01(s,2H),2.78(d,J=6.4Hz,4H),1.86-1.74(m,4H),1.40(d,J=6.6Hz,3H). 6-((3-benzyl-5-morpholino-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (97) [ka] The title compound 97 was prepared according to the procedure described for compound 47 using 6-((3-benzyl-5-bromo-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (prepared by the procedure outlined for compound 106) as the starting material to give a white solid (13 mg, 22%). MS (ESI) m / z 456 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.74(s,1H),7.41(d,J=8.5Hz,1H),7.23-7.11(m,3H),7.08(s,1H),7.05-6.94(m,5H),6.79(d,J=2.2Hz,1H),5.08(d,J =15.2Hz,1H),4.54(t,J=5.3Hz,1H),4.31(d,J=15.2Hz,1H),3.72(t,J=4.7Hz,4H),3.35-3.29(m,1H),3.21-3.08(m,5H). Mixture of 6-((5-amino-3-benzyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (98) and 6-((5-amino-1-benzyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (99) [ka] Following the procedure described for compounds 75 and 76, a mixture of 98 and 99 was prepared as a yellow solid (31 mg, 48%). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.23(d,J=8.0Hz,1H),7.19-7.15(m,3H),7.08(d,J=2.0Hz,1H),7.05-6.92(m,4H),6.55(dd,J=8.3,2.0Hz,1H ),6.44(d,J=1.9Hz,1H),5.72(s,2H),5.04(d,J=15.2Hz,1H),4.52-4.43(m,1H),4.23(d,J=15.2Hz,1H),3.21-2.97(m,2H). 6-((3-benzyl-1-oxo-5-(1H-pyrazol-4-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (100) and 6-((1-benzyl-3-oxo-5-(1H-pyrazol-4-yl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (101) [ka] The title compounds 100 and 101 were prepared according to the procedure described for compounds 57 and 58. After preparative HPLC separation, two compounds were obtained: compound 100 and compound 101. One of the two compounds was an off-white solid (10 mg, 21%) with a RT of 4.58 min (HPLC). MS (ESI) m / z 437 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 13.05 (s, 1H), 11.65 (s, 1H), 8.18 (s, 1H), 7.91 (s, 1H), 7.66 (dd, J = 8.0, 1.4 Hz, 1H), 7.57-7.50 (m, 2H), 7.19-7.11 (m, 4H), 7.05-6.97 (m, 4H), 5.12 (d, J = 15.1 Hz, 1H), 4.70 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 15.1 Hz, 1H), 3.39 (dd, J = 14.0, 4.8 Hz, 1H), 3.22 (dd, J = 14.0, 6.0 Hz, 1H). The other of the two compounds was a light brown solid (8 mg, 17%) at RT = 4.80 min (HPLC). MS(ESI)m / z 437[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 12.97(s,1H),11.65(s,1H),8.25(s,1H),8.03(s,1H),7.87-7.74(m,2H),7.25(d,J=7.9Hz,1H),7.22-7.11(m,4H),7.09-6.96(m,4H), 5.16(d,J=15.1Hz,1H),4.68(dd,J=6.3,4.2Hz,1H),4.44(d,J=15.1Hz,1H),3.38(dd,J=14.0,4.4Hz,1H)3.15(dd,J=14.0,6.4Hz,1H). 6-((5-((2-azaspiro[3.3]heptan-6-yl)amino)-1-benzyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (102) and 6-((5-((2-azaspiro[3.3]heptan-6-yl)amino)-3-benzyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (103) [ka] The title compounds 102 and 103 were prepared according to the procedure described for compound 79 using a mixture of 6-((3-benzyl-5-bromo-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one and 6-((1-benzyl-5-bromo-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as starting materials. After preparative HPLC separation, two compounds were obtained: compound 102 and compound 103. One of the two compounds was a pale yellow solid (8 mg, 20%) with a RT of 2.99 min (HPLC). MS (ESI) m / z 481 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.26(d,J=8.4Hz,1H),7.23-7.13(m,3H),7.09-6.97(m,3H),6.97-6.91(m,2H),6.52-6.48(m,2 H),6.06(s,1H),5.08(d,J=15.0Hz,1H),4.45(dd,J=6.8,4.4Hz,1H),4.27(d,J=15.0Hz,1H),3. 87-3.51 (m, 3H), 3.49-3.45 (m, 2H), 3.32 (dd, J = 13.9, 4.3 Hz, 1H), 2.93 (dd, J = 13.8, 6.6 Hz, 1H), 2.45-2.37 (m, 2H), 1.93-1.81 (m, 2H). The other of the two compounds was an off-white solid (12 mg, 30%) with a RT = 3.37 min (HPLC). MS(ESI) m / z 481 [M+H] + in 1H NMR(400MHz,DMSO-d6)δ 7.21-7.12(m,3H),7.05-6.98(m,3H),6.97-6.94(m,2H),6.87(d,J=8.0Hz,1H),6.6 4-6.57(m,2H),6.08(d,J=6.4Hz,1H),5.08(d,J=15.1Hz,1H),4.47(dd,J=6.4,4.4H z,1H),4.31(d,J=15.1Hz,1H),3.70-3.63(m,3H),3.33-3.23(m,2H),3.28(dd,J=13 .9,4.4Hz,1H),2.98(dd,J=13.9,7.1Hz,1H),2.60-2.54(m,2H),1.95-1.85(m,2H). N-(4-((1-oxoisoindolin-2-yl)methyl)phenyl)acetamide (104) [ka] The title compound 104 was prepared as a white solid (13 mg, 17%) following the procedure described for compound 82. MS (ESI) m / z 281 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 9.94(s,1H),7.60-7.47(m,1H),7.63-7.54(m,3H),7.54-7.45(m,2H),7.20(d,J=8.4Hz,2H),4.66(s,2H),4.34(s,2H),2.02(s,3H). 1-Methyl-3-(4-((1-oxoisoindolin-2-yl)methyl)phenyl)urea (105) [ka] The title compound 105 was prepared as a pale orange solid (47 mg, 36%) according to the procedure described for compound 82. MS (ESI) m / z 296 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.50(s,1H),7.71(d,J=7.6Hz,1H),7.60-7.47(m,3H),7.40-7.32(m,2H),7.17-7. 09(m,2H),5.96(q,J=4.6Hz,1H),4.63(s,2H),4.33(s,2H),2.62(d,J=4.6Hz,3H). 6-((1-benzyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (106) [ka] The title compound 106 was prepared according to general procedure F as a white solid (116 mg, 43.6%). MS (ESI) m / z 371 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.60(s,1H),7.59(d,J=7.5Hz,1H),7.55-7.50(m,1H),7.46-7.38(m,1H), 7.32(d,J=7.6Hz,1H),7.20(s,1H),7.17-7.12(m,3H),7.08-7.03(m,2H),7. 01-6.95(m,2H),5.14(d,J=15.0Hz,1H),4.72(dd,J=6.4,4.4Hz,1H),4.44(d ,J=15.1Hz,1H),3.37(dd,J=14.0,4.3Hz,1H),3.17(dd,J=14.1,6.3Hz,1H). Intermediate 106-1 was prepared as follows: [ka] To a solution of a mixture of 80-4 and 80-5 (1.5 g, 6.79 mmol) in EtOH (5 mL) was added Pd / C (150 mg). The mixture was evacuated and filled with hydrogen three times. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered, and the filtrate was concentrated to give 3-benzylisoindolin-1-one (1.3 g, 85.9%) as a white solid. MS (ESI) m / z 224 [M+H] + . (R)-6-((1-benzyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (107) and (S)-6-((1-benzyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (108) [ka] Chiral separation of compound 106 by chiral preparative HPLC (column: CHIRALPAK ID-3; column size: 2 cm x 25 cm, 5 μm; mobile phase A: MTBE; mobile phase B: MeOH:DCM) gave two enantiomers: compounds 107 and 108. One of the two enantiomers was a white solid with a RT of 2.417 min (chiral HPLC, column: CHIRALPAK ID-3; column size: 4.6 x 50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH:DCM = 1:1) = 95:5; flow rate: 1.0 mL / min). MS (ESI) m / z 371 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.58(d,J=7.5Hz,1H),7.55-7.50(m,1H),7.42(t,J=7.4Hz,1H),7.32(d,J=7. 5Hz,1H),7.19(s,1H),7.17-7.11(m,3H),7.07-7.02(m,2H),7.01-6.94(m,2H),5.14(d,J=15 .1 Hz, 1H), 4.71 (t, J = 5.4 Hz, 1H), 4.44 (d, J = 15.1 Hz, 1H), 3.37 (dd, J = 14.1, 4.3 Hz, 1H), 3.17 (dd, J = 14.0, 6.4 Hz, 1H). The other of the two enantiomers was a white solid with a RT = 3.042 min (chiral HPLC, column: CHIRALPAK ID-3; column dimensions: 4.6 * 50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH: DCM = 1:1) = 95:5; flow rate: 1.0 mL / min). MS (ESI) m / z 371 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.61(s,1H),7.58(d,J=7.5Hz,1H),7.55-7.50(m,1H),7.42(t,J=7.4Hz,1H ),7.32(d,J=7.5Hz,1H),7.19(s,1H),7.17-7.10(m,3H),7.08-7.03(m,2H),6 .99-6.95(m,2H),5.14(d,J=15.1Hz,1H),4.71(dd,J=6.4,4.4Hz,1H),4.44( d,J=15.1Hz,1H),3.37(dd,J=14.1,4.3Hz,1H),3.17(dd,J=14.0,6.3Hz,1H). 6-((3-methyl-5-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (109) and 6-((1-methyl-5-((2-methyl-2-azaspiro[3.3]heptan-6-yl)amino)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (110) [ka] The title compounds 109 and 110 were prepared according to the procedure described for compounds 50 and 51. After preparative HPLC separation, two compounds were obtained: compound 109 and compound 110. One of the two compounds was a white solid (4 mg, 4.4%) with a RT of 2.19 min (HPLC). MS (ESI) m / z 419 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 7.37(d,J=8.3Hz,1H),7.18(d,J=1.3Hz,1H),7.06-7.01(m,2H),6.58-6.52(m,2H),6.48( d,J=1.9Hz,1H),4.93(d,J=15.2Hz,1H),4.30(d,J=15.3Hz,1H),4.22(q,J=6.6Hz,1H),3.7 9-3.69 (m, 1H), 3.43-3.37 (m, 2H), 3.30-3.25 (m, 2H), 2.59-2.52 (m, 2H), 2.29 (s, 3H), 2.00-1.86 (m, 2H), 1.31 (d, J = 6.6 Hz, 3H). The other of the two compounds was a white solid (6 mg, 6.5%) with a RT = 2.46 min (HPLC). MS(ESI) m / z 419 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.26-7.08(m,2H),7.10-6.90(m,2H),6.83-6.56(m,2H),6.12(d,J=6.0Hz,1H),4.97(d,J=15.2Hz,1H),4.34(d,J=15.2Hz,1H),4.2 4(q,J=6.4Hz,1H),3.77-3.69(m,1H),3.53-3.26(m,4H),2.60-2.53(m,2H),2.37-2.28(m,2H),1.93(s,3H),1.30(d,J=6.6Hz,3H). 6-((3-methyl-5-(1-methyl-1H-pyrazol-4-yl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (111) and 6-((1-methyl-5-(1-methyl-1H-pyrazol-4-yl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (112) [ka] The title compounds 111 and 112 were prepared according to the procedure described for compounds 57 and 58. After preparative HPLC separation, two compounds were obtained: compound 111 and compound 112. One of the two compounds was a white solid (12 mg, 10%). RT = 3.90 min (HPLC). MS (ESI) m / z 375 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.69 (s, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.78 (s, 1H), 7.71-7.64 (m, 2H), 7.22 (d, J = 1.5 Hz, 1H), 7.08 (dd, J = 8.0, 1.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 4.99 (d, J = 15.2 Hz, 1H), 4.51-4.34 (m, 2H), 3.87 (s, 3H), 1.42 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (6 mg, 5%) with a RT = 4.08 min (HPLC). MS (ESI) m / z 375 [M+H] +1 H NMR(400MHz,DMSO-d6)δ 11.67(s,1H),8.27(s,1H),7.96(d,J=0.8Hz,1H),7.87(d,J=1.6Hz,1H),7.80(dd,J=7.9,1.7Hz,1H),7.55(d,J=7.9Hz,1H),7.22(d,J=1.5 Hz,1H),7.08(dd,J=8.0,1.6Hz,1H),7.03(d,J=8.0Hz,1H),5.02(d,J=15.2Hz,1H),4.46-4.36(m,2H),3.87(s,3H),1.39(d,J=6.7Hz,3H). 6-((5-benzyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (113) [ka] Step 1. Benzylzinc(II) bromide (113-2) Under N2, Zn powder (304 mg, 4.68 mmol) and dry THF (5 mL) were added to a flask. Then, TMSCl (25 mg, 0.23 mmol) was added to the above suspension, and the resulting mixture was warmed to 50 °C. (Bromomethyl)benzene (400 mg, 2.34 mmol) in THF (1 mL) was added dropwise to the above mixture. The resulting mixture was stirred at 60 °C overnight. The reaction solution was cooled and used directly in the next step. Step 2. 6-((5-benzyl-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (113-3) A dry flask was charged with 6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (300 mg, 0.8 mmol) and Pd(PPh3)4 (93 mg, 0.08 mmol) in THF (5 mL). The flask was evacuated and filled with nitrogen three times, and then the benzylzinc(II) bromide prepared above was added dropwise. The resulting mixture was stirred at 60 °C for 3 h. The reaction solution was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried and concentrated. The residue was purified by silica gel column eluted with petroleum ether and EtOAc (3:1) to give the title compound (376 mg, 90.8%) as a yellow oil. Step 3. 6-((5-benzyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (113) To a solution of 6-((5-benzyl-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (370 mg, 0.73 mmol) in DCM (10 mL) was added trifluoroacetic acid (2 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in DCM (5 mL), and then NH4OH (1 mL) was added and stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by preparative HPLC to give 6-((5-benzyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (27 mg, 9.8%) as a white solid. MS (ESI) m / z 385 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.63(d,J=7.8Hz,1H),7.47(s,1H),7.35(dd,J=7.8,1.4Hz,1H),7.31-7.15(m,6H), 7.09-6.99(m,2H),4.99(d,J=15.2Hz,1H),4.44-4.35(m,2H),4.04(s,2H),1.37(d,J=6.6Hz,3H). 6-((1-oxo-3-phenethylisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (114) [ka] The title compound 114 was prepared as a white solid (175 mg, 39.1%) according to the procedure described for compound 67. MS (ESI) m / z 385 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),7.76(d,J=7.5Hz,1H),7.70-7.61(m,2H),7.55-7.50(m,1H ),7.30(d,J=1.5Hz,1H),7.22-7.08(m,4H),7.04(d,J=7.9Hz,1H),6.96- 6.89(m,2H),4.96(d,J=15.1Hz,1H),4.62(dd,J=5.0,3.1Hz,1H),4.48(d ,J=15.1Hz,1H),2.37-2.16(m,2H),2.13-2.03(m,1H),1.91-1.81(m,1H). 6-((5-((2,6-diazaspiro[3.3]heptan-2-yl)methyl)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (115) [ka] The title compound 115 was prepared according to the procedure described for compound 96 using potassium ((6-(tert-butoxycarbonyl)-2,6-diazaspiro[3.3]heptan-2-yl)methyl)trifluoroborate as the starting material to give a white solid (16 mg, 7.5%). MS (ESI) m / z 405 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.63(d,J=7.8Hz,1H),7.42(s,1H),7.25(dd,J=8.0,1.6Hz,1H),7.17-7.14(m,1H),7.05-6.94(m,2H), 5.00(d,J=15.1Hz,1H),4.43-4.31(m,2H),3.66-3.52(m,8H),3.22(s,2H),1.37(dd,J=6.7,2.2Hz,3H). 6-((3-benzyl-5-cyclopropyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (116) [ka] The title compound 116 was prepared as a white solid (33 mg, 25%) following the procedure described for compound 100. MS (ESI) m / z 411 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.64(s,1H),7.44(d,J=7.8Hz,1H),7.20-7.11(m,5H),7.05-7.02(m,2H),7. 00-6.96(m,2H),6.83(d,J=1.5Hz,1H),5.11(d,J=15.2Hz,1H),4.61(dd,J=6. 4,4.4Hz,1H),4.39(d,J=15.2Hz,1H),3.36(dd,J=14.0,4.4Hz,1H),3.07(dd, J=14.0,6.4Hz,1H),1.98-1.91(m,1H),1.05-0.92(m,2H),0.67-0.59(m,2H). 6-((1-benzyl-3-oxo-5-((tetrahydro-2H-pyran-4-yl)amino)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (117) and 6-((3-benzyl-1-oxo-5-((tetrahydro-2H-pyran-4-yl)amino)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (118) [ka] The title compounds 117 and 118 were prepared according to the procedure described for compound 95 using a mixture of 6-((3-benzyl-5-bromo-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one and 6-((1-benzyl-5-bromo-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one as starting materials. After preparative HPLC separation, two compounds were obtained: compound 117 and compound 118. One of the two compounds was an off-white solid (5 mg, 14%) with a RT of 5.06 min (HPLC), MS (ESI) m / z 470 [M+H]. + It was.1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),7.23-7.15(m,3H),7.13(s,1H),7.06-6.97(m,4H),6.88(d,J=8.2Hz,1H),6.77-6. 70(m,2H),5.77(d,J=8.0Hz,1H),5.09(d,J=15.2Hz,1H),4.49(dd,J=6.4,4.4Hz,1H),4.36(d,J=1 5.2 Hz, 1H), 3.89-3.80 (m, 2H), 3.46-3.38 (m, 3H), 3.29 (dd, J = 14.0, 4.4 Hz, 1H), 2.99 (dd, J = 14.0, 6.4 Hz, 1H), 1.89-1.80 (m, 2H), 1.42-1.26 (m, 2H). The other of the two compounds was identified as RT = 4.94 min (HPLC), MS (ESI) m / z 470 [M+H]. + The compound was a white solid (6 mg, 17%) having the formula: 1 H NMR(400MHz,DMSO-d6)δ 11.65(s,1H),7.27(d,J=8.4Hz,1H),7.23-7.14(m,3H),7.13-6.96(m,5H),6.60 (dd,J=8.3,2.0Hz,1H),6.24-6.15(m,2H),5.04(d,J=15.2Hz,1H),4.48(dd,J=7. 2,4.4Hz,1H),4.30(d,J=15.2Hz,1H),3.91-3.79(m,2H),3.37-3.35(m,1H),3.25 -3.20(m,3H),2.91(dd,J=13.8,7.2Hz,1H),1.83-1.70(m,2H),1.4-1.21(m,2H). 6-((5-hydroxy-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (119) and 6-((5-hydroxy-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (120) [ka] Step 1. Mixture of 6-((3-methyl-1-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (119-1) and 6-((1-methyl-3-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (120-1) To a solution of a mixture of Int2 and Int3 (500 mg, 1 mmol) in 1,4-dioxane (10 mL), Pd(dppf)Cl2 (81 mg, 0.1 mmol), KOAc (196 mg, 2 mmol), and 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (380 mg, 1.5 mmol) were added at room temperature under N2. The resulting mixture was stirred at 100 °C for 1 h using a Biotage microwave reactor. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA=1 / 4) to give a mixture of 119-1 and 120-1 (400 mg, 72.6%) as a yellow oil. MS (ESI) m / z 551 [M+H] + . Step 2. Mixture of 6-((5-hydroxy-3-methyl-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (119-2) and 6-((5-hydroxy-1-methyl-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (120-2) To a solution of a mixture of 119-1 and 120-1 (200 mg, 0.36 mmol) in THF (10 mL) was added NaOH (1 M, 0.4 mL) and HO (30%, 0.4 mL) at 0 °C and stirred for 1 h. Then, it was quenched with water and extracted with EA (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous NaSO, and concentrated to give a mixture of 119-2 and 120-2 (100 mg, 62.4%) as a yellow oil. MS (ESI) m / z 441 [M+H] + . Step 3. 6-((5-hydroxy-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (119) and 6-((5-hydroxy-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (120) To a solution of a mixture of 119-2 and 120-2 (100 mg, 0.23 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (4 mL) and NH4OH (2 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to give two compounds, Compound 119 and Compound 120. One of the two compounds was a white solid (2 mg, 5.7%), RT = 3.35 min (HPLC), MS (ESI) m / z 311 [M+H]. +1 H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 7.07-6.97 (m, 2H), 6.88-6.84 (m, 2H), 4.95 (d, J = 15.2 Hz, 1H), 4.37-4.25 (m, 2H), 1.33 (d, J = 6.7 Hz, 3H). The other of the two compounds was a white solid (3 mg, 8.5%) with a RT = 3.54 min (HPLC). MS (ESI) m / z 311 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 9.85(s,1H),7.34(d,J=8.2Hz,1H),7.15(s,1H),7.05-6.94(m,4H),4.97(d,J=15.1Hz,1H),4.38-4.25(m,2H),1.33(d,J=6.6Hz,3H). 6-((3-methyl-1-oxo-5-phenoxyisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (121) and 6-((1-methyl-3-oxo-5-phenoxyisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (122) [ka] Step 1. Mixture of 6-((3-methyl-1-oxo-5-phenoxyisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (121-1) and 6-((1-methyl-3-oxo-5-phenoxyisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (122-1) To a solution of a mixture of 119-2 and 120-2 (200 mg, 0.45 mmol) in DCM (10 ml), phenylboronic acid (111 mg, 0.91 mmol), Cu(OAc) (17 mg, 0.09 mmol), and TEA (92 mg, 0.91 mmol) were added at room temperature under an oxygen atmosphere. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 4) to give a mixture of 121-1 and 122-1 (100 mg, 42.7%) as a yellow oil. MS (ESI) m / z 517 [M+H] + . Step 2. 6-((3-methyl-1-oxo-5-phenoxyisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (121) and 6-((1-methyl-3-oxo-5-phenoxyisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (122) To a solution of a mixture of 121-1 and 122-1 (100 mg, 0.19 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum. The residue was dissolved in DCM (2 mL) and NH4OH (1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give two compounds: Compound 121 and Compound 122. One of the two compounds was a white solid (9 mg, 24%) with a RT of 4.04 minutes (HPLC), MS (ESI) m / z 387 [M+H]. + It was. 1 H NMR (400 MHz, DMSO-d6) δ 7.60(d,J=8.2Hz,1H),7.49-7.38(m,2H),7.30(dd,J=8.3,2.4Hz,1H),7.21(dt, J=14.8,1.1Hz,0H),7.21(s,2H),7.13(d,J=2.4Hz,1H),7.11-7.02(m,3H),7.02( d,J=7.9Hz,1H),5.00(d,J=15.2Hz,1H),4.40(dd,J=14.7,8.6Hz,2H),1.38(dd,J =13.6,6.7Hz,3H).The other of the two compounds is a white solid (9 mg, 24%), RT=3.94 min (HPLC), MS (ESI) m / z 311[M+H] + . 6-((3-benzyl-5-(morpholinomethyl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (123) [ka] The title compound 123 was prepared according to the procedure described for compound 96 using 6-((3-benzyl-5-bromo-1-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one and hydrogen trifluoro(morpholinomethyl)borate as starting materials to give a white solid (10 mg, 31%). MS (ESI) m / z 470 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.70(s,1H),7.51(d,J=7.7Hz,1H),7.32(d,J=7.7Hz,1H),7.28(s,1H),7.20(d,J=1.5H z,1H),7.13-7.09(m,3H),7.08-7.02(m,2H),6.97-6.93(m,2H),5.15(d,J=15.2Hz,1H),4 .68(dd,J=6.0,4.4Hz,1H),4.45(d,J=15.2Hz,1H),3.57(t,J=4.6Hz,4H),3.48(d,J=2.5H z,2H),3.36(dd,J=14.0,4.4Hz,1H),3.17(dd,J=14.0,6.0Hz,1H),2.30(d,J=4.8Hz,4H). 6-((1-(2-methylbenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (124) [ka] Intermediate 124-1 was prepared according to the procedure described for Int12 as a yellow solid. Step 1. 6-((1-(2-methylbenzyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (124-2) To a solution of 3-(2-methylbenzyl)isoindolin-1-one (80 mg, 0.33 mmol) in DMF (2 mL) was added NaH (9 mg, 0.37 mmol) under N at 0°C. The mixture was stirred for 30 min. 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (133 mg, 0.37 mmol) was added and the reaction was allowed to warm to room temperature. The suspension was stirred for an additional 2 h. Water was added at 0°C and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=25 / 1) to give 6-((1-(2-methylbenzyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 34%) as a yellow solid. MS(ESI) m / z 515 [M+H] + . Step 2. 6-((1-(2-methylbenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (124) To a solution of 6-((1-(2-methylbenzyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 0.11 mmol) in DCM (3 mL) was added TFA (1 mL). The mixture was stirred for 3 h and then concentrated in vacuo. The residue was dissolved in DCM (3 mL) and ammonium hydroxide (1 mL) was added at 0° C. The suspension was stirred for an additional 1 h. The mixture was concentrated and purified by preparative HPLC to give 6-[[1-(o-tolylmethyl)-3-oxo-isoindolin-2-yl]methyl]-3H-1,3-benzoxazol-2-one (25 mg, 56%) as an off-white solid. MS(ESI) m / z 385 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.68(s,1H),7.76-7.69(m,1H),7.49-7.40(m,2H),7.22-7.11(m,3H),7.11- 7.07(m,1H),7.07-7.00(m,2H),6.96(dd,J=8.0,2.0Hz,1H),6.78(d,J=6.8Hz ,1H),5.15(d,J=15.2Hz,1H),4.64(dd,J=8.4,6.0Hz,1H),4.33(d,J=15.1Hz, 1H),3.42(dd,J=13.6,6.0Hz,1H),2.75(dd,J=13.6,8.4Hz,1H),2.09(s,3H). 6-((5-cyclopropyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (125) [ka] The title compound 125 was prepared as a white solid (7 mg, 5%) according to the procedure described for compound 57. MS (ESI) m / z 335 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 7.56(d,J=7.8Hz,1H),7.26(s,1H),7.21-7.18(m,2H),7.07-7.01(m,2H),4.98(d,J=15.2Hz,1H), 4.39-4.32(m,2H),2.07-1.99(m,1H),1.37(d,J=6.7Hz,3H),1.03-1.00(m,2H),0.80-0.70(m,2H). (R)-6-((5-cyclopropyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (126) and (S)-6-((5-cyclopropyl-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (127) [ka] The title compounds 126 and 127 were prepared according to the procedure described for compound 125. Using the stereoisomer of Int10 or Int11 with a RT of 1.728 min as starting material, one white solid (50 mg, 37%) was obtained with the following characteristics: MS (ESI) m / z 335 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.60 (s, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.26 (s, 1H), 7.22-7.18 (m, 2H), 7.08-7.02 (m, 2H), 4.98 (d, J = 15.2 Hz, 1H), 4.40-4.33 (m, 2H), 2.07-1.99 (m, 1H), 1.37 (d, J = 6.7 Hz, 3H), 1.03-1.00 (m, 2H), 0.78-0.73 (m, 2H). Using the stereoisomers of Int10 or Int11 with a RT of 1.969 min as starting materials, one white solid (43 mg, 33%) was obtained with the following characteristics: MS (ESI) m / z 335 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),7.56(d,J=7.9Hz,1H),7.26(s,1H),7.21-7.18(m,2H),7.08-7.01(m,2H),4.98(d,J=15.2H) z,1H),4.40-4.33(m,2H),2.06-2.00(m,1H),1.37(d,J=6.7Hz,3H),1.03-1.01(m,2H),0.80-0.71(m,2H). 6-((5-(3-Methoxyazetidin-1-yl)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (128) [ka] The title compound 128 was prepared as a white solid (3 mg, 4%) following the procedure described for compound 51. MS (ESI) m / z 380 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.48(d,J=8.2Hz,1H),7.18(s,1H),7.08-6.98(m,2H),6.53-6.43(m,2H),4.94(d,J=15.3Hz,1H),4 .38-4.29(m,2H),4.27(q,J=6.5Hz,1H),4.14-4.08(m,2H),3.72-3.66(m,2H),3.24(s,3H),1.34(d,J=6.6Hz,3H). 6-((1-oxo-3-(pyridin-2-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (129) [ka] The title compound 129 was prepared as a white solid (16 mg, 23%) following the procedure described for compound 124. MS (ESI) m / z 372 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.65(s,1H),8.50-8.43(m,1H),7.68-7.56(m,2H),7.54-7.40(m,2H),7.25-7.18(m,1H),7.15-7.08(m,2H),7.04-6.95(m,3H),5.1 1(d,J=15.3Hz,1H),4.95(dd,J=6.9,4.9Hz,1H),4.42(d,J=15.3Hz,1H),3.51(dd,J=14.0,5.0Hz,1H),3.18(dd,J=14.0,7.0Hz,1H). 6-((1-oxo-3-(pyridin-4-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (130) [ka] The title compound 130 was prepared as a white solid (4 mg, 4.5%) following the procedure described for compound 124. MS (ESI) m / z 372 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 8.31-8.27(m,2H),7.59-7.54(m,2H),7.49-7.42(m,2H),7.21(s,1H),7.08-6.98(m,2H),6.96-6.88(m,2H),5.14 (d,J=15.0Hz,1H),4.80(t,J=4.9Hz,1H),4.48(d,J=15.0Hz,1H),4.44-4.37(m,1H),3.39(dd,J=14.0,4.4Hz,1H). 3-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (131) [ka] The title compound 131 was prepared as a white solid (28 mg, 32%) following the procedure described for compound 124. MS (ESI) m / z 396 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.63-7.54(m,3H),7.51-7.40(m,2H),7.38-7.28(m,2H),7.24(d,J=7.9Hz,1H),7.19(s,1H), 7.10-7.00(m,2H),5.09(d,J=15.1Hz,1H),4.82(t,J=4.9Hz,1H),4.52(d,J=15.2Hz,1H),3.45-3.34(m,2H). 6-((5-((2-azaspiro[3.3]heptan-6-yl)oxy)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (132) and 6-((5-((2-azaspiro[3.3]heptan-6-yl)oxy)-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (133) [ka] Step 1. tert-Butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (132-2) To a solution of tert-butyl 6-hydroxy-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.34 mmol) in DCM (10 mL) was added MsCl (324 mg, 2.82 mmol), TEA (474 ​​mg, 4.69 mmol), and stirred at room temperature overnight. The mixture was diluted with DCM (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated to give the title compound (600 mg, 88.1%) as a yellow oil. Step 2. Mixture of tert-butyl 6-((3-methyl-1-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (132-3) and tert-butyl 6-((1-methyl-3-oxo-2-((2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-5-yl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (133-1) To a solution of a mixture of 119-2 and 120-2 (400 mg, 0.91 mmol) in DMF (10 mL), tert-butyl 6-((methylsulfonyl)oxy)-2-azaspiro[3.3]heptane-2-carboxylate (317 mg, 1.09 mmol) and Cs2CO3 (592 mg, 1.82 mmol) were added and stirred at 100 °C overnight. The reaction mixture was then quenched with water and extracted with EA (3 × 50 mL). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated to give a mixture of 132-3 and 133-1 (200 mg, 34.7%) as a yellow oil. MS (ESI) m / z 636 [M+H] + . Step 3. 6-((5-((2-azaspiro[3.3]heptan-6-yl)oxy)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (132) and 6-((5-((2-azaspiro[3.3]heptan-6-yl)oxy)-1-methyl-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (133) To a solution of a mixture of 132-3 and 132-1 (200 mg, 0.16 mmol) in DCM (10 mL) was added trifluoroacetic acid (4 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (4 mL) and NH4OH (2 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give two compounds, Compound 132 and Compound 133. One of the two compounds was a white solid (11 mg, 17%), RT = 2.07 min (HPLC), MS (ESI) m / z 406 [M+H]. + It was. 1 H NMR (400 MHz, DMSO-d6) δ 11.64(s,1H),7.61(d,J=8.4Hz,1H),7.21(s,1H),7.09-7.00(m,3H),6.92(d,J=8 .4,2.2Hz,1H),4.97(d,J=15.2Hz,1H),4.72-4.65(m,1H),4.42-4.30(m,2H),4.0 4(t,J=6.2Hz,2H),3.96(t,J=6.2Hz,2H),2.87-2.77(m,2H),2.34-2.21(m,2H),1 .37(d,J=6.6Hz,3H).The other of the two compounds is a white solid (4mg, 6%), RT=2.53min (HPLC), MS(ESI) m / z 406[M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),7.61(d,J=9.0Hz,1H),7.22(s,1H),7.10-7.02(m,4H),4.97(d,J=15.2Hz,1H),4.75-4.68(m,1H),4.42- 4.30(m,2H),4.04(t,J=6.2Hz,2H),3.96(t,J=6.2Hz,2H),2.87-2.77(m,2H),2.33-2.25(m,2H),1.37(d,J=6.6Hz,3H). 6-((1-oxo-3-(2-(trifluoromethyl)benzyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (134) [ka] The title compound 134 was prepared as a white solid (141 mg, 32.6%) following the procedure described for compound 124. MS (ESI) m / z 439 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),7.78-7.71(m,2H),7.66(t,J=7.6Hz,1H),7.55-7.40(m,4H),7.06-7.00(m,2H),6.94(dd,J=8.0,1.6Hz,1H),6.65(d,J=7.5 Hz,1H),5.11(d,J=15.3Hz,1H),4.84(t,J=7.2Hz,1H),4.27(d,J=15.3Hz,1H),3.57(dd,J=14.4,6.4Hz,1H),2.93(dd,J=14.4,8.0Hz,1H). (R)-6-((1-oxo-3-(2-(trifluoromethyl)benzyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (135) and (S)-6-((1-oxo-3-(2-(trifluoromethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (136) [ka] Chiral separation of compound 134 by chiral preparative HPLC (column: CHIRALPAK IG; column size: 2 cm x 25 cm, 5 μm; mobile phase A: Hex; mobile phase B: EtOH; flow rate: 20 mL / min; detector: 220 nm) gave two enantiomers: compounds 135 and 136. One of the two enantiomers was a white solid with a RT of 2.075 min (chiral HPLC, column: CHIRALPAK IG-3; column size: 4.6 x 50 mm, 3 μm; mobile phase: Hex (0.1% DEA): EtOH = 70:30; flow rate: 1.0 mL / min). MS (ESI) m / z 439 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.61 (s, 1H), 7.76-7.72 (m, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.55-7.40 (m, 4H), 7.05-7.00 (m, 2H), 6.94 (dd, J = 8.0, 1.6 Hz, 1H), 6.64 (d, J = 7.5 Hz, 1H), 5.10 (d, J = 15.3 Hz, 1H), 4.83 (t, J = 7.2 Hz, 1H), 4.26 (d, J = 15.3 Hz, 1H), 3.57 (dd, J = 14.4, 6.4 Hz, 1H), 2.92 (dd, J = 14.4, 8.0 Hz, 1H). The other of the two enantiomers was a white solid with a reaction time of 2.971 min (chiral HPLC, column: CHIRALPAK). IG-3; Column size: 4.6*50mm, 3μm; Mobile phase: Hex(0.1%DEA):EtOH=70:30; Flow rate: 1.0mL / min). MS(ESI)m / z 439[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.76-7.72(m,2H),7.66(t,J=7.5Hz,1H),7.55-7.40(m,4H),7.05-7.00(m,2H),6.94(dd,J=8.0,1.5Hz,1H),6.64(d,J=7.5 Hz,1H),5.10(d,J=15.3Hz,1H),4.83(t,J=7.2Hz,1H),4.26(d,J=15.3Hz,1H),3.57(dd,J=14.3,6.4Hz,1H),2.92(dd,J=14.3,8.0Hz,1H). 6-((1-oxo-3-(pyridin-3-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (137) [ka] The title compound 137 was prepared as a white solid (28 mg, 27%) following the procedure described for compound 124. MS (ESI) m / z 372 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.69(s,1H),8.28(dd,J=4.8,1.6Hz,1H),8.10(d,J=2.1Hz,1H),7.60-7.49(m,3H),7.42(t,J=7.3Hz,1H),7.29-7.25(m,1H) ,7.24(s,1H),7.15-6.98(m,3H),5.16(d,J=15.1Hz,1H),4.77(t,J=4.6Hz,1H),4.52(d,J=15.1Hz,1H),3.37(d,J=4.8Hz,2H). (R)-6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (138) and (S)-6-((5-bromo-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (139) [ka] The title compounds 138 and 139 were prepared according to the procedure described for step 2 of general procedure E. Using the stereoisomers of Int10 or Int11 with a RT of 1.728 min as starting materials, one white solid (40 mg, 67.4%) was obtained with the following characteristics: MS (ESI) m / z 373 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.62 (s, 1H), 7.89 (s, 1H), 7.72-7.62 (m, 2H), 7.25 (s, 1H), 7.12-7.01 (m, 2H), 4.99 (d, J = 15.2 Hz, 1H), 4.50-4.36 (m, 2H), 1.40 (d, J = 6.7 Hz, 3H). Using the stereoisomers of Int10 or Int11 with a RT of 1.969 min as starting materials, a white solid (40 mg, 67.4%) was obtained with the following characteristics: MS (ESI) m / z 373 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),7.89(s,1H),7.73-7.62(m,2H),7.25(s,1H),7.11-7.03( m,2H),4.99(d,J=15.2Hz,1H),4.49-4.37(m,2H),1.40(d,J=6.7Hz,3H). 6-((1-oxo-3-(thiazol-2-ylmethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (140) [ka] The title compound 140 was prepared as a white solid (4 mg, 9%) following the procedure described for compound 124. MS (ESI) m / z 378 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),7.67-7.54(m,3H),7.53-7.40(m,3H),7.26(s,1H),7.12-7.01(m,2H),5. 15(d,J=15.2Hz,1H),4.85(t,J=4.6Hz,1H),4.44(d,J=15.2Hz,1H),3.86-3.72(m,2H). 6-((3-oxo-1-(2-(trifluoromethyl)benzyl)-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (141) [ka] Step 1. 1-(2-(trifluoromethyl)benzyl)-1,2-dihydro-3H-indazol-3-one (141-2) To a solution of 1,2-dihydro-3H-indazol-3-one (200 mg, 1.49 mmol) in DMSO (2.5 mL) was added NaOH (119 mg, 2.98 mmol) and 1-(bromomethyl)-2-(trifluoromethyl)benzene (356 mg, 1.49 mmol) under N2. The mixture was stirred for 2 hours and purified on a C18 column (ACN = 55%) to give 1-(2-(trifluoromethyl)benzyl)-1,2-dihydro-3H-indazol-3-one (170 mg, 39%) as a white solid. MS (ESI) m / z 293 [M+H] + . Step 2. 6-((3-oxo-1-(2-(trifluoromethyl)benzyl)-1,3-dihydro-2H-indazol-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (141-3) To a solution of 1-(2-(trifluoromethyl)benzyl)-1,2-dihydro-3H-indazol-3-one (440 mg, 1.51 mmol) in DMF (5 mL) was added NaH (40 mg, 1.66 mmol) under N at 0° C. The mixture was stirred for 30 min. 6-(bromomethyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (701 mg, 1.96 mmol) was added. The suspension was stirred for a further 2 h. Water was added and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH=30 / 1) to give 6-((3-oxo-1-(2-(trifluoromethyl)benzyl)-1,3-dihydro-2H-indazol-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (140 mg, 16%) as a yellow solid. MS(ESI) m / z 570 [M+H] + . Step 3. 6-((3-oxo-1-(2-(trifluoromethyl)benzyl)-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (141) To a solution of 6-((3-oxo-1-(2-(trifluoromethyl)benzyl)-1,3-dihydro-2H-indazol-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (140 mg, 0.24 mmol) in THF (5 mL) was added TBAF (192 mg, 0.73 mmol) under N. The mixture was stirred at room temperature for 2 days, diluted with EtOAc, and washed with water. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give 6-((3-oxo-1-(2-(trifluoromethyl)benzyl)-1,3-dihydro-2H-indazol-2-yl)methyl)benzo[d]oxazol-2(3H)-one (9 mg, 8.3%) as a pale yellow solid. MS(ESI)m / z 440[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.81-7.74(m,2H),7.63-7.52(m,3H),7.29-7.22(m,1H),7.06(s,1H),7.04-6.95(m,3H),6.76( t,J=8.0Hz,1H),6.70(d,J=8.0Hz,1H),6.04(d,J=2.6Hz,1H),5.12(d,J=15.4Hz,1H),3.77(d,J=15.4Hz,1H). 6-((1-(2-Methoxybenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (142) [ka] The title compound 142 was prepared as a white solid (12 mg, 5.9%) following the procedure described for compound 124. MS (ESI) m / z 401 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.63(s,1H),7.71-7.62(m,1H),7.51-7.40(m,2H),7.28-7.22(m,1H),7.09 (d,J=1.5Hz,1H),7.05(d,J=7.9Hz,1H),7.02-6.91(m,4H),6.84(t,J=7.6Hz, 1H),5.17(d,J=15.1Hz,1H),4.68(dd,J=7.6,5.1Hz,1H),4.35(d,J=15.1Hz, 1H),3.67(s,3H),3.43(dd,J=13.4,5.1Hz,1H),2.81(dd,J=13.5,7.6Hz,1H). 6-((3-methyl-5-(morpholinomethyl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (143) [ka] The title compound 143 was prepared as a white solid (9 mg, 23%) following the procedure described for compound 96. MS (ESI) m / z 394 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),7.66(d,J=7.7Hz,1H),7.50(s,1H),7.44(dd,J=7.8,1.4Hz,1H),7.24(d,J=1.4Hz,1H),7.09(dd,J=8.0,1.6Hz,1H), 7.04(d,J=8.0Hz,1H),5.01(d,J=15.2Hz,1H),4.46-4.36(m,2H),3.61-3.49(m,6H),2.35(t,J=4.7Hz,4H),1.39(d,J=6.7Hz,3H). (R)-6-((3-methyl-5-(morpholinomethyl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (144) and (S)-6-((3-methyl-5-(morpholinomethyl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (145) [ka] The title compounds 144 and 145 were prepared according to the procedure described for compound 96. Using the stereoisomers of Int10 or Int11 with a RT of 1.728 min as starting materials, a white solid (69 mg, 44%) was obtained with the following characteristics: MS (ESI) m / z 394 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 7.71 (d, J = 7.7 Hz, 1H), 7.55 (s, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 1.5 Hz, 1H), 7.10 (dd, J = 8.1, 1.5 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.02 (d, J = 15.2 Hz, 1H), 4.48-4.37 (m, 2H), 3.75-3.52 (m, 6H), 2.63-2.40 (m, 4H), 1.40 (d, J = 6.7 Hz, 3H). Using the stereoisomers of Int10 or Int11 with a RT of 1.969 min as starting materials, a white solid (56 mg, 36%) was obtained with the following characteristics: MS (ESI) m / z 394[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),7.72(d,J=7.7Hz,1H),7.57(s,1H),7.50(d,J=7.8Hz,1H),7.24(d,J=1.5Hz,1H),7.10(d,J=8.1Hz,1H),7.0 5(d,J=7.9Hz,1H),5.02(d,J=15.2Hz,1H),4.49-4.37(m,2H),3.75-3.52(m,6H),2.63-2.40(m,4H),1.40(d,J=6.7Hz,3H). 2-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (147) [ka] The title compound 147 was prepared according to general procedure E as a white solid (9 mg, 7.3%). MS (ESI) m / z 396 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),7.72(dd,J=7.7,1.4Hz,1H),7.65(d,J=7.6Hz,1H),7.60-7.56(m,1H ),7.53-7.49(m,1H),7.47-7.39(m,2H),7.28(d,J=7.6Hz,1H),7.14(s,1H),7.12( d,J=7.6Hz,1H),7.04-7.00(m,2H),5.15(d,J=15.2Hz,1H),4.87(t,J=5.8Hz,1H), 4.47(d,J=15.2Hz,1H),3.60(dd,J=14.4,5.0Hz,1H),3.28(dd,J=14.4,6.4Hz,1H). 4-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (148) [ka] The title compound 148 was prepared according to general procedure E as a white solid (50 mg, 53%). MS (ESI) m / z 396 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),7.65-7.51(m,4H),7.47-7.39(m,2H),7.22(d,J=1.5Hz,1H),7.19-7.11(m,2H),7.11-7.01(m,2H),5.14(d, J=15.1Hz,1H),4.79(t,J=4.9Hz,1H),4.49(d,J=15.1Hz,1H),3.46(dd,J=14.1,4.2Hz,1H),3.37(dd,J=14.0,5.9Hz,1H). 6-((5-((2-oxaspiro[3.3]heptan-6-yl)amino)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (149) [ka] The title compound 149 was prepared as a white solid (7 mg, 7.4%) following the procedure described for compound 109. MS (ESI) m / z 406 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),7.37(d,J=8.3Hz,1H),7.15(s,1H),7.03-6.99(m,2H),6. 58-6.52(m,2H),6.49(d,J=1.9Hz,1H),4.93(d,J=15.2Hz,1H),4.62(s, 2H),4.49(s,2H),4.29(d,J=15.2Hz,1H),4.22(q,J=6.6Hz,1H),3.75-3 .63(m,1H),2.73-2.61(m,2H),2.05-1.93(m,2H),1.31(d,J=6.6Hz,3H). 6-((1-(oxazol-2-ylmethyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (150) [ka] The title compound 150 was prepared according to general procedure E as a white solid (81 mg, 26.9%). MS (ESI) m / z 362 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),7.88(d,J=0.9Hz,1H),7.66(d,J=7.5Hz,1H),7.59-7.54(m,1 H),7.47(t,J=7.5Hz,1H),7.40(d,J=7.3Hz,1H),7.23(d,J=1.4Hz,1H),7.1 1-6.98(m,3H),5.13(d,J=15.3Hz,1H),4.81(dd,J=6.2,4.2Hz,1H),4.40(d ,J=15.3Hz,1H),3.57(dd,J=15.7,4.2Hz,1H),3.42(dd,J=15.6,6.3Hz,1H). 6-((7-(2-methylbenzyl)-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)benzo[d]oxazol-2(3H)-one (151) [ka] The title compound 151 was prepared according to general procedure E using 6-((5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (prepared by the procedure outlined for Int6) as the starting material to give a white solid (97 mg, 64.9%). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.72(dd,J=4.9,1.6Hz,1H),8.08(dd,J=7.6,1.6Hz,1H),7.50(dd,J=7 .7,4.9Hz,1H),7.15-7.01(m,4H),6.97(d,J=7.9Hz,1H),6.88(d,J=1.5Hz,1H),6.82( dd,J=8.0,1.6Hz,1H),5.17(d,J=15.0Hz,1H),4.73(dd,J=6.6,4.8Hz,1H),4.22(d,J= 15.2Hz,1H),3.37(dd,J=14.6,4.9Hz,1H),3.18(dd,J=14.6,6.6Hz,1H),2.18(s,3H). 6-(((R)-1-oxo-3-((R)-1-(pyridin-2-yl)ethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (152) and 6-(((S)-1-oxo-3-((S)-1-(pyridin-2-yl)ethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (153), and Mixture of 6-(((S)-1-oxo-3-((R)-1-(pyridin-2-yl)ethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (154) and 6-(((R)-1-oxo-3-((S)-1-(pyridin-2-yl)ethyl)isoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (155) [ka] Following general procedure E, a mixture of 152 and 153 and a mixture of 154 and 155 were prepared, respectively. After preparative HPLC separation, two diastereoisomers (each containing two enantiomers) were obtained: a mixture of 152 and 153 and a mixture of 154 and 155. One of the two diastereoisomers was a white solid (45 mg, 22%) with a RT = 3.24 min (HPLC) and MS (ESI) m / z 386 [M+H]. + . 1 H NMR(400MHz,DMSO-d6)δ 11.57(s,1H),8.49-8.47(m,1H),7.75-7.71(m,2H),7.68-7.59(m,2H),7.50(t,J=7.4Hz ,1H),7.32-7.29(m,1H),7.24(d,J=7.9Hz,1H),6.91(d,J=8.3Hz,1H),6.58-6.55(m,2H) , 5.07 (d, J = 15.2 Hz, 1H), 4.97 (d, J = 2.6 Hz, 1H), 3.95 (d, J = 15.2 Hz, 1H), 3.83-3.80 (m, 1H), 1.13 (d, J = 7.2 Hz, 3H). The other of the two diastereoisomers was a white solid (40 mg, 20%) with a RT = 3.68 min (HPLC). MS(ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),8.63-8.61(m,1H),7.84-7.80(m,1H),7.73(d,J=7.5Hz,1H),7.44( t,J=7.4Hz,1H),7.36-7.31(m,3H),7.28(d,J=8.0Hz,1H),7.15(dd,J=8.0,1.5Hz ,1H),7.07(d,J=7.9Hz,1H),6.19(d,J=7.7Hz,1H),5.21(d,J=15.2Hz,1H),5.13( d,J=3.9Hz,1H),4.48(d,J=15.2Hz,1H),3.93-3.81(m,1H),0.73(d,J=7.0Hz,3H). 6-((1-((4-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (156) [ka] The title compound 156 was prepared according to general procedure E as a white solid (85 mg, 42.5%). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.33(d,J=5.0Hz,1H),7.67(d,J=6.9Hz,1H),7.55-7.42(m,2H),7. 12(d,J=7.4Hz,1H),7.07-7.04(m,2H),7.02(d,J=7.9Hz,1H),6.95(dd,J=8.0,1.5 Hz,1H),6.84(s,1H),5.04(d,J=15.3Hz,1H),4.98(t,J=6.1Hz,1H),4.40(d,J=15. 3Hz,1H),3.41(dd,J=14.2,5.4Hz,1H),3.10(dd,J=14.1,6.9Hz,1H),2.18(s,3H). 6-((1-(2-chlorobenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (157) [ka] The title compound 157 was prepared according to general procedure E as a white solid (62 mg, 58.6%). MS (ESI) m / z 405 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),7.73-7.67(m,1H),7.51-7.40(m,3H),7.35-7.19(m,3H),7.08(d,J=1.5Hz,1H),7.05-6.95(m,2H),6.93-6.87(m,1H),5 .16(d,J=15.2Hz,1H),4.77(dd,J=7.6,5.6Hz,1H),4.39(d,J=15.2Hz,1H),3.55(dd,J=13.8,5.6Hz,1H),2.98(dd,J=13.8,7.6Hz,1H). 6-((1-((6-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (158) [ka] The title compound 158 was prepared according to general procedure E as a white solid (89 mg, 67%). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),7.77(s,1H),7.68(d,J=7.4Hz,1H),7.59-7.44(m,2H),7.35(s,1H),7.25(d,J=7.6Hz,1H),7.08-7.01(m,3H),6.95 (dd,J=8.0,1.6Hz,1H),5.12-4.96(m,2H),4.42(d,J=15.3Hz,1H),3.50(dd,J=14.4,5.5Hz,1H),3.39-3.26(m,1H),2.46(s,3H). 6-((1-((3-chloropyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (159) [ka] The title compound 159 was prepared according to general procedure E as a white solid (7 mg, 6.2%). MS (ESI) m / z 406 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),8.50(dd,J=4.7,1.5Hz,1H),7.86(dd,J=8.1,1.5Hz,1H),7.76-7.69( m,1H),7.52-7.44(m,2H),7.36(dd,J=8.1,4.7Hz,1H),7.09-7.02(m,1H),7.03-6.9 5(m,2H),6.91(dd,J=8.0,1.6Hz,1H),5.13(t,J=6.4Hz,1H),5.04(d,J=15.4Hz,1H) ,4.45(d,J=15.4Hz,1H),3.59(dd,J=15.0,5.8Hz,1H),3.20(dd,J=15.1,7.2Hz,1H). 6-((5-(2-methylbenzyl)-7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)benzo[d]oxazol-2(3H)-one (160) [ka] The title compound 160 was prepared according to general procedure E using 6-((7-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (prepared by the procedure outlined for Int6) as the starting material to give a white solid (16 mg, 53%). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.64(s,1H),8.69(dd,J=4.9,1.5Hz,1H),7.41(dd,J=7.8,4.8Hz,1H),7.24-7.00(m,8H),5.19(d,J=15.1Hz,1H),4.70 (dd,J=8.7,5.8Hz,1H),4.45(d,J=15.2Hz,1H),3.50(dd,J=13.8,5.8Hz,1H),2.75(dd,J=13.8,8.7Hz,1H),2.09(s,3H). 6-((1-((5-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (161) [ka] The title compound 161 was prepared according to general procedure E as a white solid (90 mg, 58%). MS (ESI) m / z 386 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.62(s,1H),8.31(d,J=2.2Hz,1H),7.68-7.61(m,1H),7.54-7.41(m,3H),7.18-7.10(m,2H),7.06-6.96(m,2H),6.91(d,J=7.9Hz,1H),5 .10(d,J=15.3Hz,1H),4.92(dd,J=6.9,4.8Hz,1H),4.44(d,J=15.3Hz,1H),3.50-3.45(m,1H),3.16(dd,J=14.1,7.0Hz,1H),2.24(s,3H). rel-(S)-6-((3-methyl-5-(oxazol-5-yl)-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (162) [ka] The title compound 162 was prepared according to the procedure described for compound 61, starting with the stereoisomer of Int10 or Int11 with a RT of 1.969 min, to give a white solid (5 mg, 15%). MS (ESI) m / z 362 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 8.21-8.18(m,2H),8.05(d,J=0.9Hz,1H),7.94(d,J=8.3Hz,1H),7.36(d,J=0.8Hz,1H),7.25(s,1H),7.20-7.17(m,1H) ),7.07(d,J=8.0Hz,1H),5.18(d,J=15.2Hz,1H),4.53(d,J=15.3Hz,1H),4.29(t,J=6.6Hz,1H),1.53(d,J=6.8Hz,3H). rel-(S)-6-((3,5-dimethyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (163) [ka] The title compound 163 was prepared according to the procedure described for compound 125 using the stereoisomer of Int10 or Int11 with a RT of 1.969 min as starting material to give a white solid (14 mg, 33%). MS (ESI) m / z 309 [M+H] + . 1 H NMR(400MHz,CD3OD)δ 7.57(d,J=8.2Hz,1H),7.21(d,J=7.7Hz,2H),7.08(s,1H),7.04(d,J=8.0Hz,1H),6.93(d,J =8.0Hz,1H),5.02(d,J=15.3Hz,1H),4.38-4.31(m,2H),2.34(s,3H),1.33(d,J=6.7Hz,3H). 4-Methyl-2-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (164) [ka] The title compound 164 was prepared according to general procedure E as an off-white solid (27 mg, 43%). MS (ESI) m / z 410 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.66(s,1H),7.73(dd,J=6.0,2.8Hz,1H),7.62(dd,J=7.8,1.8Hz,1H),7.53(d,J=1.8Hz,1H),7. 52-7.44(m,2H),7.36(d,J=7.9Hz,1H),7.05(d,J=1.5Hz,1H),7.00(d,J=7.9Hz,1H),6.95(dd,J= 8.0,1.6Hz,1H),6.87(dd,J=5.9,2.8Hz,1H),5.09(d,J=15.2Hz,1H),4.78(dd,J=7.6,6.1Hz,1H) ,4.36(d,J=15.2Hz,1H),3.43(dd,J=14.1,6.1Hz,1H),2.90(dd,J=14.1,7.6Hz,1H),2.17(s,3H). Intermediate 164-3 was prepared as follows: [ka] Step 1. 2-(Hydroxymethyl)-4-methylbenzonitrile (164-2) To a solution of methyl 2-cyano-5-methylbenzoate (200 mg, 1.14 mmol) in methanol (5 mL) was added NaBH (173 mg, 4.57 mmol) under N at 0 °C. The mixture was stirred for 2 h and concentrated in vacuo. The residue was purified by preparative TLC (DCM / MeOH = 30 / 1) to give 2-(hydroxymethyl)-4-methylbenzonitrile (154 mg, 91%) as a colorless semi-solid. MS (ESI) m / z 148 [M+H] + . Step 2. 2-(Bromomethyl)-4-methylbenzonitrile (164-3) To a solution of 2-(hydroxymethyl)-4-methylbenzonitrile (154 mg, 1.05 mmol) and PPh3 (549 mg, 2.09 mmol) in DCM (3 mL) was added CBr4 (347 mg, 1.05 mmol) under N2 at 0 °C. The mixture was stirred for 20 min and then warmed to room temperature. The suspension was stirred for an additional 1 h. The solvent was removed in vacuo, and the residue was purified by preparative TLC (PE / EtOAc = 5 / 1) to give 2-(bromomethyl)-4-methylbenzonitrile (70 mg, 31%) as a white solid. MS (ESI) m / z 210 [M+H] + . 6-((1-((2-methylpyridin-3-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (165) [ka] The title compound 165 was prepared according to general procedure E as an off-white solid (25 mg, 24%). MS (ESI) m / z 386 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.66(s,1H),8.46(d,J=5.2Hz,1H),7.72(d,J=7.1Hz,2H),7.53-7.46(m,2H),7.41(d,J=6.3Hz,1H),7.13(s,1H),7.05-6.97(m,3H),5.11 (d,J=15.2Hz,1H),4.79(t,J=6.5Hz,1H),4.45(d,J=15.2Hz,1H),3.52(dd,J=14.9,5.3Hz,1H),3.01(dd,J=14.5,7.6Hz,1H),2.37(s,3H). 6-((1-(2-ethoxybenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (166) [ka] The title compound 166 was prepared according to general procedure E as a white solid (5 mg, 15%). MS (ESI) m / z 415 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.64(s,1H),7.71-7.64(m,1H),7.50-7.40(m,2H),7.24(td,J=7.8,1.8Hz,1H ),7.06-7.01(m,2H),7.00-6.91(m,3H),6.88-6.79(m,2H),5.16(d,J=15.2Hz, 1H),4.76(dd,J=7.8,5.4Hz,1H),4.37(d,J=15.2Hz,1H),3.98-3.83(m,2H),3. 43(dd,J=13.3,5.5Hz,1H),2.75(dd,J=13.3,7.8Hz,1H),1.11(t,J=6.9Hz,3H). 6-((1-(cyclohexylmethyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (167) [ka] The title compound 167 was prepared as a white solid (15 mg, 48%) following the procedure described for compound 67. MS (ESI) m / z 377 [M+H]+ . 1 H NMR (400 MHz, DMSO-d6) δ 11.67(s,1H),7.73(d,J=7.5Hz,1H),7.63-7.45(m,3H),7.23(s,1H),7.10- 7.02(m,2H),5.06(d,J=15.2Hz,1H),4.48(dd,J=6.8,3.7Hz,1H),4.36(d,J= 15.2Hz,1H),1.95-1.84(m,1H),1.73-1.63(m,1H),1.61-1.36(m,4H),1.24 (d,J=12.2Hz,1H),1.17-1.11(m,1H),1.09-0.84(m,4H),0.80-0.67(m,1H). 6-((1-(2-methylbenzyl)-3-oxo-1,3-dihydro-2H-pyrrolo[3,4-c]pyridin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (168) [ka] The title compound 168 was prepared as a white solid (8 mg, 24%) following the procedure described for compound 124. MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),8.93(s,1H),8.60(d,J=5.1Hz,1H),7.28-6.96(m,7H),6.78(d,J=5.1Hz,1H),5.14(d,J=15.2Hz,1H), 4.81-4.69(m,1H),4.37(d,J=15.2Hz,1H),3.46(dd,J=13.9,6.0Hz,1H),2.79(dd,J=13.9,8.5Hz,1H),2.10(s,3H). 2-((2-(4-hydroxybenzyl)-3-oxoisoindolin-1-yl)methyl)benzonitrile (169) [ka] Intermediate 169-1 was prepared according to the procedure described for Int12. Step 1. 2-((2-(4-(benzyloxy)benzyl)-3-oxoisoindolin-1-yl)methyl)benzonitrile (169-2) To a solution of 2-((3-oxoisoindolin-1-yl)methyl)benzonitrile (200 mg, 0.8 mmol) in DMF (2 mL) was added NaH (21 mg, 0.88 mmol) at 0° C. under N. The mixture was stirred for 30 min. 1-(benzyloxy)-4-(chloromethyl)benzene (187 mg, 0.8 mmol) was added, and the reaction was warmed to room temperature and stirred for an additional 2 h. Water was added at 0° C., and then extracted with EtOAc. The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (PE / EtOAc=1.5 / 1) to give 2-((2-(4-(benzyloxy)benzyl)-3-oxoisoindolin-1-yl)methyl)benzonitrile (100 mg, 27%) as a yellow solid. MS(ESI)m / z 445[M+H] + . Step 2. 2-((2-(4-hydroxybenzyl)-3-oxoisoindolin-1-yl)methyl)benzonitrile (169) TfOH (0.1 mL) was added to a stirred solution of 2-((2-(4-(benzyloxy)benzyl)-3-oxoisoindolin-1-yl)methyl)benzonitrile (100 mg, 0.22 mmol) in DCM (2 mL). The mixture was stirred for 14 h. The mixture was concentrated in vacuo and purified by preparative HPLC to give 2-((2-(4-hydroxybenzyl)-3-oxoisoindolin-1-yl)methyl)benzonitrile (6 mg, 7.3%) as a white solid. MS (ESI) m / z 355 [M+H] + . 1H NMR(400MHz,CD3OD)δ 7.62(d,J=6.9Hz,1H),7.53(d,J=7.8Hz,1H),7.44-7.32(m,3H),7.28(t,J=7.6Hz,1H),7.08-7.03(m,2H),7.00-6.93(m,2H),6.67-6.5 9(m,2H),5.12(d,J=15.1Hz,1H),4.74-4.70(m,1H),4.27(d,J=15.1Hz,1H),3.51(dd,J=14.4,5.2Hz,1H),3.19(dd,J=14.4,6.5Hz,1H). 3-Fluoro-2-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (170) [ka] The title compound 170 was prepared according to general procedure E as an off-white solid (63 mg, 40%). MS (ESI) m / z 414 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.68(s,1H),7.75-7.65(m,2H),7.65-7.52(m,2H),7.52-7.44(m,2H),7.16(s,1H),7.06-6.97(m,2H),6.86-6.79(m,1H),5.20( d,J=15.2Hz,1H),4.74(dd,J=8.0,5.6Hz,1H),4.42(d,J=15.2Hz,1H),3.70(dd,J=14.0,5.2Hz,1H),3.03(dd,J=14.0,8.0Hz,1H). (R)-3-Fluoro-2-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (171) and (S)-3-Fluoro-2-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (172) [ka] Chiral separation of compound 170 by chiral preparative HPLC (CHIRALPAK IA column; column dimensions: 2 cm x 25 cm, 5 μm; mobile phase A: MeOH:DCM); mobile phase B: MTBE was performed to give two enantiomers: compound 171 and compound 172. 171 was a white solid with a RT of 1.424 min (chiral HPLC, column: CHIRALPAK IA-3 column; column dimensions: 4.6 x 50 mm, 3 μm; mobile phase: MTBE (0.1% DEA):(MeOH:DCM = 1:1) = 80:20; flow rate: 1.0 mL / min). Mass (m / z): 414 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.74-7.65(m,2H),7.64-7.52(m,2H),7.51-7.45(m,2H),7.16( s,1H),7.06-6.97(m,2H),6.86-6.81(m,1H),5.19(d,J=15.2Hz,1H),4.74(dd ,J=8.0,5.6Hz,1H),4.42(d,J=15.4Hz,1H),3.69(dd,J=14.0,5.2Hz,1H),3.03(dd,J=14.0,8.0Hz,1H).172 is a white solid, RT=2.067 min (chiral HPLC, column: CHIRALPAK IA-3; Column size: 4.6*50mm, 3μm; Mobile phase: MTBE (0.1% DEA): (MeOH: DCM = 1:1) = 80:20; Flow rate: 1.0mL / min) Mass (m / z): 414 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 7.74-7.64 (m, 2H), 7.64-7.50 (m, 2H), 7.53-7.43 (m, 2H), 7.15 (s, 1H), 7.06-6.97 (m, 2H), 6.87-6.79 (m, 1H), 5.19 (d, J = 15.2 Hz, 1H), 4.74 (dd, J = 8.0, 5.6 Hz, 1H), 4.42 (d, J = 15.2 Hz, 1H), 3.69 (dd, J = 14.0, 5.6 Hz, 1H), 3.03 (dd, J = 14.0, 8.0 Hz, 1H). X-ray analysis confirmed the structure of 172. 2-(2-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)phenyl)acetonitrile (173) [ka] The title compound 173 was prepared according to general procedure E as a white solid (45 mg, 23%). MS (ESI) m / z 410 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.58(s,1H),7.73-7.71(m,1H),7.49-7.44(m,2H),7.40-7.27(m,3H),7.19( dd,J=7.6,1.6Hz,1H),7.07(d,J=1.4Hz,1H),7.03-6.97(m,2H),6.84-6.82(m ,1H),5.12(d,J=15.2Hz,1H),4.73(dd,J=7.9,5.9Hz,1H),4.34(d,J=15.2Hz, 1H),3.83(s,2H),3.46(dd,J=14.3,5.9Hz,1H),2.88(dd,J=14.3,8.0Hz,1H). 2-Methyl-3-((3-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindolin-1-yl)methyl)benzonitrile (174) [ka] The title compound 174 was prepared according to general procedure E using 3-(bromomethyl)-2-methylbenzonitrile (prepared by the procedure described for 164-3) as the starting material to give a white solid (136 mg, 52%). MS (ESI) m / z 410 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.75-7.65(m,2H),7.51-7.45(m,2H),7.41(d,J=7.8Hz,1H),7.31(t, J=7.7Hz,1H),7.05(d,J=1.5Hz,1H),7.01(d,J=7.9Hz,1H),6.96(d,J=8.0Hz,1H),6 .90-6.85(m,1H),5.09(d,J=15.3Hz,1H),4.74(dd,J=7.8,5.8Hz,1H),4.39(d,J=15 .3Hz,1H),3.49(dd,J=14.2,5.8Hz,1H),2.94(dd,J=14.2,7.8Hz,1H),2.26(s,3H). 6-((1-((4-chloropyridin-3-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (175) [ka] The title compound 175 was prepared according to general procedure E as a white solid (36 mg, 23.7%). MS (ESI) m / z 406 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.61(s,1H),8.38(d,J=5.3Hz,1H),8.29(s,1H),7.68(d,J=6.7Hz,1H),7. 57-7.45(m,2H),7.47(d,J=2.6Hz,1H),7.13(s,1H),7.08-7.02(m,1H),7.0 6-6.97(m,2H),5.17(d,J=15.2Hz,1H),4.82(dd,J=7.1,5.1Hz,1H),4.47(d ,J=15.2Hz,1H),3.59(dd,J=14.2,5.1Hz,1H),3.13(dd,J=14.2,7.2Hz,1H). 6-((1-((3-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (176) [ka] The title compound 176 was prepared according to general procedure E as a white solid (71 mg, 35.8%). MS (ESI) m / z 386 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.64(s,1H),8.39(d,J=4.9Hz,1H),7.76-7.71(m,1H),7.54(d,J=7.8Hz,1H), 7.52-7.42(m,2H),7.22(dd,J=7.6,4.8Hz,1H),7.02-6.94(m,3H),6.91(d,J=8. 0Hz,1H),5.19(dd,J=7.6,5.8Hz,1H),5.04(d,J=15.3Hz,1H),4.39(d,J=15.3H z,1H),3.44(dd,J=15.1,5.8Hz,1H),2.97(dd,J=15.1,7.7Hz,1H),2.05(s,3H). 176-2 was prepared according to the procedure described for step 2 of the preparation of 174-3. [ka] (R)-6-((1-((3-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (177) and (S)-6-((1-((3-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (178) [ka] Chiral separation of compound 176 by chiral preparative HPLC (CHIRALPAK IF column; column dimensions: 2 cm x 25 cm, 5 μm; mobile phase A: MeOH:DCM; mobile phase B: MtBE; flow rate: 20 mL / min; detector: 220 nm) gave two enantiomers: compounds 177 and 178. 177 was a white solid with a RT of 1.571 min (chiral HPLC, column: CHIRALPAK IF-3 column; column dimensions: 4.6 x 50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH:DCM = 1:1) = 80:20; flow rate: 1.0 mL / min). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.57(s,1H),8.38(d,J=4.8Hz,1H),7.77-7.70(m,1H),7.54(d,J=7.6Hz,1H),7.51-7.4 3(m,2H),7.21(dd,J=7.6,4.8Hz,1H),6.99(m,3H),6.91(d,J=8.0Hz,1H),5.19(t,J=6.7H) z, 1H), 5.04 (d, J = 15.3 Hz, 1H), 4.39 (d, J = 15.3 Hz, 1H), 3.43 (dd, J = 15.1, 5.8 Hz, 1H), 2.98 (dd, J = 15.1, 7.6 Hz, 1H), 2.05 (s, 3H). 178 was a white solid, RT = 2.158 min (chiral HPLC, column: CHIRALPAK IF-3; column size: 4.6*50 mm, 3 μm; mobile phase: MTBE (0.1% DEA): (MeOH:DCM = 1:1) = 80:20; flow rate: 1.0 mL / min). MS (ESI) m / z 386 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.38 (d, J = 4.8 Hz, 1H), 7.77-7.70 (m, 1H), 7.54 (d, J = 7.6 Hz, 1H), 7.51-7.43 (m, 2H), 7.21 (dd, J = 7.6, 4.8 Hz, 1H), 6.99 (m, 3H), 6.91 (d, J = 8.0 Hz, 1H), 5.19 (dd, J = 7.6, 5.6 Hz, 1H), 5.04 (d, J = 15.3 Hz, 1H), 4.39 (d, J = 15.3 Hz, 1H), 3.43 (dd, J = 15.1, 5.8 Hz, 1H), 2.98 (dd, J = 15.1, 7.6 Hz, 1H), 2.05 (s, 3H). X-ray analysis confirmed the structure of 178. 6-((1-((2-methylpyridin-4-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (179) [ka] The title compound 179 was prepared according to general procedure E as a white solid (25 mg, 26%). MS (ESI) m / z 386 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),8.18(d,J=5.1Hz,1H),7.65-7.54(m,2H),7.7.48-7.42( m,2H),7.20(s,1H),7.05(d,J=1.8Hz,2H),6.81(s,1H),6.74(d,J=5.2 Hz,1H),5.09(d,J=15.2Hz,1H),4.81(t,J=5.1Hz,1H),4.47(d,J=15.2Hz,1H),3.36-3.29(m,1H),3.24(dd,J=14.1,5.9Hz,1H),2.29(s,3H). 6-((1-(3-Methoxybenzyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (180) [ka] The title compound 180 was prepared according to general procedure E as a white solid (47 mg, 40.2%). MS (ESI) m / z 401 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),7.60(d,J=7.5Hz,1H),7.55(td,J=7.5,1.3Hz,1H),7.44(t,J=7.4Hz,1H) ,7.37(d,J=7.6Hz,1H),7.17(s,1H),7.10-7.00(m,3H),6.70(dd,J=8.2,2.6Hz,1H),6.6 0-6.53(m,1H),6.48(t,J=2.0Hz,1H),5.11(d,J=15.1Hz,1H),4.73(dd,J=6.1,4.3Hz,1H ),4.42(d,J=15.1Hz,1H),3.58(s,3H),3.31-3.27(m,1H),3.16(dd,J=14.1,6.2Hz,1H). 6-((1-((3-isopropylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (181) [ka] 181-1 was prepared according to the procedure described for step 1 of general procedure E. Step 1. 6-((1-oxo-3-((3-(prop-1-en-2-yl)pyridin-2-yl)methyl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (181-3) To a solution of 6-((1-((3-bromopyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (100 mg, 0.17 mmol) in dioxane (3 ml) and water (1 ml) was added Pd(dppf)Cl (13 mg, 0.02 mmol) and KCO (48 mg, 0.35 mmol) at room temperature under N. The resulting mixture was stirred at 100 °C for 3 h. The mixture was diluted with EA (30 mL) and washed with water (3 × 20 mL). The organic layer was separated, dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by silica gel flash column chromatography (PE / EA = 1 / 3) to give the title compound (60 mg, 64.1%) as a yellow oil. MS(ESI)m / z 542[M+H] + . Step 2. 6-((1-((3-Isopropylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (181-4) To a solution of 6-((1-oxo-3-((3-(prop-1-en-2-yl)pyridin-2-yl)methyl)isoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (60 mg, 0.11 mmol) in EtOH (5 mL) was added Pd / C (10 mg). The mixture was evacuated and filled with hydrogen three times. The resulting mixture was stirred at room temperature overnight. The reaction mixture was filtered off and the filtrate was concentrated to give the title compound (50 mg, 83%) as a yellow oil. MS (ESI) m / z 544 [M+H] + . Step 3. 6-((1-((3-Isopropylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (181) To a solution of 6-((1-((3-isopropylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)-3-((2-(trimethylsilyl)ethoxy)methyl)benzo[d]oxazol-2(3H)-one (50 mg, 0.09 mmol) in DCM (5 mL) was added trifluoroacetic acid (2 mL). The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was dissolved in DCM (2 mL) and NHOH (1 mL) was added dropwise. The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and the residue was purified by preparative HPLC to give 6-((1-((3-methylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (17 mg, 44.7%) as a white solid. MS(ESI)m / z 414[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.59(s,1H),8.40(dd,J=4.7,1.7Hz,1H),7.77-7.69(m,1H),7.67(dd,J=7.9,1.7Hz,1H),7.51-7.39 (m,2H),7.30(dd,J=7.9,4.7Hz,1H),7.09-6.97(m,2H),6.92(dd,J=7.9,1.6Hz,1H),6.80(d,J=7.1Hz, 1H),5.13(dd,J=7.8,5.8Hz,1H),5.08(d,J=15.3Hz,1H),4.39(d,J=15.3Hz,1H),3.52(dd,J=14.7,5.9 Hz,1H),3.00(dd,J=14.7,8.0Hz,1H),2.84-2.71(m,1H),0.98(d,J=6.8Hz,3H),0.95(d,J=6.8Hz,3H). 6-((1-((3-ethylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (182) [ka] The title compound 182 was prepared as a white solid (7 mg, 7.7%) following the procedure described for compound 181. MS (ESI) m / z 400 [M+H]+ . 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),8.41(dd,J=4.8,1.8Hz,1H),7.74(dd,J=6.7,1.8Hz,1H),7.56(dd,J=7.7,1.7Hz ,1H),7.53-7.40(m,2H),7.26(dd,J=7.7,4.7Hz,1H),7.03-6.96(m,2H),6.95-6.84(m,2H),5. 22(dd,J=7.6,6.0Hz,1H),5.04(d,J=15.3Hz,1H),4.38(d,J=15.3Hz,1H),3.45(dd,J=15.0,6. 0Hz,1H),3.28(s,1H),2.97(dd,J=15.0,7.8Hz,1H),2.46-2.33(m,1H),0.93(t,J=7.5Hz,3H). 6-((1-((2-fluoropyridin-3-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (183) [ka] The title compound 183 was prepared according to general procedure E as a white solid (27 mg, 32%). MS (ESI) m / z 390 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.63(s,1H),8.00(dd,J=4.9,1.8Hz,1H),7.62-7.47(m,3H),7.43(t,J =7.4Hz,1H),7.37(d,J=7.6Hz,1H),7.20(s,1H),7.16-7.11(m,1H),7.10 -7.00(m,2H),5.18(d,J=15.2Hz,1H),4.78(t,J=5.0Hz,1H),4.48(d,J=15.2Hz,1H),3.44(dd,J=14.4,4.2Hz,1H),3.28(dd,J=14.4,5.6Hz,1H). 6-((1-((3-cyclopropylpyridin-2-yl)methyl)-3-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (184) [ka] The title compound 184 was prepared according to general procedure E as a white solid (8 mg, 7.9%). MS (ESI) m / z 412 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ 11.58(s,1H),8.38(dd,J=4.9,1.6Hz,1H),7.74(dd,J=6.4,2.0Hz,1H),7.51-7.42(m,2H) ,7.37(d,J=7.9Hz,1H),7.25(t,J=6.3Hz,1H),7.02-6.96(m,2H),6.94-6.87(m,2H),5.21( t,J=6.8Hz,1H),5.08(d,J=15.3Hz,1H),4.39(d,J=15.3Hz,1H),3.63(dd,J=14.9,6.0Hz,1 H),3.18(dd,J=14.9,7.8Hz,1H),1.76-1.66(m,1H),0.78-0.68(m,2H),0.54-0.38(m,2H). Intermediate 184-3 was prepared as follows: [ka] Step 1 was carried out according to the procedure outlined for step 1 for the preparation of compound 181. Step 2 was carried out according to the procedure outlined for step 3 for the preparation of Int1. rel-(S)-6-((5-((3-methoxyazetidin-1-yl)methyl)-3-methyl-1-oxoisoindolin-2-yl)methyl)benzo[d]oxazol-2(3H)-one (185) [ka] The title compound 185 was prepared according to compound 96 using the stereoisomer of Int10 or Int11 with a RT of 1.969 min as the starting material to give a white solid (2 mg, 9%). MS (ESI) m / z 394 [M+H] + . 1H NMR(400MHz,DMSO-d6)δ 11.60(s,1H),7.64(d,J=7.7Hz,1H),7.47(s,1H),7.39(d,J=7.9Hz,1H),7.23(s,1H),7.10-7.02(m,2H),5.00(d,J=15.2 Hz,1H),4.43-4.36(m,2H),4.01-3.91(m,1H),3.70(s,2H),3.51(s,2H),3.14(s,3H),2.90(s,2H),1.38(d,J=6.7Hz,3H). rel-(S)-3-Methyl-1-oxo-2-((2-oxo-2,3-dihydrobenzo[d]oxazol-6-yl)methyl)isoindoline-5-carbonitrile (186) [ka] The title compound 186 was prepared according to the procedure descr...

Claims

1. A compound of the following structural formula 1: 【Chemical 1】 a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein X １ is C or S, but X １ is C, then W is absent and X １ is S, then W is O or absent; U is selected from O and S, with the proviso that X １ is S, U cannot be S, X ２ is C, N, or absent, and X ３ is C or N, and X ４ is C, N, or absent, Ring B is a 5- to 6-membered heterocyclic group, and ring B is X １ , X ２ , X ３ and X ４ contains 0 or 1 heteroatom at positions other than Ring C is phenyl, a 9- to 10-membered aryl, a 5- to 6-membered heteroaryl, a 9- to 10-membered heteroaryl, a 3- to 6-membered carbocyclyl, or a 4- to 12-membered heterocyclic group; L is, 【Chemistry 2】 and R Ｌ is, for each occurrence, independently, H, deuterium, halogen, and C optionally substituted with 1 to 3 groups selected from halogen. １ ~C ３ alkyl, R ｂ１ and R ｂ２ are attached to two adjacent positions of ring B, and R ｂ１ and R ｂ２ are joined to form ring A, where ring A is phenyl or a 5- to 6-membered heteroaryl group, and where ring A is R ａ is substituted with a z group of R ａ represents, for each occurrence independently, a halogen, CN, C １ ~C ４ Alkyl, —NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ S (= O) ２ R ｑ , OR ｓ , —C(═O)NR ｐ R ｑ , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; During the ceremony, R ａ The above C １ ~C ４ Alkyl is —NR ｐ R ｑ , —C(═O)NR ｐ R ｑ , phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halogen, and OR ｓ and optionally substituted with 1 to 3 groups selected from R ａ wherein said 5- to 6-membered heteroaryl, said 3- to 7-membered carbocyclyl or said 3- to 7-membered heterocyclyl is optionally １ ~C ４ Alkyl, —O(C １ ~C ４ alkyl), -N(C １ ~C ４ alkyl) ２ and -NH(C １ ~C ４ alkyl), R ｘ is H,=O,CN,C ３ ~C ６ Carbocyclyl, C １ ~C ４ Alkyl, 【Chemistry 3】 is selected from During the ceremony, R ｘ The above C １ ~C ４ alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, and OH; Here, R ｘ The above C １ ~C ４ The 6-membered aryl or the 5- to 6-membered heteroaryl of alkyl is selected from the group consisting of halogen, OR ｓ ,CN,C(=O)NR ｐ R ｑ , N.R. ｐ R ｑ , C １ ~C ６ Alkyl (which is a halogen, O-R ｚ , OR ｓ , and C １ ~C ２ optionally substituted with 1 to 3 groups selected from 4- to 6-membered heterocyclyl optionally substituted with alkyl), C １ ~C ６ Alkenyl, C １ ~C ６ Alkynyl, 3- to 6-membered carbocyclyl, and 4- to 7-membered heterocyclyl (which is optionally substituted C １ ~C ４ Alkyl, halogen, and OR ｓ optionally substituted with 1 to 3 groups selected from Here, R ｘ The above C １ ~C ４ The 5- to 9-membered heterocyclyl of alkyl is C １ ~C ６ optionally substituted with 1 to 2 groups selected from alkyl, ═O, and halogen; R ｚ is selected from H, 6-membered aryl and 5-6-membered heteroaryl; Here, R ｚ wherein said 6-membered aryl or said 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; R ｙ is H, C １ ~C ２ alkyl, and absent; R ｃ For each occurrence, deuterium, halogen, C １ ~C ４ Alkyl, ═O, ═S, OR ｓ , -NHC(=O)R ｓ , -NHC(=O)OR ｓ , N.R. ｐ R ｑ , -NHC(=O)NR ｐ R ｑ , CN, optionally substituted 5- to 6-membered heteroaryl, optionally substituted 5- to 6-membered heterocyclyl, and —C(═O)NR ｐ R ｑ are independently selected from During the ceremony, R ｃ The above C １ ~C ４ Alkyl is halogen and OR ｓ and optionally substituted with 1 to 3 groups selected from During the ceremony, R ｐ For each occurrence, H and C １ ~C ６ alkyl; R ｑ For each occurrence, H, C １ ~C ６ independently selected from alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; R ｐ and R ｑ are linked to form a 3- to 6-membered carbocyclyl, R ｓ is independently for each occurrence H, C １ ~C ６ Alkyl (which can be halogen, deuterium, O(C １ ~C ４ alkyl) and NR ｐ R ｑ optionally substituted with 1 to 3 groups selected from: phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R ｑ and R ｓ and for each occurrence, independently, １ ~C ４ Alkyl and —O(C １ ~C ４ alkyl), and During the ceremony, m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, and 3; z is an integer selected from 0, 1, 2, 3, and 4; and The sum of p and q is an integer equal to or less than 5. A compound of structural formula 1, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing.

2. The compound has the following structural formula 2a or 2a′: 【Table 1】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y １ , Y ２ , Y ３ and Y ４ is independently selected from C and N.

3. The compound has the following structural formula 2b: 【Chemistry 4】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y １ , Y ２ , Y ３ and Y ４ is independently selected from C and N.

4. The compound has the following structural formula 2c, 2c-1, or 2c-2: 【Table 2】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y １ , Y ２ , Y ３ and Y ４ are independently selected from C and N, and Y ５ , Y ６ and Y ７ is independently selected from N, S, O and C.

5. The compound has a structural formula selected from formulas 2d-2i: 【Table 3】 10. The compound of claim 1, which is a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

6. The compound has a structural formula selected from formulas 3a and 3a-1 to 3a-16: 【Table 4-1】 【Table 4-2】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Z １ and Z ２ are independently selected from C and N; Z ３ is selected from C, N, S and O, R ｃ’ 2. The compound of claim 1, wherein m is O or S, and m' is independently selected from 0, 1, and 2 for each occurrence.

7. The compound has a structural formula selected from formulas 3b-3c: 【Table 5】 2. The compound of claim 1, wherein m' is selected from 0 and 1, or a tautomer, solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

8. The compound has a structural formula selected from formulas 3d-3e: 【Table 6】 2. The compound of claim 1, wherein m' is independently selected from 0 and 1 for each occurrence, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

9. The compound has a structural formula selected from formulas 3f-3h: 【Table 7】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein m′, for each occurrence, is independently selected from 0, 1, and 2; m″, for each occurrence, is independently selected from 0 and 1; and R Ｌ The compound of claim 1 , wherein is selected from H and F.

10. The compound has a structural formula selected from formulas 4a-4h: 【Table 8】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein m′, for each occurrence, is independently selected from 0, 1, and 2; m″, for each occurrence, is independently selected from 0 and 1; and R Ｌ The compound of claim 1 , wherein is selected from H and F.

11. The compound has a structural formula selected from formulas 5a-5e: 【Table 9】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein R ｃ 2. The compound of claim 1, wherein m is deuterium and m' is selected from 0, 1 and 2.

12. The compound has a structural formula selected from formulas 6a-6d: 【Table 10】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein V １ , V ２ , V ３ , and V ４ are independently selected from C and N; R Ｌ is selected from H and F, and R ｃ is deuterium, and R ｄ independently for each occurrence halogen, CN, OCH ３ , C １ ~C ４ Alkyl, C １ ~C ４ Alkenyl, C １ ~C ４ 2. The compound of claim 1, wherein m' is selected from 0, 1, and 2; and n is selected from 0, 1, 2, and 3.

13. The compound has a structural formula selected from formulas 6e-6h: 【Table 11】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein V １ , V ２ , V ３ , and V ４ are independently selected from C, O, S, and N; R Ｌ is selected from H and F, and R ｃ is deuterium, and R ｄ independently for each occurrence halogen, CN, OCH ３ , C １ ~C ４ Alkyl, C １ ~C ４ Alkenyl, C １ ~C ４ 2. The compound of claim 1, wherein m' is selected from 0, 1, and 2; and n is selected from 0, 1, 2, and 3.

14. 10. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 and 6 to 9, wherein Ring A is selected from phenyl, pyridyl, and 5-membered heteroaryl containing 1 to 2 heteroatoms selected from N, S, and O.

15. X １ is C and X ２ does not exist and X ３ 15. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1, 6-9, and 14, wherein is C or N.

16. Ring C is 【Chemistry 5】 and ring C is selected from m R ｃ 6. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 5, substituted with a group.

17. R ａ But halogen, CN, C １ ~C ３ Alkyl, —NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ S (= O) ２ R ｑ , OR ｓ , —C(═O)NR ｐ R ｑ , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; During the ceremony, R ａ The above C １ ~C ３ Alkyl is —NR ｐ R ｑ , —C(═O)NR ｐ R ｑ , phenyl, 4- to 7-membered heterocyclyl, halogen and OR ｓ and optionally substituted with 1 to 2 groups selected from R ａ The 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, or 3- to 7-membered heterocyclyl is C １ ~C ３ Alkyl, —O(C １ ~C ３ alkyl), -N(C １ ~C ３ alkyl) ２ and -NH(C １ ~C ３ alkyl), and During the ceremony, R ｐ is, for each occurrence, independently H and C １ ~C ３ alkyl, R ｑ is independently for each occurrence H, C １ ~C ３ selected from alkyl, phenyl, 5- to 6-membered heteroaryl, and 4- to 7-membered heterocyclyl; R ｓ is independently for each occurrence H, C １ ~C ３ selected from alkyl (which is optionally substituted with 1 to 2 groups selected from halogen), phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R ｑ and R ｓ and for each occurrence, independently, １ ~C ３ Alkyl and —O(C １ ~C ３ alkyl), 17. A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 10 and 14 to 16.

18. R ａ is F, Br, Cl, CN, methyl, ethyl, -C(CH ３ ) ３ , -CH(CH ３ ) ２ , C.H. ２ N (CH ３ ) ２ , C.H. ２ CH ２ C(=O)NH ２ , 【Chemistry 6】 NH ２ 、-N(CH ３ ) ２ 、 【Chemistry 7】 -NHC(=O)CH ３ 、-NHS(=O) ２ CH ３ 、 【Chemistry 8】 OH、OCH ３ 、 【Chemistry 9】 -C(=O)NH ２ 、-C(=O)NHCH ３ 、 【Chemistry 10】 CH ２ NXCH ３ 、CH ２ OCH ３ 、-CHF ２ 、 【Chemistry 11】 and OCHF ２ 18. The compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt of any one of claims 1 to 10 and 14 to 17, selected from:

19. R ａ is selected from F, Br, Cl, CN, OH, 5- to 6-membered heteroaryl, 3- to 6-membered carbocyclyl, 3- to 6-membered heterocyclyl, and methyl optionally substituted with 3- to 6-membered heterocyclyl.

20. R ｘ is H, ═O, CN, 3-6 carbocyclyl, C １ ~C ２ Alkyl, 【Chemistry 12】 is selected from During the ceremony, R ｘ The above C １ ~C ２ alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, and OH; Here, R ｘ The above C １ ~C ２ The 6-membered aryl or the 5- to 6-membered heteroaryl of alkyl is selected from the group consisting of halogen, OR ｓ , C.N., C.O.N.H. ２ , N.H. ２ , C １ ~C ４ Alkyl (which is a halogen, O-R ｚ , OR ｓ , and C １ ~C ２ optionally substituted with 1 to 3 groups selected from 4- to 6-membered heterocyclyl optionally substituted with alkyl), C １ ~C ３ Alkenyl, C １ ~C ３ Alkynyl, 3- to 4-membered carbocyclyl, and 4- to 7-membered heterocyclyl (which is １ ~C ２ Alkyl, halogen and OR ｓ optionally substituted with 1 to 3 groups selected from In the formula, R ｘ The above C １ ~C ２ The 5- to 9-membered heterocyclyl of alkyl is C １ ~C ２ optionally substituted with 1 to 2 groups selected from alkyl, ═O and halogen, wherein R ｓ is H and halogen, O(C １ ~C ２ alkyl), -N(C １ ~C ２ alkyl) (C １ ~C ２ C optionally substituted with 1 to 3 groups selected from １ ~C ２ alkyl, and R ｚ is selected from H, 6-membered aryl and 5-6-membered heteroaryl; In the formula, R ｚ wherein said 6-membered aryl or said 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; 20. A compound, tautomer, solvate, stereoisomer or pharmaceutically acceptable salt according to any one of claims 1 to 11 and 14 to 19.

21. R ｘ is C １ ~C ２ alkyl, and R ｘ The above C １ ~C ２ The alkyl is substituted with a 6-membered aryl or a 5- to 6-membered heteroaryl, and R ｘ The above C １ ~C ２ The 6-membered aryl or the 5- to 6-membered heteroaryl of the alkyl is selected from the group consisting of halogen, OCH ３ , C.N., C.O.N.H. ２ , N.H. ２ , C １ ~C ２ Alkyl (which is a group containing halogen and O-R ｚ optionally substituted with 1 to 3 groups selected from O(C １ ~C ２ 21. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 11 and 14 to 20, optionally substituted with 1 to 3 groups selected from alkyl, 3- to 4-membered carbocyclyl, and 4- to 7-membered heterocyclyl.

22. R ｘ is H, ═O, CN, methyl, ethyl, propyl, CH ２ C.N., 【Chemistry 13-1】 【Chemistry 13-2】 【Chemistry 13-3】 phenyl, 【Chemistry 14-1】 【Chemistry 14-2】 21. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 11 and 14 to 20, selected from:

23. R ｃ independently for each occurrence, deuterium, halogen, methyl (which is optionally OR ｓ substituted with), trifluoromethyl, ═O, ═S, OR ｓ , -NHC(=O)R ｓ , -NHC(=O)OR ｓ , N.R. ｐ R ｑ , -NHC(=O)NR ｐ R ｑ ,CN, -C(=O)NR ｐ R ｑ , optionally substituted 5- to 6-membered heteroaryl and optionally substituted 5- to 6-membered heterocyclyl; R ｐ is, for each occurrence, independently H and C １ ~C ２ alkyl, R ｑ is independently for each occurrence H, C １ ~C ２ selected from alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; R ｓ is independently for each occurrence H, C １ ~C ２ selected from alkyl (which is optionally substituted with 1 to 3 groups selected from halogen and deuterium), phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R ｑ and R ｓ For each occurrence, said 4- to 7-membered heterocyclyl is １ ~C ２ Alkyl and —O(C １ ~C ２ alkyl), and wherein m is selected from 0, 1, 2, and 3; 23. A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1 to 10 and 14 to 22.

24. R ｃ is, for each occurrence independently, deuterium, F, CH ３ , C.F. ３ ,OH,=O,=S,OCH ３ , N.H. ２ , -NHC(=O)CH ３ , -NHC(=O)NHCH ３ , -NHC(=O)NH ２ , -NHC(=O)OCH ３ , 【Chemistry 15】 CN, CH ２ OH, -C(=O)NH ２ , Cl, -NHCN, OCHF ２ , 【Chemistry 16】 -SCH ３ , OCD ３ , and —C(═O)CH ３ 24. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 10 and 14 to 23, selected from:

25. 25. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 to 10 and 14 to 24, wherein m is 0.

26. R Ｌ is H or deuterium, and R ｙ 2. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein

27. 10. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, In Equation 1 【Chemistry 17】 teeth, 【Chemistry 18】 and In Equation 1 【Chemistry 19】 teeth, 【Chemistry 20】 is selected from L is -CH ２ -, -CD ２ -, 【Chemical formula 21】 is selected from R ｘ teeth, 【Chemical 22】 is selected from U is O or S; V １ , V ２ , V ３ , and V ４ is independently selected from C and N; R Ｌ is H, deuterium, F and CH for each occurrence. ３ are independently selected from R ａ is selected for each occurrence from CN, halogen, optionally substituted 3- to 4-membered carbocyclyl, optionally substituted 4- to 5-membered heterocyclyl, and optionally substituted O(C １ ~C ３ alkyl), R ｃ is, for each occurrence, independently, deuterium, halogen, OH, C １ ~C ３ Alkyl, O(C １ ~C ３ alkyl), and 5- to 6-membered heteroaryl, where R ｃ The O(C １ ~C ３ alkyl) is optionally substituted with 1 to 3 deuterium atoms; R ｄ For each occurrence, halogens, CN, C １ ~C ３ Alkyl and O(C １ ~C ３ alkyl), z, for each occurrence, is an integer independently selected from 0, 1, 2, and 3; m' for each occurrence is an integer independently selected from 0, 1, and 2; m″ for each occurrence is an integer independently selected from 0 and 1; n is an integer independently selected from 0, 1, 2, and 3 for each occurrence; and n' is an integer independently selected from 0, 1, and 2 for each occurrence; 10. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1.

28. In Equation 1 【Chemical 23】 teeth, 【Chemistry 24】 is selected from L is -CH ２ -, -CD ２ -, 【Chemistry 25】 is selected from R ｘ teeth 【Chemical 26】 is selected from R ｄ For each occurrence, halogens, CN, C １ ~C ３ Alkyl and O(C １ ~C ３ alkyl), m' for each occurrence is an integer independently selected from 0, 1, and 2; m″, for each occurrence, is an integer independently selected from 0 and 1; and n is an integer independently selected from 0, 1, 2, and 3 for each occurrence; 28. A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1, 14, and 27.

29. In Equation 1 【Chemical 27】 teeth, 【Chemical Formula 28】 is selected from L is -CH ２ -, -CD ２ -, 【Chemical 29】 is selected from R ｘ teeth 【Chemistry 30】 is selected from R ｄ For each occurrence, halogens, CN, C １ ~C ３ Alkyl and O(C １ ~C ３ alkyl), m', for each occurrence, is an integer independently selected from 0, 1, and 2; and n is an integer independently selected from 0, 1, 2, and 3 for each occurrence; 28. A compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1, 14, and 27.

30. U is O, V １ , V ２ , V ３ , and V ４ is independently selected from C and N; V １ , V ２ , V ３ , and V ４ at most two of are N, R Ｌ is H or deuterium, R ａ represents, for each occurrence, CN, F, Cl, Br, 3-membered carbocyclyl, -N(C １ ~C ２ alkyl) (C １ ~C ２ 4-5 membered heterocyclyl optionally substituted with alkyl, and OCHF ２ are independently selected from R ｃ For each occurrence, deuterium, F, OH, CH ３ , OCH ３ , OCD ３ and 【Chemical 31】 are independently selected from R ｄ For each occurrence, F, Cl, Br, CH ３ , C.H. ２ CH ３ , CN and OCH ３ are independently selected from z, for each occurrence, is an integer independently selected from 0, 1, and 2; m' for each occurrence is an integer independently selected from 0, 1, and 2; n is an integer independently selected from 0, 1, 2, and 3 for each occurrence; and n' is an integer independently selected from 0, 1, and 2 for each occurrence; 30. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 27 to 29.

31. The compound has a structural formula selected from formulas 7a-7e: 【Table 12】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein L is —CH ２ -, -CD ２ -, 【Chemical 32】 2. The compound of claim 1, wherein m' is selected from 0, 1, and 2; and z is selected from 0, 1, and 2.

32. L is -CH ２ -and-CD ２ - is selected from, R ａ is, for each occurrence, independently, C １ ~C ３ O(C) optionally substituted with 1 to 3 groups selected from alkyl, halogen, and halogen １ ~C ３ alkyl), R ｃ For each occurrence, deuterium, halogen, OH, CH ３ , OCH ３ and OCD ３ are independently selected from R ｄ For each occurrence, halogens, CN, OCH ３ and C １ ~C ４ independently selected from alkyl, R ｘ teeth, 【Chemical 33】 wherein K is selected from: ２ -and-CD ２ - selected from, and n is independently selected for each occurrence from 0, 1, 2, and 3; 32. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 31.

33. A compound of the following structural formula 8: 【Chemical 34】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, X １ is C, X ２ is C, N, or absent, and X ３ is C or N, and X ４ is C, N, or absent, Ring B is a 5- to 6-membered heterocyclic group, and ring B is X １ , X ２ , X ３ and X ４ contains 0 or 1 heteroatom at positions other than Ring C is phenyl, a 9- to 10-membered aryl, a 5- to 6-membered heteroaryl, a 9- to 10-membered heteroaryl, a 3- to 6-membered carbocyclyl, or a 4- to 12-membered heterocyclic group; L is, 【Chemical 35】 and R Ｌ is, for each occurrence, independently, H, deuterium, halogen, and C optionally substituted with 1 to 3 groups selected from halogen. １ ~C ３ alkyl, R ｂ１ and R ｂ２ are attached to two adjacent positions of ring B, and R ｂ１ and R ｂ２ are joined to form ring A, where ring A is phenyl or a 5- to 6-membered heteroaryl group, and where ring A is R ａ is substituted with a z group of R ｂ３ and R ｂ４ is H and C １ ~C ３ alkyl, or R ｂ３ and R ｂ４ are linked to form a 3- or 4-membered carbocyclyl, R ａ represents, for each occurrence independently, a halogen, CN, C １ ~C ４ Alkyl, —NR ｐ R ｑ , -NR ｐ C(=O)R ｓ , -NR ｐ S (= O) ２ R ｑ , OR ｓ , —C(═O)NR ｐ R ｑ , 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, and 3- to 7-membered heterocyclyl; During the ceremony, R ａ The above C １ ~C ４ Alkyl is —NR ｐ R ｑ , —C(═O)NR ｐ R ｑ , phenyl, 5- to 6-membered heteroaryl, 3- to 7-membered carbocyclyl, 3- to 7-membered heterocyclyl, halogen, and OR ｓ and optionally substituted with 1 to 3 groups selected from R ａ wherein said 5- to 6-membered heteroaryl, said 3- to 7-membered carbocyclyl or said 3- to 7-membered heterocyclyl is optionally １ ~C ４ Alkyl, —O(C １ ~C ４ alkyl), -N(C １ ~C ４ alkyl) ２ and -NH(C １ ~C ４ alkyl), R ｘ is H,=O,CN,C ３ ~C ６ Carbocyclyl, C １ ~C ４ Alkyl, 【Chemical Formula 36】 is selected from During the ceremony, R ｘ The above C １ ~C ４ alkyl is optionally substituted with 1 to 3 groups selected from halogen, deuterium, CN, 5- to 6-membered carbocyclyl, 5- to 9-membered heterocyclyl, 6-membered aryl, 5- to 6-membered heteroaryl, and OH; Here, R ｘ The above C １ ~C ４ The 6-membered aryl or the 5- to 6-membered heteroaryl of alkyl is selected from the group consisting of halogen, OR ｓ ,CN,C(=O)NR ｐ R ｑ , N.R. ｐ R ｑ , C １ ~C ６ Alkyl (which is a halogen, O-R ｚ , OR ｓ , and C １ ~C ２ optionally substituted with 1 to 3 groups selected from 4- to 6-membered heterocyclyl optionally substituted with alkyl), C １ ~C ６ Alkenyl, C １ ~C ６ Alkynyl, 3- to 6-membered carbocyclyl, and 4- to 7-membered heterocyclyl (which is optionally substituted C １ ~C ４ Alkyl, halogen, and OR ｓ optionally substituted with 1 to 3 groups selected from Here, R ｘ The above C １ ~C ４ The 5- to 9-membered heterocyclyl of alkyl is C １ ~C ６ optionally substituted with 1 to 2 groups selected from alkyl, ═O, and halogen; R ｚ is selected from H, 6-membered aryl and 5-6-membered heteroaryl; Here, R ｚ wherein said 6-membered aryl or 5- to 6-membered heteroaryl is optionally substituted with 1 to 2 groups selected from halogen; R ｙ is H, C １ ~C ２ alkyl, and absent; R ｃ For each occurrence, deuterium, halogen, C １ ~C ４ Alkyl, ═O, ═S, OR ｓ , -NHC(=O)R ｓ , -NHC(=O)OR ｓ , N.R. ｐ R ｑ , -NHC(=O)NR ｐ R ｑ , CN, optionally substituted 5- to 6-membered heteroaryl or optionally substituted 5- to 6-membered heterocyclyl and —C(═O)NR ｐ R ｑ are independently selected from During the ceremony, R ｃ The above C １ ~C ４ Alkyl is halogen and OR ｓ and optionally substituted with 1 to 3 groups selected from During the ceremony, R ｐ For each occurrence, H and C １ ~C ６ alkyl; R ｑ For each occurrence, H, C １ ~C ６ independently selected from alkyl, phenyl, 5- to 6-membered heteroaryl, 4- to 7-membered heterocyclyl, and CN; R ｐ and R ｑ are linked to form a 3- to 6-membered carbocyclyl, R ｓ is independently for each occurrence H, C １ ~C ６ Alkyl (which can be deuterium, halogen, O(C １ ~C ４ alkyl) and NR ｐ R ｑ optionally substituted with 1 to 3 groups selected from phenyl, and 4- to 7-membered heterocyclyl; During the ceremony, R ｑ and R ｓ For each occurrence, said 4- to 7-membered heterocyclyl is １ ~C ４ Alkyl and —O(C １ ~C ４ alkyl), and During the ceremony, m is an integer selected from 0, 1, 2, and 3; p is an integer selected from 0, 1, 2, and 3; q is an integer selected from 0, 1, 2, and 3; z is an integer selected from 0, 1, 2, 3, and 4; and The sum of p and q is an integer of 5 or less. A compound of structural formula 8 or a tautomer thereof, a solvate or stereoisomer of the compound or tautomer, or a pharmaceutically acceptable salt of any of the foregoing:

34. The compound has a structural formula selected from formulas 9a-9h: 【Table 13】 a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein: L is -CH ２ -, -CD ２ -, 【Chemical 37】 wherein m' is independently selected from 0, 1, and 2 for each occurrence; m'' is independently selected from 0 and 1 for each occurrence; and z is independently selected from 0, 1, and 2 for each occurrence; 34. The compound of claim 33.

35. L is -CH ２ -, -CD ２ - and 【Chemical Formula 38】 is selected from R ａ is C １ ~C ３ selected from alkyl, CN and halogen; R ｘ teeth 【Chemical 39】 and K is selected from: ２ -and-CD ２ - is selected from, R ｃ is, for each occurrence independently, deuterium, C １ ~C ３ O(C) optionally substituted with 1 to 3 groups selected from alkyl, halogen, 5- to 6-membered heteroaryl, OH, and halogen and deuterium １ ~C ３ alkyl), R ｄ For each occurrence, halogens, CN, OCH ３ , —C(═O)NH ２ and C １ ~C ４ alkyl, and n is independently selected for each occurrence from 0, 1, 2, and 3; 35. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 34.

36. R ａ is selected from F and Cl; R ｘ teeth, 【Chemistry 40】 is selected from R ｃ For each occurrence, deuterium, F, OH, OCH ３ , OCD ３ and C(=O)NH ２ are independently selected from m, for each occurrence, is independently 0, 1, or 2; m′, for each occurrence, is independently 0, 1, or 2; and z, for each occurrence, is independently 0, 1, or 2; 36. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 35.

37. 34. The compound of claim 1 or 33, wherein the compound is selected from compounds 1 to 645 of Table 1, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of the foregoing.

38. 38. A pharmaceutical composition comprising the compound of any one of claims 1 to 37, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, and at least one pharmaceutically acceptable carrier.

39. 40. A method of treating a disease or condition comprising administering to a subject in need thereof a therapeutically effective amount of a compound of any one of claims 1 to 37, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 38, wherein said disease or condition is selected from cardiac disease, renal disease, hyperproliferative diseases or conditions, cancer, chemotherapy-induced tissue damage, renal disease, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, eye diseases, diseases caused by impaired stem cell function, DNA damage, primary mitochondrial disorders, obesity, atherosclerosis, insulin resistance, diabetes, complications associated with diabetes, Alzheimer's disease, Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, depression, Down's syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barré syndrome, nerve injury, polio (poliomyelitis), and spinal cord injury.

40. 39. A method of treating a disease or condition responsive to NAMPT activation, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 37, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 38.

41. 39. A method of modulating NAMPT, comprising contacting a subject in need thereof with a compound according to any one of claims 1 to 37, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition according to claim 38.

42. 39. A method of increasing NAD+ levels, comprising contacting a subject in need thereof with a compound of any one of claims 1-37, a tautomer thereof, a solvate or stereoisomer of said compound or said tautomer, or a pharmaceutically acceptable salt of any of the foregoing, or a pharmaceutical composition of claim 38.

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