WO2025231630A1

WO2025231630A1 - Nampt modulators, preparations, and uses thereof

Info

Publication number: WO2025231630A1
Application number: PCT/CN2024/091582
Authority: WO
Inventors: Xiaoqing Wang; Weijie HOU; Ming Jiang; Yingtao LIU; Yu Chen; Lianzhu LIU; Yimin Jiang; Yanping Xu; Zhiyuan Zhang
Original assignee: Sironax Beijing Co Ltd
Current assignee: Sironax Beijing Co Ltd
Priority date: 2024-05-08
Filing date: 2024-05-08
Publication date: 2025-11-13
Anticipated expiration: 2026-11-08

Abstract

This disclosure provides compounds of Formula (1), compositions comprising the same, and methods of using the same, including uses in modulating NAMPT and treating various diseases and conditions that are responsive to NAMPT activation.

Description

NAMPT MODULATORS, PREPARATIONS, AND USES THEREOF

Field of the Disclosure

The present disclosure relates to compounds that modulate nicotinamide phosphoribosyltransferase (NAMPT) , compositions comprising the compounds, methods of preparing the compounds, and methods of using the compounds to treat various diseases or conditions that benefit from NAMPT activation.

Background of the Disclosure

Nicotinamide phosphoribosyltransferase (NAMPT) , a dimeric type II phosphoribosyl transferase, is a key enzyme in the dominant nicotinamide adenine dinucleotide (NAD⁺) metabolism pathway in humans. Specifically, NAMPT catalyzes the rate limiting reaction in this pathway to convert nicotinamide and phosphoribosyl pyrophosphate to an intermediate nicotinamide mononucleotide (NMN) , which is subsequently converted to NAD⁺. NAD⁺, in turn, is important in serving as an electron-carrying coenzyme for oxidoreductases that play key roles in cellular energy generation pathways including the tricarboxylic acid cycle (TCA) . NAD⁺ also serves as an ADP donator for other enzymes such as sirtuins (SIRTs) and poly (ADP-ribose) polymerases (PARPs) which have critical functions in energy homeostasis, cell signaling and division, and DNA repair. Because of the prominence of NAD⁺ to human biology, especially its function in connection with SIRTs and PARPs, deficiency in NAD⁺ has been shown to cause a wide spectrum of diseases such as cardiac diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury.

There is significant interest in NAD⁺ as a potential target for therapeutics and various strategies have been proposed to boost NAD⁺ levels in patients. One approach seeks to increase levels of NAD⁺ directly by supplementing its biosynthetic precursors including nicotinic acid (NA) and nicotinamide mononucleotide (NAM) and another approach seeks to do so by inhibiting NAD⁺ consumption, such as by prescribing PARP inhibitors. However, these efforts have not achieved desired results due to challenges in pharmacological efficacy and safety. For example, NA supplement could cause cutaneous flushing through GPR109A activation and PARP inhibitors could cause side effects as a result of underlying toxicity.

Recently, NAMPT activation has emerged as an alternative treatment approach that promises safe and effective elevation of NAD⁺ levels. A number of small-molecule activators were discovered that demonstrated non-toxicity and efficacy in boosting NAD⁺ levels. For example, a series of aminopropyl carbazole derivatives, named P7C3, have been identified that have been shown to significantly increase levels of NAD⁺ in human cell line. Additionally, other NAMPT activator candidates including a series of urea-containing small molecules SBI-797812 and DS68702229 have been identified, with varying degrees of efficacy and pharmacokinetic profiles.

Certain NAMPT activators are disclosed in WO 2020/010252A1, WO2017161261A1, WO2018132372Al, WO2021159015, WO2021226276, WO2022109311A1, US20230365521A1, Gordon-Blake et al., ACS Med. Chem. Lett. 2024, 15, 205-214, and WO2024061340A1. Background information about NAMPT and certain NAMPT activators are 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) .

More research in this area is needed to identify new candidates for NAMPT activation. Described herein are small molecule activators of NAMPT and use of such activators for treating or preventing diseases or conditions responsive to increased NAMPT activity.

Summary of the Disclosure

One aspect of this disclosure provides a compound selected from compounds of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, which can be employed in the treatment of various diseases or conditions, such as diseases or conditions that benefit from NAMPT activation. For example, disclosed herein is a compound of the following structural Formula 1:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

In one aspect of the disclosure, the compounds of the Formulae disclosed herein are selected from Compounds 1 to 107 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

In some embodiments, the disclosure provides pharmaceutical compositions comprising a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical compositions may comprise a compound selected from Compounds 1 to 107 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and a pharmaceutically acceptable carrier. These compositions may further comprise an additional active pharmaceutical agent.

Another aspect of the disclosure provides methods of treating a disease or condition, comprising administering to a subject in need thereof, an effective amount of a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury.

A further aspect of the disclosure provides methods of treating a disease or condition that benefit from NAMPT activation (e.g., the disease or condition is responsive to NAMPT activation) , comprising administering to a subject in need thereof, an effective amount of a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, the methods of treatment comprise administering to a subject in need thereof, a compound selected from Compounds 1 to 107 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, the methods of treatment comprise administration of an additional active pharmaceutical agent to the subject in need thereof, either in the same pharmaceutical composition as a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or in a separate composition. In some embodiments, the methods of treatment comprise administering a compound selected from Compounds 1 to 107 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing with an additional active pharmaceutical agent either in the same pharmaceutical composition or in a separate composition. When administered as a separate composition, the additional therapeutic agent may be administered prior to, at the same time as, or following administration of the compound, tautomer, solvate, stereoisomer, or a pharmaceutically acceptable salt disclosed herein.

Also disclosed herein are methods of modulating, e.g., activating, NAMPT in a subject or cell in need thereof, comprising contacting the subject or the cell with a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) , a tautomer thereof, a solvate or stereoisomer of the compound or the 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, the methods of modulating, e.g., activating, NAMPT in a subject or a cell in need thereof comprise contacting the subject or the cell with a compound selected from Compounds 1 to 107 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the 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.

Also disclosed herein are methods of increasing NAD+ level in a subject or a cell in need thereof, comprising contacting the subject or the cell with a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, the methods of increasing NAD+level mediated by NAMPT in a subject or a cell in need thereof comprise contacting the subject or the cell with a compound selected from Compounds 1 to 107 shown in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the 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.

Detailed Description of the Disclosure

I. Definitions

The term “a” or “an” when referring to a noun as used herein encompasses the expression “at least one” and therefore encompasses both singular and plural units of the noun. For example, “an additional pharmaceutical agent” means a single or two or more additional pharmaceutical agents.

The term "alkyl" refers to a hydrocarbon group selected from linear and branched saturated hydrocarbon groups, containing 1-20, e.g., 1-18, 1-12, 1-10, 1-8, 1-6, 1-4, or 1-3, carbon atoms. Examples of the alkyl group include 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" ) , and 1, 1-dimethylethyl or t-butyl ( "t-Bu" ) . Other examples of an alkyl group include 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-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. Lower alkyl contains 1-8, preferably 1-6, more preferably 1-4 carbon atoms, and more preferably 1-3 carbon atoms.

The term "alkenyl" refers to a hydrocarbon group selected from linear and branched hydrocarbon groups, comprising at least one C=C double bond and 2-20, e.g., 2-18, 2-12, 2-10, 2-8, 2-6, or 2-4, carbon atoms. Examples of the alkenyl group 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-diene, hex-1-enyl, hex-2-enyl, hex-3-enyl, hex-4-enyl, and hexa-1, 3-dienyl groups. Lower alkenyl contains 2-8, preferably 2-6, and more preferably 2-4 carbon atoms.

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

The term “heteroalkyl” refers to an alkyl group, as defined herein, in which one or more of the constituent carbon atoms have been replaced by a heteroatom, e.g., nitrogen, oxygen, or sulfur, e.g., CH₃CH₂OH, CH₃CH₂OC₂H₅, CH₃CH₂SH, CH₃CH₂SC₂H₅, CH₃CH₂NH₂, CH₃CH₂NHC₂H₅, etc. In some embodiments, in addition to the replacement of one or more of the constituent carbon atoms by nitrogen, oxygen, or sulfur, a heteroalkyl group is further optionally substituted as defined herein.

The term “ring” or “ring system” refers to a monocyclic and a polycyclic (e.g., bicyclic and tricyclic) group. A ring or ring system can be a carbon cycle or heterocycle, aromatic or non-aromatic. For example, a bicyclic ring can be a fused, bridged, or spiro cyclic system.

The term "cycloalkyl" refers to a hydrocarbon group selected from saturated and partially unsaturated cyclic hydrocarbon groups, e.g., monocyclic and polycyclic (e.g., bicyclic and tricyclic) groups. For example, the cycloalkyl group may be of 3-12, 3-10, 3-8, 3-6, 3-4, or 5-6 carbon atoms. Even further for example, the cycloalkyl group may be a monocyclic group of 3-12, 3-8, 3-6, 3-4, or 5-6 carbon atoms. Examples of the monocyclic cycloalkyl group include 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, and cyclododecyl groups. Examples of the bicyclic cycloalkyl groups include those having 7-12 ring atoms arranged as a bicycle ring selected from [4, 4] , [4, 5] , [5, 5] , [5, 6] , and [6, 6] ring systems, or as a bridged bicyclic ring selected from bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane, and bicyclo [3.2.2] nonane. The ring may be saturated or have at least one double bond (i.e., partially unsaturated) , but is not fully conjugated, and is not an aromatic ring, as “aromatic ring” is defined herein.

The term "heterocyclic" or "heterocycle" or "heterocyclyl" refers to a ring selected from 3-to 12-membered, e.g., 3-to 6-membered, 3-to 5-membered, 4-to 5-membered, or 5-to 6-membered, monocyclic, bicyclic, and tricyclic, saturated and partially unsaturated rings comprising 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 heterocyclic ring comprising at least one heteroatom selected from N, O, and S fused with 5-, 6-, and/or 7-membered cycloalkyl, carbocyclic aromatic, or heteroaromatic ring, provided that the point of attachment is at the heterocyclic ring when the heterocyclic ring is fused with a carbocyclic aromatic or a heteroaromatic ring, and that the point of attachment can be at the cycloalkyl or heterocyclic ring when the heterocyclic ring is fused with cycloalkyl.

“Heterocycle” also refers to an aliphatic spirocyclic ring comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the heterocyclic ring. The rings may be saturated or have at least one double bond (i.e., partially unsaturated) . A heterocycle may be substituted with oxo. The point of the attachment may be carbon or heteroatom in the heterocyclic ring. A heterocycle is not a heteroaryl as defined herein.

Examples of heterocycles include, but are not limited to, (as numbered from the linkage position assigned 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, thioxanyl, piperazinyl, homopiperazinyl, homopiperidinyl, azepanyl, oxepanyl, thiepanyl, 1, 4-oxathianyl, 1, 4-dioxepanyl, 1, 4-oxathiepanyl, 1, 4-oxaazepanyl, 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, 2H-pyranyl, 4H-pyranyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, pyrazolinyl, pyrazolidinyl, dithianyl, dithiolanyl, pyrazolidinylimidazolinyl, pyrimidinonyl, 1, 1-dioxo-thiomorpholinyl, 3-azabicyco [3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl and azabicyclo [2.2.2] hexanyl. Substituted heterocycle also includes 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.

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

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

The term “unsaturated” , as used herein, means that a moiety has one or more units or degrees of unsaturation. Unsaturation is the state in which not all of the available valence bonds in a compound are satisfied by substituents and thus the compound contains one or more double or triple bonds. A double bond may be depicted as(two solid lines) . The depiction of (asolid line and a dashed line) , as used herein, denotes a bond that may be a double bond or a single bond.

The term “alkoxy” as used herein, refers to an alkyl group, as defined above, wherein one carbon of the alkyl group is replaced by an oxygen atom, provided that the oxygen atom is linked between two carbon atoms.

The term “halogen” includes F, Cl, Br, and I, i.e., fluoro, chloro, bromo, and iodo, respectively.

As used herein, a “CN, ” “cyano, ” or “nitrile” group refers to -C≡N.

As used herein, an “aromatic ring” refers to a carbocyclic or heterocyclic ring that contains conjugated, planar ring systems with delocalized pi electron orbitals comprised of [4n+2] p orbital electrons, wherein n is an integer of 0 to 6. A “non-aromatic” ring refers to a carbocyclic or heterocyclic that does not meet the requirements set forth above for an aromatic ring, and can be either completely or partially saturated. Non-limiting examples of aromatic rings include aryl and heteroaryl rings that are further defined as follows. An “aromatic ring” may be depicted as a cycle with conjugated double bonds, such asor as a cycle with an inside circle, such as

The term “aryl” herein refers to a group selected from: monocyclic carbocyclic aromatic rings, for example, phenyl; bicyclic ring systems such as 7-12 membered, e.g., 9-10 membered, bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, selected, for example, from naphthalene, indane, and 1, 2, 3, 4-tetrahydroquinoline; and tricyclic ring systems such as 10-15 membered tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.

For example, the aryl group may be a 6-membered carbocyclic aromatic ring fused to a 5-to 7-membered cycloalkyl or heterocyclic ring optionally comprising at least one heteroatom selected from N, O, and S, provided that the point of attachment is at the carbocyclic aromatic ring when the carbocyclic aromatic ring is fused with a heterocyclic ring, and the point of attachment can be at the carbocyclic aromatic ring or at the cycloalkyl group when the carbocyclic aromatic ring is fused with a cycloalkyl group.

The term "heteroaryl" refers to a group selected from: 5-to 7-membered, e.g., 5-to 6-membered, aromatic, monocyclic rings comprising 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 comprising 1, 2, 3, or 4 heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in the aromatic ring; and 11-to 14-membered tricyclic rings comprising 1, 2, 3, or 4 heteroatoms, selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one ring is aromatic and at least one heteroatom is present in an aromatic ring.

For example, the heteroaryl group may be a 5-to 7-membered heterocyclic aromatic ring fused to a 5-to 7-membered cycloalkyl ring. For such fused, bicyclic heteroaryl ring systems wherein only one of the rings comprises at least one heteroatom, the point of attachment may be at the heteroaromatic ring or at the cycloalkyl ring.

When the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another. In some embodiments, the total number of S and O atoms in the heteroaryl group is not more than 2. In some embodiments, the total number of S and O atoms in the aromatic heterocycle is not more than 1.

Examples of the heteroaryl group include, but are not limited to, (as numbered from the linkage position assigned priority 1) pyridyl (such as 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, benzoimidazolyl, indolyl, isoindolyl, indolinyl, phthalazinyl, pyrazinyl, pyridazinyl, pyrrolyl, triazolyl, quinolinyl, isoquinolinyl, pyrazolyl, pyrrolopyridinyl (such as 1H-pyrrolo [2, 3-b] pyridin-5-yl) , pyrazolopyridinyl (such as 1H-pyrazolo [3, 4-b] pyridin-5-yl) , benzoxazolyl (such as 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 (such as benzo [d] thiazol-6-yl) , indazolyl (such as 1H-indazol-5-yl) and 5, 6, 7, 8-tetrahydroisoquinolinyl.

The term “acyl” refers to a substituent group where a point of attachment in the substituent group is a carbonyl. Exemplary acyl groups include, but are not limited to, -C (=O) R’, -C (=O) NR’R”, or -C (=O) OR’, wherein R’ and R” are independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, cycloalkyl, aryl, heterocyclyl, or heteroaryl, any of which may be further substituted by one or more substituents.

Some of the compounds may exist with different points of attachment of hydrogen, referred to as “tautomers. ” For example, compounds including carbonyl -CH₂C (O) -groups (keto forms) may undergo tautomerism to form hydroxyl -CH=C (OH) -groups (enol forms) . Both keto and enol forms, individually as well as mixtures thereof, are also intended to be included where applicable.

The compounds, tautomers, solvates, or pharmaceutically acceptable salts of the disclosure may contain an asymmetric center and may thus exist as enantiomers. For example, where the compounds possess two or more asymmetric centers, they may additionally exist as diastereoisomers. Enantiomers and diastereoisomers fall within the broader class of stereoisomers. All such possible stereoisomers as substantially pure resolved enantiomers, racemic mixtures thereof, as well as mixtures of diastereoisomers are intended to be included in this disclosure. All stereoisomers of the compounds, tautomers, solvates, and pharmaceutically acceptable salts thereof are intended to be included. Unless specifically mentioned otherwise, reference to one isomer applies to any of the possible isomers. Whenever the isomeric composition is unspecified, all possible isomers are included.

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 by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride) , separating the diastereoisomers and converting (e.g., hydrolyzing) the individual diastereoisomers to the corresponding pure enantiomers. Enantiomers can also be separated by use of a chiral HPLC column.

A single stereoisomer, e.g., a substantially pure enantiomer, may be obtained by resolution of the racemic mixture using a method such as formation of diastereoisomers using optically active resolving agents. Racemic mixtures of chiral compounds of the 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 reagents, separation of the diastereoisomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions.

The term “substantially pure” in the context of stereoisomers means that the target stereoisomer contains no more than 35%, such as no more than 30%, further such as no more than 25%, even further such as no more than 20%, by weight of any other stereoisomer (s) . In some embodiments, the term “substantially pure” means that the target stereoisomer contains no more than 10%, for example, no more than 5%, such as no more than 1%, by weight of any other stereoisomer (s) .

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

The 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.

The term “pharmaceutically acceptable, ” as used herein, 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, and are 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 this disclosure.

“Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, selected, for example, from hydrochlorates, phosphates, diphosphates, hydrobromates, sulfates, sulfinates, and nitrates; as well as salts with organic acids, selected, for example, from malates, maleates, fumarates, tartrates, succinates, citrates, lactates, methanesulfonates, p-toluenesulfonates, 2-hydroxyethylsulfonates, benzoates, salicylates, stearates, alkanoates such as acetate, and salts with HOOC- (CH₂) n-COOH, wherein 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, for example, those disclosed in S.M. Berge, et al. J. Pharmaceutical Sciences, 1977, 66, pp. 1 to 19.

Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as 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. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate (i.e., caprate) , caprylate, acrylate, formate, isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-1, 4-dioate, hexyne-l, 6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, tartrate, methanesulfonate, 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.

Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N⁺ (C_1-4 alkyl) ₄ salts. This disclosure also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Suitable non-limiting examples of alkali and alkaline earth metal salts include sodium, lithium, potassium, calcium, and magnesium salts. Further non-limiting examples of pharmaceutically acceptable salts include salts of ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate. Other suitable, non-limiting examples of pharmaceutically acceptable salts include besylate and glucosamine salts.

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, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used without undue experimentation to prepare non-toxic pharmaceutically acceptable addition salts.

The compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salts of the 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 contains one or more deuteriums in place of hydrogen. For example, the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (³H) , iodine-125 (¹²⁵I) , or carbon-14 (¹⁴C) . All isotopic variations of the compounds of the disclosure, whether radioactive or not, are intended to be encompassed within the scope of the disclosure.

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 indicated, 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 chosen from a specified group, the substituent may be either the same or different at every position.

Combinations of chemical components, e.g., substituents, ring structures, linkers, and/or heteroatoms, envisioned by this disclosure are those that result in the formation of stable or chemically feasible compounds.

In some embodiments, substituents (such as in situations where a group is optionally substituted with one or more substituents, e.g., optionally substituted phenyl) are independently selected from optionally substituted heteroatom and optionally substituted, optionally hetero-, optionally cyclic C₁-C₁₈ hydrocarbyl, particularly wherein the optionally substituted, optionally hetero-, optionally cyclic C₁-C₁₈ hydrocarbyl is optionally-substituted, optionally hetero-, optionally cyclic alkyl, alkenyl or alkynyl, or optionally-substituted, optionally hetero-, aryl; and/or the optionally substituted heteroatom is halogen, optionally substituted hydroxyl (such as alkoxy, aryloxy) , optionally substituted acyl (such as formyl, alkanoyl, carbamoyl, carboxyl, amido) , optionally substituted amino (such as amino, alkylamino, dialkylamino, amido, sulfamidyl) , optionally substituted thiol (such as mercapto, alkylthiol, aryl thiol) , optionally substituted sulfinyl or sulfonyl (such as alkylsulfinyl, arylsulfinyl, alkyl sulfonyl, arylsulfonyl) , nitro, or cyano.

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', -CO₂R', -C (=O) NR'R", -OC (=O) NR'R", -NR"C (=O) R', -NR'-C (=O) NR"R'", -NR'-SO₂NR"R'", -NR"CO₂R', -NH-C (NH₂) =NH, -NR'C (NH₂) =NH, -NH-C (NH₂) =NR', -S (O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R', -CN, -NO₂, -N₃, -CH (Ph) ₂, perfluoro (C₁-C₄) alkoxy, and perfluoro (C₁-C₄) alkyl, in a number ranging from zero to three, with those groups having zero, one, or two substituents being particularly preferred. R', R", and R'" each independently refer to 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 groups, or aryl- (C₁-C₄) alkyl groups. 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. Hence, -NR'R" includes 1-pyrrolidinyl and 4-morpholinyl. When the aryl group is 1, 2, 3, 4-tetrahydronaphthalenyl, it may be substituted with a substituted or unsubstituted C₃-C₇ spirocycloalkyl group. The C₃-C₇ spirocycloalkyl group may be substituted in the same manner as defined herein for "cycloalkyl. "

In some embodiments, substituents are selected from: halogen, -R', -OR', =O, -NR'R", -SR', -SiR'R"R'", -OC (=O) R', -C (=O) R', -CO₂R', -C (=O) NR'R", -OC (=O) NR'R", -NR"C (=O) R', -NR"CO₂R', -NR'-SO₂NR"R'", -S (=O) R', -SO₂R', -SO₂NR'R", -NR"SO₂R', -CN, -NO₂, perfluoro C₁-C₄ alkoxy and perfluoro C₁-C₄ alkyl, where R' and R" are as defined above.

In some embodiments, substituents are independently selected from substituted or unsubstituted heteroatom, substituted or unsubstituted, 0-3 heteroatom-containing C₁-C₆ alkyl (e.g., C₁-C₃ alkyl or C₁-C₂ alkyl) , substituted or unsubstituted, 0-3 heteroatom-containing C₂-C₆ alkenyl (e.g., C₂-C₄ alkenyl) , substituted or unsubstituted, 0-3 heteroatom-containing C₂-C₆ alkynyl (e.g., C₂-C₄ alkynyl) , or substituted or unsubstituted, 0-3 heteroatom-containing C₅-C₁₄ aryl (e.g., C₅-C₆ aryl) , wherein each heteroatom is independently oxygen, phosphorus, sulfur, or nitrogen.

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

In some embodiments, substituents are structurally depicted herein. For example, when a substituent is attached to a ring structure without a specified position such as inthe substituent, e.g., R, may be attached to any chemically feasible position of Ring X regardless of whether Ring X is a single cyclic or multi-cyclic structure, when x is a positive integer. For example, unless otherwise specified, R^x, as shown inmay be attached to any chemically feasible position of the 6-membered cyclic structure of Ring X or any chemically feasible position of the 5-membered cyclic structure of Ring X, when x is a positive integer.

Preferred substituents are disclosed herein and exemplified in the tables, structures, examples, and claims, and may be applied across different compounds of this disclosure. For example, substituents of a given compound may be combinatorically used with other compounds.

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 the techniques common in the art. Typically such separations involve multiphase extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatography. Chromatography can involve 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, as well as techniques of small scale thin layer and flash chromatography. One skilled in the art may apply such techniques to achieve a desired separation.

Non-limiting examples of suitable solvents that may be used in this disclosure include water, methanol (MeOH) , ethanol (EtOH) , dichloromethane or methylene chloride (CH₂Cl₂) , toluene, acetonitrile (MeCN) , dimethylformamide (DMF) , dimethyl sulfoxide (DMSO) , methyl acetate (MeOAc) , ethyl acetate (EtOAc) , heptanes, isopropyl acetate (IPAc) , tert-butyl acetate (t-BuOAc) , isopropyl alcohol (IPA) , tetrahydrofuran (THF) , 2-methyl tetrahydrofuran (2-Me THF) , methyl ethyl ketone (MEK) , tert-butanol, diethyl ether (Et₂O) , methyl-tert-butyl ether (MTBE) , 1, 4-dioxane, and N-methyl pyrrolidone (NMP) .

Non-limiting examples of suitable bases that may be used in this disclosure include 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU) , potassium tert-butoxide (KOtBu) , potassium carbonate (K₂CO₃) , N-methylmorpholine (NMM) , triethylamine (Et₃N; TEA) , diisopropyl-ethyl amine (i-Pr₂EtN; DIPEA) , pyridine, potassium hydroxide (KOH) , sodium hydroxide (NaOH) , lithium hydroxide (LiOH) , and sodium methoxide (NaOMe; NaOCH₃) .

The term “subject” refers to an animal including a human.

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

As used herein, the term “treatment” and its cognates refer to slowing or stopping disease progression. “Treatment” and its cognates as used herein include, but are not limited to the following: complete or partial remission, curing a disease or condition or a symptom thereof, lower risk of a disease or condition, e.g., a disease or condition that can benefit from NAMPT activation. Improvements in or lessening the severity of any of these symptoms can be assessed according to methods and techniques known in the art.

The terms “about” and “approximately, ” when used in connection with a number such as a percentage include the number as specified, and a range of the number (e.g., a range of percentages, for example, a range of ±10%with respect to a specific point value) that is recognized by one of ordinary skill in the art.

II. Compounds and Compositions

In a 1^st embodiment, a compound of this disclosure is a compound of the following structural Formula 1:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein:

Ring A is selected from 6-to 10-membered aryl, 5-to 10-membered heteroaryl, 3-to 12-membered heterocyclyl, and 3-to 12-membered cycloalkyl, wherein Ring A is substituted with m groups of R^a;

Ring B is selected from 6-to 10-membered aryl, 5-to 10-membered heteroaryl, 3-to 12-membered heterocyclyl, and 3-to 12-membered cycloalkyl, wherein Ring B is substituted with n groups of R^b;

Ring C is selected from 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein Ring C is substituted with p groups of R^c;

R^a, for each occurrence, is independently selected from halogen, -NR^pR^q, -OR^s, =O, and optionally substituted C₁-C₆ alkyl;

R^b, for each occurrence, is independently selected from halogen, -CN, -C (=O) NR^pR^q, -S (=O) ₂R^s, optionally substituted C₁-C₆ alkyl, optionally substituted 3-to 6-membered cycloalkyl, optionally substituted 3-to 6-membered heterocyclyl, optionally substituted 5-to 6-membered heteroaryl, and optionally substituted phenyl;

R^c, for each occurrence, is independently selected from halogen, CN, and optionally substituted C₁-C₆ alkyl; wherein:

R^p, R^q , and R^s, for each occurrence, are each independently selected from H and optionally substituted C₁-C₆ alkyl;

L¹, L², and L³ are each independently selected from: a bond, C₁-C₆ alkylenyl (e.g., -CH₂-, -CH₂CH₂-, - (CH₂) ₃-, - (CH₂) ₄-, - (CH₂) ₅-, - (CH₂) ₆-) , C₂-C₆ alkenylenyl (e.g., -CH=CH-, -CH₂CH=CH-, -CH=CHCH₂-, -CH₂CH₂CH=CH-, -CH₂CH=CHCH₂-, -CH=CHCH₂CH=CH-, -CH₂CH₂CH₂CH=CH-, -CH₂CH₂CH₂CH=CHCH₂-, etc. ) , C₂-C₆ alkynylenyl (e.g., -C≡C-, -CH₂C≡C-, -C≡CCH₂-, -CH₂CH₂C≡C-, -CH₂C≡CCH₂-, -C≡CCH₂C≡C-, -CH₂CH₂CH₂C≡C-, -CH₂CH₂CH₂C≡CCH₂-, etc. ) , C₀-C₆ alkylenyl- (C=O) -C₀-C₆ alkylenyl, C₀-C₆ alkylenyl-S (=O) ₂-C₀-C₆ alkylenyl, C₀-C₆ alkylenyl-NHC (=O) -C₀-C₆ alkylenyl, and C₀-C₆ alkylenyl-C (=O) NH-C₀-C₆ alkylenyl, and wherein Ring D is selected from optionally substituted 3-to 6-membered cycloalkyl and optionally substituted 3-to 6-membered heterocyclyl;

provided that when one of Ring A and Ring B is phenyl orneither the other one of Ring A and Ring B nor Ring C isoptionally substituted with 1 to 3 groups selected from C₁-C₃ alkyl;

m is an integer selected from 0, 1, 2, and 3;

n is an integer selected from 0, 1, 2, and 3; and

p is an integer selected from 0, 1, 2, and 3.

Combinations of substituents as disclosed herein are those that result in the formation of stable or chemically feasible compounds. For abbreviation or according to common practice, certain hydrogen atoms attached to a certain atom (e.g., a carbon atom C or a nitrogen atom N) are not specifically spelled out in a chemical structure, formula, or notation; hydrogen atoms are deemed to be present to the extent the valences of the certain atom (e.g., C or N) are completed.

In each occurrence in this disclosure, C₁ to C₃ can be C₁, C₂, and C₃; C₁ to C₆ can be C₁, C₂, C₃, C₄, C₅, or C₆; C₀ to C₄ can be C₀ (i.e., absent) , C₁, C₂, C₃, or C₄; 5-to 10-membered means 5-, 6-, 7-, 8-, 9-, or 10-membered; 6-to 10-membered means 6-, 7-, 8-, 9-, or 10-membered; 5-to 14-membered means 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered; 3-to 12-membered means 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered; 3-to 14-membered means 3-, 4-, 5-, 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, or 14-membered; 3-to 6-membered means 3-, 4-, 5-, or 6-membered; 1-3 or 1 to 3 groups means 1 group, 2 groups, or 3 groups.

The compounds, tautomers, solvates, stereoisomers and salts of this disclosure do not encompass any compound disclosed in US20230365521A1 or Gordon-Blake et al., ACS Med. Chem. Lett. 2024, 15, 205-214.

In a 2^nd embodiment, a compound of the disclosure is a compound of the following structural Formula 2a, Formula 2b, Formula 2c, or Formula 2d:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein X¹, X², X³, X⁴, and X⁵, where applicable, are each independently selected from C and N; Z¹, Z², Z³, and Z⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Z¹, Z², Z³, and Z⁴ can be S or O; W¹ and W², where applicable, are each independently selected from C, N, S, and O; U¹, U², U³, U⁴, and U⁵, where applicable, are each independently selected from C and N; and all other variables not specifically defined herein are as defined in the preceding embodiment.

In a 3^rd embodiment, a compound of the disclosure is a compound of the following structural Formula 3a, Formula 3b, Formula 3c, or Formula 3d:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein X¹, X², X³, X⁴, and X⁵, where applicable, are each independently selected from C and N; Y¹, Y², Y³, and Y⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Y¹, Y², Y³, and Y⁴ can be S or O; Z¹, Z², Z³, and Z⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Z¹, Z², Z³, and Z⁴ can be S or O; W¹ and W², where applicable, are each independently selected from C, N, S, and O; U¹, U², U³, U⁴, and U⁵, where applicable, are each independently selected from C and N; V¹, V², V³, V⁴, and V⁵, where applicable, are each independently selected from C and N; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 4^th embodiment, a compound of the disclosure is a compound of the following structural Formula 4a, Formula 4b, Formula 4c, or Formula 4d:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y¹, Y², Y³, and Y⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Y¹, Y², Y³, and Y⁴ can be S or O; Z¹, Z², Z³, and Z⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Z¹, Z², Z³, and Z⁴ can be S or O; W¹ and W², where applicable, are each independently selected from C, N, S, and O; U¹, U², U³, and U⁴, where applicable, are each independently selected from C and N; V¹, V², V³, V⁴, and V⁵, where applicable, are each independently selected from C and N; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 5^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring A is selected from phenyl, benzoxazolyl, dihydrobenzoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrotriazinyl, benzotriazolyl, benzimidazolyl, indazolyl, triazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, and 5-oxa-7-azaspiro [3.4] octanyl, wherein Ring A is substituted with m groups of R^a; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 6^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring A is selected from: wherein Ring A is substituted with m groups of R^a; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 7^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, of Formula 1 is selected from: and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 8^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring B is selected from phenyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrotriazinyl, quinolinyl, benzoimidazolyl, indazolyl, benzothiazolyl, tetrahydropyridinylthiazolyl, triazolyl and piperidinyl, wherein Ring B is substituted with b groups of R^b; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 9^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring B is selected from: wherein Ring B is substituted with n groups of R^b; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 10^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, of Formula 1 is selected from: and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 11^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring C is selected from phenyl, thiazolyl, imidazolyl, thiophenyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyridinyl, triazolyl, triazinyl, and benzothiazolyl, wherein Ring C is substituted with p groups of R^c; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 12^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring C is selected from: wherein Ring C is substituted with p groups of R^c; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 13^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure of Formula 1 is selected from: and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 14^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, Ring A is selected from:

Ring B is selected from:

Ring C is selected from: and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 15^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^a is selected from: halogen, -NR^pR^q, -OR^s, C₁-C₄ alkyl, and =O, wherein R^p and R^q are each independently selected from H and C₁-C₃ alkyl, an R^s is selected from H and C₁-C₃ alkyl, wherein the C₁-C₃ alkyl of R^s, R^p, and R^q is optionally substituted with 1-3 groups selected from halogen; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 16^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^a is selected from: F, -OCHF₂, -OH, -OCH₃, -NHCH₃, and =O; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 17^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^b is selected from: halogen, C₁-C₆ alkyl, -CN, -C (=O) NR^pR^q, -S (=O) ₂R^s, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl (optionally substituted with =O) , 5-to 6-membered heteroaryl, and phenyl, wherein the C₁-C₆ alkyl of R^b is optionally substituted with 1-3 groups selected from halogen, -NR^pR^q, and -OR^s, wherein R^p, R^q , and R^s, for each occurrence, are each independently selected from H and C₁-C₃ alkyl optionally substituted with 1-3 groups selected from halogen; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 18^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^b is selected from: Cl, Br, -CN, -CH₃, -CH₂CH₃, -CH (CH₃) ₂, -CHF₂, -CF₃, -CH₂N (CH₃) ₂, -CH₂CH₂OCH₃, -C (=O) NH₂, -S (=O) ₂CH₃, and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 19^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^c is selected from: halogen, C₁-C₄ alkyl, and -CN; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 20^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^c is selected from: Cl, Br, -CH₃, and -CN; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 21^st embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, R^a is selected from: halogen, NR^pR^q, OR^s, C₁-C₄ alkyl, and =O;

R^b is selected from: halogen, C₁-C₃ alkyl, -CN, -C (=O) NR^pR^q, -S (=O) ₂R^s, wherein the C₁-C₃ alkyl of R^b is optionally substituted with 1-3 groups selected from halogen, -NR^pR^q, and -OR^s;

R^c is selected from: halogen, C₁-C₂ alkyl, and -CN;

wherein R^p, R^q , and R^s, for each occurrence, are each independently selected from H and C₁-C₂ alkyl optionally substituted with 1-3 groups selected from halogen;

and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 22^nd embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure,

R^a is selected from: OH and =O; and

R^c is selected from: Cl, Br, CH₃, and -CN; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 23^rd embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, L¹ is selected from: a bond, C₁-C₄ alkylenyl, C₂-C₄ alkenylenyl, and C₂-C₄ alkynylenyl; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 24^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, L¹ is selected from: -CH₂-, -CH₂CH=CH-, andand all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 25^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, L² is selected from: a bond, C₀-C₄ alkylenyl- (C=O) -C₀-C₄ alkylenyl, C₀-C₄ alkylenyl-S (=O) ₂C₀-C₄ alkylenyl, C₀-C₄ alkylenyl-NHC (=O) -C₀-C₄ alkylenyl, and C₀-C₄ alkylenyl-C (=O) NH-C₀-C₄ alkylenyl; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 26^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, L² is selected from: a bond, -C (=O) -, -S (=O) ₂-, -CH₂C (=O) -, and -NHC (=O) -; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 27^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, L³ is selected from: a bond, C₁-C₄ alkylenyl, C₀-C₄ alkylenyl-NHC (=O) -C₀-C₄ alkylenyl, C₀-C₄ alkylenyl-C (=O) NH-C₀-C₄ alkylenyl, andwherein Ring D is selected from 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 28^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, L³ is selected from: a bond, -CH₂-, -CH₂CH₂-, and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 29^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, m is 1; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 30^th embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, n is selected from: 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In a 31^st embodiment, in a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt of this disclosure, p is selected from: 0, 1, and 2; and all other variables not specifically defined herein are as defined in any one of the suitable preceding embodiments.

In certain embodiments, a compound of the disclosure is selected from Compounds 1 to 107 depicted in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.

Table 1. Compounds 1 to 107

Another aspect of the disclosure provides a pharmaceutical composition comprising at least one compound selected from a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, and at least one pharmaceutically acceptable carrier.

In some embodiments, the pharmaceutically acceptable carrier is selected from pharmaceutically acceptable vehicles and pharmaceutically acceptable adjuvants. In some embodiments, the pharmaceutically acceptable carrier is chosen from pharmaceutically acceptable fillers, disintegrants, surfactants, binders, and lubricants.

It will also be appreciated that a pharmaceutical composition of this disclosure can be employed in combination therapies; that is, the pharmaceutical compositions described herein can further include an additional active pharmaceutical agent. Alternatively, a pharmaceutical composition comprising a compound selected from a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing can be administered as a separate composition concurrently with, prior to, or subsequent to, a composition comprising an additional active pharmaceutical agent.

In some embodiments, the pharmaceutically acceptable carrier may be chosen from adjuvants and vehicles. The pharmaceutically acceptable carrier, as used herein, can be chosen, for example, from any and all solvents, diluents, other liquid vehicles, dispersion aids, suspension aids, surface active agents, isotonic agents, thickening agents, emulsifying agents, preservatives, solid binders, and lubricants, which are suited to the particular dosage form desired. 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 discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier is incompatible with the compounds of this disclosure, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component (s) of the pharmaceutical composition, its use is contemplated to be within the scope of this disclosure. Non-limiting examples of suitable pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin) , buffer substances (such as phosphates, glycine, sorbic acid, and potassium sorbate) , partial glyceride mixtures of saturated vegetable fatty acids, water, salts, and electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts) , colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, wool fat, sugars (such as lactose, glucose and sucrose) , starches (such as corn starch and potato starch) , cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate) , powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes) , oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil) , glycols (such as propylene glycol and polyethylene glycol) , esters (such as ethyl oleate and ethyl laurate) , agar, buffering agents (such as magnesium hydroxide and aluminum hydroxide) , alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, phosphate buffer solutions, non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate) , coloring agents, releasing agents, coating agents, sweetening agents, flavoring agents, perfuming agents, preservatives, and antioxidants.

A compound selected from a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition disclosed herein can be administered orally in solid dosage forms, such as capsules, tablets, troches, dragées, granules and powders, or in liquid dosage forms, such as elixirs, syrups, emulsions, dispersions, and suspensions. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein can also be administered parenterally, in sterile liquid dosage forms, such as dispersions, suspensions or solutions. Other dosages forms that can also be used to administer the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein as an ointment, cream, drops, transdermal patch or powder for topical administration, as an ophthalmic solution or suspension formation, e.g., eye drops, for ocular administration, as an aerosol spray or powder composition for inhalation or intranasal administration, or as a cream, ointment, spray or suppository for rectal or vaginal administration.

Gelatin capsules containing a compound, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, and/or a pharmaceutically acceptable salt of the foregoing disclosed herein and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like, can also be used. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication 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.

Liquid dosage forms for oral administration can further comprise at least one agent selected from coloring and flavoring agents to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols can be examples of suitable carriers for parenteral solutions. Solutions for parenteral administration may comprise a water-soluble salt of the at least one compound describe herein, at least one suitable stabilizing agent, and if necessary, at least one buffer substance. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, can be examples of suitable stabilizing agents. Citric acid and its salts and sodium EDTA can also be used as examples of suitable stabilizing agents. In addition, parenteral solutions can further comprise at least one preservative, selected, for example, from benzalkonium chloride, methyl-and propylparaben, and chlorobutanol.

A pharmaceutically acceptable carrier is, for example, selected from carriers that are compatible with active ingredients of the composition (and in some embodiments, capable of stabilizing the active ingredients) and not deleterious to the subject to be treated. For example, solubilizing agents, such as cyclodextrins (which can form specific, more soluble complexes with the at least one compound and/or at least one pharmaceutically acceptable salt disclosed herein) , can be utilized as pharmaceutical excipients for delivery of the active ingredients. Examples of other 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.

For administration by inhalation, the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein may be conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein may also be delivered as powders, which may be formulated, and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. One exemplary delivery system for inhalation can be metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in at least one suitable propellant, selected, for example, from fluorocarbons and hydrocarbons.

For ocular administration, an ophthalmic preparation may be formulated with an appropriate weight percentage of a solution or suspension of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein in an appropriate 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 sufficient time period to allow the compound to penetrate the corneal and internal regions of the eye.

Useful pharmaceutical dosage-forms for administration of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein include, but are not limited to, hard and soft gelatin capsules, tablets, parenteral injectables, and oral suspensions. In some embodiments, the pharmaceutical compositions disclosed herein may be in the form of controlled release or sustained release compositions as known in the art.

The term "unit dosage forms" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, lozenges or the like in the case of solid compositions. In such compositions, the active material is usually a component ranging 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 helpful for forming the desired dosing form. Unit dosage formulations are preferably about of 5, 10, 25, 50, 100, 250, 500, or 1,000 mg per unit. In a particular embodiment, unit dosage forms are packaged in a multipack adapted for sequential use, such as blisterpack comprising sheets of at least 6, 9 or 12 unit dosage forms.

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

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

In some embodiments, tablets can be prepared by conventional procedures so that the dosage unit comprises, for example, 100 milligrams of the compound, stereoisomers thereof, or pharmaceutically acceptable salts 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.

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

In some embodiment, an aqueous suspension can be prepared for oral administration. For example, each 5 milliliters of an aqueous suspension comprising 100 milligrams of finely divided compound, stereoisomers thereof, or pharmaceutically acceptable salts thereof, 100 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin can be used.

The same dosage forms can generally be used when the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is administered stepwise or in conjunction with at least one other therapeutic agent. When drugs are administered in physical combination, the dosage form and administration route should be selected depending on the compatibility of the combined drugs. Thus, the term coadministration is understood to include the administration of at least two agents concomitantly or sequentially, or alternatively as a fixed dose combination of the at least two active components.

The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt disclosed herein can be administered as the sole active ingredient or in combination with at least one second active ingredient.

The compound, tautomer, solvate, or stereoisomer described herein may be used in the aforementioned form or in the form of their pharmaceutically acceptable salts, such as hydrochlorides, hydrobromides, acetates, sulfates, citrates, carbonates, trifluoroacetates and the like. When the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein contain relatively acidic functionalities, salts can be obtained by addition of the 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, or the like. When the compound, tautomer, solvate, or stereoisomer described herein contain relatively basic functionalities, salts can be obtained by addition of the desired acid, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galacturonic acids and the like (see, for example, Berge et al., “Pharmaceutical Salts, ” Journal of Pharmaceutical Science, 1977, 66, 1-19) .

Neutral forms of the pharmaceutically acceptable salt described herein may be regenerated by contacting the salt with a base or acid, and isolating the parent compound in the conventional manner.

This disclosure provides prodrugs. Prodrugs of the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein that readily undergo chemical changes under physiological conditions to provide the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of the present disclosure. Additionally, prodrugs can be converted to the compound, tautomer, solvate, stereoisomer, or a pharmaceutically acceptable salt of the present disclosure by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt 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. They may, for instance, be more bioavailable by oral administration than the parent drug. The prodrug may also have improved solubility in pharmacological compositions over 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. An example, without limitation, of a prodrug would be a compound of the present disclosure which is administered as an ester (the "prodrug" ) , but then is metabolically hydrolyzed to the carboxylic acid, i.e., the active entity.

Certain compound, tautomer, stereoisomer, or pharmaceutically acceptable salt of the disclosure can exist in unsolvated forms as well as solvated forms, including hydrate forms. Certain compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of the disclosure may exist in multiple crystalline or amorphous forms.

Certain compound, tautomer, solvate, or pharmaceutically acceptable salt in this disclosure possesses 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.

III. Methods of Treatment and Uses

The present disclosure provides methods of treatment and uses utilizing a compound set forth in any one of the various embodiments of Section II (Compounds and Compositions) and Table 1, e.g., a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) , a tautomer thereof, a solvate or stereoisomer of the compound or the 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.

One aspect of the disclosure provides a method of treating a disease or condition, comprising administering to a subject in need thereof, an effective amount of a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 includes, but is not limited to, cardiac diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury. In some embodiments, the disease or condition can benefit from NAMPT activation, e.g., the disease or condition is responsive to NAMPT activation.

In another aspect, disclosed herein is a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) , a tautomer thereof, a solvate or stereoisomer of the compound or the 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, for use as a medicament.

In another aspect, disclosed herein is use of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, for the manufacture of a medicament for treating a disease or condition that includes, but is not limited to, cardiac diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury. In some embodiments, the disease or condition can benefit from NAMPT activation, e.g., the disease or condition is responsive to NAMPT activation.

In a further aspect of this disclosure, a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) , a tautomer thereof, a solvate or stereoisomer of the compound or the 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, is for use in treating a disease or condition that includes, but is not limited to, cardiac diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury. In some embodiments, the disease or condition can benefit from NAMPT activation, e.g., the disease or condition is responsive to NAMPT activation.

Another aspect of the disclosure provides a method of increasing NAD+levels, comprising administering to a subject or a cell in need thereof, an effective amount of a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 another aspect, disclosed herein is use of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, for increasing NAD+ levels in a cell or for the manufacture of a medicament for increasing NAD+ levels in a subject in need thereof.

In a further aspect of this disclosure, a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, is for use in increasing NAD+ levels in a subject or a cell in need thereof.

Another aspect of the disclosure provides a method of modulating, e.g., activating, NAMPT in a subject or a cell in need thereof, comprising administering to the subject or the cell, an effective amount of a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 another aspect, disclosed herein is use of a compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, for modulating, e.g., activating, NAMPT in a subject or a cell in need thereof.

In another aspect of this disclosure, a compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, or pharmaceutically acceptable salt as described herein, including a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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, is for use in modulating, e.g., activating, NAMPT in a subject or a cell in need thereof by contacting the subject or the cell with the compound, tautomer, a solvate or stereoisomer of the compound or the tautomer, pharmaceutically acceptable salt, or pharmaceutical composition.

A compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 may be administered once daily, twice daily, or three times daily, for example, for the treatment of a disease or condition, that includes, but is not limited to, cardiac diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury. In some embodiments, the disease or condition can benefit from NAMPT activation.

A compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 may be administered, for example, various manners, such as 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 nature and severity of the conditions for which the active ingredient is being administered. The term “parenteral” as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intraarterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques. The compositions disclosed herein may be conveniently presented in unit dosage form and 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 forms of administration contemplated in this disclosure are as described in International Patent Application Nos. WO 2013/075083, WO 2013/075084, WO 2013/078320, WO 2013/120104, WO 2014/124418, WO 2014/151142, and WO 2015/023915.

The contacting is generally effected by administering to the subject an effective amount of one or more compounds, tautomers, solvates, stereoisomers, and pharmaceutically acceptable salt disclosed herein. Generally, administration is adjusted to achieve a therapeutic dosage of about 0.1 to 50 mg/kg, preferably 0.5 to 10 mg/kg, more preferably 1 to 10 mg/kg, though optimal dosages are compound specific, and generally empirically determined for each compound.

The dosage administered will be dependent on factors, such as the age, health and weight of the recipient, the extent of disease, type of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired. In general, a daily dosage of the active ingredient can vary, for example, from 0.1 to 2000 milligrams per day. For example, 10-500 milligrams once or multiple times per day may be effective to obtain the desired results.

In some embodiments, 2 mg to 1500 mg or 5 mg to 1000 mg of a compound of Formulae 1, 2a, 2b, 2c, 2d, 3a, 3b, 3c, 3d, 4a, 4b, 4c, and 4d (e.g., Compounds 1 to 107 in Table 1) disclosed herein, a tautomer thereof, a solvate or stereoisomer of the compound or the 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 are administered once daily, twice daily, or three times daily. The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt described herein is administered for morning/daytime dosing, with off period at night.

Examples

In order that the disclosure described herein may be more fully understood, the following examples are disclosed herein. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this disclosure in any way.

Example I. Synthesis of Exemplary Compounds

The compounds of the disclosure, selected from a compound of the Formulae depicted herein, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt 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 to 107 as representative examples of Formula 1.

6- (bromomethyl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) benzo [d] oxazol-2 (3H) -one (Int 1)

Step 1. 6-methylbenzo [d] oxazol-2 (3H) -one (Int 1-2)

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 r.t. The mixture was stirred for 14 h at 80℃. The mixture was diluted with EAand washed with water. The organic layer was separated, dried over anhydrous Na₂SO₄ and concentrated under vacuum to give 6-methylbenzo [d] oxazol-2 (3H) -one (22 g) as a light 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 (Int 1-3) 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) at 0℃ under N₂. The mixture was stirred for 30 min. SEM-Cl (24.59 g, 148 mmol) was added and the reaction was warmed to r.t. This suspension was stirred for an additional 2 h. Water was added at 0℃ and then extracted with EA. The organic layer was separated, dried over anhydrous Na₂SO₄ 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. ¹H NMR (400 MHz, DMSO-d₆) δ 7.29 –7.19 (m, 2H) , 7.19 –7.08 (m, 1H) , 5.28 (s, 2H) , 3.66 (t, J = 7.9 Hz, 2H) , 2.40 (s, 3H) , 0.92 (t, J = 7.9 Hz, 2H) , 0.06 (s, 9H) .

Step 3. 6- (bromomethyl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) benzo [d] oxazol-2 (3H) -one (Int 1)

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) were added NBS (2.29 g, 12.9 mmol) and AIBN (176 mg, 1.07 mmol) at r.t. The mixture was stirred for 14 h at 80℃. 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/EA=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 semi-solid. ¹H NMR (400 MHz, 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 = 7.9 Hz, 2H) , 0.95 (t, J = 7.9 Hz, 2H) , 0.06 (s, 9H) .

N- ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl) methyl) -N-phenethylbenzamide (1)

Step 1: N- ( (2-oxo-3- ( (2- (trimethylsilyl) ethoxy) methyl) -2, 3-dihydrobenzo [d] oxazol-6-yl) methyl) -N-phenethylbenzamide (1-2)

To a solution of N-phenethylbenzamide (200 mg, 0.89 mmol) in DMF (3 mL) was added NaH (38 mg, 0.95 mmol, 60%in oil) . The mixture was stirred at r.t. for 30min, then added 6-(bromomethyl) -3- ( (2- (trimethylsilyl) ethoxy) methyl) benzo [d] oxazol-2 (3H) -one (358 mg, 1 mmol) , the mixture was stirred at r.t. for 16 h. The mixture was quenched with NH₄Cl (aq. ) , extracted with EA (3*10 mL) . The combined organic layer was washed with water (8 mL) and brine (8 mL) , dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (Petroleum ether/Ethyl acetate =3/1～1/1) to give 1-2 (220 mg, 49%) as a yellow oil. MS (ESI) m/z 503 [M+H] ⁺.

Step 2: N- ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl) methyl) -N-phenethylbenzamide (1)

To a solution of 1-2 (220 mg, 0.44 mmol) in DCM (2 mL) were added TFA (2 ml) at r.t. The mixture was stirred for 1 h at r.t. The mixture was concentrated in vacuo and the residue was dissolved in methanol (2 mL) and ammonium hydroxide (2 ml) . The mixture was stirred at r.t. for 1 h. The solvent was removed under vacuum and the residue was purified by Prep-HPLC to give 1 (55 mg, 40%) as a yellow solid. MS (ESI) m/z 373 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.61 (s, 1H) , 7.45-7.38 (m, 3H) , 7.36-7.30 (m, 2H) , 7.27-7.17 (m, 6H) , 7.12-7.04 (m, 1H) , 6.95-6.89 (m, 1H) , 4.76 (s, 1.2H) , 4.35 (s, 0.8H) , 3.53 (s, 0.8H) , 3.28 (s, 1.2H) , 2.88 (s, 1H) , 2.76 (s, 1.2H) .

N- (4-hydroxybenzyl) -N- (2-phenylcyclopropyl) benzamide (2)

Step 1. 4- ( ( (2-phenylcyclopropyl) amino) methyl) phenol (2-2)

A mixture of 4-hydroxybenzaldehyde (460 mg, 3.76 mmol) and 2-phenylcyclopropan-1-amine (500 mg, 3.76 mmol) in MeOH (10 mL) was stirred at r.t. for 16 h. Then NaBH₄ (157 mg, 4.13 mmol) was added. The reaction was stirred at r.t. for 1 h. The mixture was purified by HPLC to give 2-2 (300 mg, 33%) as a colorless oil. MS (ESI) m/z 240 [M+H] ⁺.

Step 2. N- (4-hydroxybenzyl) -N- (2-phenylcyclopropyl) benzamide (2)

The mixture of 2-2 (100 mg, 0.418 mmol) , benzoyl chloride (58 mg, 0.418 mmol) and DIEA (160 mg, 1.26 mmol) in DMF (3 mL) was stirred at r.t. for 2 h. The mixture was concentrated and purified by prep-HPLC to give 2 (30 mg, 21%) as a white solid. MS (ESI) m/z 344 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H) , 7.44 (d, J = 6.4 Hz, 2H) , 7.35-7.31 (m, 3H) , 7.10-7.09 (m, 5H) , 6.73-6.66 (m, 4H) , 4.78-4.53 (m, 2H) , 2.76 (s, 1H) , 2.00 (s, 1H) , 1.11-1.05 (m, 2H) .

N- (2-chlorophenethyl) -N- (4-hydroxybenzyl) benzamide (3)

The title compound 3 was prepared according to the procedure described for compound 2 as a white solid (291 mg, 30%) . MS (ESI) m/z 366 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ 9.37 (s, 1H) , 7.42-6.73 (m, 13H) , 4.66 (s, 1H) , 4.22 (s, 1H) , 3.52 (s, 1H) , 3.29 (s, 1H) , 3.01 (s, 1H) , 2.83 (s, 1H) .

3-chloro-N- (4-hydroxybenzyl) -N-phenethylbenzamide (4)

4-1 was prepared according to the procedure outlined for step 1 for the preparation of 2-2. To a solution of 3-chlorobenzoic acid (150 mg, 0.96 mmol) , 4- ( (phenethylamino) methyl) phenol (218 mg, 0.96 mmol) , EDCI (203 mg, 1.06 mmol) and DIEA (136 mg, 1.06 mmol) in DMF (10 mL) was added HOBT (206 mg, 1.92 mmol) at 0℃. The mixture was stirred at r.t. overnight. Ice water (60 mL) was added, extracted with EA (50 mL*3) , the combined organic layers were washed with water (50 mL*2) and brine (50 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by prep-HPLC to give 4 (47 mg, 13.3%) as a white solid. MS (ESI) m/z 366 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H) , 7.48-6.92 (m, 11H) , 6.78-6.74 (m, 2H) , 4.65 (s, 1H) , 4.20 (s, 1H) , 3.50 (s, 1H) , 3.23 (s, 1H) , 2.85-2.73 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) nicotinamide (5)

Step 1 was performed according to the procedure outlined for step 1 for the preparation of 62-1.

Step 2 was performed according to the procedure outlined for step 4 for the preparation of 46 to afford 5 (23 mg, 7.5%, last two steps) as a pale yellow solid. MS (ESI) m/z 411 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 0.4H) , 9.38 (s, 0.6H) , 8.60 (s, 1H) , 8.56 (s, 0.4H) , 8.32 (s, 0.6H) , 7.78-7.59 (m, 1H) , 7.52-7.35 (m, 3H) , 7.31-7.09 (m, 3H) , 6.94 (d, J = 8.0 Hz, 1H) , 6.77 (d, J = 7.9 Hz, 1H) , 6.71 (d, J = 7.6 Hz, 1H) , 4.69 (s, 1.2H) , 4.23 (s, 0.8H) , 3.55 (s, 0.8H) , 3.30 (s, 1.2H) , 3.03 (s, 0.8H) , 2.84 (s, 1.2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) isonicotinamide (6)

The title compound 6 was prepared according to the procedure described for compound 5 as a pale yellow solid (24 mg, 7.8%, last two steps) . MS (ESI) m/z 411 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 0.4H) , 9.40 (s, 0.6H) , 8.64 (d, J = 5.0 Hz, 0.8H) , 8.57 (d, J = 5.2 Hz, 1.2H) , 7.60 (d, J = 7.9 Hz, 0.4H) , 7.47 (d, J = 7.9 Hz, 0.6H) , 7.38-7.06 (m, 6H) , 6.94 (d, J = 8.2 Hz, 1H) , 6.78-6.7 (m, 2H) , 4.68 (s, 1.2H) , 4.16 (s, 0.8H) , 3.53 (t, J = 7.3 Hz, 0.8H) , 3.27 (t, J = 7.2 Hz, 1.2H) , 3.01 (t, J = 7.3 Hz, 0.8H) , 2.83 (t, J = 7.2 Hz, 1.2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) benzamide (7)

7-1 was prepared according to the procedure outlined for step 2 of the preparation of 2. To a solution of N- (2-bromophenethyl) -N- (4- ( (tert-butyldimethylsilyl) oxy) benzyl) benzamide (160 mg, 0.30 mmol) in DCM (10 ml) was added TFA (1 ml) , the reaction mixture was stirred at r.t. for 2h. The solvent was removed in vacuo, and the residue was purified by pre-HPLC to afford 7 as a white solid (33 mg, 26.4%) . MS (ESI) m/z 410 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H) , 7.82-7.59 (m, 1H) , 7.54 –7.28 (m, 5H) , 7.24-7.06 (m, 4H) , 6.92 (s, 1H) , 6.80 –6.69 (m, 2H) , 4.66 (s, 1H) , 4.20 (s, 1H) , 3.51 (q, J = 6.8 Hz, 1H) , 3.30-3.24 (m, 1H) , 3.02 –2.94 (m, 1H) , 2.83 (s, 1H) .

N- (2-bromophenethyl) -N- ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl) methyl) benzamide (8)

The title compound 8 was prepared according to the procedure described for compound 1 as a white solid (68 mg, 58%) . MS (ESI) m/z 451 [M+H] ⁺. ¹H NMR (400 MHz, DMSO) δ 7.59-7.27 (m, 7H) , 7.22-7.00 (m, 4H) , 6.93-6.70 (m, 1H) , 5.22 (d, J = 7.9 Hz, 1H) , 4.80 (d, J = 10.0 Hz, 1H) , 4.41-4.32 (m, 0.4H) , 3.59-3.50 (m, 0.8H) , 3.40-3.35 (m, 0.8 H) , 3.04 (bs, 0.8H) , 2.86 (bs, 1.2H) .

N- (4-hydroxybenzyl) -N- (2- (pyridin-2-yl) ethyl) benzamide (9)

The title compound 9 was prepared according to the procedure described for compound 2 as a white solid (146 mg, 40.1%) . MS (ESI) m/z 333 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ9.37 (s, 1H) , 8.36-8.50 (m, 1H) , 7.65-7.71 (m, 1H) , 6.94-7.40 (m, 9H) , 6.74 (s, 2H) , 4.61 (s, 1H) , 4.23 (s, 1H) , 3.63 (s, 1H) , 3.42 (s, 1H) , 3.02 (s, 1H) , 2.90 (s, 1H) .

N- (4-hydroxybenzyl) -N- (2- (pyridin-3-yl) ethyl) benzamide (10)

The title compound 10 was prepared according to the procedure described for compound 2 as a yellow solid (11 mg, 14.7%) . MS (ESI) m/z 333 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H) , 8.43 (s, 2H) , 7.67-7.15 (m, 8H) , 6.95 (s, 1H) , 6.70 (s, 2H) , 4.65 (s, 1H) , 4.25 (s, 1H) , 3.53 (s, 1H) , 3.29 (s, 1H) , 2.88-2.76 (m, 2H) .

N- (4-hydroxybenzyl) -N- (2- (pyridin-4-yl) ethyl) benzamide (11)

The title compound 11 was prepared according to the procedure described for compound 2 as a white solid (9 mg, 1.76%) . MS (ESI) m/z 333 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H) , 8.50-8.40 (m, 2H) , 7.43-7.21 (m, 7H) , 6.75-6.70 (m, 4H) , 4.66 (s, 1H) , 4.27 (s, 1H) , 3.56 (s, 1H) , 3.34 (s, 1H) , 2.89-2.73 (m, 2H) .

N- (4-hydroxybenzyl) -N- (2- (3-methylpyridin-2-yl) ethyl) benzamide (12)

The title compound 12 was prepared according to the procedure described for compound 2 as a white solid (95 mg, 44.1 %) . MS (ESI) m/z 347 [M+H] ⁺. ¹H NMR (400 MHz, DMSO_d6) δ 9.39-9.36 (m, 1H) , 8.31 (s, 0.5H) , 8.18 (s, 0.5H) , 7.52-7.29 (m, 6H) , 7.18-7.07 (m, 2H) , 6.98-6.96 (m, 1H) , 6.75-6.73 (m, 2H) , 4.66 (s, 1H) , 4.30 (s, 1H) , 3.63-3.43 (m, 2H) , 3.03-2.89 (m, 2H) , 2.29 (s, 1.5H) , 1.97 (s, 1.5H) .

N- (2- (1H-imidazol-5-yl) ethyl) -N- (4-hydroxybenzyl) benzamide (13)

Step 1 was performed according to the procedure outlined for step 1 for the preparation of 2-2.

Step 2 was performed according to the procedure outlined for the preparation of 4 to afford 13 (10 mg, 16.9%) as a white solid. MS (ESI) m/z 322 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ11.76 (s, 1H) , 9.38 (s, 1H) , 7.52-7.16 (m, 7H) , 6.94-6.70 (m, 4H) , 4.58 (s, 1H) , 4.22 (s, 1H) , 3.50 (s, 1H) , 3.32 (s, 1H) , 2.77-2.65 (m, 2H) .

N- (4-hydroxybenzyl) -N-phenethylthiazole-2-carboxamide (14)

The title compound 14 was prepared according to the procedure described for compound 4 as a colorless oil (35 mg, 18%) . MS (ESI) m/z 339 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.06-8.00 (m, 2H) , 7.29-7.08 (m, 7H) , 6.75-6.71 (m, 2H) , 5.17 (s, 1H) , 4.62 (s, 1H) , 4.08 (t, J = 7.6 Hz, 1H) , 3.61-3.48 (m, 1H) , 2.90-2.78 (m, 2H) .

N- (4-hydroxybenzyl) -N-phenethylbenzenesulfonamide (15)

To a solution of 4-1 (150 mg, 0.66 mmol) in pyridine (3 mL) was added benzenesulfonyl chloride (129 mg, 0.73 mmol) at 0 ℃. The resulting solution was stirred at r.t. overnight. Then water was added, and the mixture was extracted with EA and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give 15 (95 mg, 39%) as a white solid. MS (ESI) m/z 368 [M+H] ⁺. ¹H NMR (400 MHz, DMSO_d6) δ 9.43 (s, 1H) , 7.85 (d, J = 7.2 Hz, 2H) , 7.69-7.60 (m, 3H) , 7.22-7.10 (m, 5H) , 6.97 (d, J = 7.2 Hz, 2H) , 6.72 (d, J = 8.4 Hz, 2H) , 4.23 (s, 2H) , 3.19 (t, J = 8.0 Hz, 2H) , 2.52-2.48 (m, 2H) .

N- (2-chlorophenethyl) -4-cyano-N- (4-hydroxybenzyl) benzamide (16)

The title compound 16 was prepared according to the procedure described for compound 4 as a white solid (24 mg, 32%) . MS (ESI) m/z 391 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H) , 7.91-7.83 (m, 2H) , 7.55-6.70 (m, 10H) , 4.68-4.17 (m, 2H) , 3.55 (s, 1H) , 3.26 (s, 1H) , 3.01-2.82 (m, 2H) .

N- (2-chlorophenethyl) -N- (4-hydroxybenzyl) quinoline-6-carboxamide (17)

The title compound 17 was prepared according to the procedure described for compound 4 as a white solid (31 mg, 39.2%) . MS (ESI) m/z 417 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ 9.36 (s, 1H) , 8.94-8.95 (m, 1H) , 8.37 (d, J = 4.0 Hz, 1H) , 7.98-8.03 (m, 1H) , 7.72 (s, 1H) , 7.57-7.60 (m, 1H) , 7.39-7.48 (m, 7H) , 6.67-6.80 (m, 2H) , 6.71 (s, 1H) , 4.28 (s, 1H) , 3.57-3.58 (m, 1H) , 3.25-3.26 (m, 1H) , 3.03-3.04 (m, 1H) , 2.84-2.87 (m, 1H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) benzamide (18)

The title compound 18 was prepared according to the procedure described for compound 2 as a white solid (10 mg, 18.4%) . MS (ESI) m/z 411 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ9.37 (s, 1H) , 8.52-8.38 (m, 1H) , 8.03-7.94 (m, 1H) , 7.40-7.39 (m, 4H) , 7.41-7.31 (m, 3H) , 7.94 (s, 1H) , 6.73 (s, 2H) , 4.63 (s, 1H) , 4.26 (s, 1H) , 3.68 (s, 1H) , 3.38 (s, 1H) , 3.21 (s, 1H) , 3.05 (s, 1H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -2- (pyridin-3-yl) acetamide (19)

The title compound 19 was prepared according to the procedure described for compound 5 as a pale yellow solid (60 mg, 19.3%for last two steps) . MS (ESI) m/z 425 [M+H] ⁺.

1- (2-chlorophenethyl) -1- (4-hydroxybenzyl) -3- (1- (methylsulfonyl) piperidin-4-yl) urea (20)

The title compound 20 was prepared according to the procedure described for compound 46 as a white solid (50 mg, 43%) . MS (ESI) m/z 466 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.28 (s, 1H) , 7.40 (d, J = 6.8 Hz, 1H) , 7.31-7.16 (m, 3H) , 7.00 (d, J = 8.4 Hz, 2H) , 6.70 (d, J = 8.4 Hz, 2H) , 6.12 (d, J = 7.6 Hz, 1H) , 4.25 (s, 2H) , 3.60 (brs, 1H) , 3.50 (d, J = 11.6 Hz, 2H) , 2.88-2.64 (m, 7H) , 2.48-2.39 (m, 2H) , 1.84-1.80 (m, 2H) , 1.52-1.42 (m, 2H) .

N- (2-chlorophenethyl) -3-cyano-N- (4-hydroxybenzyl) benzamide (21)

The title compound 21 was prepared according to the procedure described for compound 4 as a white solid (28 mg, 19%) . MS (ESI) m/z 391 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41-9.37 (m, 1H) , 7.88-6.70 (m, 12H) , 4.69 (s, 1.3H) , 4.20 (s, 0.7H) , 3.55-3.52 (m, 0.7H) , 3.33-3.30 (m, 1.3H) , 3.01-3.00 (m, 0.7H) , 2.85-2.82 (m, 1.3H) .

N- (2-chlorophenethyl) -N- (4-hydroxybenzyl) isoquinoline-6-carboxamide (22)

The title compound 22 was prepared according to the procedure described for compound 4 as a white solid (92 mg, 38.4%) . MS (ESI) m/z 417 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H) , 9.35 (s, 1H) , 8.55 (d, J = 5.6 Hz, 1H) , 8.19-8.11 (m, 1H) , 7.87-7.81 (m, 1H) , 7.66-7.62 (m, 1H) , 7.46-6.94 (m, 7H) , 6.81-6.69 (m, 2H) , 4.74 (s, 1.4H) , 4.24 (s, 0.6H) , 3.61-3.58 (m, 0.6H) , 3.32-3.30 (m, 1.4H) , 3.05-3.02 (m, 0.6H) , 2.88-2.84 (m, 1.4H) .

1- (2-chlorophenethyl) -1- (4-hydroxybenzyl) -3- (pyrimidin-4-yl) urea (23)

The title compound 23 was prepared according to the procedure described for compound 46 as a white solid (32 mg, 24.2%) . MS (ESI) m/z 383 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.46 (s, 1H) , 9.34 (s, 1H) , 8.73 (s, 1H) , 8.48 (d, J = 6.0 Hz, 1H) , 7.75 (d, J = 6.0 Hz, 1H) , 7.38-7.32 (m, 2H) , 7.26-7.20 (m, 2H) , 7.07 (d, J = 8.0 Hz, 2H) , 6.72 (d, J = 8.0 Hz, 2H) , 4.47 (s, 2H) , 3.55 (t, J = 7.6 Hz, 2H) , 2.91 (t, J = 7.6 Hz, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -3-methylbenzamide (24)

The title compound 24 was prepared according to the procedure described for compound 7 as a white solid (24 mg, 6.4%for last two steps) . MS (ESI) m/z 424 [M+H] ⁺.

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) pyrimidine-2-carboxamide (25)

The title compound 25 was prepared according to the procedure described for compound 5 as a white solid (70 mg, 44.7%) . MS (ESI) m/z 412 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (d, J = 3.5 Hz, 1H) , 8.91 (dd, J = 7.5, 5.0 Hz, 2H) , 7.61-7.58 (m, 1.2H) , 7.44-7.43 (m, 0.8H) , 7.36-7.32 (m, 0.8H) , 7.29 –7.05 (m, 4.2H) , 6.81 –6.67 (m, 2H) , 4.66 (s, 1.2H) , 4.11 (s, 0.8H) , 3.50-3.46 (m, 0.8H) , 3.23 –3.14 (m, 1.2H) , 2.99 –2.91 (m, 0.8H) , 2.89-2.83 (m, 1.2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -5-methyl-4, 5, 6, 7-tetrahydrothiazolo [5, 4-c] pyridine-2-carboxamide (26)

The title compound 26 was prepared according to the procedure described for compound 5 as a pale yellow solid (120 mg, 53%) , MS (ESI) m/z 486 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H) , 7.58 (d, J = 8.0 Hz, 0.3H) , 7.47 (d, J = 8.0 Hz, 0.7H) , 7.36 –7.26 (m, 2H) , 7.19 –7.05 (m, 3H) , 6.77 –6.68 (m, 2H) , 5.16 (s, 0.7H) , 4.62 (s, 1.3H) , 4.12 (t, J = 7.4 Hz, 1.3H) , 3.68-3.59 (m, 2H) , 3.48 (t, J = 7.7 Hz, 0.7H) , 3.02 (t, J = 7.4 Hz, 1.3H) , 2.95 (t, J = 7.6 Hz, 0.7H) , 2.88-2.71 (m, 3H) , 2.39 (d, J = 2.8 Hz, 2.8H) , 2.07 (s, 1.2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (27)

The title compound 27 was prepared according to the procedure described for compound 5 as a pale yellow solid (120 mg, 61%) , MS (ESI) m/z 431 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H) , 7.62 –7.55 (m, 0.7H) , 7.55 –7.45 (m, 1.3H) , 7.37 –7.25 (m, 2H) , 7.22 –7.05 (m, 3H) , 6.77 –6.68 (m, 2H) , 5.17 (s, 0.7H) , 4.63 (s, 1.3H) , 4.13 (t, J = 7.4 Hz, 1.3H) , 3.49 (dd, J =9.0, 6.2 Hz, 0.7H) , 3.04 (t, J = 7.4 Hz, 1.3H) , 2.96 (dd, J = 8.9, 6.4 Hz, 0.7H) , 2.45 (s, 2H) , 2.40 (s, 1H) .

N- (2-bromophenethyl) -5- (difluoromethyl) -N- (4-hydroxybenzyl) pyrazine-2-carboxamide (28)

The title compound 28 was prepared according to the procedure described for compound 5 as a yellow solid (122 mg, 76%) , MS (ESI) m/z 462 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H) , 9.00 –8.93 (m, 1.4H) , 8.44 (d, J = 1.4 Hz, 0.6H) , 7.60 –7.00 (m, 7H) , 6.82 –6.70 (m, 2H) , 4.72 (s, 1.4H) , 4.34 (s, 0.6H) , 3.59-3.53 (m, 2H) , 3.05 –2.97 (m, 0.6H) , 2.91 (t, J = 7.0 Hz, 1.4H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) thiazole-5-carboxamide (29)

The title compound 29 was prepared according to the procedure described for compound 4 as a white solid (10 mg, 7.3%) . MS (ESI) m/z 417 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ 9.18 (s, 1H) , 8.06 (s, 1H) , 7.53 (s, 1H) , 7.30-7 (d, J = 2.0 Hz, 2H) , 7.16 (t, J = 8.4 Hz, 2H) , 7.02-7.06 (m, 2H) , 6.74 (d, J = 4.4 Hz, 2H) , 4.58 (s, 2H) , 3.57-3.58 (m, 2H) , 2.96-2.97 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1-methyl-1H-imidazole-2-carboxamide (30)

The title compound 30 was prepared according to the procedure described for compound 4 as a white solid (6 mg, 4.9%) . MS (ESI) m/z 414 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H) , 7.57 (d, J = 8.0 Hz, 0.4H) , 7.48 (d, J = 8.0 Hz, 0.6H) , 7.33-7.10 (m, 6H) , 6.96 (d, J = 6.4 Hz, 1H) , 6.75-6.70 (m, 2H) , 4.78 (s, 0.8H) , 4.61 (s, 1.2H) , 3.88 (t, J = 6.8 Hz, 1.2H) , 3.72 (s, 1.2H) , 3.54 (s, 1.8H) , 3.48 (t, J = 6.8 Hz, 0.8H) , 3.01-2.95 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) oxazole-2-carboxamide (31)

The title compound 31 was prepared according to the procedure described for compound 4 as a yellow solid (59 mg, 22.1%) . MS (ESI) m/z 401 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ9.42 (s, 1H) , 8.32 (s, 0.4H) , 8.21 (s, 0.6H) , 7.59-7.43 (m, 2H) , 7.34-7.24 (m, 2H) , 7.19-7.08 (m, 3H) , 6.72 (t, J = 8.4 Hz, 2H) , 4.82 (s, 1H) , 4.60 (s, 1H) , 3.87 (t, J = 7.2 Hz, 1H) , 3.50 (t, J = 7.2 Hz, 1H) , 3.02 (t, J = 7.6 Hz, 1H) , 2.95 (t, J = 7.6 Hz, 1H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -2-methylbenzamide (32)

The title compound 32 was prepared according to the procedure described for compound 4 as a white solid (66 mg, 28.5%) . MS (ESI) m/z 424 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.57-7.42 (m, 1H) , 7.37-7.07 (m, 7H) , 6.94-6.85 (m, 2H) , 6.81-6.71 (m, 2H) , 5.08-5.03 (m, 0.6H) , 4.90-4.84 (m, 1.4H) , 4.49-4.47 (m, 0.4H) , 4.22-4.20 (m, 0.6H) , 3.77-3.63 (m, 1H) , 3.11 (t, J =7.6 Hz, 0.8H) , 2.87 (t, J = 7.6 Hz, 1.2H) , 2.26 (s, 1.2H) , 2.16 (s, 1.8H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) thiazole-2-carboxamide (33)

Step 1: 2- (3-bromopyridin-2-yl) ethanamine (33-2)

To a solution of 2- (3-bromopyridin-2-yl) acetonitrile (1.0 g, 5.12 mmol) in THF (30 mL) was added BH₃/THF (25.6 mL) . The mixture was stirred at r.t. overnight. The mixture was quenched with water (10 mL) and extracted with DCM (10 mL*2) . The combined organic layer was washed with water (15 mL*2) and dried over anhydrous Na₂SO₄, filtered and concentrated, and the crude product was purified by flash column chromatography on silica gel (DCM/MeOH=15/1) to give 33-2 (150 mg, 14.7%) as a yellow solid. MS (ESI) m/z 201 [M+H] ⁺.

Step 2: 4- ( ( (2- (3-bromopyridin-2-yl) ethyl) amino) methyl) phenol (33-3)

A mixture of 33-2 (150 mg, 0.75 mmol) , 4-hydroxybenzaldehyde (92 mg, 0.75 mmol) and AcOH (2 mg, 0.03 mmol) in DCM (15 mL) was stirred at r.t. for 2 h. Then NaBH (OAc) ₃ (277 mg, 7.5 mmol) was added. The mixture was stirred at r.t. overnight. The mixture was quenched with water (10 mL) and extracted with DCM (10 mL*2) . The combined organic layer was washed with water (15 mL*2) and dried over anhydrous Na₂SO₄, filtered and concentrated, and the crude product was purified by flash column chromatography on silica gel (DCM/MeOH=15/1) to give 33-3 (85 mg, 37%) as a yellow solid. MS (ESI) m/z 307 [M+H] ⁺.

Step 3 was performed according to the procedure outlined for the preparation of 4 to afford 33 (4 mg, 5.9%) as a white solid. MS (ESI) m/z 418 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ9.36 (s, 1H) , 8.42-8.49 (m, 1H) , 7.93-8.04 (m, 3H) , 6.73-7.23 (m, 3H) , 6.70-6.73 (m, 2H) , 5.18 (s, 1H) , 4.58 (s, 1H) , 4.29-4.33 (m, 1H) , 3.34-3.37 (m, 1H) , 3.24 (t, J = 4.0 Hz, 1H) , 3.18 (t, J =4.0 Hz, 1H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1-methyl-1H-benzo [d] imidazole-6-carboxamide (34)

The title compound 34 was prepared according to the procedure described for compound 4 as a white solid (31 mg, 20.3%) . MS (ESI) m/z 464 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.20 (s, 1H) , 7.70-7.59 (m, 2H) , 7.32-6.75 (m, 9H) , 4.81 (s, 1.2H) , 4.32 (s, 0.8H) , 3.88 (s, 3H) , 3.72-3.70 (m, 0.8H) , 3.55 (s, 1.2H) , 3.16 (s, 0.8H) , 2.90 (s, 1.2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -2-methyl-2H-indazole-5-carboxamide (35)

The title compound 35 was prepared according to the procedure described for compound 4 as a white solid (77 mg, 51%) . MS (ESI) m/z 464 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H) , 8.39 (s, 1H) , 7.60-7.56 (m, 9H) , 6.76 (s, 2H) , 4.67 (s, 1H) , 4.36-4.32 (m, 1H) , 4.18 (s, 3H) , 3.52-3.39 (m, 2H) , 3.00-2.89 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1H-indazole-5-carboxamide (36)

The title compound 36 was prepared according to the procedure described for compound 4 as a white solid (45 mg, 36.9%) . MS (ESI) m/z 450 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 13.20 (s, 1H) , 9.37 (s, 1H) , 8.10 (s, 1H) , 7.55-6.68 (m, 11H) , 4.69-4.26 (m, 2H) , 3.52-3.40 (m, 2H) , 3.00-2.88 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -5-methylthiazole-2-carboxamide (37)

The title compound 37 was prepared according to the procedure described for compound 4 as a white solid (68 mg, 22.7%) . MS (ESI) m/z 325 [M+H-106] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.37 (s, 1H) , 7.70 (d, J = 9.4 Hz, 1H) , 7.58-7.50 (m, 1H) , 7.32-7.29 (m, 2H) , 7.16-7.14 (m, 2H) , 7.06 (d, J = 8.4 Hz, 1H) , 6.72 (t, J = 8.4 Hz, 2H) , 5.14 (s, 1H) , 4.57 (s, 1H) , 4.08 (t, J = 7.6 Hz, 1H) , 3.48 (t, J = 7.2 Hz, 1H) , 3.04 (t, J = 7.6 Hz, 1H) , 2.96 (t, J = 7.6 Hz, 1H) , 2.51 (s, 3H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) thiazole-2-carboxamide (38)

The title compound 38 was prepared according to the procedure described for compound 4 as a white solid (40 mg, 20.2%) . MS (ESI) m/z 417 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.38 (s, 1H) , 8.05-7.99 (m, 2H) , 7.59-7.48 (m, 1H) , 7.33-7.29 (m, 2H) , 7.18-7.06 (m, 3H) , 6.74-6.70 (m, 2H) , 5.15 (s, 1H) , 4.61 (s, 1H) , 4.10 (t, J = 7.6 Hz, 1H) , 3.51 (t, J = 6.4 Hz, 1H) , 3.07-2.95 (m, 2H) .

4- ( ( (2-bromophenethyl) (pyrimidin-2-yl) amino) methyl) phenol (39)

To a solution of 2-fluoropyrimidine (24 mg, 0.24 mmol) in DMSO (5 mL) were added 2- (2-bromophenyl) -N- (4- ( (tert-butyldimethylsilyl) oxy) benzyl) ethan-1-amine (100 mg, 0.24 mmol) and DIEA (62 mg, 0.48 mmol) at r.t. The reaction mixture was stirred at 60℃ for 8 h. Water (15 mL) was added, and the mixture was extracted with EA (20 mL*2) . The combined organic layers were washed with water (20 mL*2) and brine (20 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-HPLC to give 39 (30 mg, 32.5%) as a white solid. MS (ESI) m/z 384 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (s, 1H) , 8.38 (d, J = 4.8 Hz, 2H) , 7.57 (d, J = 8.0 Hz, 1H) , 7.31-7.28 (m, 2H) , 7.18-7.13 (m, 1H) , 7.04 (d, J = 8.4 Hz, 2H) , 6.68 (d, J = 8.4 Hz, 2H) , 6.63 (t, J = 4.4 Hz, 1H) , 4.64 (s, 2H) , 3.69 (t, J = 7.2 Hz, 2H) , 2.96 (t, J = 8.0 Hz, 2H) .

4- ( ( (2-bromophenethyl) (pyrimidin-4-yl) amino) methyl) phenol (40)

To a solution of 4- ( ( (2-bromophenethyl) amino) methyl) phenol (150 mg, 0.5 mmol) and 4-chloropyrimidine (75 mg, 0.5 mmol) in DMF (5 mL) was added DIEA (258 mg, 2.0 mmol) at r.t. The mixture was stirred at r.t. overnight. The mixture was added water (20 mL) and extracted with EA (20 mL*3) . The combined organic layers were washed with water (20 mL*2) and brine (20 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC to give 40 (8 mg, 4.1%) as a white solid. MS (ESI) m/z 384 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (brs, 1H) , 8.51 (s, 1H) , 8.15 (d, J = 6.4 Hz, 1H) , 7.58 (d, J = 8.0 Hz, 1H) , 7.36-7.30 (m, 2H) , 7.20-7.15 (m, 1H) , 7.04 (d, J = 8.4 Hz, 2H) , 6.72-6.68 (m, 3H) , 4.59 (brs, 2H) , 3.61 (brs, 2H) , 2.96 (t, J = 7.6 Hz, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -2- (pyridin-4-yl) acetamide (41)

The title compound 41 was prepared according to the procedure described for compound 4 as a white solid (6 mg, 4.4%) . MS (ESI) m/z 425 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (brs, 1H) , 8.47-8.43 (m, 2H) , 7.62-7.54 (m, 1H) , 7.36 (d, J = 4.0 Hz, 1H) , 7.30-7.14 (m, 4H) , 7.08-7.00 (m, 2H) , 6.75-6.69 (m, 2H) , 4.45 (s, 1.2H) , 4.42 (s, 0.8H) , 3.78 (s, 0.8H) , 3.68 (s, 1.2H) , 3.45-3.40 (m, 2H) , 2.98 (t, J = 8.0 Hz, 1.2H) , 2.86 (t, J = 7.2 Hz, 0.8H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1-methyl-1H-benzo [d] imidazole-5-carboxamide (42)

The title compound 42 was prepared according to the procedure described for compound 4 as a white solid (139 mg, 53%) . MS (ESI) m/z 464 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H) , 8.25 (s, 1H) , 7.60-7.58 (m, 3H) , 7.43-6.93 (m, 6H) , 6.75 (s, 2H) , 4.65 (s, 1H) , 4.28 (s, 1H) , 3.85 (s, 3H) , 3.53-3.41 (m, 2H) , 3.04-2.86 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1-methyl-1H-indazole-5-carboxamide (43)

The title compound 43 was prepared according to the procedure described for compound 4 as a white solid (64 mg, 43%) . MS (ESI) m/z 464 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H) , 8.08 (s, 1H) , 7.66-6.75 (m, 11H) , 4.72-4.64 (m, 1H) , 4.33-4.26 (m, 1H) , 4.05 (s, 3H) , 3.54-3.38 (m, 2H) , 3.01-2.86 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1H-benzo [d] imidazole-6-carboxamide (44)

The title compound 44 was prepared according to the procedure described for compound 4 as a white solid (47 mg, 32.1%) . MS (ESI) m/z 450 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H) , 9.37 (s, 1H) , 8.28 (s, 1H) , 7.55-6.75 (m, 11H) , 4.68 (brs, 1H) , 4.28 (brs, 1H) , 3.52 (brs, 2H) , 3.02-2.90 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1-methyl-1H-pyrazole-3-carboxamide (45)

The title compound 45 was prepared according to the procedure described for compound 4 as a white solid (38 mg, 28.5%) . MS (ESI) m/z 414 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (d, J = 5.6 Hz, 1H) , 7.77-7.73 (m, 1H) , 7.56-7.50 (m, 1H) , 7.32-7.27 (m, 2H) , 7.18-7.05 (m, 3H) , 6.73-6.69 (m, 2H) , 6.59 (d, J = 2.0 Hz, 0.4H) , 6.48 (d, J = 2.0 Hz, 0.6H) , 4.84 (s, 0.8H) , 4.58 (s, 1.2H) , 3.92 (s, 1.8H) , 3.87 (s, 1.2H) , 3.79 (t, J = 7.6 Hz, 1.2H) , 3.43 (t, J = 7.2 Hz, 0.8H) , 3.00-2.90 (m, 2H) .

1- (2-bromophenethyl) -1- (4-hydroxybenzyl) -3- (thiazol-5-yl) urea (46)

Step 1 was performed according to the procedure outlined for the preparation of 2-2.

Step 2.2- (2-bromophenyl) -N- (4- ( (tert-butyldimethylsilyl) oxy) benzyl) ethan-1-amine (46-3)

To a solution of 4- ( ( (2-bromophenethyl) amino) methyl) phenol (3.0 g, 9.84 mmol) and imidazole (803 mg, 11.81 mmol) in DCM (80 mL) was added TBSCl (1.6 g, 10.82 mmol) at 0℃, and then the mixture was stirred at r.t. for 2 h. The mixture was poured into ice water (20 mL) and extracted with DCM (20 mL*2) , washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 1/1) to give 46-3 (3.5 g, 85%) as a yellow oil. MS (ESI) m/z 420 [M+H] ⁺.

Step 3.1- (2-bromophenethyl) -1- (4- ( (tert-butyldimethylsilyl) oxy) benzyl) -3- (thiazol-5-yl) urea (46-4)

To a solution of 46-3 (100 mg, 1.0 mmol) in THF (10 mL) were added DIEA (387 mg, 3.0 mmol) and BTC (120 mg, 0.4 mmol) at -78 ℃ and the mixture was stirred for 30 min. A solution of thiazol-5-amine (419 mg, 1.0 mmol) and DIEA (258 mg, 2.0 mmol) in THF (10 mL) was added to the above solution at -78℃. After the mixture was stirred for 1 h, water (20 mL) was added to the mixture and the mixture was extracted with EA (20 mL*3) , washed with brine (15 mL*2) and dried over anhydrous Na₂SO₄, filtered and concentrated to give 46-4 (500 mg, 92%) as a yellow oil. MS (ESI) m/z 546 [M+H] ⁺.

Step 4. 1- (2-bromophenethyl) -1- (4-hydroxybenzyl) -3- (thiazol-5-yl) urea (46) To a solution of 46-4 (500 mg, 0.92 mmol) in THF (15 mL) was added TBAF (1.1 mL, 1.1 mmol) at 0 ℃, the reaction mixture was stirred at r.t. for 1 h. Water (20 mL) was added and the mixture was extracted with EA (20 mL*2) , the combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC to give 46 (38 mg, 10%) as a white solid. MS (ESI) m/z 432 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (s, 1H) , 9.34 (s, 1H) , 8.44 (s, 1H) , 7.59-7.53 (m, 2H) , 7.35-7.31 (m, 2H) , 7.19-7.15 (m, 1H) , 7.04 (d, J = 8.4 Hz, 2H) , 6.72 (d, J = 8.4 Hz, 2H) , 4.38 (s, 2H) , 3.45 (t, J = 7.2 Hz, 2H) , 2.92 (t, J = 8.0 Hz, 2H) .

1- (2-bromophenethyl) -1- (4-hydroxybenzyl) -3- (thiazol-4-yl) urea (47)

The title compound 47 was prepared according to the procedure described for compound 46 as a white solid (19 mg, 40.4%) . MS (ESI) m/z 432 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.44 (s, 1H) , 9.31 (s, 1H) , 8.91 (d, J = 2.8 Hz, 1H) , 7.58 (d, J = 8.0 Hz, 1H) , 7.38-7.32 (m, 3H) , 7.18 (d, J = 2.0 Hz, 1H) , 7.06 (d, J = 8.0 Hz, 2H) , 6.71 (d, J = 8.4 Hz, 2H) , 4.44 (s, 2H) , 3.49 (t, J = 6.8 Hz, 2H) , 2.93 (t, J = 7.6 Hz, 2H) .

1- (2-bromophenethyl) -1- (4-hydroxybenzyl) -3- (piperidin-4-yl) urea (48)

Step 1. benzyl (1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl) carbamate (48-2)

To a solution of benzyl piperidin-4-ylcarbamate (500 mg, 2.13 mmol) in DCM (20 mL) were added TEA (0.41 mL, 3.21 mmol) and TFAA (0.35 mL, 2.55 mmol) and the mixture was stirred at 0℃ for 2 h. After concentrated, the mixture was adjusted to pH=9 with sat. NaHCO₃ (aq. ) and extracted with DCM (20 mL*2) , dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 3/1) to give 48-2 (500 mg, 70%) as a colorless oil. MS (ESI) m/z 331 [M+H] ⁺.

Step 2. 1- (4-aminopiperidin-1-yl) -2, 2, 2-trifluoroethan-1-one (48-3)

To a solution of 48-2 (500 mg, 1.51 mmol) in MeOH (15 mL) was added Pd/C (75 mg) . The mixture was stirred at r.t. for 4 h under H₂. The mixture was filtrated and concentrated to give crude 48-3 (200 mg) as a white solid. MS (ESI) m/z 197 [M+H] ⁺.

Step 3 was performed according to the procedure outlined for step 3 for the preparation of 46-4.

Step 4 was performed according to the procedure outlined for step 4 for the preparation of 46.

Step 5.1- (2-bromophenethyl) -1- (4-hydroxybenzyl) -3- (piperidin-4-yl) urea (48)

To a solution of 1- (2-bromophenethyl) -1- (4-hydroxybenzyl) -3- (1- (2, 2, 2-trifluoroacetyl) piperidin-4-yl) urea (100 mg, 0.18 mmol) in MeOH/THF/H₂O (1 mL/1 mL/1 mL) was added LiOH·H₂O (24 mg, 0.568 mmol) . The mixture was stirred at r.t. for 2 h. The mixture was concentrated and purified by prep-HPLC to give 48 (30 mg, 36.6%) as a white solid. MS (ESI) m/z 432 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.30 (brs, 1H) , 7.56 (d, J = 7.6 Hz, 1H) , 7.38-7.23 (m, 2H) , 7.21-7.10 (m, 1H) , 7.01 (d, J = 8.4 Hz, 2H) , 6.69 (d, J = 8.4 Hz, 2H) , 5.94 (d, J = 7.4 Hz, 1H) , 4.25 (s, 2H) , 3.52 (d, J = 6.8 Hz, 1H) , 3.31-3.12 (m, 4H) , 2.92-2.79 (m, 4H) , 2.44 (d, J = 11.6 Hz, 1H) , 1.67 (d, J = 10.4 Hz, 2H) , 1.32-1.22 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -2- (1-methylpiperidin-4-yl) acetamide (49)

The title compound 49 was prepared according to the procedure described for compound 5 as an off-white solid (11 mg, 44.7%) . MS (ESI) m/z 445 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.37–9.31 (m, 1H) , 7.63 –7.52 (m, 1H) , 7.36–7.25 (m, 2H) , 7.23 –7.11 (m, 1H) , 7.08 –7.01 (m, 1H) , 6.98 (d, J = 8.5 Hz, 1H) , 6.77 –6.66 (m, 2H) , 4.43–4.36 (m, 2H) , 3.46 –3.34 (m, 2H) , 2.93–2.84 (m, 4H) , 2.40–2.15 (m, 8H) , 1.68–1.65 (m, 2H) , 1.1-1.15 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -4- (piperazin-1-yl) benzamide (50)

The title compound 50 was prepared according to the procedure described for compound 5 as an off-white solid (130 mg, 61%) . MS (ESI) m/z 494 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.37 (s, 1H) , 7.52 (s, 1H) , 7.30 (s, 1H) , 7.20 –7.13 (m, 6H) , 6.96 (d, J = 8.5 Hz, 2H) , 6.73 (d, J = 8.0 Hz, 2H) , 3.49 –3.48 (m, 3H) , 3.14 –3.06 (m, 6H) , 2.97 –2.87 (m, 3H) , 2.68 –2.65 (m, 1H) , 2.34 –2.31 (m, 1H) .

N- (2-bromophenethyl) -2- (2-cyanopyridin-4-yl) -N- (4-hydroxybenzyl) acetamide (51)

The title compound 51 was prepared according to the procedure described for compound 4 as a yellow solid (26 mg, 17%) . MS (ESI) m/z 450 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 0.4H) , 9.33 (s, 0.6H) , 8.66 (t, J = 4.0 Hz, 1H) , 7.85 (s, 0.4H) , 7.80 (s, 0.6H) , 7.62-7.50 (m, 2H) , 7.42-7.16 (m, 3H) , 7.09-7.06 (m, 2H) , 6.76-6.70 (m, 2H) , 4.47 (s, 0.8H) , 4.44 (s, 1.2H) , 3.91 (s, 0.8H) , 3.86 (s, 1.2H) , 3.49-3.41 (m, 2H) , 3.02 (t, J = 7.2 Hz, 1.2H) , 2.87 (t, J = 8.4 Hz, 0.8H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -2- (1- (methylsulfonyl) piperidin-4-yl) acetamide (52)

The title compound 52 was prepared according to the procedure described for compound 4 as a white solid (67 mg, 40.3%) . MS (ESI) m/z 509 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) : δ 9.38 (s, 0.4H) , 9.34 (s, 0.6H) , 7.61-7.55 (m, 1H) , 7.36-7.25 (m, 2H) , 7.21-7.13 (m, 1H) , 7.09 –7.02 (m, 1H) , 7.06 –6.96 (m, 1H) , 6.75-6.69 (m, 2H) , 4.43 (s, 1.2 H) , 4.37 (s, 0.8 H) , 3.51-3.36 (m, 4H) , 2.94-2.85 (m, 2H) , 2.83 (s, 3H) , 2.70-2.63 (m, 2H) , 2.30-2.19 (m, 2H) , 1.84-1.79 (m, 1H) , 1.75 –1.67 (m, 2H) , 1.19-1.06 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1- (piperidin-4-yl) -1H-pyrazole-3-carboxamide (53)

Step 1. tert-butyl 4- ( (methylsulfonyl) oxy) piperidine-1-carboxylate (53-2)

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (2 g, 10.0 mmol) and TEA (2 g, 20.0 mmol) in DCM (50 mL) was added MsCl (1.4 g, 12.2 mmol) at 0℃. The reaction mixture was warmed to r.t. The suspension was stirred for an additional 1 h. The mixture was extracted with DCM (100 mL*3) . The combined organic layers were washed with water (100 mL*2) and brine (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated to give 53-2 (2.5 g, 89.6%) as an off-white solid. MS (ESI) m/z 280 [M+H] ⁺.

Step 2. tert-butyl 4- (3- (ethoxycarbonyl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (53-3) To a solution of 53-3 (2.5 g, 8.96 mmol) and K₂CO₃ (3.71g, 2.69 mmol) in DMF (20 mL) was added ethyl 1H-pyrazole-3-carboxylate (1.26 g, 8.96 mmol) . The reaction mixture was stirred at 70℃ for 12 h. The mixture was cooled to r.t. and extracted with EA (150 mL*3) . The combined organic layers were washed with water (100 mL*2) and brine (100 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by FCC (PE/EA=5/1) to give 53-3 (880 mg, 33.3%) as a colorless oil. MS (ESI) m/z 324 [M+H] ⁺.

Step 3. 1- (1- (tert-butoxycarbonyl) piperidin-4-yl) -1H-pyrazole-3-carboxylic acid (53-4)

The mixture of 53-3 (200 mg, 0.62 mmol) and NaOH (74 mg, 1.86 mmol) in EtOH/H₂O (4 /2 mL) was stirred at r.t. for 2 h. The solvent was removed, and the residue was adjusted to pH=3 with 1M HCl (aq. ) . The mixture was extracted with EA (20 mL*3) . The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by FCC (PE/EA=1/1) to 53-4 (120 mg, 65.6%) as a colorless oil. MS (ESI) m/z 296 [M+H] ⁺.

Step 4 was performed according to the procedure outlined for the preparation of 4.

Step 5. N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -1- (piperidin-4-yl) -1H-pyrazole-3-carboxamide (53)

To a solution of tert-butyl 4- (3- ( (2-bromophenethyl) (4-hydroxybenzyl) carbamoyl) -1H-pyrazol-1-yl) piperidine-1-carboxylate (60 mg, 0.10 mmol) in EA (5 mL) was added HCl in EA (1 mL) . The reaction mixture was stirred at r.t. for 1 h. The mixture was adjusted to pH=8 and extracted with EA (20 mL*3) , the combined organic layers were washed with water (20 mL*2) and brine (20 mL) , dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 53 (1.8 mg, 3.6%) as a white solid. MS (ESI) m/z 483 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H) , 7.84 (m, 1H) , 7.58-7.51 (m, 1H) , 7.32-7.25 (m, 2H) , 7.18-7.09 (m, 3H) , 6.71 (t, J = 8.4 Hz, 2H) , 6.60-6.49 (m, 1H) , 4.85 (s, 1H) , 4.57 (s, 1H) , 4.25-4.22 (m, 1H) , 3.84 (t, J = 7.2 Hz, 1H ) , 3.43 (t, J = 7.6 Hz, 1H ) , 3.03-2.90 (m, 4H) , 2.60-2.54 (m, 2H) , 1.95-1.92 (m, 2H) , 1.80-1.72 (m, 2H) .

N- (2-bromophenethyl) -N- (4-hydroxybenzyl) -4-morpholinothiazole-2-carboxamide (54)

Step 1. ethyl 4-morpholinothiazole-2-carboxylate (54-2)

A mixture of ethyl 4-bromothiazole-2-carboxylate (1.0 g, 4.2 mmol) , morpholine (730 mg, 8.4 mmol) , Brettphos G₃ (380 mg, 0.42 mmol) and Cs₂CO₃ (4.09 g, 12.6 mmol) in dioxane (30 mL) was stirred at 80 ℃ for 5 h under N₂. The mixture was filtered. The filtrate was added with water (30 mL) and extracted with EA (20 mL*3) . The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (PE/EA = 3/1) to give 54-2 (415 mg, 41%) as a yellow oil. MS (ESI) m/z 243 [M+H] ⁺.

Step 2. Lithium 4-morpholinothiazole-2-carboxylate (54-3)

To a solution of 54-2 (400 mg, 1.65 mmol) in THF/H₂O (4 mL/1 mL) was added LiOH·H₂O (104 mg, 2.47 mmol) at r.t. The mixture was stirred at r.t. for 1 h. The mixture was concentrated to give crude 54-3 (254 mg, 70%) as a yellow solid. MS (ESI) m/z 213 [M-H] ^-.

Step 3 was performed according to the procedure outlined for the preparation of 4 to afford 54 (7 mg, 2%) as a white solid. MS (ESI) m/z 502 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (s, 1H) , 7.58-7.53 (m, 1H) , 7.30-7.08 (m, 5H) , 6.72-6.64 (m, 3H) , 5.11 (s, 1H) , 4.56 (s, 1H) , 4.14 (s, 1H) , 3.68-3.44 (m, 5H) , 3.14-2.95 (m, 6H) .

N2- (2-bromophenethyl) -N2- (4-hydroxybenzyl) thiazole-2, 4-dicarboxamide (55)

The title compound 55 was prepared according to the procedure described for compound 4 as a white solid (21 mg, 4.5%) . MS (ESI) m/z 460 [M+1] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.40-9.36 (m, 1H) , 8.51 (s, 0.4H) , 8.42 (s, 0.6H) , 7.70-7.43 (m, 3H) , 7.32-7.06 (m, 5H) , 6.75-6.66 (m, 2H) , 5.19 (s, 0.8H) , 4.60 (s, 1.2H) , 4.20 (t, J = 6.8 Hz, 1.2H) , 3.55 (t, J = 8.0 Hz, 0.8H) , 3.03-2.96 (m, 2H) .

N- (2-bromophenethyl) -4-cyano-N- (4-hydroxybenzyl) thiazole-2-carboxamide (56)

Step 1. ethyl 4-cyanothiazole-2-carboxylate (55-2)

To a solution of ethyl 4-bromothiazole-2-carboxylate (1.0 g, 4.23 mmol) in DMF (15 mL) were added Zn (CN) ₂ (497 mg, 4.23 mmol) , dppf (116 mg, 0.21 mmol) and Pd₂ (dba) ₃ (200 mg, 0.21 mmol) at r.t. The mixture was stirred at 65 ℃ for 4 h under N₂. The mixture was filtered. The filtrate was added with water (50 mL) and extracted with EA (30 mL*3) . The combined organic layers were washed with water (50 mL*2) and brine (50 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (PE/EA = 5/1) to give 55-2 (400 mg, 51%) as a brown solid. MS (ESI) m/z 183 [M+H] ⁺.

Step 2 was performed according to the procedure outlined for the preparation of 54-3.

Step 3 was performed according to the procedure outlined for the preparation of 4 to afford 55 (13 mg, 7.8%) as a white solid. MS (ESI) m/z 442 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.42 (brs, 1H) , 9.10 (s, 0.3H) , 8.99 (s, 0.7 H) , 7.58 (d, J = 8.4 Hz, 0.3H) , 7.44 (d, J = 8.0 Hz, 0.7H) , 7.33-7.19 (m, 4H) , 7.12-7.08 (m, 1H) , 6.76-6.72 (m, 2H) , 5.04 (s, 0.6H) , 4.66 (s, 1.4H) , 4.10 (t, J = 6.8 Hz, 1.4H) , 3.52 (t, J = 7.2 Hz, 0.6H) , 3.06-2.95 (m, 2H) .

N- (2-bromophenethyl) -4- ( (dimethylamino) methyl) -N- (4-hydroxybenzyl) thiazole-2-carboxamide (57)

The title compound 57 was prepared according to the procedure described for compound 54 as a white solid (30 mg, 48.1%) . MS (ESI) m/z 474 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.38 (s, 1H) , 7.76-7.72 (m, 1H) , 7.59-7.28 (m, 3H) , 7.19-7.07 (m, 3H) , 6.75-6.09 (m, 2H) , 5.16 (s, 0.7H) , 4.63 (s, 1.3H) , 4.08 (t, J = 7.2 Hz, 1.3H) , 3.59-3.49 (m, 2.7H) , 3.08-2.94 (m, 2H) , 2.19 (s, 3.9H) , 2.14 (s, 2.1H) .

The intermediate 57-3 was prepared as follows:

Step 1. ethyl 4- (chloromethyl) thiazole-2-carboxylate (57-2)

A solution of ethyl 2-amino-2-thioxoacetate (1.0 g, 7.52 mmol) and 1, 3-dichloropropan-2-one (1.1 g, 8.65 mmol) in toluene (20 mL) was stirred at 115℃ for 2 h. The mixture was concentrated. The residue was diluted with water (50 mL) and extracted with EA (50 mL*2) , and the combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (PE/EA = 5/1) to give 57-2 (800 mg, 51%) as a yellow oil. MS (ESI) m/z 206 [M+H] ⁺.

Step 2. Ethyl 4- ( (dimethylamino) methyl) thiazole-2-carboxylate (57-3)

To a solution of 57-2 (700 mg, 3.4 mmol) in THF (20 mL) were added TEA (2.0 g, 20.5 mmol) and dimethylamine (8.5 mL, 0.5 M in THF, 17.0 mmol) at r.t. The mixture was stirred at 50℃overnight. The mixture was concentrated under vacuum. The residue was purified by FCC (EA) to give 57-3 (370 mg, 50%) as a yellow solid. MS (ESI) m/z 215 [M+H] ⁺.

4-bromo-N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) thiazole-2-carboxamide (58)

The title compound 58 was prepared according to the procedure described for compound 33 as a white solid (18 mg, 23%) . MS (ESI) m/z 496 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.39 (d, J = 6.0 Hz, 1H) , 8.48 (d, J = 4.4 Hz, 0.45H) , 8.41 (d, J = 4.0 Hz, 0.55H) , 8.18 (s, 0.45H) , 8.07 (s, 0.55H) , 8.01 (d, J = 8.0 Hz, 0.45H) , 7.93 (d, J = 8.4 Hz, 0.55H) , 7.24 –7.07 (m, 3H) , 6.74 –6.71 (m, 2H) , 5.12 (s, 0.9H) , 4.60 (s, 1.1H) , 4.29 (t, J = 6.8 Hz, 1.1H) , 3.70 (t, J = 7.2 Hz, 0.9H) , 3.31 –3.15 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4-phenylthiazole-2-carboxamide (59)

The title compound 59 was prepared according to the procedure described for compound 33 as a white solid (34 mg, 42.2%) . MS (ESI) m/z 494 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.38 (s, 1H) , 8.50-8.38 (m, 2H) , 8.02 (t, J = 8.8 Hz, 1H) , 7.88-7.85 (m, 2H) , 7.44-7.32 (m, 3H) , 7.24-7.16 (m, 3H) , 6.76-6.72 (m, 2H) , 5.29 (s, 1H) , 4.66 (s, 1H) , 4.23 (t, J = 6.8 Hz, 1H) , 3.74 (t, J = 7.2 Hz, 1H) , 3.39 (t, J = 7.6 Hz, 1H) , 3.21 (t, J = 7.6 Hz, 1H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4-isopropylthiazole-2-carboxamide (60)

The title compound 60 was prepared according to the procedure described for compound 33 as a white solid (22 mg, 29%) . MS (ESI) m/z 460 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (s, 1H) , 8.49-8.42 (m, 1H) , 8.03-7.96 (m, 1H) , 7.59 (s, 0.4H) , 7.52 (s, 0.6H) , 7.23-7.11 (m, 3H) , 6.74-6.70 (m, 2H) , 5.19 (s, 0.8H) , 4.60 (s, 1.2H) , 4.30 (t, J = 6.8 Hz, 1.2H) , 3.69 (t, J = 7.6 Hz, 0.8H) , 3.30-3.26 (m, 1H) , 3.17 (t, J = 6.8 Hz, 1H) , 3.03-2.95 (m, 1H) , 1.20 (d, J = 6.8 Hz, 3H) , 1.11 (d, J = 6.8 Hz, 3H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1-methyl-1H-pyrazole-3-carboxamide (61)

The title compound 61 was prepared according to the procedure described for compound 33 as a white solid (23 mg, 34.6%) . MS (ESI) m/z 415 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.32 (d, J = 6.6 Hz, 1H) , 8.48 (d, J = 4.0 Hz, 0.5H) , 8.43 (d, J = 4.0 Hz, 0.5H) , 8.01 (d, J = 7.6 Hz, 0.5H) , 7.95 (d, J = 7.6 Hz, 0.5H) , 7.76 (s, 0.5H) , 7.69 (s, 0.5H) , 7.22-7.05 (m, 3H) , 6.73-6.70 (m, 2H) , 6.58 (s, 0.5H) , 6.44 (s, 0.5H) , 4.88 (s, 1H) , 4.56 (s, 1H) , 3.99 (t, J = 6.8 Hz, 1H) , 3.84 (d, J = 15.6 Hz, 3H) , 3.61 (t, J = 7.2 Hz, 1H) , 3.21-3.11 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl) methyl) thiazole-2-carboxamide (62)

Step 1. N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (62-1) A solution of 33-2 (100 mg, 0.5 mmol) , 4-methylthiazole-2-carboxylic acid (70 mg, 0.5 mmol) , HATU (200 mg, 0.5 mmol) and DIEA (180 mg, 1.5 mmol) in DMF (1 mL) was stirred at r.t. for 16 h. The mixture was purified by HPLC to give 62-1 (100 mg, 57%) as a yellow solid. MS (ESI) m/z 326 [M+H] ⁺.

Step 2 was performed according to the procedure outlined for the preparation of 1-2.

Step 3 was performed according to the procedure outlined for step 3 for the preparation of 1 to afford 62 (16 mg, 40%) as a white solid. MS (ESI) m/z 473 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.60 (s, 1H) , 8.47-8.40 (m, 1H) , 7.99 (d, J = 8.0, Hz, 0.45H) , 7.91 (d, J = 6.8, Hz, 0.55H) , 7.61 (s, 0.45H) , 7.49 (s, 0.55H) , 7.26-7.05 (m, 4H) , 5.33 (s, 0.9H) , 4.73 (s, 1.1H) , 4.39 (t, J = 6.8 Hz, 1.1H) , 3.72 (t, J = 7.2 Hz, 0.9H) , 3.32-3.16 (m, 2H) , 2.39-2.35 (m, 3H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1-isopropyl-1H-pyrazole-3-carboxamide (63)

The title compound 63 was prepared according to the procedure described for compound 33 as a white solid (25 mg, 34.7%) . MS (ESI) m/z 443 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.32 (s, 1H) , 8.45 (d, J = 4.4 Hz, 0.45H) , 8.42 (d, J = 4.4 Hz, 0.55H) , 8.00-7.97 (m, 1H) , 7.83 (d, J = 2.0 Hz, 0.45H) , 7.77 (d, J = 2.0 Hz, 0.55H) , 7.22-7.10 (m, 3H) , 6.71 (t, J = 8.4 Hz, 2H) , 6.55 (d, J = 2.0 Hz, 0.45H) , 6.50 (d, J = 2.4 Hz, 0.55H) , 4.87 (s, 0.9H) , 4.57 (s, 1.1H) , 4.53-4.44 (m, 1H) , 4.10 (t, J = 7.2 Hz, 1.1H) , 3.62 (t, J = 7.2 Hz, 0.9H) , 3.25 (t, J = 7.6 Hz, 1.1H) , 3.13 (t, J =7.2 Hz, 0.9H) , 1.38 (d, J = 6.8 Hz, 2.6H) , 1.30 (d, J = 6.8 Hz, 3.4H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -1-ethyl-N- (4-hydroxybenzyl) -1H-pyrazole-3-carboxamide (64)

The title compound 64 was prepared according to the procedure described for compound 33 as a white solid (26 mg, 36.6%) . MS (ESI) m/z 429 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.34 (brs, 1H) , 8.40-8.42 (m, 1H) , 8.02-7.96 (m, 1H) , 7.81-7.74 (m, 1H) , 7.22-7.07 (m, 3H) , 6.71 (t, J = 7.6 Hz, 2H) , 6.58-6.47 (m, 1H) , 4.88-4.56 (m, 2H) , 4.18-4.07 (m, 2H) , 4.02-3.60 (m, 2H) , 3.23-3.11 (m, 2H) , 1.36-1.27 (m, 3H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -1- (difluoromethyl) -N- (4-hydroxybenzyl) -1H-pyrazole-3-carboxamide (65)

The title compound 65 was prepared according to the procedure described for compound 33 as a white solid (30 mg, 41%) . MS (ESI) m/z 451 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.36 (d, J = 9.2 Hz, 1H) , 8.49-8.26 (m, 2H) , 8.03-7.64 (m, 2H) , 7.23-7.05 (m, 3H) , 6.80-6.62 (m, 3H) , 4.71 (s, 1H) , 4.59 (s, 1H) , 3.89 (t, J = 6.8 Hz, 1H) , 3.67 (t, J = 7.2 Hz, 1H) , 3.15 (t, J = 7.6 Hz, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -1-cyclopropyl-N- (4-hydroxybenzyl) -1H-pyrazole-3-carboxamide (66)

The title compound 66 was prepared according to the procedure described for compound 33 as a white solid (22 mg, 29.5%) . MS (ESI) m/z 441 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.32-9.31 (m, 1H) , 8.49-8.43 (m, 1H) , 8.02-7.97 (m, 1H) , 7.87-7.81 (m, 1H) , 7.22-7.06 (m, 3H) , 6.72-6.47 (m, 3H) , 4.83 (s, 0.9H) , 4.55 (s, 1.1H) , 3.96 (t, J = 6.8 Hz, 1H) , 3.80-3.72 (m, 1H) , 3.63-3.58 (m, 1H) , 3.22-3.10 (m, 2H) , 1.04-0.84 (m, 4H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1-phenyl-1H-pyrazole-3-carboxamide (67)

The title compound 67 was prepared according to the procedure described for compound 33 as a white solid (7 mg, 9%) . MS (ESI) m/z 477 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H) , 8.55-8.46 (m, 2H) , 8.03-7.97 (m, 1H) , 7.84-7.79 (m, 2H) , 7.52-7.43 (m, 2H) , 7.36-7.30 (m, 1H) , 7.24-7.14 (m, 3H) , 6.89-6.72 (m, 3H) , 4.90 (s, 0.8H) , 4.63 (s, 1.2H) , 4.08 (t, J = 6.8 Hz, 1.2H) , 3.68 (t, J = 7.2 Hz, 0.8H) , 3.33 (t, J = 8.4 Hz, 1.2H) , 3.12 (t, J = 8.4 Hz, 0.8H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1- (2-methoxyethyl) -1H-pyrazole-3-carboxamide (68)

The title compound 68 was prepared according to the procedure described for compound 33 as a white solid (35 mg, 36.5%) . MS (ESI) m/z 459 [M+H] ⁺. ¹H NMR (400 MHz, CDCl₃) δ 8.42 (t, J = 5.6 Hz, 1H) , 7.82-7.77 (m, 2H) , 7.42 (s, 1H) , 7.14 (d, J = 8.0 Hz, 1H) , 7.04-7.00 (m, 2H) , 6.70-6.67 (m, 3H) , 4.96 (s, 1H) , 4.69 (s, 1H) , 4.27-4.23 (m, 2H) , 4.17 (t, J = 6.8 Hz, 1H) , 3.80 (t, J = 7.2 Hz, 1H) , 3.71-3.66 (m, 2H) , 3.36-3.33 (m, 2H) , 3.26 (d, J = 5.6 Hz, 3H) .

The intermediate 68-3 was prepared as follows:

Step 1. ethyl 1- (2-methoxyethyl) -1H-pyrazole-3-carboxylate (68-2)

The mixture of ethyl 1H-pyrazole-3-carboxylate (1.0 g, 7.1 mmol) , 1-bromo-2-methoxyethane (1.2 g, 9.1 mmol) and Cs₂CO₃ (4.6 g, 14.0 mmol) in DMF (40 mL) was stirred at r.t. overnight. The mixture was poured into water (100 mL) , extracted with EA (50 mL*2) . The combined organic layers were washed with water (50 mL*2) and brine (50 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (PE/EA =10/1) to give 68-2 (600 mg, 43%) as a yellow oil. MS (ESI) m/z 199 [M+H] ⁺.

Step 2. 1- (2-methoxyethyl) -1H-pyrazole-3-carboxylic acid (68-3)

To a solution of 68-2 (500 mg, 2.52 mmol) in EtOH (11 mL) was added 5 mL NaOH (10%in water) at r.t. The reaction mixture was stirred for 3h at r.t. Then the mixture was concentrated, diluted with water (5 mL) , acidified to pH=4 with 1N HCl, filtered to give 68-3 (224 mg, 53%) as a yellow solid. MS (ESI) m/z 171 [M+H] ⁺.

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1, 5-dimethyl-1H-pyrazole-3-carboxamide (69)

The title compound 69 was prepared according to the procedure described for compound 33 (25 mg, 33%) as a white solid. MS (ESI) m/z 429 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.42 (d, J = 4.0 Hz, 0.45H) , 8.37 (d, J = 3.6 Hz, 0.55H) , 7.95 (d, J = 7.6 Hz, 0.45H) , 7.88 (d, J = 8.0 Hz, 0.55H) , 7.18-7.05 (m, 3H) , 6.75-6.70 (m, 2H) , 6.36 (s, 0.45H) , 6.14 (s, 0.55H) , 4.83 (s, 1H) , 4.67 (s, 1H) , 4.11 (t, J = 6.8 Hz, 1H) , 3.78-3.72 (m, 4H) , 3.31-3.22 (m, 2H) , 2.30 (s, 1.4H) , 2.26 (s, 1.6H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4- (trifluoromethyl) thiazole-2- carboxamide (70)

The title compound 70 was prepared according to the procedure described for compound 33 as a white solid (34 mg, 42.6%) . MS (ESI) m/z 486 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.40 (s, 1H) , 8.79 (s, 0.45H) , 8.69 (s, 0.55H) , 8.49 (d, J = 8.0 Hz, 0.45H) , 8.39 (d, J = 7.6 Hz, 0.55H) , 8.02 (d, J = 7.6 Hz, 0.45H) , 7.93 (d, J = 8.0 Hz, 0.55H) , 7.24-7.09 (m, 3H) , 6.75-6.70 (m, 2H) , 5.10 (s, 0.9H) , 4.62 (s, 1.1H) , 4.29 (t, J = 7.2 Hz, 1.1H) , 3.73 (t, J = 6.8 Hz, 0.9H) , 3.24-3.17 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4, 5-dimethylthiazole-2-carboxamide (71)

The title compound 71 was prepared according to the procedure described for compound 33 as a white solid (10 mg, 13.7%) . MS (ESI) m/z 446 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.36 (s, 1H) , 8.49-8.42 (m, 1H) , 8.02-7.93 (m, 1H) , 7.23 –7.05 (m, 3H) , 6.73 –6.70 (m, 2H) , 5.21 (s, 0.9H) , 4.56 (s, 1.1H) , 4.31 (t, J = 6.8 Hz, 1.1H) , 3.65 (t, J = 6.8 Hz, 0.9H) , 3.28 –3.13 (m, 2H) , 2.28 –2.21 (m, 6H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrazole-3-carboxamide (72)

The title compound 72 was prepared according to the procedure described for compound 33 as a white solid (61 mg, 50.3%) . MS (ESI) m/z 494 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 11.92 (brs, 1H) , 9.33 (d, J = 5.2 Hz, 1H) , 8.50 (d, J = 3.6 Hz, 1H) , 8.35-8.30 (m, 1H) , 8.04-7.86 (m, 3H) , 7.23-7.08 (m, 3H) , 6.81-6.71 (m, 3H) , 6.49-6.45 (m, 1H) , 4.85 (s, 0.8H) , 4.62 (s, 1.2H) , 4.00 (t J = 6.4 Hz, 1.2H) , 3.65 (t J = 7.6 Hz, 0.8H) , 3.28-3.12 (m, 2H) .

The intermediate 72-4 was prepared as follows:

Step 1. ethyl 1- (6- (benzyloxy) pyridin-3-yl) -1H-pyrazole-3-carboxylate (72-2)

A mixture of ethyl 1H-pyrazole-3-carboxylate (500 mg, 3.57 mmol) , (6- (benzyloxy) pyridin-3-yl) boronic acid (980 mg, 4.28 mmol) , Cu (OAc) ₂ (65 mg, 0.36 mmol) , pyridine (1.4 g, 17.72 mmol) and molecular sieve (500 mg) in DCM (10 mL) was stirred at r.t. overnight under 1atm O₂. The mixture was concentrated and purified by FCC (PE/EA = 5/1) to give 72-2 (220 mg, 19%) as a white solid. MS (ESI) m/z 324 [M+H] ⁺.

Step 2. ethyl 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrazole-3-carboxylate (72-3) To a solution of 72-2 (220 mg, 0.68 mmol) in MeOH (10 mL) was added Pd/C (22 mg) at r.t. The mixture was stirred at r.t. overnight under 1atm H₂. The mixture was filtrated and concentrated to give crude 72-3 (150 mg, 95%) as a white solid. MS (ESI) m/z 234 [M+H] ⁺.

Step 3. 1- (6-oxo-1, 6-dihydropyridin-3-yl) -1H-pyrazole-3-carboxylic acid (72-4) To a solution of 72-3 (150 mg, 0.64 mmol) in THF/H₂O (5 mL/5 mL) was added LiOH·H₂O (54 mg, 1.28 mmol) at r.t. The reaction mixture was stirred at r.t. for 8 h. The mixture was concentrated, diluted with water (5 mL) , adjusted to pH=2 with HCl (aq. ) and filtered to give 72-4 (100 mg, 76%) as a white solid. MS (ESI) m/z 206 [M+H] ⁺.

(E) -N- (3- (1H-1, 2, 3-triazol-4-yl) allyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (73)

Step 1: (4- (2- ( (methylsulfonyl) oxy) ethyl) -1H-1, 2, 3-triazol-1-yl) methyl pivalate (73-2)

To a solution of but-3-yn-1-yl methanesulfonate (500 mg, 3.38 mmol) , azidomethyl pivalate (800 mg, 5.07 mmol) in THF/H₂O (10 mL/10 mL) were added CuSO₄·5H₂O (43 mg, 0.17 mmol) , TBAF (5 mL, 5.07 mmol) , sodium ascorbate (68 mg, 0.34 mmol) at r.t. The reaction mixture was stirred at r.t. overnight. The mixture was added with water (20 mL) and extracted with EA (20 mL*3) , washed with brine (20 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 3/1) to give 73-2 (900 mg, 87%) as a yellow oil. MS (ESI) m/z 306 [M+H] ⁺.

Step 2: (4-vinyl-1H-1, 2, 3-triazol-1-yl) methyl pivalate (73-3)

To a solution of 73-2 (900 mg, 2.95 mmol) in DME (20 mL) were added KI (1.47 g, 8.85 mmol) and DBU (897 mg, 5.9 mmol) at r.t. The mixture was stirred at 90 ℃ for 30 min. The mixture was added with water (50 mL) and extracted with EA (30 mL*3) , washed with brine (50 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 5/1) to give 73-3 (281 mg, 45%) as a yellow oil. MS (ESI) m/z 210 [M+H] ⁺.

Step 3. (E) - (4- (3- (N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamido) prop-1-en-1-yl) -1H-1, 2, 3-triazol-1-yl) methyl pivalate (73-5) The mixture of 73-4 (188 mg, 0.51 mmol) , 73-3 (117 mg, 0.56 mmol) and Grubbs G₂ (42 mg, 0.05 mmol) in DCE (10 mL) was stirred at 80℃ for 12 h under N₂. The mixture was concentrated and purified by FCC (PE/EA=1/1) to give 73-5 (81 mg, 29%) as a brown oil. MS (ESI) m/z 547 [M+H] ⁺.

Step 4: (E) -N- (3- (1H-1, 2, 3-triazol-4-yl) allyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (73)

The mixture of 73-5 (81 mg, 0.15 mmol) and KOH (42 mg, 0.75 mmol) in MeOH/H₂O (5 mL/15 mL) was stirred at r.t. for 2 h. The mixture was concentrated and purified by prep-HPLC to give 73 (24.8 mg, 32%) as a white solid. MS (ESI) m/z 433 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ8.43 (d, J = 4.4 Hz, 0.45H) , 8.37 (d, J = 4.8 Hz, 0.55H) , 7.96-7.82 (m, 2H) , 7.36 (s, 0.45H) , 7.27 (s, 0.55H) , 7.17-7.07 (m, 1H) , 6.67-6.55 (m, 1H) , 6.47-6.40 (m, 1H) , 4.81 (d, J = 6.4 Hz, 0.9H) , 4.58 (t, J = 6.8 Hz, 1.1H) , 4.34 (d, J = 5.2 Hz, 1.1H) , 3.94 (t, J = 7.2 Hz, 0.9H) , 3.40-3.36 (m, 2H) , 2.45 (d, J = 12.0 Hz, 3H) .

The intermediate 73-4 was prepared as follows:

To a solution of 62-1 (200 mg, 0.61 mmol) in DMF (10 mL) was added NaH (27 mg, 0.67 mmol, 60%in mineral oil) in an ice-bath. The reaction mixture was stirred at 0℃ for 30 min under N₂. Then 3-bromoprop-1-ene (88 mg, 0.73 mmol) was added. The mixture was stirred at r.t. for 2 h. The mixture was quenched with water (30 mL) and extracted with EA (30 mL*2) . The combined organic layers were washed with water (30 mL*2) and brine (30 mL) , dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (PE/EA = 3/1) to give 73-4 (188 mg, 84%) as a yellow oil. MS (ESI) m/z 366 [M+H] ⁺.

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4- (piperazin-1-yl) thiazole-2-carboxamide (74)

Step 1. ethyl 4- (4- (tert-butoxycarbonyl) piperazin-1-yl) thiazole-2-carboxylate (74-2)

To a solution of ethyl 4-bromothiazole-2-carboxylate (1.0 g, 0.42 mmol) , tert-butyl piperazine-1-carboxylate (1.5 g, 0.85 mmol) , and Cs₂CO₃ (4.1 g, 1.22 mmol) in dioxane (100 mL) was added t-BuBrettphos G₃ (360 mg, 0.04 mmol) at r.t. under N₂. The reaction was stirred at 80℃for 5 h under N₂. The mixture was filtered and the filtrate was added with H₂O (50 mL) , and extracted with EA (50 mL*2) . The combined organic layers were dried over Na₂SO₄, filtered, concentrated and purified by FCC (PE/EA = 5/1) to give 74-2 (500 mg, 36%) as a white solid. MS (ESI) m/z 342 [M+H] ⁺.

Step 2 was performed according to the procedure outlined for step 2 for the preparation of 54-3.

Step 3 was performed according to the procedure outlined for step 3 for the preparation of 54.

Step 4. N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4- (piperazin-1-yl) thiazole-2-carboxamide (74)

A solution of tert-butyl 4- (2- ( (2- (3-bromopyridin-2-yl) ethyl) (4-hydroxybenzyl) carbamoyl) thiazol-4-yl) piperazine-1-carboxylate (80 mg, 0.13 mmol) in DCM/TFA (2 mL/1 mL) was stirred at r.t. for 1 h. The mixture was added with water (5 mL) and adjusted to pH=9 with sat. NaHCO₃ (aq. ) . The organic phase was separated, dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC to give 74 (4 mg, 6.8%) as a yellow solid. MS (ESI) m/z 502 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H) , 8.63 (t, J = 6.4 Hz, 1H) , 8.53-8.50 (m, 1H) , 8.06-8.02 (m, 1H) , 7.25-7.21 (m, 1H) , 7.15 (d, J = 8.4 Hz, 1H) , 7.05-7.02 (m, 1H) , 6.74-6.68 (m, 2H) , 4.59 (s, 1H) , 3.98 (s, 1H) , 3.70-3.61 (m, 2H) , 3.20-3.11 (m, 6H) , 3.00-2.89 (m, 4H) .

N- ( (1H-benzo [d] [1, 2, 3] triazol-5-yl) methyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (75)

Step 1. 1H-benzo [d] [1, 2, 3] triazole-5-carbaldehyde (75-2)

To a solution of 5-bromo-1H-benzo [d] [1, 2, 3] triazole (1.0 g, 5.1 mmol) in THF (50 mL) was added i-PrMgCl (2.8 mL, 5.6 mmol, 2 M in THF) at 0℃. The reaction was stirred at 0℃ for 1 h. n-BuLi (8.0 mL, 20.0 mmol, 2.5 M in THF) was added at -40℃. The reaction was stirred at -10℃ for 30 min. DMF (3.7 g, 50.7 mmol) was added at -10℃ and the mixture was gradually raised to r.t. The reaction was stirred at r.t. for 30min. The mixture was poured into water (50 mL) and extracted with EA (50 mL*3) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was wash with ether (3 mL) to give 75-2 (440 mg, 59%) as a yellow solid. MS (ESI) m/z 148 [M+H] ⁺.

Step 2 was performed according to the procedure outlined for step 2 for the preparation of Int 1-3.

Step 3. 2- (3-bromopyridin-2-yl) -N- ( (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazol-5-yl) methyl) ethan-1-amine (75-4)

To a solution of 1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazole-5-carbaldehyde (290 mg, 1.0 mmol) and 33-2 (210 mg, 1.0 mmol) in THF (5 mL) was added Ti (O-iPr) ₄ (596 mg, 2.1 mmol) at r.t. The reaction mixture was stirred at 60℃ for 3 h. The mixture was cooled to r.t. and added with NaBH (OAc) ₃ (1.1 g, 5.2 mmol) and MeOH (1 mL) . The mixture was stirred at r.t. overnight. The mixture was poured into water (50 mL) and adjusted to pH=9 with sat. Na₂CO₃ (aq. ) . The mixture was extracted with EA (50 mL*3) . The organic layer was separated, dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (PE/EA=1/1 to DCM/MeOH=20/1) to give 75-4 (220 mg, 45%) as a yellow oil. MS (ESI) m/z 462 [M+H] ⁺.

Step 4. N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- ( (1- ( (2- (trimethylsilyl) ethoxy) methyl) -1H-benzo [d] [1, 2, 3] triazol-5-yl) methyl) thiazole-2-carboxamide (75-5)

A mixture of 75-4 (100 mg, 0.22 mmol) , 4-methylthiazole-2-carboxylic acid (43 mg, 0.26 mmol) , HATU (125 mg, 0.33 mmol) and DIEA (85 mg, 0.66 mmol) in DMF (10 mL) was stirred at r.t. overnight. Ice water (20 mL) was added, and the mixture was extracted with EA (20 mL*3) . The combined organic layers were washed with water (20 mL*2) and brine (20 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by TLC (DCM/MeOH=20/1) to give 75-5 (110 mg, 85%) as a yellow oil. MS (ESI) m/z 588 [M+H] ⁺.

Step 5. N- ( (1H-benzo [d] [1, 2, 3] triazol-5-yl) methyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (75)

A solution of 75-5 (100 mg, 0.17 mmol) in DCM/TFA (4 mL/2 mL) was stirred at r.t. for 5 h. The mixture was added with water (5 mL) and DCM (5 mL) , basified to Ph=9 with sat. NaHCO₃. The organic layer was dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by prep-HPLC to give 75 (35.4 mg, 45%) as a yellow solid. MS (ESI) m/z 457 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.46-8.39 (m, 1H) , 7.99-7.74 (m, 3H) , 7.61 (s, 0.4H) , 7.50 (s, 0.6H) , 7.38-7.31 (m, 1H) , 7.20-7.10 (m, 1H) , 5.51 (s, 0.8H) , 4.90 (s, 1.2H) , 4.43 (t, J = 6.8 Hz, 1.2H) , 3.76 (t, J = 7.6 Hz, 0.8H) , 3.27-3.17 (m, 2H) , 2.37 (d, J = 5.2 Hz, 3H) .

4- ( ( (2- (3-bromopyridin-2-yl) ethyl) (6-methylpyrimidin-4-yl) amino) methyl) phenol (76)

A mixture of 33-3 (33 mg, 0.26 mmol) , 4-chloro-6-methylpyrimidine (80 mg, 0.26 mmol) and DIEA (134 mg, 1.04 mmol) in DMF (1 mL) was stirred at r.t. overnight. The mixture was diluted with water (10 mL) , and extracted with EA (5 mL*2) . The combined organic layers were washed with water (5 mL*2) and brine (5 mL) , dried over anhydrous Na₂SO₄, filtered, concentrated and purified by FCC (DCM/MeOH = 10/1) to give a crude product. The crude product was purified by prep-HPLC to give 76 (2 mg, 1.5%) as a white solid. MS (ESI) m/z 399 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.44 (dd, J = 5.2, 1.2 Hz, 1H) , 8.33 (s, 1H) , 7.96 (dd, J = 8.0, 1.2 Hz, 1H) , 7.17 (dd, J = 8.4, 4.8 Hz, 1H) , 7.04 (d, J = 8.8 Hz, 2H) , 6.71 (d, J = 8.8 Hz, 2H) , 6.54 (s, 1H) , 4.56 (s, 4H) , 3.88 (s, 2H) , 2.29 (s, 3H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (77)

Step 1 was performed according to the procedure outlined for the preparation of 4.

Step 2 was performed according to the procedure outlined for step 4 for the preparation of 74 to afford 77 (8 mg, 16.3%) as a white solid. MS (ESI) m/z 470 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.42-8.41 (m, 1H) , 7.98-7.92 (m, 1H) , 7.70-7.69 (m, 1H) , 7.19-7.16 (m, 2H) , 7.10 (d, J = 8.4 Hz, 1H) , 6.75-6.73 (m, 2H) , 6.63-6.59 (m, 1H) , 5.03-4.89 (m, 1H) , 4.85 (s, 1H) , 4.69 (s, 1H) , 4.20-4.09 (m, 1H) , 3.83-3.76 (m, 1H) , 3.35-3.33 (m, 1H) , 3.26-3.13 (m, 2H) , 3.09-2.79 (m, 3H) , 2.34-2.02 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (78)

The title compound 78 was prepared according to the procedure described for compound 33 as a white solid (4 mg, 5.9%) . MS (ESI) m/z 432 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H) , 8.48 (d, J = 4.0 Hz, 0.45H) , 8.40 (d, J = 3.6 Hz, 0.55H) , 8.01 (d, J = 8.4 Hz, 0.45H) , 7.92 (d, J = 7.2 Hz, 0.55H) , 7.59 (s, 0.45H) , 7.48 (s, 0.55H) , 7.15-7.06 (m, 3H) , 6.74-6.70 (m, 2H) , 5.75 (s, 0.45H) , 5.20 (s, 0.55H) , 4.59 (s, 1H) , 4.33 (t, J = 6.4 Hz, 1.1H) , 3.66 (t, J = 8.0 Hz, 0.9H) , 3.25-3.14 (m, 2H) , 2.40 (s, 1.35H) , 2.34 (s, 1.65H) .

N- (1- (3-bromopyridin-2-yl) azetidin-3-yl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (79)

Step 1. tert-butyl (1- (3-bromopyridin-2-yl) azetidin-3-yl) carbamate (79-2)

A solution of 3-bromo-2-fluoropyridine (1 g, 5.71 mmol) , tert-butyl azetidin-3-ylcarbamate (1.1 g, 6.28 mmol) , DIEA (2.2 g, 17.1 mmol) in DMSO (30 mL) was stirred at 70℃ overnight. The mixture was added with water (50 mL) and extracted with EA (50 mL*3) . The combined organic layers were washed with water (50 mL*2) and brine (50 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated to give 79-2 (1.83 g, 97%) as a white solid. MS (ESI) m/z 328 [M+H] ⁺.

Step 2 was performed according to the procedure outlined for step 4 for the preparation of 74.

Step 3 was performed according to the procedure outlined for step 2 for the preparation of 33-3.

Step 4 was performed according to the procedure outlined for step 3 for the preparation of 33 to afford 79 (23 mg, 33%) as white solid. MS (ESI) m/z 459 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H) , 8.10 (dd, J = 4.8, 1.2 Hz, 1H) , 7.79 (dd, J = 7.6, 2.0 Hz, 1H) , 7.61 (s, 1H) , 7.09-6.98 (m, 2H) , 6.71-6.68 (m, 3H) , 5.88-4.60 (m, 3H) , 4.31-4.20 (m, 4H) , 2.40-2.32 (m, 3H) .

N- (3- (1H-pyrazol-4-yl) prop-2-yn-1-yl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole -2-carboxamide (80)

Step 1 was performed according to the procedure outlined for the preparation of 1-2.

Step 2. N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- (3- (1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-yl) prop-2-yn-1-yl) thiazole-2-carboxamide (80-2)

A solution of N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- (prop-2-yn-1-yl) thiazole-2-carboxamide (100 mg, 0.27 mmol) in THF (3 mL) were added TEA (3 mL) , 4-iodo-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazole (76 mg, 0.27 mmol) , CuI (10 mg, 0.05 mmol) and Pd (PPh₃) ₂Cl₂ (20 mg, 0.03 mmol) at r.t. The mixture was stirred at 30℃ overnight under N₂. The reaction mixture was filtered and concentrated. The residue was purified by FCC (PE/EA = 2/1) to give 80-2 (67 mg, 46%) as a yellow oil. MS (ESI) m/z 514 [M+H] ⁺ _.

Step 3. N- (3- (1H-pyrazol-4-yl) prop-2-yn-1-yl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (80)

To a solution of 80-2 (67 mg, 0.13 mmol) in DCM (9 mL) were added TFA (3 mL) and H₂O (1 drop) at r.t. The mixture was stirred at r.t. for 2 h. The mixture was concentrated, diluted with water (10 mL) , adjusted to pH=7 with sat. NaHCO₃ and extracted with DCM (10 mL*2) . The combined organic layers were dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 1/1 to 0/1) to give 80 (18 mg, 32%) as a white solid. MS (ESI) m/z 430 [M+H] ⁺ _. ¹H NMR (400 MHz, CDCl₃) δ 8.47-8.41 (m, 1H) , 7.83 –7.67 (m, 3H) , 7.09 –6.99 (m, 2H) , 5.35 (s, 0.8H) , 4.69 (t, J = 6.0 Hz, 1.2H) , 4.60 (s, 1.2H) , 4.11 (t, J = 6.0 Hz, 0.8H) , 3.43 (t, J = 7.2 Hz, 2H) , 2.50 (s, 1.2H) , 2.44 (s, 1.8H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (81)

The title compound 81 was prepared according to the procedure described for compound 79 as a white solid (5 mg, 33%) . MS (ESI) m/z 391 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.39-7.26 (m, 2H) , 7.20-7.12 (m, 2H) , 6.77-6.74 (m, 2H) , 5.17 (s, 1H) , 4.69 (s, 1H) , 4.26 (t, J = 7.2 Hz, 1H) , 3.79-3.76 (m, 3H) , 3.57 (t, J = 7.2 Hz, 1H) , 3.09 (t, J = 6.8 Hz, 1H) , 2.98 (t, J = 7.2 Hz, 1H) , 2.46 (s, 3H) .

The intermediate 81-2 was prepared as follows:

To a solution of 2- (4-chloro-1-methyl-1H-pyrazol-5-yl) acetonitrile (80 mg, 6.51 mmol) in THF (8 mL) was added LAH (0.56 mL, 0.56 mmol, 1M in THF) slowly at 0℃. The reaction mixture was stirred at 0℃ for 1 h. The mixture was diluted with EA (10 mL) , adjusted to pH=5～6 with 1N H₂SO₄ at 0℃ and stirred at r.t. for 30 min. Then the mixture was adjusted to pH=9～10 with sat. Na₂CO₃, extracted with EA (20 mL*2) , dried over anhydrous Na₂SO₄, filtered and concentrated to give 2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethan-1-amine (50 mg, crude) as a pink solid. MS (ESI) m/z 160 [M+H] ⁺.

N- (2- (1H-pyrazol-4-yl) ethyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (82)

Step 1. tert-butyl 4- (2-hydroxyethyl) -1H-pyrazole-1-carboxylate (82-2)

A mixture of 2- (1H-pyrazol-4-yl) ethan-1-ol (5 g, 45 mmol) , Boc₂O (10.71 g, 49 mmol) , DMAP (0.54 g, 4.5 mmol) and TEA (6.76 g, 6.7 mmol) in DCM (30 mL) was stirred at r.t. overnight. The mixture was concentrated and purified by FCC (PE/EA = 1/1) to give 82-2 (7 g, 74%) as a colorless oil. MS (ESI) m/z 213 [M+H] ⁺.

Step 2. tert-butyl 4- (2-bromoethyl) -1H-pyrazole-1-carboxylate (82-3)

To a solution of 82-2 (2.12 g, 10 mmol) in DCM (20 mL) were added CBr₄ (3.31 g, 10 mmol) and PPh₃ (2.62 g, 10 mmol) in an ice-bath. The mixture was stirred at r.t. overnight. The mixture was concentrated and purified by FCC (PE/EA = 5/1 ～ 1/1) to give 82-3 (1.6 g, 58%) as a colorless oil. MS (ESI) m/z 275 [M+H] ⁺.

Step 3. tert-butyl 4- (2- ( (2- (3-bromopyridin-2-yl) ethyl) amino) ethyl) -1H-pyrazole-1-carboxylate (82-4)

A mixture of 82-3 (138 mg, 0.5 mmol) , 33-2 (100 mg, 0.5 mmol) , K₂CO₃ (276 mg, 1 mmol) and KI (83 mg, 0.5 mmol) in DCM (2 mL) was stirred at 60℃ overnight. The mixture was poured into water (10 mL) , extracted with DCM (10 mL*2) , concentrated and purified by FCC (DCM/MeOH = 20/1) to give 82-4 (40 mg, 20%) as a yellow solid. MS (ESI) m/z 395 [M+H] ⁺.

Step 5. N- (2- (1H-pyrazol-4-yl) ethyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (82)

To a solution of tert-butyl 4- (2- (N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamido) ethyl) -1H-pyrazole-1-carboxylate (40 mg, 0.078 mmol) in dioxane (2 mL) was added HCl (2 mL, 4M in dioxane) . The mixture was stirred at r.t. for 4 h and then adjusted to pH=8 with sat. NaHCO₃, extracted with DCM (10 mL*2) . The organic layer was concentrated and purified by prep-HPLC to give 82 (17 mg, 54%) as a white solid. MS (ESI) m/z 420 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.47-8.36 (m, 1H) , 8.00-7.85 (m, 1H) , 7.51 (s, 1H) , 7.41 (s, 1H) , 7.34 (s, 0.5H) , 7.24 (s, 0.5H) , 7.19-7.07 (m, 1H) , 4.48 (t, J = 6.8 Hz, 1H) , 4.17-4.07 (m, 1H) , 3.92 (t, J = 7.2 Hz, 1H) , 3.76-3.63 (m, 1H) , 3.36 (t, J = 7.2 Hz, 1H) , 3.28 (d, J = 6.8 Hz, 1H) , 2.89 (t, J = 7.2 Hz, 2H) , 2.49 (s, 1.5H) , 2.43 (s, 1.5H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- ( (6-oxo-5-oxa-7-azaspiro [3.4] octan-2-yl) methyl) thiazole-2-carboxamide (83)

83-1 was prepared according to the procedure outlined for the preparation of 80-1.

Step 1. N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- ( (3-oxocyclobutyl) methyl) thiazole-2-carboxamide (83-2)

A solution of N- ( (5, 8-dioxaspiro [3.4] octan-2-yl) methyl) -N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamide (190 mg, 0.42 mmol) in HCl (4 mL, 4 mol/L in EA) was stirred at r.t. for 1 h. The mixture was concentrated to give crude 83-2 (120 mg) as a yellow oil. MS (ESI) m/z 408 [M+H] ⁺.

Step 2. tert-butyl 2- (3- ( (N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamido) methyl) -1-hydroxycyclobutyl) acetate (83-3)

To a solution of LDA (0.29 mL, 0.58 mmol, 2M in THF) in THF (2 mL) was added tert-butyl acetate (68 mg, 0.58 mmol) dropwise at -78℃. The mixture was stirred at -78℃ for 30 min. Then a solution of 83-2 (120 mg, 0.29 mmol) in THF (2 mL) was added dropwise at -78℃. The reaction was stirred at -78℃ for 30 min. The mixture was added with sat. NH₄Cl (10 mL) , extracted with EA (5 mL*3) . The combined organic layers were washed with brine (5 mL) , dried over Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 2/1) to give 83-3 (40 mg, 28%) as a yellow oil. MS (ESI) m/z 524 [M+H] ⁺.

Step 3. 2- (3- ( (N- (2- (3-bromopyridin-2-yl) ethyl) -4-methylthiazole-2-carboxamido) methyl) -1-hydroxycyclobutyl) acetic acid (83-4)

To a solution of 83-3 (40 mg, 0.08 mmol) in DCM (2 mL) was added TFA (1 mL) in an ice-bath. The reaction mixture was stirred at r.t. for 30 min. The mixture was concentrated to crude 83-4 (30 mg) as a yellow oil. MS (ESI) m/z 468 [M+H] ⁺.

Step 4. N- (2- (3-bromopyridin-2-yl) ethyl) -4-methyl-N- ( (6-oxo-5-oxa-7-azaspiro [3.4] octan-2-yl) methyl) thiazole-2-carboxamide (83)

A mixture of 83-4 (30 mg) , DPPA (35 mg, 0.12 mmol) and DIEA (25 mg, 0.19 mmol) in toluene (2 mL) was refluxed for 16 h under N₂. The mixture was cooled to r.t. and concentrated. The residue was purified by prep-HPLC to give 83 (9.9 mg, 32%) as a white solid. MS (ESI) m/z 465 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.47 –8.35 (m, 1H) , 7.99 (d, J = 8.0 Hz, 0.4H) , 7.85 (d, J = 8.0 Hz, 0.6H) , 7.35 –7.07 (m, 2H) , 4.55 (t, J = 6.8 Hz, 2H) , 4.17 –4.16 (m, 1H) , 3.90 (t, J = 7.2 Hz, 1H) , 3.68 –3.65 (m, 3H) , 3.36 –3.30 (m, 2H) , 2.42 –2.27 (m, 7H) .

N- (2- (2-cyano-4-methylpyridin-3-yl) ethyl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (84)

Step 1 was performed according to the procedure outlined for the preparation of 81-2.

Step 2. 2-bromo-3- (bromomethyl) -4-methylpyridine (84-3)

To a solution of (2-bromo-4-methylpyridin-3-yl) methanol (2.3 g, 11.38 mmol) in DCM (30 mL) was added PBr₃ (2.8 mL, 22.77 mmol) slowly at 0℃. The reaction was stirred at 0℃ for 2 h. To the mixture was added H₂O (40 mL) at 0℃. The mixture was extracted with DCM (40 mL*2) , dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 3/1) to give 84-3 (1.7 g, 56%) as a colorless liquid. MS (ESI) m/z 264 [M+H] ⁺.

Step 3. 2- (2-bromo-4-methylpyridin-3-yl) acetonitrile (84-4)

To a solution of 84-3 (1.7 g, 6.43 mmol) in DMF (20 mL) was added NaCN (473 mg, 9.64 mmol) . The reaction mixture was stirred at 50℃ for 5 h. The mixture was added with H₂O (40 mL) , extracted with EA (40 mL*2) , dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by FCC (PE/EA = 3/1) to give 84-4 (1.0 g, 79%) as a colorless liquid. MS (ESI) m/z 211 [M+H] ⁺.

Step 4. 2- (2-bromo-4-methylpyridin-3-yl) ethan-1-amine (84-5)

To a solution of 84-4 (200 mg, 0.94 mmol) in THF (10 mL) were added AlCl₃ (138 mg, 1.04 mmol) and LAH (1.04 mL, 1.04 mmol, 1M in THF) slowly at 0℃. The reaction mixture was stirred at r.t. for 1 h. The mixture was diluted with EA (10 mL) and adjusted to pH=6～7 with 1N H₂SO₄. After stirred for 20 min, the mixture was adjusted to pH=8～9 with sat. Na₂CO₃ and extracted with EA (20 mL*2) , dried over anhydrous Na₂SO₄, filtered and concentrated to give 84-5 (100 mg, 49%) as a yellow liquid. MS (ESI) m/z 215 [M+H] ⁺.

Step 5. 4- ( ( (2- (2-bromo-4-methylpyridin-3-yl) ethyl) amino) methyl) phenol (84-6)

To a solution of 84-5 (100 mg, 0.46 mmol) , 4-hydroxybenzaldehyde (56.7 mg, 0.46 mmol) , AcOH (2 drops) in MeOH (10 mL) was added NaBH (OAc) ₃ (147 mg, 0.69 mmol) . The mixture was stirred at r.t. for 16 h. Then NaBH₄ (115 mg, 2.76 mmol) was added. The mixture was stirred at r.t. for 4 h. The reaction mixture was adjusted to pH=8～9 with sat. Na₂CO₃, and extracted with DCM (20 mL*2) . The combined organic layers were washed with brine (30 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (DCM/MeOH = 10/1) to give 84-6 (100 mg, 67%) as a white solid. MS (ESI) m/z 321 [M+H] ⁺.

Step 6 was performed according to the procedure outlined for the preparation of 4.

Step 7. N- (2- (2-cyano-4-methylpyridin-3-yl) ethyl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (84)

To a solution of N- (2- (2-bromo-4-methylpyridin-3-yl) ethyl) -N- (4-hydroxybenzyl) -4-methylthiazole-2-carboxamide (40 mg, 0.08 mmol) in DMA (3 mL) were added Zn (CN) ₂ (28.17 mg, 0.24 mmol) , t-Buxphos (4 mg, 0.08 mmol) and t-Buxphos G3 (4 mg, 0.08 mmol) at r.t. under N₂. The mixture was stirred at 120℃ for 16 h. The mixture was added with water (10 mL) , extracted with EA (20 mL*2) , dried over Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by prep-HPLC to give 84 (2 mg, 6.3%) as a white solid. MS (ESI) m/z 393 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.38-8.27 (m, 1H) , 7.39-7.15 (m, 4H) , 6.77-6.70 (m, 2H) , 5.30 (s, 1H) , 4.80 (s, 2H) , 4.41 (t, J = 7.2 Hz, 1H) , 3.62 (s, 1H) , 3.25-3.19 (m, 1H) , 2.47-2.44 (m, 6H) .

N- ( (5-bromothiophen-2-yl) methyl) -N- (4-hydroxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (85)

85-3 was prepared according to the procedure outlined for the preparation of 53-4.

Step 1 was performed according to the procedure outlined for the preparation of 33-3.

Step 2 was performed according to the procedure outlined for the preparation of 4.

Step 3 was performed according to the procedure outlined for the preparation of 74 to afford 85 (28 mg, 27%) as a white solid. MS (ESI) m/z 461 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.77-7.72 (m, 1H) , 7.16 –7.13 (m, 2H) , 6.97 (d, J = 3.6 Hz, 0.35H) , 6.90 (d, J = 3.6 Hz, 0.65H) , 6.79 –6.72 (m, 4H) , 5.08 –4.90 (m, 3H) , 4.62-4.54 (m, 2H) , 3.23 –2.83 (m, 4H) , 2.31 –2.02 (m, 2H) .

N- ( (4-bromothiophen-2-yl) methyl) -N- (4-hydroxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (86)

The title compound 86 was prepared according to the procedure described for compound 85 as a white solid (21 mg, 13%) . MS (ESI) m/z 461 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.27-8.29 (m, 1H) , 7.85-7.56 (m, 1H) , 7.69-6.91 (m, 3H) , 6.87 (s, 1H) , 6.75-6.62 (m, 3H) , 4.91-4.86 (m, 1H) , 4.52-4.40 (m, 2H) , 3.89 (s, 2H) , 3.19-2.63 (m, 4H) , 2.38-2.14 (m, 2H) , 1.99 (d, J = 4.2 Hz, 1H) .

N- ( (3-bromothiophen-2-yl) methyl) -N- (4-hydroxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (87)

The title compound 87 was prepared according to the procedure described for compound 85 as a white solid (12 mg, 14.6%) . MS (ESI) m/z 461 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.81-7.73 (m, 1H) , 7.43 (d, J = 5.6 Hz, 1H) , 7.17-7.14 (m, 2H) , 7.00-6.93 (m, 1H) , 6.78-6.72 (m, 3H) , 5.18 (s, 1H) , 5.04-4.92 (m, 3H) , 4.74 (s, 1H) , 4.58 (s, 1H) , 3.25-3.12 (m, 2H) , 2.90-2.84 (m, 1H) , 2.39-2.00 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4-methoxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (88)

Step 1. 2- (3-bromopyridin-2-yl) -N- (4-methoxybenzyl) ethan-1-amine (88-2)

A solution of (4-methoxyphenyl) methanamine (500 mg, 3.64 mmol) , 3-bromo-2-vinylpyridine (696 mg, 4.73 mmol) , and AcOH (3 mL) in MeOH (15 mL) was stirred at 65℃ for 16 h. The reaction was quenched with water (20 mL) . The mixture was extracted with EA (20 mL*2) . The combined organic layers were washed with sat. NaHCO₃ (20 mL*2) and brine (30 mL) , dried over anhydrous Na₂SO₄, filtered and concentrated under vacuum. The residue was purified by FCC (DCM/MeOH = 20/1) to give 88-2 (30 mg, 3%) as a brown liquid. MS (ESI) m/z 321 [M+H] ⁺.

Step 3 was performed according to the procedure outlined for the preparation of 74 to afford 88 (8 mg, 32.6%) as a white solid. MS (ESI) m/z 484 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.55-8.41 (m, 1H) , 7.98 (d, J = 8.0 Hz, 1H) , 7.76 (dd, J = 10.0, 2.0 Hz, 1H) , 7.31 (d, J = 8.6 Hz, 1H) , 7.21-7.17 (m, 2H) , 6.91-6.87 (m, 2H) , 6.67-6.61 (m, 1H) , 5.26-5.12 (m, 1H) , 4.82-4.71 (m, 1H) , 4.09-3.95 (m, 1H) , 3.82-3.74 (m, 4H) , 3.66-3.31 (m, 5H) , 3.30-3.11 (m, 2H) , 2.58-2.15 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- ( (6-methoxypyridin-3-yl) methyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (89)

The title compound 89 was prepared according to the procedure described for compound 88 as a gummy solid (35 mg, 28.2%) . MS (ESI) m/z 485 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ8.51 –8.45 (m, 1H) , 8.20 –8.01 (m, 2H) , 7.80 –7.64 (m, 2H) , 7.23 (dd, J = 8.0, 4.8 Hz, 1H) , 6.84 –6.81 (m, 1H) , 6.69 –6.64 (m, 1H) , 5.37 –5.26 (m, 1H) , 4.92 –4.73 (m, 2H) , 4.13 –3.91 (m, 5H) , 3.84 –3.33 (m, 6H) , 2.62 –2.30 (m, 2H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- ( (6- (methylamino) pyridin-3-yl) methyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (90)

The title compound 90 was prepared according to the procedure described for compound 88 as a white solid (12.6 mg, 15%) . MS (ESI) m/z 484 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.45-8.42 (m, 1H) , 8.37 (s, 1H) , 8.02-7.54 (m, 3H) , 7.56-7.20 (m, 2H) , 6.68-6.51 (m, 2H) , 5.35-5.26 (m, 1H) , 4.79-4.61 (m, 2H) , 4.03-3.35 (m, 8H) , 2.85 (s, 3H) , 2.59-2.38 (m, 2H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- (4-hydroxybenzyl) -1- (1-methylpyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (91) and N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- (4-hydroxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (92)

The title compound 92 was prepared according to the procedure described for compound 81 as a white solid (5 mg, 6.1%) . MS (ESI) m/z 429 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.73 (d, J = 2.4 Hz, 1H) , 7.34 (s, 1H) , 7.17 –7.08 (m, 2H) , 6.81 –6.72 (m, 2H) , 6.60 –6.50 (m, 1H) , 4.96 (s, 1H) , 4.81 –4.51 (m, 2H) , 4.02 –3.74 (m, 3H) , 3.64 –3.51 (m, 2H) , 3.25 –2.93 (m, 5H) , 2.89 –2.87 (m, 1H) , 2.33 –2.09 (m, 2H) .

To a solution of 92 (35 mg, 0.08 mmol) in MeOH (6 mL) were added HCHO (0.5 mL, 35%) and NaBH (OAc) ₃ (35 mg, 0.16 mmol) at 0℃. The mixture was stirred at r.t. for 3 h. The mixture was concentrated and purified by prep-HPLC to give 91 (11 mg, 31%) as a white solid. MS (ESI) m/z 443 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.76 (d, J = 2.4 Hz, 1H) , 7.54-7.36 (m, 1H) , 7.15 (d, J = 8.4 Hz, 2H) , 6.79 –6.72 (m, 2H) , 6.53 –6.52 (m, 1H) , 5.07 –4.91 (m, 1H) , 4.80 (s, 1H) , 4.59 (s, 1H) , 3.98 (t, J = 6.8 Hz, 1H) , 3.80 –3.63 (m, 3H) , 3.56 (t, J = 7.2 Hz, 1H) , 3.18 –2.94 (m, 3H) , 2.92 –2.60 (m, 3H) , 2.52 –2.09 (m, 5H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (3-fluoro-4-methoxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (93)

The title compound 93 was prepared according to the procedure described for compound 88 as a white solid (12 mg, 9%) . MS (ESI) m/z 502 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.48-8.44 (m, 1H) , 8.26 (s, 1H) , 8.02-7.99 (m, 1H) , 7.90-7.86 (m, 1H) , 7.25 –7.03 (m, 4H) , 6.62-6.57 (m, 1H) , 5.00 –4.80 (m, 2H) , 4.71 –4.55 (m, 1H) , 4.06 –3.98 (m, 1H) , 3.81 (s, 3H) , 3.68 –3.61 (m, 1H) , 3.29 –2.86 (m, 6H) , 2.22 –2.13 (m, 1H) , 2.07 –1.96 (m, 1H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (2-fluoro-4-methoxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (94)

The title compound 94 was prepared according to the procedure described for compound 88 as a waxy oil (10 mg, 40%) . MS (ESI) m/z 502 [M+H] ⁺. ¹H NMR (400 MHz, CDCl₃) δ ppm 8.64 (br, 1H) , 7.90 (1H) , 7.50 (s, 1H) , 7.36 (t, J = 8.7 Hz, 1H) , 7.20 –6.99 (m, 1H) , 6.85 (m, 1H) , 6.63 (m, 2H) , 5.05 (br, 1H) , 4.99-4.82 (m, 2H) , 4.09 (m, 1H) , 3.91 (m, 2H) , 3.77 (s, 3H) , 3.73-3.68 (m, 1H) , 3.48 (m, 4H) , 3.18 –2.69 (m, 1H) , 2.56 (s, 1H) , 2.22 (s, 1H) .

N- (2- (3-bromopyridin-2-yl) ethyl) -N- (4- (difluoromethoxy) benzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3-carboxamide (95)

Step 1 was performed according to the procedure outlined for the preparation of Int 1-2.

Step 2 was performed according to the procedure outlined for step 4 for the preparation of 74 to afford 95 (10 mg, 22%) as white solid. MS (ESI) m/z 520 [M+H] ⁺. ¹H NMR (400 MHz, CDCl₃) δ 10.09 (s, 1H) , 8.61 (d, J = 4.3 Hz, 1H) , 7.93 (d, J = 7.9 Hz, 1H) , 7.55 (d, J = 2.0 Hz, 1H) , 7.42 (d, J = 8.5 Hz, 2H) , 7.19 (dd, J = 8.0, 4.8 Hz, 1H) , 7.07 (d, J = 8.4 Hz, 2H) , 6.97 (d, J = 2.2 Hz, 1H) , 6.48 (t, J = 73.9 Hz, 1H) , 5.13 (s, 1H) , 5.01 –4.91 (m, 1H) , 4.78 (d, J = 14.8 Hz, 1H) , 4.05 (m, 1H) , 3.98 –3.70 (m, 3H) , 3.68 –3.01 (m, 4H) , 2.61 (m, 1H) , 2.24 (m, 1H) .

N- (benzo [d] thiazol-2-ylmethyl) -N- (4-hydroxybenzyl) -1- (pyrrolidin-3-yl) -1H-pyrazole-3- carboxamide (96)

The title compound 96 was prepared according to the procedure described for compound 85 as a white solid (5 mg, 12.8%) . MS (ESI) m/z 434 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.94 (dd, J = 7.6, 4.4 Hz, 2H) , 7.78 –7.67 (m, 1H) , 7.55 –7.46 (m, 1H) , 7.45 –7.39 (m, 1H) , 7.20 (d, J = 6.4 Hz, 2H) , 6.84 –6.70 (m, 3H) , 5.44 (s, 1H) , 5.11 (s, 1H) , 4.97 –4.92 (m, 2H) , 4.78 (s, 1H) , 3.20 –3.06 (m, 2H) , 3.06 –2.69 (m, 2H) , 2.36 –1.88 (m, 2H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (2-oxo-1, 2-dihydropyridin-4-yl) methyl) thiazole-2-carboxamide (97)

Step 1 was performed according to the procedure outlined for the preparation of 62-1.

Step 2 was performed according to the procedure outlined for the preparation of Int 1-2.

Step 3. N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (2-oxo-1, 2-dihydropyridin-4-yl) methyl) thiazole-2-carboxamide (97)

To a solution of N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- ( (2-methoxypyridin-4-yl) methyl) -4-methylthiazole-2-carboxamide (70 mg, 0.073 mmol) in AcOH (1 mL) was added HBr (1 mL, 40%in water) . The mixture was stirred at 80℃ for 6 h. The mixture was cooled to r.t., diluted with DCM (5 mL) , poured into water (2 mL) , and adjusted to pH=8-9 with sat. NaHCO₃. The organic layer was concentrated under vacuum. The residue was purified by prep-HPLC to give 97 (25 mg, 37%) as a white solid. MS (ESI) m/z 392 [M+H] ⁺. ¹H NMR (300 MHz, CD₃OD) δ 7.51 –7.23 (m, 3H) , 6.49 –6.39 (m, 2H) , 5.29 (s, 1H) , 4.75 (s, 1H) , 4.48 (t, J = 6.6 Hz, 1H) , 3.91 –3.85 (m, 3H) , 3.74 (t, J = 7.2 Hz, 1H) , 3.22 –3.15 (m, 2H) , 2.54 (s, 1.8H) , 2.44 (s, 1.2H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (2-oxo-2, 3-dihydrobenzo [d] oxazol-6-yl) methyl) thiazole-2-carboxamide (98)

The title compound 98 was prepared according to the procedure described for compound 62 as a white solid (5 mg, 13%) . MS (ESI) m/z 432 [M+H] ⁺ _. ¹H NMR (400 MHz, DMSO-d₆) δ 10.90 (s, 1H) , 7.62 –7.54 (m, 1H) , 7.43 –7.30 (m, 1H) , 7.25 (d, J = 7.2 Hz, 1H) , 7.14 –7.07 (m, 2H) , 5.28 (s, 1H) , 4.76 (d, J = 12.0 Hz, 1H) , 4.20 (t, J = 6.8 Hz, 1H) , 3.74 (d, J = 5.2 Hz, 3H) , 3.51 –3.47 (m, 1H) , 3.03 (t, J = 7.2 Hz, 1H) , 2.90 (t, J = 7.2 Hz, 1H) , 2.41 (s, 3H) .

2- ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) (4-hydroxybenzyl) amino) thiazole-5-carbonitrile (99)

Step 1 was performed according to the procedure outlined for the preparation of 84-6.

Step 2.2- ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) (4-hydroxybenzyl) amino) thiazole-5-carbonitrile (99)

A mixture of 4- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) amino) methyl) phenol (30 mg, 0.11 mmol) , 2-chlorothiazole-5-carbonitrile (18 mg, 0.12 mmol) and DIEA (29 mg, 0.23 mmol) in NMP (3 mL) was stirred at 30℃ for 16 h. The mixture was diluted with EA (10 mL) , poured into water (10 mL) , and extracted with EA (10 mL*2) and the combined organic layers were concentrated under vacuum. The residue was purified by prep-HPLC to give 99 (10 mg, 24.2%) as a white solid. MS (ESI) m/z 374 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.77 (s, 1H) , 7.34 (s, 1H) , 7.09 (d, J = 8.4 Hz, 2H) , 6.76 (d, J = 8.4 Hz, 2H) , 4.51 (s, 2H) , 3.76 –3.71 (m, 5H) , 3.05 (t, J = 6.8 Hz, 2H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (6-oxo-1, 6-dihydropyridin-3-yl) methyl) thiazole-2-carboxamide (100)

The title compound 100 was prepared according to the procedure described for compound 97 as a white solid (30 mg, 30%) . MS (ESI) m/z 392 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 7.85 –7.21 (m, 4H) , 6.56 (t, J = 9.2 Hz, 1H) , 5.08 (s, 1H) , 4.61 (s, 1H) , 4.39 (s, 1H) , 3.84 (d, J = 5.6 Hz, 3H) , 3.66 (d, J = 7.2 Hz, 1H) , 3.17 –3.08 (m, 2H) , 2.50 (s, 3H) .

4- ( (benzo [d] thiazol-2-yl (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) amino) methyl) phenol (101)

A mixture of 4- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) amino) methyl) phenol (30 mg, 0.11 mmol) , 2-chlorobenzo [d] thiazole (28 mg, 0.17 mmol) and t-BuONa (22 mg, 0.23 mmol) in dioxane (5 mL) was degassed with N₂. Then Ruphos (26 mg, 0.056 mmol) and Pd₂dba₃ (10 mg, 0.011 mmol) were added. The mixture was stirred at 80℃ for 16 h. The mixture was diluted with EA (10 mL) , poured into water (10 mL) , and extracted with EA (10 mL*2) and the combined organic layers were concentrated under vacuum. The residue was purified by prep-HPLC to give 101 (3 mg, 7%) as a white solid. MS (ESI) m/z 399 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H) , 7.74 (d, J = 7.6 Hz, 1H) , 7.48 –7.39 (m, 2H) , 7.32 –7.24 (m, 1H) , 7.13 (d, J = 8.4 Hz, 2H) , 7.10 –7.02 (m, 1H) , 6.74 (d, J = 8.4 Hz, 2H) , 4.55 (s, 2H) , 3.80 (s, 3H) , 3.64 (t, J = 7.2 Hz, 2H) , 3.02 (t, J = 7.2 Hz, 2H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- (3-fluoro-4-methoxybenzyl) -4-methylthiazole-2-carboxamide (102)

The title compound 102 was prepared according to the procedure described for compound 81 as a white solid (60 mg, 40%) . MS (ESI) m/z 423 [M+H] ⁺. ¹H NMR (400 MHz, CDCl₃) δ 7.40 (t, J = 8.6 Hz, 0.5H) , 7.33 (d, J = 14.0 Hz, 1H) , 7.25 (t, J = 8.6 Hz, 0.5H) , 7.12 (d, J = 6.7 Hz, 1H) , 6.71 –6.57 (m, 2H) , 5.39 (s, 1H) , 4.76 (s, 1H) , 4.24 (t, J = 7.4 Hz, 1H) , 3.86 (d, J = 5.6 Hz, 3H) , 3.78 (s, 3H) , 3.53 (t, J = 7.6 Hz, 1H) , 3.. 09 (t, J = 7.6 Hz, 1H) , 2.95 (t, J = 8Hz, 1H) , 2.47 (d, J = 2.4 Hz, 3H)

4- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) (thiazol-2-yl) amino) methyl) phenol (103)

The title compound 103 was prepared according to the procedure described for compound 101 as a white solid (4 mg, 4.1%) . MS (ESI) m/z 349 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.84 –8.99 (brs, 1H) , 7.43 (s, 1H) , 7.14 (d, J = 3.6 Hz, 1H) , 7.09 (s, 1H) , 7.07 (s, 1H) , 6.74 –6.71 (m, 3H) , 4.43 (s, 2H) , 3.73 (s, 3H) , 3.55 (t, J = 7.2 Hz, 2H) , 2.95 (t, J = 7.2 Hz, 2H) .

4- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) (pyrimidin-4-yl) amino) methyl) phenol (104)

Step 1: N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) pyrimidin-4-amine (104-2)

A mixture of 4-chloropyrimidine (150 mg, 1.31 mmol) , 81-2 (240 mg, 1.5 mmol) and TEA (202 mg, 2 mmol) in DMF (5 mL) was stirred at 80℃ for 16 h. The mixture was diluted with water (15 mL) and extracted with EA (3*10 mL) . The combined organic layer was washed with water (2*8 mL) and brine (2*8 mL) , dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EA = 2/1～1/2) to give 104-2 (70 mg, 23%) as a brown solid. MS (ESI) m/z 238 [M+H] ⁺.

Step 2: N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- (4-methoxybenzyl) pyrimidin-4-amine (104-3)

To a solution of 104-2 (70 mg, 0.3 mmol) in DMF (3 mL) was added NaH (16 mg, 0.4 mmol, 60%in oil) at 0℃. The mixture was stirred at r.t. for 30 min. Then PMBCl (63 mg, 0.4 mmol) was added. The mixture was stirred at r.t. for 2 h. The mixture was quenched with NH₄Cl (aq. ) , and extracted with EA (2*10 mL) . The combined organic layer was washed with water (8 mL) and brine (8 mL) , dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EA =5/1～2/1) to give 104-3 (40 mg, 37%) as a yellow oil. MS (ESI) m/z 358 [M+H] ⁺.

Step 3: 4- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) (pyrimidin-4-yl) amino) methyl) phenol (104)

To a solution of 104-3 (40 mg, 0.11 mmol) in DCM (3 mL) was added BBr₃ (0.2 mL, 0.2 mmol, 1M in DCM) dropwise at -20℃. Then the mixture was stirred at r.t. for 1 h. Sat. NaHCO₃ (aq. ) (8 mL) was added to the mixture. The organic layer was separated and washed with water (5 mL) and brine (5 mL) , dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (PE/EA =3/1～1/1) to give 104 (5 mg, 13%) as a white solid. MS (ESI) m/z 344 [M+H] ⁺. ¹H NMR (400 MHz, CD₃OD) δ 8.48 (s, 1H) , 8.08 (d, J = 5.8 Hz, 1H) , 7.31 (s, 1H) , 7.05 (d, J = 8.4 Hz, 2H) , 6.75 (d, J = 8.5 Hz, 2H) , 6.69 (d, J = 6.4 Hz, 1H) , 4.59 (s, 2H) , 3.88-3.81 (m, 5H) , 3.04 (t, J = 6.9 Hz, 2H) .

N- (4-hydroxybenzyl) -4-methyl-N- (2-oxo-2- (thiazol-5-ylamino) ethyl) thiazole-2-carboxamide (105)

Step 2 was performed according to the procedure outlined for the preparation of 62-1.

Step 3 was performed according to the procedure outlined for the preparation of 72-4.

Step 4 was performed according to the procedure outlined for the preparation of 4 to afford 105 (20 mg, 23%) as a white solid. MS (ESI) m/z 389 [M+H] ⁺. 1H NMR (400 MHz, CDCl₃) δ 8.73 (s, 0.35H) , 8.72 (s, 0.65H) , 7.78 (s, 0.35H) , 7.77 (s, 0.65H) , 7.62-7.55 (m, 1H) , 7.39 (d, J = 8.4 Hz, 2H) , 6.94 (d, J = 8.4 Hz, 2H) , 5.61 (s, 0.7H) , 5.02 (s, 1.3H) , 4.94 (s, 1.3H) , 4.40 (s, 0.7H) , 2.67 (s, 1H) , 2.51 (s, 2H) .

6- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) (pyrimidin-4-yl) amino) methyl) benzo [d] oxazol-2 (3H) -one (106)

106-1 was performed according to the procedure outlined for the preparation of 99-1.

A solution of 6- ( ( (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) amino) methyl) benzo [d] oxazol-2 (3H) -one (50 mg, 0.16 mmol) , 4-chloropyrimidine (49 mg, 0.33 mmol) and TEA (0.1 mL, 0.82 mmol) in EtOH (2 mL) was stirred at 100℃ for 6 h in a microwave reactor. The mixture was concentrated under vacuum. The residue was purified by prep-HPLC to give 106 (4 mg, 6.7%) as a white solid. MS (ESI) m/z 385 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (s, 1H) , 8.14 (d, J = 6.0 Hz, 1H) , 7.40 (s, 1H) , 7.09 (s, 1H) , 7.00 –6.97 (m, 2H) , 6.65 (d, J = 6.4 Hz, 1H) , 4.64 (s, 2H) , 3.81 –3.70 (m, 5H) , 2.95 (t, J = 6.8 Hz, 2H) .

N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (6-oxo-5-oxa-7-azaspiro [3.4] octan-2-yl) methyl) thiazole-2-carboxamide (107)

Step 1. N- ( (5, 8-dioxaspiro [3.4] octan-2-yl) methyl) -N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methylthiazole-2-carboxamide (107-1)

To a solution of 97-1 (1 g, 3.5 mmol) in NMP (10 mL) was added NaH (211 mg, 5.3 mmol, 60%in mineral oil) at 0℃. The mixture was stirred at 0℃ for 30 min. A solution of 2- (bromomethyl) -5, 8-dioxaspiro [3.4] octane (1.5 g, 7.0 mmol) in NMP (10 mL) was added to the mixture. The mixture was stirred at 70℃ overnight under N₂. The mixture was cooled to r.t, poured into NH₄Cl (aq. ) (20 mL) , extracted with EA (20 mL*2) and the combined organic layers were concentrated under vacuum. The residue was purified by reversed phase column to give 107-1 (250 mg, 17%) as a yellow solid. MS (ESI) m/z 411 [M+H] ⁺.

Step 2 was performed according to the procedure outlined for the preparation of 83-2.

Step 3. N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -N- ( (3-hydroxy-3- (nitromethyl) cyclobutyl) methyl) -4-methylthiazole-2-carboxamide (107-3)

A mixture of N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (3-oxocyclobutyl) methyl) thiazole-2-carboxamide (200 mg, 0.55 mmol) and K₂CO₃ (98 mg, 0.71 mmol) in MeNO₂ (4 mL) and DMSO (4 mL) was stirred at 35℃ overnight under N₂. The mixture was poured into water (10 mL) , extracted with EA (10 mL*3) and the combined organic layers were concentrated under vacuum. The residue was purified by FCC (PE/EA = 1/1) to give 107-3 (140 mg, 60%) as a yellow solid. MS (ESI) m/z 428 [M+H] ⁺.

Step 4. N- ( (3- (aminomethyl) -3-hydroxycyclobutyl) methyl) -N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methylthiazole-2-carboxamide (107-4)

A mixture of 107-3 (140 mg, 0.33 mmol) , Zn (406 mg, 6.56 mmol) and NH₄Cl (351 mg, 6.56 mmol) in EtOH/H₂O (10 mL/5 mL) was stirred at r.t. overnight under N₂. The mixture was filtered. The filtrate was concentrated. The residue was stirred in DCM for 10 min and filtered, and the filtrate was concentrated to give 107-4 (130 mg, crude) as a yellow oil. MS (ESI) m/z 398 [M+H] ⁺.

Step 5. N- (2- (4-chloro-1-methyl-1H-pyrazol-5-yl) ethyl) -4-methyl-N- ( (6-oxo-5-oxa-7-azaspiro [3.4] octan-2-yl) methyl) thiazole-2-carboxamide (107)

A mixture of 107-4 (130 mg, 0.33 mmol) and CDI (80 mg, 0.49 mmol) in ACN (5 mL) was stirred at 70℃ for 3 h. The mixture was poured into water (10 mL) and extracted with EA (10 mL*3) and the combined organic layers were concentrated under vacuum. The residue was purified by prep-HPLC to give 107 (22 mg, 16.3%) as a yellow solid. MS (ESI) m/z 424 [M+H] ⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 7.58 (s, 0.5H) , 7.49-7.46 (m, 2H) , 7.30 (s, 0.5H) , 4.27 –4.08 (m, 2H) , 3.83 (s, 1H) , 3.73 (s, 2H) , 3.60 –3.49 (m, 4H) , 2.96 –2.99 (m, 2H) , 2.44-2.40 (m, 3H) , 2.36 –2.04 (m, 5H) .

Example II. NAMPT Enzymatic and Cellular Assays

A. NMN Fluorescence Biochemical Assay

Certain compounds described herein were assayed for their ability to stimulate the synthesis of nicotinamide mononucleotide (NMN) by human enzyme NAMPT (full length) . The enzymatic assay was performed in a 384-well plate using a TMD buffer (50 mM Tris-HCl, 10 mM MgCl2, 2 mM DTT, pH 7.5) . Purified NAMPT (100 nM) was pre-incubated with 0.2 μL DMSO solution of the test compound (with a series of concentrations) in 10 μL TMD buffer for 15 min at 37 ℃. The reaction was initiated by adding a 10 μL solution of NAM (50 μM) , PRPP (100 μM) , and ATP (4 mM) in TMD buffer. After 1 h of incubation at 37 ℃, an aliquot (20μL) of the NMN-containing sample was sequentially mixed with 5μL of 20%acetophenone (in DMSO) and 5μL of 2M KOH. The mixture was placed on ice for 10 min. Next, 22.5μL of 100%formic acid was added to each sample, vortexed, and then incubated at 37 ℃for 20 min. Fluorescence (Ex/Em = 382/445 nm) was measured using an Envision plate reader. The potency measurements for the test compounds were quantified and represented as EC50 (concentration of a compound that gives half-maximal activation) and Emax (fold change of a compound’s maximal activation compared to DMSO) .

B. Cellular NAD+ Modulation Assay.

Certain compounds described herein were also assayed for their ability to stimulate the endogenous NAMPT in a native cellular environment in a cellular NAD+modulation assay. U2OS cells were grown in McCoy's 5A medium with 10%fetal bovine serum, in a humidified incubator with an atmosphere of 95%air and 5%CO₂ at 37℃. The assays were initiated by plating 30 μL of U2OS cells in a culture medium with 10%fetal bovine serum, at a density of 3000 cells per well in a 384-well White/Clear Bottom Polystyrene Microplate. The plates were incubated in 37℃ incubators for a period of 16 hours. Test compounds with a series of concentrations in DMSO were added to the plates in a volume of 150nL using Echo Liquid handlers. The plates were then incubated for 24 hours. The medium was removed from the wells, and then 10 μL PBS was added to each well. To each well of cells in 10μL of PBS, 10 μL of a base solution with 1%DTAB was added. The plate was briefly mixed on a plate shaker to ensure homogeneity and cell lysis (5 mins) . 10μL of 0.4N HCl was added per well. The plate was coved, and all samples were incubated for 15 minutes at 60℃. Then the plate was equilibrated for 10 minutes at room temperature. 10μL of 0.5M base was added to each well of acid-treated cells to neutralize the acid. Finally, 30μL of NAD/NADH-Glo^TM Detection Reagent was added. The plate was gently shaken to mix the samples. The plate was incubated for 40 minutes at room temperature. Luminescence was recorded using a luminometer. The potency measurements for the test compounds were quantified and represented as EC50 (concentration of a compound that gives half-maximal activation) and Emax (fold change of a compound’s maximal activation compared to DMSO) .

Activities of the compounds as tested in the above-described two assays are summarized in Table 2. In Table 2, the activities (EC50 and Emax for the enzymatic assay and the cellular assay, respectively) are provided as follows:

Enzymatic EC50: A < 0.5 μM ≤ B < 5 μM ≤ C < 50 μM ≤ D

Enzymatic Emax: A > 3 ≥ B > 2 ≥ C

Cellular EC50: A< 0.5 μM ≤ B< 5 μM ≤ C < 50 μM ≤ D

Cellular Emax: A > 1.5 ≥ B > 1.2 ≥ C

Table 2

All publications, including but not limited to disclosures and disclosure applications, cited in this specification are herein incorporated by reference as though fully set forth. If certain content of a publication cited herein contradicts or is inconsistent with the present disclosure, the present disclosure controls.

One skilled in the art will readily recognize from the disclosure and claims that various changes, modifications, and variations can be made therein without departing from the spirit and scope of the disclosure as defined in the following claims.

Claims

A compound of the following structural Formula 1:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein:

Ring A is selected from 6-to 10-membered aryl, 5-to 10-membered heteroaryl, 3-to 12-membered heterocyclyl, and 3-to 12-membered cycloalkyl, wherein Ring A is substituted with m groups of R^a;

Ring B is selected from 6-to 10-membered aryl, 5-to 10-membered heteroaryl, 3-to 12-membered heterocyclyl, and 3-to 12-membered cycloalkyl, wherein Ring B is substituted with n groups of R^b;

Ring C is selected from 6-to 10-membered aryl and 5-to 10-membered heteroaryl, wherein Ring C is substituted with p groups of R^c;

R^a, for each occurrence, is independently selected from halogen, -NR^pR^q, -OR^s, =O, and optionally substituted C₁-C₆ alkyl;

R^b, for each occurrence, is independently selected from halogen, -CN, -C (=O) NR^pR^q, -S (=O) ₂R^s, optionally substituted C₁-C₆ alkyl, optionally substituted 3-to 6-membered cycloalkyl, optionally substituted 3-to 6-membered heterocyclyl, optionally substituted 5-to 6-membered heteroaryl, and optionally substituted phenyl;

R^c, for each occurrence, is independently selected from halogen, CN, and optionally substituted C₁-C₆ alkyl; wherein:

R^p, R^q, and R^s, for each occurrence, are each independently selected from H and optionally substituted C₁-C₆ alkyl;

L¹, L², and L³ are each independently selected from: a bond, C₁-C₆ alkylenyl, C₂-C₆ alkenylenyl, C₂-C₆ alkynylenyl, C₀-C₆ alkylenyl- (C=O) -C₀-C₆ alkylenyl, C₀-C₆ alkylenyl-S (=O) ₂-C₀-C₆ alkylenyl, C₀-C₆ alkylenyl-NHC (=O) -C₀-C₆ alkylenyl, and C₀-C₆ alkylenyl-C (=O) NH-C₀-C₆ alkylenyl, andwherein Ring D is selected from optionally substituted 3-to 6-membered cycloalkyl and optionally substituted 3-to 6-membered heterocyclyl;

provided that when one of Ring A and Ring B is phenyl orneither the other one of Ring A and Ring B nor Ring C isoptionally substituted with 1 to 3 groups selected from C₁-C₃ alkyl;

m is an integer selected from 0, 1, 2, and 3;

n is an integer selected from 0, 1, 2, and 3; and

p is an integer selected from 0, 1, 2, and 3.
The compound of claim 1, wherein the compound has the following structural Formula 2a, Formula 2b, Formula 2c, or Formula 2d:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein X¹, X², X³, X⁴, and X⁵, where applicable, are each independently selected from C and N; Z¹, Z², Z³, and Z⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Z¹, Z², Z³, and Z⁴ can be S or O; W¹ and W², where applicable, are each independently selected from C, N, S, and O; U¹, U², U³, U⁴, and U⁵, where applicable, are each independently selected from C and N.
The compound of claim 1, wherein the compound has the following structural Formula 3a, Formula 3b, Formula 3c, or Formula 3d:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein X¹, X², X³, X⁴, and X⁵, where applicable, are each independently selected from C and N; Y¹, Y², Y³, and Y⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Y¹, Y², Y³, and Y⁴ can be S or O; Z¹, Z², Z³, and Z⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Z¹, Z², Z³, and Z⁴ can be S or O; W¹ and W², where applicable, are each independently selected from C, N, S, and O; U¹, U², U³, U⁴, and U⁵, where applicable, are each independently selected from C and N; V¹, V², V³, V⁴, and V⁵, where applicable, are each independently selected from C and N.
The compound of claim 1, wherein the compound has the following structural Formula 4a, Formula 4b, Formula 4c, or Formula 4d:

a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, wherein Y¹, Y², Y³, and Y⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Y¹, Y², Y³, and Y⁴ can be S or O; Z¹, Z², Z³, and Z⁴, where applicable, are each independently selected from C, N, S, and O, provided that only one of Z¹, Z², Z³, and Z⁴ can be S or O; W¹ and W², where applicable, are each independently selected from C, N, S, and O; U¹, U², U³, and U⁴, where applicable, are each independently selected from C and N; V¹, V², V³, V⁴, and V⁵, where applicable, are each independently selected from C and N.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein: Ring A is selected from phenyl, benzoxazolyl, dihydrobenzoxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrotriazinyl, benzotriazolyl, benzimidazolyl, indazolyl, triazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, and 5-oxa-7-azaspiro [3.4] octanyl, wherein Ring A is substituted with m groups of R^a.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 and 5, wherein: Ring A is selected from: wherein Ring A is substituted with m groups of R^a.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein: of Formula 1 is selected from:
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1, 2, and 5-7, wherein: Ring B is selected from phenyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, dihydropyridinyl, dihydropyrimidinyl, dihydrotriazinyl, quinolinyl, benzoimidazolyl, indazolyl, benzothiazolyl, tetrahydropyridinylthiazolyl, triazolyl, and piperidinyl, wherein Ring B is substituted with b groups of R^b.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1, 2, and 5-8, wherein: Ring B is selected from:
wherein Ring B is substituted with n groups of R^b.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1, 2, and 5-9, wherein: of Formula 1 is selected from:
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 and 5-10, wherein: Ring C is selected from phenyl, thiazolyl, imidazolyl, thiophenyl, pyrazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, dihydropyridinyl, triazolyl, triazinyl, and benzothiazolyl, wherein Ring C is substituted with p groups of R^c.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 and 5-11, wherein: Ring C is selected from: wherein Ring C is substituted with p groups of R^c.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1 and 5-12, wherein: of Formula 1 is selected from:
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of claim 1, wherein:

Ring A is selected from:

Ring B is selected from:

Ring C is selected from:
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-6 and 8-14, wherein: R^a is selected from: halogen, -NR^pR^q, -OR^s, C₁-C₄ alkyl, and =O,

wherein R^p and R^q are each independently selected from H and C₁-C₃ alkyl, and

R^s is selected from H and C₁-C₃ alkyl,

wherein the C₁-C₃ alkyl of R^s, R^p, and R^q is optionally substituted with 1-3 groups selected from halogen.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-6 and 8-15, wherein: R^a is selected from: F, -OCHF₂, -OH, -OCH₃, -NHCH₃, and =O.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-9 and 11-16, wherein: R^b is selected from: halogen, C₁-C₆ alkyl, -CN, -C (=O) NR^pR^q, -S (=O) ₂R^s, 3-to 6-membered cycloalkyl, 3-to 6-membered heterocyclyl (optionally substituted with =O) , 5-to 6-membered heteroaryl, and phenyl,

wherein the C₁-C₆ alkyl of R^b is optionally substituted with 1-3 groups selected from halogen, -NR^pR^q, and -OR^s,

wherein R^p, R^q , and R^s, for each occurrence, are each independently selected from H and C₁-C₃ alkyl optionally substituted with 1-3 groups selected from halogen.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-9 and 11-17, wherein: R^b is selected from: Cl, Br, -CN, -CH₃, -CH₂CH₃, -CH (CH₃) ₂, -CHF₂, -CF₃, -CH₂N (CH₃) ₂, -CH₂CH₂OCH₃, -C (=O) NH₂, -S (=O) ₂CH₃,
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-12 and 14-18, wherein: R^c is selected from: halogen, C₁-C₄ alkyl, and -CN.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-12 and 14-19, wherein: R^c is selected from: Cl, Br, -CH₃, and -CN.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-6, 8-9, 11-12, and 14, wherein:

R^a is selected from: halogen, NR^pR^q, OR^s, C₁-C₄ alkyl, and =O;

R^b is selected from: halogen, C₁-C₃ alkyl, -CN, -C (=O) NR^pR^q, -S (=O) ₂R^s, wherein the C₁-C₃ alkyl of R^b is optionally substituted with 1-3 groups selected from halogen, -NR^pR^q, and -OR^s;

R^c is selected from: halogen, C₁-C₂ alkyl, and -CN;

wherein R^p, R^q, and R^s, for each occurrence, are each independently selected from H and C₁-C₂ alkyl optionally substituted with 1-3 groups selected from halogen.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-6, 8-9, 11-12, 14, and 21, wherein:

R^a is selected from: OH and =O; and

R^c is selected from: Cl, Br, CH₃, and -CN.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-22, wherein: L¹ is selected from: a bond, C₁-C₄ alkylenyl, C₂-C₄ alkenylenyl, and C₂-C₄ alkynylenyl.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-23, wherein: L¹ is selected from: -CH₂-, -CH₂CH=CH-, and
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-24, wherein: L² is selected from: a bond, C₀-C₄ alkylenyl- (C=O) -C₀-C₄ alkylenyl, C₀-C₄ alkylenyl-S (=O) ₂C₀-C₄ alkylenyl, C₀-C₄ alkylenyl-NHC (=O) -C₀-C₄ alkylenyl, and C₀-C₄ alkylenyl-C (=O) NH-C₀-C₄ alkylenyl.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-25, wherein: L² is selected from: a bond, -C (=O) -, -S (=O) ₂-, -CH₂C (=O) -, and -NHC (=O) -.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-26, wherein: L³ is selected from: a bond, C₁-C₄ alkylenyl, C₀-C₄ alkylenyl-NHC (=O) -C₀-C₄ alkylenyl, C₀-C₄ alkylenyl-C (=O) NH-C₀-C₄ alkylenyl, andwherein Ring D is selected from 3-to 6-membered cycloalkyl and 3-to 6-membered heterocyclyl.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-27, wherein: L³ is selected from: a bond, -CH₂-, -CH₂CH₂-,
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-28, wherein: m is 1.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-29, wherein: n is selected from: 0, 1, and 2.
The compound, tautomer, solvate, stereoisomer, or pharmaceutically acceptable salt of any one of claims 1-30, wherein: p is selected from: 0, 1, and 2.
The compound according to claim 1, wherein the compound is selected from Compounds 1 to 107 in Table 1, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing.
A pharmaceutical composition comprising a compound according to any one of claims 1 to 32, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing and at least one pharmaceutically acceptable carrier.
A method of treating a disease or condition, comprising administering to a subject in need thereof, an effective amount of a compound according to any one of claims 1 to 32, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or the pharmaceutical composition according to claim 33, wherein the disease or condition is selected from cardiac diseases, renal diseases, hyperproliferative diseases or conditions, cancer, chemotherapy induced tissue damage, renal diseases, metabolic diseases, muscular diseases, neurological diseases and injuries, inflammatory diseases or conditions, mitochondrial diseases, ocular diseases, diseases caused by impaired stem cell function, DNA damages, 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 syndrome, neonatal nerve injury, aging, axonal degeneration, carpal tunnel syndrome, Guillain-Barre syndrome, nerve damage, polio (poliomyelitis) , and spinal cord injury.
A method of treating a disease or condition responsive to NAMPT activation, comprising administering to a subject in need thereof, an effective amount of a compound according to any one of claims 1 to 32, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition according to claim 33.
A method of modulating NAMPT, comprising contacting a subject or a cell in need thereof with a compound according to any one of claims 1 to 32, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition according to claim 33.
A method of increasing NAD+ level, comprising contacting a subject or a cell in need thereof with a compound according to any one of claims 1 to 32, a tautomer thereof, a solvate or stereoisomer of the compound or the tautomer, or a pharmaceutically acceptable salt of the foregoing, or a pharmaceutical composition according to claim 33.