HK40032693B - Selective inhibitors of nlrp3 inflammasome - Google Patents

Description

Selective inhibitors of the NLRP3 inflammasome

Related applications

This application claims priority to UK Patent Application No. 1712282.1, filed on July 31, 2017, the entire contents of which are incorporated herein by reference.

open field

This disclosure relates to specific novel compounds and their directly related prodrugs or pharmaceutically acceptable salts, which have inflammasome-inhibiting activity and are therefore suitable for use in treating human or animal bodies. This disclosure also relates to methods of preparing these compounds, to pharmaceutical compositions comprising them, and to their use in treating conditions involving inflammasome activity, such as autoinflammatory and autoimmune diseases and neoplastic diseases.

background

Autoimmune diseases are associated with the overproduction of pro-inflammatory factors. One of these is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells. It is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Seth L.al.Rev.Immunol.2009.27:621–68).

In humans, 22 NLR proteins are classified into four NLR subfamilies based on their N-terminal domains. NLRA contains the CARD-AT domain, NLRB (NAIP) contains the BIR domain, NLRC (including NOD1 and NOD2) contains the CARD domain, and NLRP contains the pyrin domain. Several NLR family members are involved in inflammasome formation, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to endogenous or exogenous sterile danger signals. Many such sterile signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in patients with gout are potent triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of sterile danger signals as NLRP3 activators leads to the involvement of IL-1 and IL-18 in a variety of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

This disclosure stems from the need to provide novel compounds for the specific regulation of NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties relative to existing compounds are desired.

Overview

In some respects, this disclosure particularly provides compounds of formula (I):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt, wherein:

_R1 is a _C3 - _C7 monocyclic cycloalkyl, polycyclic cycloalkyl, _C5 - _C10 aryl, 8- to 12-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl, wherein the _C3 - _C7 monocyclic cycloalkyl, polycyclic cycloalkyl, _C5 - _C6 aryl, 8- to 12-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more _R6 ;

_R3 is H or a _C1 - _C4 alkyl group optionally substituted with one or more _R7s ;

_R4 is H, _C1 - _C6 alkyl, -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl), or -( _CH2 )O- ₃ - _C5 - _C6 aryl;

_R6 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, halogen, oxo, -OH, -CN, _-NH2 , -NH( _C1 - _C6 alkyl), -N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 ;

_R7 is _-OR8 , _C5 - _C10 aryl, or 5- to 10-membered heteroaryl, wherein the _C5 - _C10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more _R7S , wherein each _R7S is independently _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 5- to 10-membered heteroaryl, halogen, -OH, -CN, -( _CH2 ) _{O-3- NH2} , -( _CH2 ) _O-3- NH( _C1 - _C6 alkyl), -( _CH2 ) _O-3- N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 ; and

_R8 is a _C1 - _C6 alkyl or a 5- to 7-membered heterocyclic alkyl, wherein the _C1 - _C6 alkyl or the 5- to 7-membered heterocyclic alkyl is optionally substituted by one or more _R7S .

In some aspects, this disclosure provides compounds that are obtainable or acquired by methods of preparation of compounds as described herein (e.g., methods comprising one or more steps as described in schemes 1-5).

In some aspects, this disclosure provides pharmaceutical compositions comprising a compound of the disclosure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier.

In some respects, this disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein (e.g., the intermediates are selected from those described in Examples 1-126).

In some aspects, this disclosure provides a method for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo), which includes contacting cells with an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, this disclosure provides methods for treating or preventing diseases or conditions disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

In some aspects, this disclosure provides compounds of the disclosure or pharmaceutical salts thereof for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome), either in vitro or in vivo.

In some respects, this disclosure provides compounds of this disclosure or pharmaceutical salts thereof for the treatment or prevention of diseases or conditions disclosed herein.

In some aspects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo).

In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

In some respects, this disclosure provides methods for preparing the compounds of this disclosure.

In some aspects, this disclosure provides methods for compounding a compound, which include one or more steps described herein.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the specification, the singular form also includes the plural unless the context clearly indicates otherwise. Although similar or equivalent methods and materials to those described herein may be used in the practice or testing of this disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. References cited herein are not to be acknowledged as prior art to the claimed invention. In case of conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are illustrative only and are not intended to be restrictive. In case of conflict between chemical structures and the names of compounds disclosed herein, the chemical structure shall prevail.

Other features and advantages of this disclosure will become apparent from the following detailed description and claims.

Detailed description

Autoimmune diseases are associated with the overproduction of pro-inflammatory factors. One of these is interleukin-1 (IL-1), produced by activated macrophages, monocytes, fibroblasts, and other components of the innate immune system, such as dendritic cells. It is involved in a variety of cellular activities, including cell proliferation, differentiation, and apoptosis (Seth L.al.Rev.Immunol.2009.27:621–68).

IL-1 family cytokines are highly active and act as important mediators of inflammation, primarily associated with acute and chronic inflammation (Sims J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)). Overproduction of IL-1 is considered a mediator of certain autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and seemingly unprovoked inflammation in the absence of autoantibodies, infection, or antigen-specific T lymphocytes.

The IL-1 superfamily of pro-inflammatory cytokines includes IL-1α, IL-1β, IL-18, and IL-36α,β,γ, which are produced as part of the host's innate immune response in response to pathogens and other cellular stressors. Unlike many other secreted cytokines that are processed and released via standard cellular secretory organs composed of the endoplasmic reticulum and Golgi apparatus, IL-1 family members lack the leader sequences required for endoplasmic reticulum entry and are therefore retained intracellularly after translation. Furthermore, IL-1β, IL-18, and IL-36α,β,γ are synthesized as procytokines, which require proteolytic activation to become optimal ligands for binding to their homologous receptors on target cells.

In the case of IL-1α, IL-1β, and IL-18, it is now recognized that a multimeric protein complex called the inflammasome is responsible for activating the proforms of IL-1β and IL-18 and for the extracellular release of these cytokines. The inflammasome complex typically consists of sensor molecules such as NLR (nucleotide-oligomery domain (NOD)-like receptors), adaptor molecules such as ASC (apoptosis-associated speckled protein containing CARD (caspase recruitment domain)), and caspase precursor-1. In response to various “danger signals,” including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), the subunits of the inflammasome oligomerize intracellularly to form supramolecular structures. PAMPs include molecules such as peptidoglycans, viral DNA or RNA, and bacterial DNA or RNA. DAMPs, on the other hand, consist of a variety of endogenous or exogenous sterile triggers, including monosodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and aggregates of β-amyloid peptides. Assembly of the inflammasome platform facilitates the autocatalysis of caspase precursor-1, producing highly active cysteine proteases responsible for activating and releasing pre-IL-1β and pre-IL-18. Thus, the release of these highly inflammatory cytokines occurs only in response to the detection and activation of inflammasome sensors that respond to specific molecular danger signals.

In humans, 22 NLR proteins are classified into four NLR subfamilies based on their N-terminal domains. NLRA contains the CARD-AT domain, NLRB (NAIP) contains the BIR domain, NLRC (including NOD1 and NOD2) contains the CARD domain, and NLRP contains the thermoprotein domain. Several NLR family members are involved in inflammasome formation, including NLRP1, NLRP3, NLRP6, NLRP7, NLRP12, and NLRC4 (IPAF).

Two other structurally distinct inflammasome structures containing the PYHIN domain (proteins containing both the thermoprotein and the HIN domain) (i.e., the absence of melanoma2 (AIM2) and IFNλ-inducible protein 16 (IFI16)) (Latz et al., Nat Rev Immunol 2013 13(6) 397-311) serve as intracellular DNA sensors. The thermoprotein (encoded by the MEFV gene) represents another inflammasome platform associated with pre-IL-1β activation (Chae et al., Immunity 34, 755-768, 2011).

The assembly of the inflammasome platform is required to activate and release IL-1 and IL-1β from monocytes and macrophages, ensuring their production is a carefully coordinated two-step process. First, the cell must encounter a priming ligand (e.g., TLR4 receptor ligand LPS or inflammatory cytokines such as TNFα) that induces NFkB-dependent transcription of NLRP3, pre-IL-1β, and pre-IL-18. The newly translated procytokines remain intracellular and inactive unless the producing cell encounters a second signal that leads to inflammasome scaffold activation and maturation of pro-cysteine 1.

In addition to proteolytic activation of pre-IL-1β and pre-IL-18, active caspase-1 also triggers a form of inflammatory cell death called pyroptosis by cleaving gasdermin-D. Pyroptosis externalizes the mature forms of IL-1β and IL-18, while releasing alarm molecules (compounds that promote inflammation and activate innate and adaptive immunity), such as high-mobility group box 1 (HMGB1), IL-33, and IL-1α.

Although inflammasome activation appears to have evolved as an important component of host immunity to pathogens, the NLRP3 inflammasome is unique in its ability to activate in response to both endogenous and exogenous aseptic danger signals. Many such aseptic signals have been elucidated, and their formation is associated with specific disease states. For example, uric acid crystals found in patients with gout are potent triggers for NLRP3 activation. Similarly, cholesterol crystals found in patients with atherosclerosis can also promote NLRP3 activation. The recognition of the role of aseptic danger signals as NLRP3 activators leads to the involvement of IL-1β and IL-18 in a variety of pathophysiological indications, including metabolic, physiological, inflammatory, hematological, and immunological disorders.

The link to human diseases is best illustrated by the following findings: mutations in the NLRP3 gene that lead to gain of function result in a range of autoinflammatory conditions collectively known as cold pyridine-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal onset of multisystem inflammatory disease (NOMID) (Hoffman et al., Nat Genet. 29(3)(2001) 301-305). Similarly, sterile mediator-induced NLRP3 activation is involved in a variety of conditions, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system disorders (Alzheimer's disease, Parkinson's disease, multiple sclerosis), gastrointestinal disorders (Crohn's disease, ulcerative colitis), lung disorders (chronic obstructive pulmonary disease, asthma), and fibrosis (non-alcoholic fatty liver disease, non-alcoholic hepatic steatosis, idiopathic pulmonary fibrosis). Furthermore, it is believed that NLRP3 activation promotes kidney inflammation, thus leading to chronic kidney disease (CKD).

Current treatment options for diseases involving IL-1 as a pathogenic factor include the IL-1 receptor antagonist anakinase, the Fc-containing fusion construct of the extracellular domain of the IL-1 receptor and the IL-1 receptor accessory protein (linasip), and the anti-IL-1β monoclonal antibody nabamazanol. For example, nabamazanol is licensed for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalerate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

Several small molecules have been reported to inhibit the function of the NLRP3 inflammasome. For example, glibenclamide is a specific inhibitor of NLRP3 activation, although at micromolar concentrations that are impossible to achieve in vivo. Non-specific drugs such as parthenolide, Bay11-7082, and 3,4-methylenedioxy-β-nitrostyrene have been reported to reduce NLRP3 activation, but are expected to have limited therapeutic use due to their shared structural feature of consisting of electron-withdrawing groups replacing activated olefins; this leads to undesirable covalent adducts with proteins containing thiol groups. Numerous natural products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to inhibit NLRP3 activation. Similarly, many effectors/regulators of other molecular targets have been reported to reduce NLRP3 activation, including agonists of the G protein-coupled receptor TGR5, the sodium-glucose cotransporter epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, the fenamic acid ester NSAID, and the β-adrenergic receptor blocker nebivolol. The use of these molecules as long-term treatments for NLRP3-dependent inflammatory conditions remains to be established. A number of sulfonylurea-containing molecules have previously been identified as potent and selective inhibitors of pre-IL-1β post-translational processing (Perregaux et al., J Pharmacol. Exp. Ther. 299, 187-197, 2001). The example molecule CP-456,773 from this work was recently characterized as a specific inhibitor of NLRP3 activation (Coll et al., Nat Med 21.3 (2015): 248-255.).

This disclosure relates to compounds that can be used to specifically regulate NLRP3-dependent cellular processes. In particular, compounds with improved physicochemical, pharmacological, and pharmaceutical properties relative to existing NLRP3-regulating compounds are desired.

definition

Unless otherwise stated, the following terms used in the specification and claims have the following meanings as described below.

It should be understood that references to “treating” or “treatment” include the relief of established symptoms of a condition. Therefore, “treating” or “treatment” for a state, condition or illness includes: (1) preventing or delaying the onset of clinical symptoms of the state, condition or illness in a person who may have or is susceptible to the state, condition or illness but has not yet experienced or exhibited clinical or subclinical symptoms of the state, condition or illness; (2) suppressing the state, condition or illness, i.e., preventing, reducing or delaying the disease or its recurrence (in the case of maintenance treatment) or the formation of at least one of its clinical or subclinical symptoms; or (3) alleviating or reducing the disease, i.e. causing the disappearance of the state, condition or illness or at least one of its clinical or subclinical symptoms.

"Therapeutic effective amount" refers to the amount of a compound that is sufficient to achieve the therapeutic effect when administered to a mammal to treat a disease. The "therapeutic effective amount" will vary depending on the compound, the disease and its severity, and the age, weight, etc. of the mammal to be treated.

As used herein, “alkyl,” “ _C1 , _C2 , _C3 , _C4 , _C5 , or _C6 alkyl,” or “ _C1 - _C6 alkyl” is intended to include _C1 , _C2 , C3, _C4 , _C5 , or _C6 straight-chain (linear) saturated aliphatic hydrocarbon groups and _{C3 , C4} , C5, or _C6 branched saturated aliphatic hydrocarbon groups. For example, _C1 - _C6 alkyl is intended to include _C1 , _C2 , _C3 , _C4 , _C5 , and _C6 alkyl groups. Examples of alkyl groups include moieties having 1 _to 6 carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, the straight-chain or branched alkyl group has six or fewer carbon atoms (e.g., _C1 - _C6 for straight-chain and _C3 - _C6 for branched-chain), and in another embodiment, the straight-chain or branched alkyl group has four or fewer carbon atoms.

As used herein, the term "cycloalkyl" refers to a monocyclic or polycyclic (e.g., fused, bridged, or spirocyclic) system of a saturated or partially unsaturated hydrocarbon having 3 to 30 carbon atoms (e.g., _C3 - _C12 , _C3 - _C10 , or _C3 - _C8 ). Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthyl, and adamantyl. In some embodiments, the cycloalkyl group is a hexahydroindahalyl group.

As used herein, the term "heterocyclic alkyl" refers to a saturated or partially unsaturated 3-8 membered monocyclic, 7-12 membered bicyclic (fused, bridged, or spirocyclic), or 11-14 membered tricyclic (fused, bridged, or spirocyclic) system having one or more heteroatoms (e.g., O, N, S, P, or Se), such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or such as 1, 2, 3, 4, 5, or 6 heteroatoms, which are independently selected from nitrogen, oxygen, and sulfur, unless otherwise stated. Examples of heterocyclic alkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolyl, dioxyl, tetrahydrofuranyl, isoindolinyl, indololinyl, imidazoalkyl, pyrazolyl, oxazolyl, isoxazolyl, triazolyl, oxacyclopropane, aziridine, oxacyclobutane, thiohexacyclobutane, 1,2,3,6-tetrahydropyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiaranyl, 1,4-diazacycloheptane, and 1,4-oxazhexacycloheptane. 2-oxa-5-azabicyclo[2.2.1]heptyl, 2,5-diazabicyclo[2.2.1]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.3]heptyl, 1,4-dioxa-8-azaspiro[4.5]decyl, 1,4-dioxaspiro[4.5]decyl, l-oxaspiro[4.5]decyl, l-azaspiro[4.5]decyl, 3'H-spiro[cyclohexane-1,1'-isobenzofuran]-yl, 7 'H-spiro[cyclohexane-1,5'-furano[3,4-b]pyridinyl]-yl, 3'H-spiro[cyclohexane-1,1'-furano[3,4-c]pyridinyl]-yl, 3-azabicyclo[3.1.0]hexyl, 3-azabicyclo[3.1.0]hex-3-yl, 1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazole [3,4-c]pyridyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptyl, 2-methyl-2-azaspiro[3.3]heptyl, 2-azaspiro[3.5]nonyl, 2-methyl-2-azaspiro[3.5]nonyl, 2-azaspiro[4.5]decyl, 2-methyl-2-azaspiro[4.5]decyl, 2-oxa-azaspiro[3.4]octyl, 2-oxa-azaspiro[3.4]oct-6-yl, etc. In the case of polycyclic non-aromatic rings, only one ring needs to be non-aromatic (e.g., 1,2,3,4-tetrahydronaphthyl or 2,3-dihydroindole).

As used herein, the term "optionally substituted alkyl" means an unsubstituted alkyl or an alkyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbons of the hydrocarbon backbone. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, phosphonite, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amide (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moieties.

As used herein, the term "alkenyl" includes unsaturated aliphatic groups with lengths and possible substitutions similar to the alkyl groups described above, but containing at least one double bond. For example, the term "alkenyl" includes straight-chain alkenyl groups (e.g., vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In some embodiments, the straight-chain or branched alkenyl group has six or fewer carbon atoms in its backbone (e.g., _C2 - _C6 for straight chains and _C3 - _C6 for branched chains). The term " _C2 - _C6 " includes alkenyl groups containing 2-6 carbon atoms. The term " _C3 - _C6 " includes alkenyl groups containing 3-6 carbon atoms.

As used herein, the term "optionally substituted alkenyl" refers to an unsubstituted alkenyl or an alkenyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, phosphonite, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amide (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties.

As used herein, the term "alkynyl" includes an unsaturated aliphatic group with a length and possible substitutions similar to the alkyl groups described above, but containing at least one triple bond. For example, "alkynyl" includes straight-chain alkynyl groups (e.g., ethynyl, propynyl, butynyl, pentyynyl, hexynyl, heptyynyl, octyynyl, nonynyl, decynyl) and branched-chain alkynyl groups. In some embodiments, the straight-chain or branched alkynyl group has six or fewer carbon atoms in its main chain (e.g., _C2 - _C6 for straight chains and _C3 - _C6 for branched chains). The term " _C2 - _C6 " includes alkynyl groups containing 2-6 carbon atoms. The term " _C3 - _C6 " includes alkynyl groups containing 3-6 carbon atoms. As used herein, “ _C2 - _C6 alkenyl linker” or “ _C2 - _C6 alkyne linker” is intended to include _C2 , _C3 , _C4 , _C5 , or _C6 chain (straight or branched) divalent unsaturated aliphatic hydrocarbon groups. For example, _C2 - _C6 alkenyl linker is intended to include _C2 , _C3 , _C4 , _C5 , and _C6 alkenyl linkers.

As used herein, the term "optionally substituted alkynyl" refers to an unsubstituted alkynyl or an alkynyl with a specified substituent that replaces one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. These substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkyl carbonyloxy, aryl carbonyloxy, alkoxy carbonyloxy, aryloxy carbonyloxy, carboxylic acid ester, alkyl carbonyl, aryl carbonyl, alkoxy carbonyl, amino carbonyl, alkylamino carbonyl, dialkylamino carbonyl, alkyl thiocarbonyl, alkoxy, phosphate ester, phosphonate, phosphonite, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), amide (including alkyl carbonylamino, aryl carbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate, alkyl sulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkyl aryl, or aromatic or heteroaromatic moieties.

Other optional substituted portions (e.g., optional substituted cycloalkyl, heterocycloalkyl, aryl, or heteroaryl) include unsubstituted portions and portions having one or more specified substituents. For example, substituted heterocycloalkyl includes those substituted with one or more alkyl groups, such as 2,2,6,6-tetramethyl-piperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

As used herein, the term "aryl" includes an aromatic group, including a "conjugated" or polycyclic system having one or more aromatic rings, and without any heteroatoms in the ring structure. The term aryl includes both monovalent and divalent types. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, etc. Conveniently, aryl is phenyl.

As used herein, the term "heteroaryl" is intended to include stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocycles consisting of a carbon atom and one or more heteroatoms, such as 1 or 1-2 or 1-3 or 1-4 or 1-5 or 1-6 heteroatoms, or for example 1, 2, 3, 4, 5, or 6 heteroatoms, said heteroatoms being independently selected from nitrogen, oxygen, and sulfur. The nitrogen atom may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents as defined). The nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→O and S(O) _p , where p = 1 or 2). It should be noted that the total number of S and O atoms in an aromatic heterocycle is not greater than 1. Examples of heteroaryl compounds include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetraazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine, etc.

In addition, the terms "aryl" and "heteroaryl" include polycyclic aryl and heteroaryl, such as tricyclic and bicyclic, such as naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthidine, indole, benzofuran, purine, benzofuran, deazopurine, and indazine.

Cycloalkyl, heterocycloalkyl, aryl, or heteroaryl rings may be substituted at one or more ring positions (e.g., the cyclic carbon or heteroatom such as N) with substituents as described above, such as alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylic ester, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylthio Carbonyl, phosphate ester, phosphonate, phosphonite, amino (including alkylamino, dialkylamino, arylamino, diarylamino, and alkylarylamino), amide (including alkylcarbonylamino, arylcarbonylamino, carbamoyl, and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylic acid ester, sulfate ester, alkylsulfinyl, sulfonate, aminosulfonyl, sulfonamide, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moieties. Aryyl and heteroaryl groups may also be fused or bridged with alicyclic or heterocyclic rings that are not aromatic rings to form polycyclic systems (e.g., naphthyl, methylenedioxyphenyl such as benzo[d][1,3]dioxacyclopenten-5-yl).

As used herein, the term "substituted" means that any one or more hydrogen atoms on a specified atom are selectively replaced by a specified group, provided that the substitution does not exceed the normal valence of the specified atom, and that the substitution results in a stable compound. When the substituent is an oxo or ketone group (i.e., =O), two hydrogen atoms on the atom are replaced. Ketone substituents are not present on aromatic moieties. As used herein, a cyclic double bond is a double bond formed between two adjacent ring atoms (e.g., C=C, C=N, or N=N). "Stable compound" and "stable structure" mean that the compound is robust enough to withstand separation from the reaction mixture to a useful purity and formulation into an effective therapeutic agent.

When a cross bond is shown between the substituent and the two atoms in the linking ring, the substituent can bond to any atom in the ring. When a substituent is listed without indicating the atom through which it bonds to the rest of the compound in the given formula, the substituent can bond to any atom in the formula. Combinations of substituents and/or variables are permitted, but only if such combinations produce stable compounds.

When any variable (e.g., R) appears more than once in any component or chemical formula of a compound, its definition for each occurrence is independent of its definition for every other occurrence. Thus, for example, if a substituent group is substituted by 0-2 R moieties, that group may optionally be substituted by up to two R moieties, and the R for each occurrence is independently selected from the definition of R. Combinations of substituents and/or variables are also permitted, but only if such combinations produce stable compounds.

As used herein, the term "hydroxyl" or "hydroxyl group" includes groups having -OH or ^-O- .

As used in this article, the term "halogenated" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

As used herein, the term "alkoxy" or "alkoxy group" includes substituted and unsubstituted alkyl, alkenyl, and alkynyl groups covalently linked to an oxygen atom. Examples of alkoxy or alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, propoxy, butoxy, and pentoxy. Examples of substituted alkoxy groups include haloalkoxy groups. Alkoxy groups can be substituted by groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxy, phosphate ester, phosphonate, phosphonite, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and urea), amido, imino, mercapto, alkylthio, arylthio, thiocarboxylate, sulfate, alkylsulfinyl, sulfonate, aminosulfonyl, sulfonylamino, nitro, trifluoromethyl, cyano, azide, heterocyclic, alkylaryl, or aromatic or heteroaromatic moiety. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy, and trichloromethoxy.

As used herein, the expressions “one or more of A, B or C”, “one or more A, B or C”, “one or more of A, B and C”, “one or more A, B and C”, “selected from the group consisting of A, B and C”, “selected from A, B and C”, etc., are used interchangeably and all refer to selection from the group consisting of A, B, and/or C, that is, one or more A, one or more B, one or more C or any combination thereof, unless otherwise stated.

It should be understood that this disclosure provides methods for synthesizing compounds of any of the formulas described herein. This disclosure also provides detailed methods for synthesizing various disclosed compounds according to the schemes shown in the following examples and embodiments.

It should be understood that throughout this specification, when a composition is described as having, including, or comprising specific components, it is anticipated that the composition is substantially composed of or consisting of the listed components. Similarly, when a method or process is described as having, including, or comprising specific process steps, these processes are also substantially composed of or consisting of the listed processing steps. Furthermore, it should be understood that the order of the steps or the sequence of certain actions is irrelevant as long as the invention remains operable. Moreover, two or more steps or actions can be performed simultaneously.

It should be understood that the synthetic methods disclosed herein are tolerant of a wide range of functional groups, and therefore can use a variety of substituted starting materials. Although in some cases it may be necessary to further convert the compound into its pharmaceutically acceptable salt, the method typically provides the desired final compound at or near the end of the process.

It should be understood that the compounds disclosed herein can be prepared in a variety of ways using commercially available starting materials, compounds known in the literature, or from readily prepared intermediates, using standard synthetic methods and procedures known to those skilled in the art or obvious to those skilled in the art based on the teachings herein. Standard synthetic methods and procedures for the preparation of organic molecules and the transformation and manipulation of functional groups are available from relevant scientific literature or standard textbooks in the art. Although not limited to any one or several sources, classic texts, such as Smith, M.B., March, J., March’s Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition, John Wiley & Sons: New York, 2001; Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999; R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) (incorporated herein by reference), are known and widely accepted reference textbooks on organic synthesis to those skilled in the art.

Those skilled in the art will notice that the order of certain steps can be altered during the reaction sequences and synthetic schemes described herein, such as the introduction and removal of protecting groups. Those skilled in the art will recognize that certain groups may need to be protected from the effects of reaction conditions by using protecting groups. Protecting groups can also be used to distinguish similar functional groups in a molecule. A list of protecting groups and how to introduce and remove these groups can be found in Greene, T.W., Wuts, P.G.M., Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons: New York, 1999.

It should be understood that, unless otherwise stated, any description of a treatment method includes the use of the said compound to provide the treatment or prevention described herein, as well as the use of the said compound to prepare a medicament for the treatment or prevention of this condition. Treatment includes treatment on humans or non-human animals, including rodents and other disease models.

As used herein, the term “subject” may be used interchangeably with the term “subject in need of it,” both referring to a subject who has a disease or an increased risk of developing a disease. “Subject” includes mammals. Mammals can be, for example, humans or suitable non-human mammals such as primates, mice, rats, dogs, cats, cattle, horses, goats, camels, sheep, or pigs. Subjects can also be birds or fowl. In one embodiment, the mammal is a human. Subjects in need of it can be subjects who have been previously diagnosed or identified with an imprinting disease. Subjects in need of it can also be subjects who have (e.g., suffer from) an imprinting disease. Alternatively, subjects in need of it can be subjects who have an increased risk of developing the disease relative to the general population (i.e., subjects who are susceptible to the disease relative to the general population). Subjects in need of it may have a treatment-resistant or resistant imprinting disease (i.e., an imprinting disease that is unresponsive to treatment or has not yet responded to treatment). Subjects may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, subjects in need of it receive and discontinue all known effective therapies for imprinting diseases. In some embodiments, the subject requiring the treatment has received at least one prior treatment. In a preferred embodiment, the subject suffers from imprinting disorder.

As used herein, the term "treatment" or "treatment" describes patient management and care aimed at combating a disease, condition, or symptom, and includes administering the compounds of this disclosure or their pharmaceutically acceptable salts, polymorphs, or solvates to alleviate or eliminate symptoms or complications of a disease, condition, or symptom. The term "treatment" may also include treatment in in vitro cell or animal models.

It should be understood that the compounds disclosed herein, or their pharmaceutically acceptable salts, polymorphs, or solvates, may also be used for the prevention of related diseases, conditions, or symptoms, or for the identification of suitable candidates for this purpose.

As used in this article, the terms “prevention,” “avoidance,” or “avoidance” describe the reduction or elimination of the onset of symptoms or complications of a disease, condition, or ailment.

It should be understood that those skilled in the art can obtain a detailed description of the known or equivalent techniques discussed herein by referring to general reference texts. These texts include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed.), Cold Spring Harbor Press, Cold Spring Harbor, New York (2000); Coligan et al., Current Protocols in Immunology, John Wiley & Sons, N.Y.; Enna et al., Current Protocols in Pharmacology, John Wiley & Sons, N.Y.; Fingl et al., The Pharmacological Basis of Therapeutics (1975), Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 18th ed. (1990). Of course, these texts may also be referenced in the formation or use of aspects of this disclosure.

It should be understood that this disclosure also provides pharmaceutical compositions comprising any of the compounds described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term "pharmaceutical composition" is a formulation comprising a compound of the present disclosure in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is in bulk or unit dosage form. Unit dosage form is any of a variety of forms, including, for example, capsules, IV bags, tablets, a single pump or vial on an aerosol inhaler. The amount of active ingredient (e.g., a formulation of the disclosed compound or its salts, hydrates, solvates or isomers) in a unit dosage composition is an effective amount and varies depending on the specific treatment involved. Those skilled in the art will understand that it is sometimes necessary to routinely change the dosage according to the patient's age and condition. The dosage will also depend on the route of administration. A variety of routes are considered, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, oral, sublingual, intrapleural, intrathecal, intranasal, etc. Dosage forms for topical or transdermal administration of the compounds of the present disclosure include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalers. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any desired preservatives, buffers, or propellants.

As used herein, the term “pharmaceutically acceptable” means those compounds, anionic, cationic, materials, compositions, carriers, and/or dosage forms that are suitable for use in human and animal tissue contact without excessive toxicity, irritation, allergic reactions, or other problems or complications, within the bounds of reasonable medical judgment, and that meet a reasonable benefit/risk ratio.

As used herein, the term "pharmaceuticalally acceptable excipient" means an excipient that can be used to prepare pharmaceutical compositions that are generally safe, non-toxic, and biologically or otherwise undesirable, and includes excipients acceptable for veterinary and human pharmaceutical use. As used in the specification and claims, "pharmaceuticalally acceptable excipient" includes one or more such excipients.

It should be understood that the pharmaceutical compositions of this disclosure are formulated to be compatible with their intended route of administration. Examples of routes of administration include parenteral administration, such as intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (topical), and transmucosal administration. Solutions or suspensions for parenteral, intradermal, or subcutaneous application may include the following components: a sterile diluent, such as water for injection, saline solution, non-volatile oil, polyethylene glycol, glycerol, propylene glycol, or other synthetic solvents; an antibacterial agent, such as benzyl alcohol or methylparaben; an antioxidant, such as ascorbic acid or sodium bisulfite; a chelating agent, such as ethylenediaminetetraacetic acid; a buffer, such as acetate, citrate, or phosphate; and a tonic agent, such as sodium chloride or glucose. The pH may be adjusted with an acid or base, such as hydrochloric acid or sodium hydroxide. Parenteral formulations may be packaged in ampoules, disposable syringes, or multi-dose vials made of glass or plastic.

It should be understood that the compounds or pharmaceutical compositions of this disclosure can be administered to a subject using many of the well-known methods currently used for chemotherapy. For example, the compounds of this disclosure can be injected into the bloodstream or body cavity, or administered orally or through a patch. The chosen dose should be sufficient to constitute an effective treatment, but not high enough to cause unacceptable side effects. Close monitoring of the disease condition (e.g., imprinting) and the patient's health is preferred during and for a reasonable period after treatment.

As used herein, the term "therapeutic effective amount" refers to the amount of a drug agent used to treat, improve, or prevent an identified disease or condition, or to exhibit a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The exact effective amount for a subject will depend on the subject's weight, size, and health; the nature and severity of the condition; and the choice of the therapeutic agent or combination of therapeutic agents used for administration. The therapeutic effective amount for a given situation can be determined by routine testing within the skill and judgment of a clinician. In a preferred aspect, the disease or condition to be treated is an imprinted disease.

It should be understood that for any compound, the therapeutically effective dose can first be estimated in cell culture assays, such as in tumor cells, or in animal models (typically rats, mice, rabbits, dogs, or pigs). Animal models can also be used to determine appropriate concentration ranges and routes of administration. This information can then be used to determine the useful dose and route of administration in humans. Therapeutic/prophylactic efficacy and toxicity can be determined using standard pharmaceutical procedures in cell cultures or laboratory animals, such as _ED50 (the dose effective for 50% of the population) and _LD50 (the dose lethal to 50% of the population). The dose ratio between toxicity and therapeutic effect is the therapeutic index, which can be expressed as the ratio _LD50 / _ED50 . Pharmaceutical compositions with a large therapeutic index are preferred. The dose can vary within this range, depending on the dosage form used, patient sensitivity, and route of administration.

Adjust the dosage and administration to provide sufficient levels of active agent or maintain the desired effect. Factors that may be considered include the severity of the disease state, the subject's overall health, the subject's age, weight and sex, diet, timing and frequency of administration, drug combination, sensitivity to response, and tolerance/response to treatment. Long-acting drug compositions may be administered every 3 to 4 days, weekly, or every two weeks, depending on the half-life and clearance of the specific formulation.

Pharmaceutical compositions comprising the active compounds of this disclosure can be produced in a manner generally known, such as by conventional methods of mixing, dissolving, granulation, sugar coating, grinding, emulsification, encapsulation, embedding, or lyophilization. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers comprising excipients and/or adjuvants that facilitate the processing of the active compounds into pharmaceutically acceptable preparations. Of course, the appropriate formulation depends on the chosen route of administration.

Pharmaceutical compositions suitable for injection include sterile aqueous solutions (when water-soluble) or dispersions, as well as sterile powders for the ad hoc preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, antibacterial water, Cremophor EL ^™ (BASF, Parsippany, NJ), or phosphate-buffered saline (PBS). In all cases, the composition must be sterile and should have a degree of flowability sufficient for easy injectability. It must be stable under manufacturing and storage conditions and must be preserved to prevent contamination by microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium comprising, for example, water, ethanol, polyols (e.g., glycerol, propylene glycol, and liquid polyethylene glycol), and suitable mixtures thereof. Appropriate flowability can be maintained, for example, by using coatings such as lecithin, by maintaining the desired particle size in the case of dispersions, and by using surfactants. Microbial action can be prevented by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases, it is preferable to include isotonic agents in the composition, such as sugars, polyols like mannitol and sorbitol, and sodium chloride. Extended absorption of injectable compositions can be achieved by including agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

Sterile injectable solutions can be prepared by incorporating the desired amount of the active compound with one or a combination of the desired ingredients listed above into a suitable solvent, followed by filtration and sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile medium containing a basic dispersion medium and other desired ingredients from those listed above. In the case of sterile powders used to prepare sterile injectable solutions, the preparation method is vacuum drying and freeze-drying, which yields powders of the active ingredient and any other desired ingredients from its previously sterile filtered solution.

Oral compositions typically contain an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and administered in tablet, lozenge, or capsule form. Oral compositions may also be prepared using fluid carriers for use as mouthwashes, wherein the compound in the fluid carrier is administered orally, gargled, and spat out or swallowed. Pharmaceutically compatible binder and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compound is delivered in the form of an aerosol spray from a pressurized container or dispenser or nebulizer containing a suitable propellant, such as a gas, like carbon dioxide.

Systemic administration can also be performed via transmucosal or transdermal routes. For transmucosal or transdermal administration, a permeabilizing agent suitable for the barrier to be penetrated is used in the formulation. Such permeabilizing agents are generally known in the art and include, for example, cleansers, bile salts, and fusidic acid derivatives used for transmucosal administration. Transmucosal administration can be achieved by using nasal sprays or suppositories. For transdermal administration, the active compound is formulated as an ointment, cream, gel, or lotion, as is generally known in the art.

Active compounds can be prepared with pharmaceutically acceptable carriers that protect the compounds from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulation delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Methods for preparing such formulations are readily apparent to those skilled in the art. These materials are also commercially available from Alza Corporation and Nova Pharmaceuticals, Inc. Liposome suspensions (including liposomes targeting infected cells with monoclonal antibodies against antiviral antigens) can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

Particularly advantageous are oral or parenteral compositions formulated in unit dosage form for ease of administration and uniform dosage. As used herein, unit dosage form refers to physically discrete units suitable as a unit dose for a subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect, along with the desired drug carrier. The specifications of the unit dosage forms disclosed herein are determined by and directly depend on the unique characteristics of the active compound and the specific therapeutic effect to be achieved.

In therapeutic applications, the dosage of the pharmaceutical composition used according to this disclosure varies depending on the dosage, the patient's age, weight, and clinical condition, as well as the experience and judgment of the clinician or practitioner administering the treatment, and other factors that influence the selected dosage. Generally, the dosage should be sufficient to reduce, and preferably eliminate, the symptoms of the imprinting, and preferably cause complete elimination of the imprinting. The dosage can range from about 0.01 mg/kg per day to about 5000 mg/kg per day. In a preferred aspect, the dosage can range from about 1 mg/kg per day to about 1000 mg/kg per day. In one aspect, the dosage will be in the range of about 0.1 mg/day to about 50 g/day; about 0.1 mg/day to about 25 g/day; about 0.1 mg/day to about 10 g/day; about 0.1 mg to about 3 g/day; or about 0.1 mg to about 1 g/day, in a single, divided, or continuous administration (the dosage may be adjusted according to the patient's weight (in kg), body surface area (in ^m² ), and age (in years). An effective dose of a drug is the amount that provides an objectively identifiable improvement, such as that noticed by a clinician or other qualified observer. Improvements in survival and growth indicate regression. As used herein, the term "dose-effective mode" refers to the amount of active compound that produces the desired biological effect in a subject or cell.

It should be understood that the pharmaceutical composition may be included in a container, package, or dispenser along with the instructions for use.

It should be understood that all these forms are also covered within the scope of the claimed disclosure for compounds of this disclosure that are capable of further forming salts.

As used herein, the term "pharmaceutically acceptable salt" refers to a derivative of the compounds disclosed herein, wherein the parent compound is modified by preparing its acidic or basic salt. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic residues (e.g., amines), alkali metal or organic salts of acidic residues (e.g., carboxylic acids), etc. Pharmaceutically acceptable salts include, for example, conventional non-toxic salts or quaternary ammonium salts of parent compounds formed from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, salts derived from inorganic and organic acids selected from: 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, ethacrylic acid, ethanedisulfonic acid, 1,2-ethanesulfonic acid, fumaric acid, glucoheponic acid, gluconic acid, glutamic acid, glycolamide arsenoic acid, hexylresorcinic acid, hyaluronic acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, hydroxyethyl acetic ... hydroxyethyl acetic acid, hydroxyethyl acetic acid, hydroxyethyl acetic acid, hydrochloric acid, hydroiodic acid, hydroxyethyl acetic acid, hydroxyethyl acetic acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, hydrochloric acid, Maleic acid, hydroxynaphthyl carboxylic acid, hydroxyethanesulfonic acid, lactic acid, lactobionic acid, lauryl sulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, naphthalenesulfonic acid, nitric acid, oxalic acid, dihydroxynaphthyl carboxylic acid, pantothenic acid, phenylacetic acid, phosphoric acid, polygalacturonic acid, propionic acid, salicylic acid, stearic acid, subacetic acid, succinic acid, aminosulfonic acid, aminobenzenesulfonic acid, sulfuric acid, tannic acid, tartaric acid, toluenesulfonic acid, and common amino acids such as glycine, alanine, phenylalanine, and arginine.

Other examples of pharmaceutically acceptable salts include hexanoic acid, cyclopentanepropionic acid, pyruvic acid, malonic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo-[2.2.2]-oct-2-ene-1-carboxylic acid, 3-phenylpropionic acid, trimethylacetic acid, tert-butylacetic acid, mucoconic acid, etc. This disclosure also includes salts formed when the acidic protons present in the parent compound are replaced by metal ions such as alkali metal ions, alkaline earth ions, or aluminum ions; or when they are combined with organic bases such as ethanolamine, diethanolamine, triethanolamine, thiocyanate, N-methylglucosamine, etc. In salt form, it should be understood that the ratio of the compound to the cation or anion of the salt can be 1:1, or any ratio other than 1:1, such as 3:1, 2:1, 1:2, or 1:3.

It should be understood that all pharmaceutically acceptable salts mentioned include the same salt in its solvation form (solvent) or crystalline form (polymorph) as defined herein.

It should be understood that the compounds disclosed herein can also be prepared into esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functional group in the compound can be converted into its corresponding ester, such as methyl, ethyl, or other esters. Moreover, the alcohol group in the compound can be converted into its corresponding ester, such as acetate, propionate, or other esters.

The compound or a pharmaceutically acceptable salt thereof may be administered orally, nasally, transdermally, pulmonaryly, by inhalation, orally, sublingually, intraperitoneally, subcutaneously, intramuscularly, intravenously, rectally, intrapleurally, intrathecally, or parenterally. In one embodiment, the compound is administered orally. Those skilled in the art will recognize the advantages of certain routes of administration.

The dosage regimen for the compound is selected based on several factors, including the patient's type, species, age, weight, sex, and medical condition; the severity of the condition to be treated; the route of administration; the patient's renal and hepatic function; and the specific compound or its salt used. A physician or veterinarian with general skills can easily determine and prescribe the effective amount of drug needed to prevent, resist, or halt the progression of the condition.

Techniques for formulating and administering the disclosed compounds of this disclosure can be found in Remington: The Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co., Easton, PA (1995). In one embodiment, the compounds described herein, and their pharmaceutically acceptable salts, are combined with a pharmaceutically acceptable carrier or diluent in a pharmaceutical preparation. Suitable pharmaceutically acceptable carriers include inert solid fillers or diluents and sterile aqueous or organic solutions. The compounds will be present in such pharmaceutical compositions in an amount sufficient to provide the desired dosage within the range described herein.

Unless otherwise stated, all percentages and ratios used herein are by weight. Other features and advantages of this disclosure will be apparent from different embodiments. The provided embodiments illustrate different components and methods that can be used to practice this disclosure. The embodiments do not limit the claimed disclosure. Based on this disclosure, those skilled in the art can identify and employ other components and methods that can be used to practice this disclosure.

In the synthetic schemes described herein, compounds may be drawn in a specific configuration for simplicity. Such a specific configuration should not be construed as limiting this disclosure to one or another isomer, tautomer, regio isomer, or stereoisomer, nor does it exclude mixtures of isomers, tautomers, regio isomers, or stereoisomers; however, it should be understood that a given isomer, tautomer, regio isomer, or stereoisomer may have a higher level of activity than another isomer, tautomer, regio isomer, or stereoisomer.

All publications and patent documents cited herein are incorporated herein by reference as if each such publication or document were specifically and individually indicated to be incorporated herein by reference. The citation of publications and patent documents is not intended to acknowledge any relevant prior art, nor does it constitute any admission of their content or dates. The invention has now been described in writing, and those skilled in the art will recognize that the invention can be practiced in various embodiments, and that the foregoing description and the following examples are for illustrative purposes and not to limit the scope of the following claims.

As used herein, the phrase “compounds disclosed herein” refers to those compounds disclosed generally and specifically herein.

The compounds disclosed herein

In some respects, this disclosure relates to compounds of formula (I):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt, wherein:

_R1 is a _C3 - _C7 monocyclic cycloalkyl, polycyclic cycloalkyl, _C5 - _C10 aryl, 8- to 12-membered heterocyclic cycloalkyl, or 5- to 6-membered heteroaryl, wherein the _C3 - _C7 monocyclic cycloalkyl, polycyclic cycloalkyl, 8- to 12-membered heterocyclic cycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more _R6 ;

_R3 is H or a _C1 - _C4 alkyl group optionally substituted with one or more _R7s ;

_R4 is H, _C1 - _C6 alkyl, -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl), or -( _CH2 )O- ₃ - _C5 - _C6 aryl;

_R6 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, halogen, oxo, -OH, -CN, _-NH2 , -NH( _C1 - _C6 alkyl), -N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 ;

_R7 is _-OR8 , _C5 - _C10 aryl, or 5- to 10-membered heteroaryl, wherein the _C5 - _C10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more _R7S , wherein each _R7S is independently _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 5- to 10-membered heteroaryl, halogen, -OH, -CN, -( _CH2 ) _{O-3- NH2} , -( _CH2 ) _O-3- NH( _C1 - _C6 alkyl), -( _CH2 ) _O-3- N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 ; and

_R8 is a _C1 - _C6 alkyl or a 5- to 7-membered heterocyclic alkyl, wherein the _C1 - _C6 alkyl or the 5- to 7-membered heterocyclic alkyl is optionally substituted by one or more _R7S .

It should be understood that for compounds of formula (I), _R1 , _R3 , _R4 , _R6 , _R7 , _R7S and _R8 may each be selected from the groups described herein where applicable, and any group described herein for any one of _R1 , _R3 , _R4 , _R6 , _R7 , _R7S and _R8 may, where applicable, combine with any of the remaining groups described herein for one or more of _R1 , _R3 , _R4 , _R6 , _R7 , _R7S and _R8 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl, _C8 - _C16 polycyclic cycloalkyl, _C5 - _C10 aryl, 8- to 12-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl, wherein the _C3 - _C7 monocyclic cycloalkyl, _C8 - _C16 polycyclic cycloalkyl, 8- to 12-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl, _C9 - _C10 bicyclic cycloalkyl, _C12 - _C16 tricyclic cycloalkyl, _C5 - _C10 aryl, 8- to 12-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl, wherein the _C3 - _C7 monocyclic cycloalkyl, _C9 - _C10 bicyclic cycloalkyl, _C12 - _C16 tricyclic cycloalkyl, 8- to 12-membered heterocyclic alkyl, or 5- to 6-membered heteroaryl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl, polycyclic cycloalkyl, or _C5 - _C10 aryl, wherein the _C3 - _C7 monocyclic cycloalkyl, polycyclic cycloalkyl, or _C5 - _C6 aryl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl, _C8 - _C16 polycyclic cycloalkyl, or _C5 - _C10 aryl, wherein the _C3 - _C7 monocyclic cycloalkyl, _C8 - _C16 polycyclic cycloalkyl, or _C5 - _C6 aryl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl, _C9 - _C10 bicyclic cycloalkyl, _C12 - _C16 tricyclic cycloalkyl, or _C5 - _C10 aryl, wherein the _C3 - _C7 monocyclic cycloalkyl, _C9 - _C10 bicyclic cycloalkyl, _C12 - _C16 tricyclic cycloalkyl, or _C5 - _C10 aryl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl, _C9 - _C10 bicyclic cycloalkyl, or _C12 - _C16 tricyclic cycloalkyl, wherein the _C3 - _C7 monocyclic cycloalkyl, _C9 - _C10 bicyclic cycloalkyl, or _C12 - _C16 tricyclic cycloalkyl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a _C3 - _C7 monocyclic cycloalkyl group optionally substituted with one or more _R6 .

In some embodiments, _R1 is a _C9 - _C10 bicyclic cycloalkyl group optionally substituted with one or more _R6 .

In some embodiments, _R1 is a _C9 - _C10 bicyclic cycloalkyl saturated cycloalkyl group, which is optionally substituted with one or more _R6 .

In some embodiments, _R1 is a _C9 - _C10 bicyclic cycloalkyl partially saturated cycloalkyl group, which is optionally substituted with one or more _R6 .

In some embodiments, _R1 is a _C12 - _C16 tricyclic cycloalkyl group optionally substituted with one or more _R6 .

In some embodiments, _R1 is a _C12 - _C16 tricyclic saturated cycloalkyl group optionally substituted with one or more _R6 .

In some embodiments, _R1 is a _C12 - _C16 tricyclic partially unsaturated cycloalkyl group optionally substituted with one or more _R6 .

In some embodiments, _R1 is cyclopentyl, cyclohexyl, or cycloheptyl, wherein the cyclopentyl, cyclohexyl, or cycloheptyl is optionally replaced by one or more _R6 .

In some implementations, _R1 is cyclopentyl, cyclohexyl, or cycloheptyl.

In some implementations, _R1 is

In some implementations, _R1 is

In some embodiments, _R1 is a _C8 - _C16 polycyclic alkyl group substituted with one or more _R6 .

In some embodiments, _R1 is adamantyl, norbornel, or bicyclo[2.2.2]octyl, wherein the adamantyl, norbornel, or bicyclo[2.2.2]octyl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is adamantyl, norbornel, or bicyclo[2.2.2]octyl.

In some implementations, _R1 is

In some implementations, _R1 is

In some implementations, _R1 is a hexahydrogen ionizer optionally replaced by one or more _R6 .

In some implementations, _R1 is a hexahydrogen ionizer.

In some implementations, _R1 is where n and _na are each independently 0, 1, 2 or 3.

In some implementations, _R1 is where n and _na are each independently 0, 1, 2 or 3.

In some embodiments, _R1 is wherein n and _na are each independently 0, 1, 2 or 3, and wherein _R6 is _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, oxo, -OH or _-CF3 .

In some embodiments, _R1 is wherein n and _na are each independently 0, 1, 2 or 3, and wherein _R6 is _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, oxo, -OH or _-CF3 .

In some implementations, _R1 is

In some embodiments, _R1 is wherein _R6 is a _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, oxo, -OH, or _-CF3 .

In some implementations, _R1 is

In some embodiments, _R1 is wherein _R6 is a _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, oxo, -OH, or _-CF3 .

In some embodiments, _R1 is a hexahydroindole that is optionally substituted with one, two, three or four substituents independently selected from _C1 - _C4 alkyl, _C1 - _C6 alkoxy, halogen, oxo, -OH and _-CF3 .

In some implementations, _R1 is an unsubstituted hexahydroindah base.

In some implementations, _R1 is

In some implementations, _R1 is a _C5 - _C10 aryl group optionally replaced by one or more _R6 .

In some implementations, _R1 is a _C5 - _C10 aryl group substituted with one or more _R6 .

In some implementations, _R1 is a _C5 - _C6 monocyclic aryl group optionally substituted with one or more _R6 .

In some implementations, _R1 is a _C5 - _C6 monocyclic aryl group substituted with one or more _R6 .

In some embodiments, _R1 is a phenyl group optionally substituted with one or more _R6 groups.

In some implementations, _R1 is a phenyl group substituted with one or more _{R6 groups} .

In some implementations, _R1 is a phenyl group substituted with an _R6 .

In some implementations, _R1 is

In some implementations, _R1 is a phenyl group substituted with two _{R6 groups} .

In some implementations, _R1 is

In some implementations, _R1 is a phenyl group substituted with three _{R6 groups} .

In some implementations, _R1 is

In some implementations, _R1 is

In some embodiments, _R1 is a phenyl group substituted with one or more substituents independently selected from _C1 - _C4 alkyl, halogen, -CN, and _-CF3 .

In some embodiments, _R1 is a phenyl group optionally substituted with one, two, or three substituents independently selected from Cl and F.

In some implementations, _R1 is

In some implementations, _R1 is

In some implementations, _R1 is

In some implementations, _R1 is

In some implementations, _R1 is

In some implementations, _R1 is

In some embodiments, _R1 is a naphthyl group optionally substituted with one or more _R6 groups.

In some implementations, _R1 is an unsubstituted naphthyl group.

In some implementations, _R1 is _...

In some embodiments, _R1 is an 8- to 12-membered heterocyclic alkyl group optionally substituted with one or more _R6 .

In some embodiments, _R1 is benzofuranyl or dihydrobenzofuranyl, wherein the benzofuranyl or dihydrobenzofuranyl is optionally substituted by one or more _R6 .

In some embodiments, _R1 is a benzofuran group optionally substituted with one or more _R6 .

In some embodiments, _R1 is a dihydrobenzofuranyl group optionally substituted with one or more _R6 groups.

In some implementations, _R1 is

In some implementations, _R1 is

In some implementations, _R1 is a 5- to 6-membered heteroaryl group optionally substituted with one or more _R6 .

In some implementations, _R1 is a thiophene group optionally replaced by one or more _R6 .

In some implementations, _R1 is a thiophene group substituted with one or more _R6 .

In some implementations, _R1 is

In some implementations, _R3 is H.

In some implementations, _R3 is not H.

In some embodiments, _R3 is a _C1 - _C4 alkyl group optionally substituted with one or more _R7 .

In some implementations, _R3 is a _C1 - _C4 alkyl group.

In some implementations, _R3 is a methyl group.

In some implementations, _R3 is ethyl.

In some embodiments, _R3 is a _C1 - _C4 alkyl group substituted with one or more _R7s .

In some implementations, _R3 is a methyl group substituted with one or more _R7s .

In some embodiments, _R3 is a methyl group substituted with one or more _C1 - _C6 alkoxy groups, wherein the _C1 - _C6 alkoxy groups are optionally substituted with one or more _C1 - _C6 alkoxy groups.

In some implementations, _R3 is a methyl group substituted with one or more methoxy groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more ethoxy groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more ethoxy groups, wherein the ethoxy group is substituted with one or more methoxy groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more propoxy groups (e.g., isopropoxy groups).

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more -O- (5 to 7-membered heterocyclic alkyl groups).

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group having one or more _C5 - _C10 aryl groups, wherein the _C5 - _C10 aryl groups are optionally substituted by one or more 5- to 10-membered heteroaryl groups or -CN.

In some embodiments, _R3 is a methyl group having one or more phenyl groups, wherein the phenyl group is optionally substituted with one or more 5- to 10-membered heteroaryl groups or -CN.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group having one or more phenyl groups, wherein the phenyl group is optionally substituted with one or more 5- to 10-membered heteroaryl groups (e.g., pyrazolyl groups).

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group having one or more phenyl groups, wherein the phenyl group is optionally substituted with one or more -CN groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more 5- to 10-membered heteroaryl groups, wherein the 5- to 10-membered heteroaryl groups are optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyridyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl groups, wherein the pyridyl, pyrazolyl, imidazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, or triazolyl groups are optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ , or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyridinyl groups, wherein the pyridinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyridyl groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyrazolyl groups, wherein the pyrazolyl groups are optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyrazolyl groups, wherein the pyrazolyl group is optionally substituted with one or more methyl, methoxy, F, Cl, -CN, -CH2 _- N( _CH3 ) ₂ or _-CF3 .

In some implementations, _R3 is a methyl group substituted with one or more pyrazol groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyrazol groups, wherein the pyrazol group is substituted with one or more methyl, methoxy, F, Cl, -CN, -CH2 _- N( _CH3 ) ₂ or _-CF3 .

In some implementations, _R3 is

In some implementations, _R3 is

In some implementations, _R3 is

In some implementations, _R3 is

In some implementations, _R3 is

In some implementations, _R3 is

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more imidazole groups, wherein the imidazole groups are optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some implementations, _R3 is a methyl group substituted with one or more imidazole groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more imidazole groups, wherein the imidazole group is substituted with one or more methyl groups or -CN.

In some implementations, _R3 is

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyridazinyl groups, wherein the pyridazinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyridazinyl groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyrimidinyl groups, wherein the pyrimidinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyrimidinyl groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyrimidinyl groups, wherein the pyrimidinyl group is substituted with one or more methyl groups or -CN.

In some implementations, _R3 is

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyrazinyl groups, wherein the pyrazinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some embodiments, _R3 is a methyl group substituted with one or more pyrazinyl groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more pyrazinyl groups, wherein the pyrazinyl group is substituted with one or more methyl groups or -CN.

In some implementations, _R3 is

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more triazolyl groups, wherein the triazolyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 .

In some implementations, _R3 is a methyl group substituted with one or more triazolyl groups.

In some implementations, _R3 is

In some embodiments, _R3 is a methyl group substituted with one or more triazole groups, wherein the triazole group is substituted with one or more methyl groups or -CN.

In some implementations, _R3 is

In some implementations, _R3 is

In some implementations, _R3 is an ethyl group substituted with one or more _{R7 groups} .

In some embodiments, _R3 is an ethyl group substituted with one or more _C5 - _C10 aryl groups.

In some embodiments, _R3 is an ethyl group substituted with one or more phenyl groups.

In some implementations, _R3 is

In some implementations, _R4 is H.

In some embodiments, _R4 is a _C1 - _C6 alkyl, -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl), or -( _CH2 ) _O-3 - _C5 - _C6 aryl.

In some implementations, _R4 is a _C1 - _C6 alkyl group.

In some implementations, _R4 is methyl, ethyl, propyl, or butyl.

In some implementations, _R4 is a methyl group.

In some implementations, _R4 is ethyl.

In some embodiments, _R4 is _propyl . In some embodiments, _R4 is...

In some embodiments, _R4 is _butyl . In some embodiments, _R4 is _...

In some implementations, _R4 is -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl).

In some embodiments, _R4 is _{a C3} - _C6 cycloalkyl group. In some embodiments, _{R4 is ...}

In some embodiments, _R4 is -( _CH2 ) _1-3- ( _C3 - _C6 cycloalkyl). In some embodiments, _R4 is -CH2-(C3- _C6 cycloalkyl). In some embodiments, _R4 is -( _CH2 ) _2- ( _{C3 -C6 cycloalkyl). In some embodiments, R4 is -(CH2)3- ( C3 - C6 cycloalkyl ) .}

_In some implementations, _{R4 is ...}

In some implementations, _R4 is -( _CH2 ) _0-3 - _C5 - _C6 aryl.

In some embodiments, _R4 is a _C5 - _C6 aryl group. In some embodiments, _R4 is...

In some embodiments, _R4 is -( _CH2 ) _1-3 - _C5 - _C6 aryl. In some embodiments, _R4 is -CH2 _-C5 -C6 aryl. In some embodiments, _R4 is -( _CH2 ) ₂ - _C5 - _C6 aryl. In some embodiments, _R4 is -( _CH2 ) ₃ - _{C5 - C6 aryl} .

In some embodiments, _R4 is -( _CH2 ) _1-3- phenyl. In some embodiments, _R4 is...

In some embodiments, at least one _R6 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C1 - _C6 alkoxy, or _C3 - _C8 cycloalkyl.

In some embodiments, at least one _R6 is a _C1 - _C6 alkyl group. In some embodiments, at least one _R6 is a methyl group. In some embodiments, at least one _R6 is an ethyl group. In some embodiments, at least one _R6 is a propyl group. In some embodiments, at least one _R6 is a butyl group. In some embodiments, at least one _R6 is an pentyl group. In some embodiments, at least one _R6 is a hexyl group.

In some embodiments, at least one _R6 is _C2 - _C6 alkenyl. In some embodiments, at least one _R6 is vinyl. In some embodiments, at least one _R6 is propenyl. In some embodiments, at least one _R6 is butenyl. In some embodiments, at least one _R6 is pentenyl. In some embodiments, at least one _R6 is hexenyl.

In some embodiments, at least one _R6 is a _C1 - _C6 alkoxy. In some embodiments, at least one _R6 is a methoxy. In some embodiments, at least one _R6 is an ethoxy. In some embodiments, at least one _R6 is a propoxy. In some embodiments, at least one _R6 is a butoxy. In some embodiments, at least one _R6 is a pentoxy. In some embodiments, at least one _R6 is a hexoxy.

In some embodiments, at least one R ₆ is a _C3 - _C8 cycloalkyl group. In some embodiments, at least one R ₆ is cyclopropyl. In some embodiments, at least one R ₆ is cyclobutyl. In some embodiments, at least one R ₆ is cyclopentyl. In some embodiments, at least one R ₆ is cyclohexyl. In some embodiments, at least one R ₆ is cycloheptyl. In some embodiments, at least one R ₆ is cyclooctyl.

In some embodiments, at least one _R6 is a halogen, oxo, -OH, -CN, _-NH2 , -NH( _C1 - _C6 alkyl), -N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 .

In some embodiments, at least one _R6 is a halogen. In some embodiments, at least one _R6 is F, Cl, or Br. In some embodiments, at least one _R6 is F or Cl. In some embodiments, at least one _R6 is F. In some embodiments, at least one _R6 is Cl.

In some embodiments, at least one _R6 is oxo. In some embodiments, at least one _R6 is -OH. In some embodiments, at least one _R6 is -CN. In some embodiments, at least one _R6 is _-NH₂ . In some embodiments, at least one _R6 is -NH( _C₁ - _C₆ alkyl). In some embodiments, at least one _R6 is -N( _C₁ - _C₆ alkyl) _₂ . In some embodiments, at least one _R6 is _-CH₂F . In some embodiments, at least one _R6 is _-CHF₂ . In some embodiments, at least one _R6 is _-CF₃ .

In some implementations, at least one _R7 is _-OR8 .

In some embodiments, at least one _R7 is a _C1 - _C6 alkoxy group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is a methoxy group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an ethoxy group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is a propoxy group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is a butoxy group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is a pentoxy group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is a hexoxy group optionally substituted with one or more _R7S .

In some embodiments, at least one _R7 is an -O-(5- to 7-membered heterocyclic alkyl) optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-pyrrolidinyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-tetrahydrofuranyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-pyrazolyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-imidazolyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-oxazolyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-isooxazolyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-dioxolaneyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-piperidinyl optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is an -O-tetrahydropyranyl group optionally substituted with one or more _{R7S groups} . In some embodiments, at least one _R7 is an -O-piperazinyl group optionally substituted with one or more _{R7S groups} . In some embodiments, at least one _R7 is an -O-morpholinyl group optionally substituted with one or more _{R7S groups} . In some embodiments, at least _{one R7} is an -O-dioxane group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is an -O-triazinyl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is an -O-trioxanehexyl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is an -O-diazacycloheptanyl group optionally substituted with one or more _{R7S groups} .

In some embodiments, at least one _R7 is a _C5 - _C10 aryl group optionally substituted with one or more _R7S . In some embodiments, at least one _R7 is a phenyl group optionally substituted with one or more _R7S .

In some embodiments, at least one _R7 is a 5- to 10-membered heteroaryl group optionally substituted with one or more _R7S .

In some embodiments, at least one R ₇ is a 5- to 6-membered heteroaryl group optionally substituted with one or more R _7S .

In some embodiments, at least one _R7 is a 5-membered heteroaryl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a pyrrole group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a pyrazolyl group optionally substituted with one or more _{R7S groups} . In some embodiments, at least one _R7 is an imidazolyl group optionally substituted with one or more _{R7S groups} . In some embodiments, at least one _R7 is a triazolyl group optionally substituted with one or more R7S _groups .

In some embodiments, at least one _R7 is a 6-membered heteroaryl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a pyridyl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a diazinyl group optionally substituted with one or more _{R7S groups} . In some embodiments, at least one _R7 is a pyridazinyl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a pyrazinyl _group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a triazinyl group optionally substituted with one or more _R7S groups. In some embodiments, at least one _R7 is a tetraazinyl group optionally substituted with one _R7S group. In some embodiments, at least one _R7 is a pentaazinyl group.

In some embodiments, at least one _R7S is a _C1 - _C6 alkyl, _C1 - _C6 alkoxy, or a 5- to 10-membered heteroaryl group.

In some embodiments, at least one _R7S is a _C1 - _C6 alkyl group. In some embodiments, at least one _R7S is a methyl group. In some embodiments, at least one _R7S is an ethyl group. In some embodiments, at least one _R7S is a propyl group. In some embodiments, at least one _R7S is a butyl group. In some embodiments, at least one _R7S is an pentyl group. In some embodiments, at least one _R7S is a hexyl group.

In some embodiments, at least one R _7S is a _C1 - _C6 alkoxy group. In some embodiments, at least one R _7S is a methoxy group. In some embodiments, at least one R _7S is an ethoxy group. In some embodiments, at least one R _7S is a propoxy group. In some embodiments, at least one R _7S is a butoxy group. In some embodiments, at least one R _7S is a pentoxy group. In some embodiments, at least one R _7S is a hexoxy group.

In some embodiments, at least one R _7S is a 5- to 10-membered heteroaryl group. In some embodiments, at least one R _7S is a 5- to 6-membered heteroaryl group.

In some embodiments, at least one R _7S is a 5-membered heteroaryl group. In some embodiments, at least one R _7S is a pyrrole group. In some embodiments, at least one R _7S is a pyrazolyl group. In some embodiments, at least one R _7S is an imidazolyl group. In some embodiments, at least one R _7S is a triazolyl group.

In some embodiments, at least one R _7S is a 6-membered heteroaryl group. In some embodiments, at least one R _7S is pyridyl. In some embodiments, at least one R _7S is diazinyl. In some embodiments, at least one R _7S is pyridazinyl. In some embodiments, at least one R _7S is pyrazinyl. In some embodiments, at least one R _7S is triazinyl. In some embodiments, at least _{one R 7S is tetraazinyl. In some embodiments, at least one R 7S is pentaazinyl} .

In some embodiments, at least one _R7S is a halogen, -OH, -CN, -( _CH2 ) _{O- 3-} NH2, -( _CH2 ) _O-3- NH( _C1 - _C6 alkyl), -( _CH2 ) _O-3 -N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 .

In some embodiments, at least one R _7S is a halogen. In some embodiments, at least one R _7S is F, Cl, or Br. In some embodiments, at least one R _7S is F or Cl. In some embodiments, at least one R _7S is F. In some embodiments, at least one R _7S is Cl.

In some embodiments, at least one R _7S is -OH. In some embodiments, at least one R _7S is -CN.

In some embodiments, at least one _R7S is -( _CH2 ) _O-3 - _NH2 , -( _CH2 ) _O-3 -NH( _C1 - _C6 alkyl) or -( _CH2 ) _O-3 -N( _C1 - _C6 alkyl) ₂ .

In some embodiments, at least one _R7S is -( _CH2 ) _0-3 - _NH2 . In some embodiments, at least one _R7S is _-NH2 . In some embodiments, at least one _R7S is -( _CH2 ) _1-3 - _NH2 . In some embodiments, at least one _R7S is _-CH2 - _NH2 . In some embodiments, at least one _R7S is -( _CH2 ) ₂ -NH2. In some embodiments, at least one _R7S is -( _CH2 ) _{3 - NH2} .

In some embodiments, at least one _R7S is -( _CH2 ) _0-3- NH ( _C1 - _C6 alkyl). In some embodiments, at least one _R7S is -NH ( _C1 - _C6 alkyl). In some embodiments, at least one _R7S is -NH( _CH3 ). In some embodiments, at least one _R7S is -( _CH2 ) _1-3 -NH ( _C1 - _C6 alkyl). In some embodiments, at least one _R7S is -( _CH2 ) _1-3 -NH ( _CH3 ). In some embodiments, at least one _R7S is _-CH2- NH ( _C1 - _C6 alkyl). In some embodiments, at least one _R7S is -CH2 _- NH ( _CH3 ). In some embodiments, at least one _R7S is -( _CH2 ) ₂ -NH ( _C1 - _C6 alkyl). In some embodiments, at least one _R7S is -( _CH2 ) ₂ -NH ( _CH3 ). In some embodiments, at least one _R7S is -( _CH2 ) ₃ -NH( _C1 - _C6 alkyl). In some embodiments, at least one _R7S is -( _CH2 ) ₃ -NH( _CH3 ).

In some embodiments, at least one _R7S is -( _CH2 ) _O-3 -N( _C1 - _C6 alkyl) ₂ . In some embodiments, at least one _R7S is -N( _C1 - _C6 alkyl) ₂ . In some embodiments, at least one _R7S is N( _CH3 ) ₂ . In some embodiments, at least one _R7S is -( _CH2 ) _1-3 -N( _C1 - _C6 alkyl) ₂ . In some embodiments, at least one _R7S is -( _CH2 ) _1-3 -N( _CH3 ) ₂ . In some embodiments, at least one _R7S is _-CH2 -N( _C1 - _C6 alkyl) ₂ . In some embodiments, at least one _R7S is -CH2 _- N( _CH3 ) ₂ . In some embodiments, at least one _R7S is -( _CH2 ) ₂ -N( _C1 - _C6 alkyl) ₂ . In some embodiments, at least one _R7S is -( _CH2 ) ₂ -N( _CH3 ) ₂ . In some embodiments, at least one _R7S is -( _CH2 ) ₃ -N( _C1 - _C6 alkyl) ₂ . In some embodiments, at least one _R7S is -( _CH2 ) ₃ -N( _CH3 ) ₂ .

In some embodiments, at least one R _7S is _-CH2F . In some embodiments, at least one R _7S is _-CHF2 . In some embodiments, at least one R _7S is _-CF3 .

In some embodiments, _R8 is a _C1 - _C6 alkyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a methyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is an ethyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a propyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a butyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is an pentyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a hexyl group optionally substituted with one or more _R7S .

In some embodiments, _R8 is a 5- to 7-membered heterocyclic alkyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a pyrrolidinyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a tetrahydrofuranyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a pyrazolyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is an imidazoalkyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is an oxazolyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is an isoxazolyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a dioxolaneyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a piperidinyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a tetrahydropyranyl group optionally substituted with one or more _R7S . In some embodiments, _R8 is a piperazine group optionally substituted with one or more _R7S . In some embodiments, _R8 is a morpholino group optionally substituted with one or more R7S. In some embodiments, _R8 is a dioxane group optionally substituted with one or more _R7S . In some embodiments, _R8 is a triazine group optionally substituted with one or more _R7S . In some embodiments, _R8 is a trioxane-hexane group optionally substituted with one or more _R7S . In some embodiments, _R8 is an azirne-heptane group optionally substituted with one or more _R7S . In some embodiments, _R8 is a diazirne _- heptane group optionally substituted with one or more _R7S .

In some embodiments, the compound is a compound of formula (Ia) or (Ib):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

In some embodiments, the compound is any one of formulas (II), (IIa), and (IIb):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

In some embodiments, the compound is a compound of any one of formulas (III), (IIIa), and (IIIb):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

In some embodiments, the compound is a compound of any one of formulas (IV), (IVa), and (IVb):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

In some embodiments, the compound is a compound of any one of formulas (V), (Va), (Vb), (VI), (VIa), and (VIb):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

In some embodiments, the compound is a compound of any one of formulas (VII), (VIIa), (VIIb), (VIII), (VIIIa), and (VIIIb):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

In some embodiments, the compound is a compound of any one of formulas (IX), (IXa), (IXb), (X), (Xa), and (Xb):

Or its prodrug, hydrate, solvate or pharmaceutically acceptable salt.

It should be understood that for any compound of formula (I)-(X), (Ia)-(Xa), and (Ib)-(Xb), _R1 , _R3 , _R4 , R6, _{R7 , R7S ,} and _R8 may each be selected from the groups described herein where applicable, and any group described herein for any one of _R1 , _R3 , _R4 , _R6 , _R7 , _R7S , and _R8 may, where applicable, combine with any of the remaining groups described herein for one or more of _R1 , _R3 , _R4 , _R6 , _R7 , _R7S , and _R8 .

In some embodiments, the compound is selected from the compounds described in Table 1, their prodrugs, and pharmaceutically acceptable salts.

In some embodiments, the compound is selected from the compounds described in Table 1 and their pharmaceutically acceptable salts.

In some embodiments, the compound is selected from the compounds described in Table 1.

Table 1

In some embodiments, the compound is selected from:

2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}ethyl acetate

2-{[(2,6-difluorophenyl)carbamoyl]oxy}ethyl acetate

2-{[(2,6-dichlorophenyl)carbamoyl]oxy}ethyl acetate

2-{[(naphthyl-1-yl)carbamoyl]oxy}ethyl acetate

2-{[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)carbamoyl]oxy}ethyl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-methoxypropionate ethyl ester

2-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}oxy)ethyl acetate

2-{[(2,6-dimethylphenyl)carbamoyl]oxy}ethyl acetate

2-{[(2,6-diethylphenyl)carbamoyl]oxy}ethyl acetate

2-({[2-(chloro-6-methylphenyl)carbamoyl]oxy}ethyl acetate)

2-{[(2-cyanophenyl)carbamoyl]oxy}ethyl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyridin-3-yl)propionate ethyl ester

2-{[(2-tert-butylphenyl)carbamoyl]oxy}ethyl acetate

2-((2,4,6-trimethylcarbamoyl)oxy)ethyl acetate

2-(((2-isopropylphenyl)carbamoyl)oxy)ethyl acetate

2-(((2-ethyl-6-methylphenyl)carbamoyl)oxy)ethyl acetate

2-(((1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl)oxy)-3-phenylpropionate ethyl ester

2-(((1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl)oxy)-3-(pyridin-2-yl)propionate ethyl ester

(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}ethyl propionate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}propyl-2-yl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}cyclopropyl methyl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}cyclobutyl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}methylpropyl acetate

3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}ethyl propionate

2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)ethyl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid

2-{[(2,6-diethyl-4-methylphenyl)carbamoyl]oxy}ethyl acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}methyl acetate

(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-4-phenylbutyrate ethyl ester

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate ethyl ester

2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}cyclopentyl acetate; and

2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionate ethyl ester.

In some embodiments, the compound is not any of the following:

Where X is CN, Cl or Br, and R is H, _C1 - _C6 alkyl, -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl) or -( _CH2 ) _O-3 - _C5 - _C6 aryl.

In some aspects, this disclosure provides compounds that are isotopic derivatives (e.g., isotopically labeled compounds) of any of the compounds of formula (I)-(X), (Ia)-(Xa), and (Ib)-(Xb).

In some embodiments, the compound is any of the compounds described in Table 1, as well as its prodrug and pharmaceutically acceptable salt isotopic derivatives.

In some embodiments, the compound is any of the compounds described in Table 1 and isotopic derivatives of their pharmaceutically acceptable salts.

In some embodiments, the compound is an isotopic derivative of any of the compounds described in Table 1.

It should be understood that any of a variety of techniques recognized in the art can be used to prepare isotope derivatives. For example, isotope derivatives can generally be prepared by performing the procedures disclosed in the scheme and/or the embodiments described herein, by replacing non-isotope-labeled reagents with isotope-labeled reagents.

In some implementations, the isotope derivative is a deuterium-labeled compound.

In some embodiments, the isotopic derivative is a deuterium-labeled compound of any one of the compounds of formula (I)-(X), (Ia)-(Xa), and (Ib)-(Xb).

In some embodiments, the compound is any of the compounds described in Table 1, as well as its prodrug and a deuterated compound of a pharmaceutically acceptable salt.

In some embodiments, the compound is any of the compounds described in Table 1 and deuterated compounds of pharmaceutically acceptable salts thereof.

In some embodiments, the compound is a deuterium-labeled compound of any of the compounds described in Table 1.

It should be understood that deuterium-labeled compounds contain deuterium atoms with a deuterium abundance significantly greater than the natural abundance of deuterium (0.015%).

In some embodiments, the deuterium-labeled compound has the following deuterium enrichment factor for each deuterium atom: at least 3500 (52.5% deuterium doped at each deuterium atom), at least 4000 (60% deuterium doped), at least 4500 (67.5% deuterium doped), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium doped), at least 6000 (90% deuterium doped), at least 6333.3 (95% deuterium doped), at least 6466.7 (97% deuterium doped), at least 6600 (99% deuterium doped), or at least 6633.3 (99.5% deuterium doped). As used herein, the term "deuterium enrichment factor" refers to the ratio between the abundance of deuterium and the natural abundance of deuterium.

It should be understood that deuterium-labeled compounds can be prepared using any of a variety of techniques recognized in the art. For example, deuterium-labeled compounds can generally be prepared by performing the procedures disclosed in the schemes and/or the examples described herein, by replacing non-deuterium-labeled reagents with deuterium-labeled reagents.

Compounds of the present invention containing the aforementioned deuterium atoms, or pharmaceutically acceptable salts or solvates thereof, are within the scope of the present invention. Furthermore, substitution with heavier deuterium (i.e., ^2H ) may provide certain therapeutic advantages due to greater metabolic stability, such as prolonged in vivo half-life or reduced dosage requirements.

To avoid any doubt, it should be understood that when a group is defined as “described herein” in this specification, the group includes the first and broadest definition as well as the specific definition of each and all of the group.

Specific compounds disclosed herein include, for example, compounds of any one of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) or pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of _R1 , _R3 , _R4 and any associated substituents has any meaning as previously defined herein.

Typically, various functional groups and substituents of the compound of formula (I) are chosen so that the molecular weight of the compound does not exceed 1000 Daltons. More generally, the molecular weight of the compound will be less than 900, for example less than 800, or less than 750, or less than 700, or less than 650 Daltons. More conveniently, the molecular weight is less than 600, for example 550 Daltons or less.

Suitable pharmaceutically acceptable salts of the compounds disclosed herein are, for example, acid addition salts of sufficiently basic compounds of the present disclosure, such as acid addition salts with, for example, inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, trifluoroacetic acid, formic acid, citrate methanesulfonate, or maleic acid. Additionally, suitable pharmaceutically acceptable salts of sufficiently acidic compounds of the present disclosure are alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium or magnesium salts, ammonium salts, or salts with organic bases that provide pharmaceutically acceptable cations, such as salts formed with methylamine, dimethylamine, trimethylamine, piperidine, morpholine, or tri-(2-hydroxyethyl)amine.

It should be understood that compounds of any one of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) and any pharmaceutically acceptable salt thereof include stereoisomers, mixtures of stereoisomers, and polymorphs of all isomers of the compounds.

As used herein, the term "isomer" refers to compounds with the same molecular formula but different atomic bonding sequences or spatial arrangements. Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," while non-overlapping mirror images of each other are called "enantiomers" or sometimes optical isomers. A mixture containing equal amounts of enantiomers with opposite chirality is called a "racemic mixture."

As used in this article, the term "chiral center" refers to a carbon atom bonded to four different substituents.

As used herein, the term "chiral isomer" refers to a compound having at least one chiral center. Compounds having more than one chiral center may exist as individual diastereomers or mixtures of diastereomers (referred to as a "diastereomer mixture"). When a chiral center is present, the stereoisomer can be characterized by the absolute configuration (R or S) of that chiral center. Absolute configuration refers to the spatial arrangement of the substituents attached to the chiral center. Substituents attached to the chiral center under consideration were ordered according to the order rules of Cahn, Ingold, and Prelog (Cahn et al., Angew. Chem. Inter. Edit. 1966, 5, 385; Errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J. Chem. Educ. 1964, 41, 116).

As used herein, the term “geometric isomer” refers to a diastereomer whose existence is due to hindered rotation around a double bond or a cycloalkyl linker (e.g., 1,3-cyclobutyl). These configurations are distinguished in their names by the prefixes cis and trans, or Z and E, which indicate that, according to the Cahn-Ingold-Prelog rule, these groups are on the same or opposite sides of the double bond in the molecule.

It should be understood that the compounds disclosed herein may be described as different chiral or geometric isomers. It should also be understood that when a compound has chiral or geometric isomers, all isomers are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any isomer, and it should be understood that not all isomers may have the same level of activity.

It should be understood that the structures and other compounds discussed in this disclosure include all their transisomers. It should also be understood that not all transisomers have the same level of activity.

As used herein, the term "transisomer" refers to a type of stereoisomer in which the atoms of two isomers are arranged differently in space. The presence of transisomers is due to rotational restriction caused by the obstruction of rotation of the large group around the central bond. These transisomers usually exist in the form of mixtures, but due to recent advancements in chromatographic techniques, it is now possible to separate mixtures of two transisomers under selective conditions.

As used herein, the term "tautomer" is one of two or more structural isomers existing in equilibrium and readily converting from one isomer form to another. This conversion results in the migration of hydrogen atoms, accompanied by the conversion of adjacent conjugated double bonds. Tautomers exist in solution as a mixture of tautomer groups. In a solution of possible tautomers, a chemical equilibrium of tautomers will be reached. The exact proportions of tautomers depend on several factors, including temperature, solvent, and pH. The concept of tautomers that can interconvert through tautomerism is called tautomerism. Of the various possible types of tautomerism, two are commonly observed. In keto-enol tautomerism, the movement of electrons and hydrogen atoms occurs simultaneously. Ring-chain tautomerism occurs when the aldehyde group (-CHO) in a sugar molecule reacts with one of the hydroxyl groups (-OH) in the same molecule, giving it a cyclic (ring) form similar to glucose.

It should be understood that the compounds of this disclosure may be described as different tautomers. It should also be understood that when a compound has tautomer forms, all tautomer forms are intended to be included within the scope of this disclosure, and the naming of the compound does not exclude any tautomer form. It will be understood that some tautomers may have higher levels of activity than others.

Compounds with the same molecular formula but different atomic bonding properties, sequences, or spatial arrangements are called "isomers." Isomers with different atomic spatial arrangements are called "stereoisomers." Stereoisomers that are not mirror images of each other are called "diastereomers," and stereoisomers that are non-overlapping mirror images of each other are called "enantiomers." When a compound has an asymmetry center, for example, it is bonded to four different groups, it may have a pair of enantiomers. Enantiomers can be characterized by the absolute configuration of their asymmetry center and described by the R and S sequence rules of Cahn and Prelog, or by rotating the molecular polarization plane and being called dextrorotatory or levorotatory (i.e., (+) or (-)- isomers, respectively). Chiral compounds can exist as individual enantiomers or mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture."

The compounds disclosed herein may have one or more asymmetric centers; therefore, such compounds may be produced as individual (R)- or (S)- stereoisomers or mixtures thereof. Unless otherwise stated, the description or naming of specific compounds in the specification and claims is intended to include individual enantiomers and mixtures thereof, racemates, or other forms. Methods for determining stereochemistry and separating stereoisomers are well known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry," 4th edition, J. March, John Wiley and Sons, New York, 2001), for example, by synthesis from optically active starting materials or by resolving racemic forms. Some compounds of this disclosure may have geometric isomer centers (E- and Z-isomers). It should be understood that this disclosure covers all optical, diastereomeric, and geometric isomers and mixtures thereof having inflammasome inhibitory activity.

This disclosure also covers compounds of this disclosure as defined herein that contain one or more isotopic substitutions.

It should be understood that any compound of any kind described herein includes the compound itself, as well as their salts and their solvates, if applicable. For example, salts can be formed between an anion and a positively charged group (e.g., amino) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, hydrogen sulfate, aminosulfonate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, toluenesulfonate, salicylate, lactate, naphthalenesulfonate, and acetate (e.g., trifluoroacetate).

As used herein, the term "pharmaceutically acceptable anion" refers to an anion suitable for forming pharmaceutically acceptable salts. Similarly, salts can also be formed between a cation and a negatively charged group (e.g., a carboxyl group) on a substituted benzene compound. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations, such as tetramethylammonium ions. Substituted benzene compounds also include those containing a quaternary nitrogen atom.

It should be understood that the compounds disclosed herein, such as salts of the compounds, may exist in hydrated or non-hydrated (anhydrous) forms or as solvates with other solvent molecules. Non-limiting examples of hydrates include monohydrates, dihydrates, etc. Non-limiting examples of solvates include ethanol solvates, acetone solvates, etc.

As used herein, the term "solvate" refers to a solvation form containing stoichiometric or non-stoichiometric amounts of solvent. Some compounds tend to capture solvent molecules in a fixed molar ratio in a crystalline solid state, thus forming a sovate. If the solvent is water, the resulting sovate is a hydrate; if the solvent is an alcohol, the resulting sovate is an alcohol. A hydrate is formed by one or more water molecules combined with one molecule of the substance, wherein the water retains its molecular state as _H₂O .

As used herein, the term "analogue" refers to a compound that is structurally similar to another compound but has a slightly different composition (e.g., an atom is replaced by an atom of a different element or a specific functional group is present, or a functional group is replaced by another functional group). Thus, an analogue is a compound that is similar or comparable to a reference compound in function and performance, but not similar or comparable in structure or origin.

As used herein, the term “derivative” refers to a compound having a common core structure and being substituted by various groups as described herein.

As used herein, the term "bioisostere" refers to a compound resulting from the exchange of an atom or group of atoms with another atom or group of atoms that is broadly similar. The aim of bioisostere substitution is to produce new compounds with biological properties similar to those of the parent compound. Bioisostere substitution can be based on physicochemical or topological structures. Examples of carboxylic acid bioisosteres include, but are not limited to, acylsulfonylimides, tetrazolium, sulfonates, and phosphonates. See, for example, Patani and LaVoie, Chem. Rev. 96, 3147-3176, 1996.

It should also be understood that certain compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) may exist in both solvated and non-solvated forms, such as hydrates. Suitable pharmaceutically acceptable solvates are, for example, hydrates, such as hemihydrates, monohydrates, dihydrates, or trihydrates. It should be understood that this disclosure covers all such solvated forms having inflammasome-inhibiting activity.

It should also be understood that certain compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) may exhibit polymorphism, and this disclosure covers all such forms or mixtures thereof that have inflammasome-inhibiting activity. It is well known that conventional techniques can be used to analyze crystalline materials, such as X-ray powder diffraction analysis, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, and solution and/or solid-state nuclear magnetic resonance spectroscopy. The water content of such crystalline materials can be determined by Karl Fischer analysis.

Compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) can exist in a variety of different tautomeric forms, and compounds referring to formula I include all of these forms. For the avoidance of doubt, when a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all other forms are still covered by formula (I). Examples of tautomeric forms include ketone-, enol-, and enolate forms, for example, found in the following tautomeric pairs: ketone/enol (as shown below), imine/enamine, amide/imino alcohol, amidine/amidinium, nitroso/oxime, thionone/enthiol, and nitro/acid nitro.

Compounds containing any of the formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) with amine functional groups can also form N-oxides. Compounds of formula I containing amine functional groups mentioned herein also include N-oxides. When a compound contains multiple amine functional groups, one or more nitrogen atoms can be oxidized to form N-oxides. Specific examples of N-oxides are N-oxides of tertiary amines or nitrogen atoms in nitrogen-containing heterocycles. N-oxides can be formed by treating the corresponding amines with an oxidizing agent such as hydrogen peroxide or a peracid (e.g., peroxycarboxylic acid), see, for example, Advanced Organic Chemistry, Jerry March, 4th ed., Wiley Interscience, page number. More specifically, N-oxides can be prepared by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514), in which an amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as dichloromethane.

Compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) can be administered as prodrugs, which decompose in humans or animals to release the compounds of this disclosure. Prodrugs can be used to modify the physical and/or pharmacokinetic properties of the compounds of this disclosure. Prodrugs can be formed when the compounds of this disclosure contain suitable groups or substituents that can be attached to the modifying group. Examples of prodrugs include in vivo cleavable ester derivatives that can be formed from the carboxyl or hydroxyl groups of compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb), and in vivo cleavable amide derivatives that can be formed from the carboxyl or amino groups of compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb).

Therefore, this disclosure includes compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) as defined above, which are available in humans or animals as well as those obtained through organic synthesis and through the cleavage of their prodrugs. Thus, this disclosure includes compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) produced by organic synthesis, as well as such compounds produced in humans or animals through the metabolism of prodrug compounds, i.e., compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) can be synthetically produced or metabolically produced.

A suitable pharmaceutically acceptable prodrug of any of the compounds of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) is a prodrug that is appropriate for administration to humans or animals without undesirable pharmacological activity and without excessive toxicity, based on reasonable medical judgment. Various forms of prodrugs have been described, for example, in the following documents: a) Methods in Enzymology, Vol. 42, pp. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, H. Bundgaard, pp. 113-191 (1991); d) H. Bundgaard, A (e) Advanced Drug Delivery Reviews, 8, 1-38 (1992); (f) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); (g) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); (h) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Vol. 14; and (h) E. Roche (ed.), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

Suitable pharmaceutically acceptable prodrugs of compounds containing any of the formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) with a carboxyl group are, for example, their in vivo cleavable esters. In vivo cleavable esters of compounds containing any of the formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) with a carboxyl group are, for example, pharmaceutically acceptable esters that cleave in humans or animals to produce a parent acid. Suitable pharmaceutically acceptable esters for the carboxyl group include: _C1 - _C6 alkyl esters, such as methyl, ethyl, and tert-butyl esters; _C1 - _C6 alkoxymethyl esters, such as methoxymethyl esters; _C1 - _C6 alkyloxymethyl esters, such as neopentyloxymethyl esters, 3-phthalyl esters; _C3 - _C8 cycloalkylcarbonyloxy- _C1 - _C6 alkyl esters, such as cyclopentylcarbonyloxymethyl esters and 1-cyclohexylcarbonyloxyethyl esters; 2-oxo-1,3-dioxacyclopentenylmethyl esters, such as 5-methyl-2-oxo-1,3-dioxacyclopenten-4-ylmethyl esters and _C1 - _C6 alkoxycarbonyloxy-C1-6 alkyl esters, such as methoxycarbonyloxymethyl esters and 1-methoxycarbonyloxyethyl esters.

Suitable pharmaceutically acceptable prodrugs of compounds having any of the formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) containing a hydroxyl group are, for example, esters or ethers that are cleavable in vivo. Suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include inorganic esters, such as phosphate esters (including phosphoramide cyclic esters). Other suitable pharmaceutically acceptable ester-forming groups for the hydroxyl group include _C1 - _C10 alkyl acyl groups, such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups; _C1 - _C10 alkoxycarbonyl groups, such as ethoxycarbonyl; N,N-( _C1 - _C6 alkyl) _2- carbamoyl, 2-dialkylaminoacetyl, and 2-carboxyacetyl. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-( _C1 - _C4 alkyl)piperazine-1-ylmethyl. Suitable pharmaceutically acceptable ether-forming groups for the hydroxyl group include α-acyloxyalkyl groups, such as acetoxymethyl and neopentyloxymethyl.

Suitable pharmaceutically acceptable prodrugs of compounds having any of the formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) having a carboxyl group are, for example, amides that are cleavable in vivo, such as amides formed with amines such as ammonia, C1-4 alkylamines such as methylamine, ( _C1 - _C4 alkyl)2amines such as dimethylamine, N-ethyl-N-methylamine or diethylamine, _C1 - _C4 alkoxy- _C2 - _C4 alkylamines such as 2-methoxyethylamine, phenyl- _C1 - _C4 alkylamines such as benzylamine, and amino acids such as glycine or their esters.

Suitable pharmaceutically acceptable prodrugs of compounds having an amino group of the formula (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) are, for example, their in vivo cleavable amide derivatives. Suitable pharmaceutically acceptable amides derived from the amino group include, for example, amides formed with _C1 - _C10 alkyl acyl groups such as acetyl, benzoyl, phenylacetyl, and substituted benzoyl and phenylacetyl groups. Examples of cyclic substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N-dialkylaminomethyl, morpholinomethyl, piperazine-1-ylmethyl, and 4-( _C1 - _C4 alkyl)piperazine-1-ylmethyl.

The in vivo effects of compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) can be exerted in part by one or more metabolites formed in humans or animals following administration of compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb). As mentioned above, the in vivo effects of compounds of any of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb) can also be exerted through the metabolism of prodrugs.

While this disclosure may relate to any compound or particular group of compounds defined herein by optional, preferred, or suitable features or otherwise in a particular embodiment, this disclosure may also relate to compounds or particular groups of compounds that specifically exclude the optional, preferred, or suitable features or particular embodiments. Features of this disclosure relate to specific structural groups at R1, which relate to the scope of the claims as defined herein. In some cases, the definition of a specific group is irrelevant to the invention and therefore the structure may be abandoned. Such a structure may be abandoned when R1 corresponds to a phenyl group directly substituted by at least two groups, including: one halogen group and one methyl group; two or more halogen groups; or two methyl groups.

Appropriately, this disclosure excludes any individual compound that does not have the biological activity defined herein.

Synthesis method

In some respects, this disclosure provides methods for preparing the compounds of this disclosure.

In some aspects, this disclosure provides methods for compounding a compound, which include one or more steps described herein.

In some aspects, this disclosure provides compounds that can be obtained by the methods of preparation of compounds described herein, or directly obtained by the methods of preparation of compounds described herein.

In some respects, this disclosure provides intermediates described herein that are suitable for use in methods for preparing the compounds described herein.

The compounds disclosed herein can be prepared by any suitable technique known in the art. Specific methods for preparing these compounds are further described in the appended examples.

In the description of the synthetic methods described herein, as well as in any reference synthetic methods used to prepare the starting materials, it should be understood that all proposed reaction conditions (including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration, and post-treatment procedures) can be selected by those skilled in the art.

Those skilled in the field of organic synthesis should understand that the functional groups present on various parts of a molecule must be compatible with the reagents and reaction conditions used.

It will be understood that during the synthesis of the disclosed compounds in the methods defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituents from undesirable reactions. Those skilled in the art of chemistry will understand when such protection is necessary and how such protecting groups can be placed in place and then removed. For examples of protecting groups, see one of the many general texts on the subject, such as Theodora Green’s ‘Protective Groups in Organic Synthesis’ (published by John Wiley & Sons). Protecting groups can be removed by any convenient method described in the literature or known to those skilled in the art of chemistry suitable for removing the protecting groups in question, chosen so as to achieve removal of the protecting groups with minimal interference to groups at other positions in the molecule. Therefore, if the reactants include, for example, groups such as amino, carboxyl, or hydroxyl, it may be necessary to protect such groups in some of the reactions described herein.

For example, suitable protecting groups for amino or alkylamino groups are, for example, acyl groups, such as alkanoyl groups like acetyl, alkoxycarbonyl groups, such as methoxycarbonyl, ethoxycarbonyl, or tert-butoxycarbonyl, arylmethoxycarbonyl groups, such as benzyloxycarbonyl, or aromatic acyl groups, such as benzoyl. The deprotection conditions for these protecting groups necessarily vary depending on the choice of protecting group. Thus, for example, acyl groups such as alkanoyl, alkoxycarbonyl, or aromatic acyl groups can be removed by hydrolysis, for example, with a suitable base, such as an alkali metal hydroxide, such as lithium hydroxide or sodium hydroxide. Alternatively, acyl groups, such as tert-butoxycarbonyl, can be removed, for example, by treatment with a suitable acid (e.g., hydrochloric acid, sulfuric acid, or phosphoric acid or trifluoroacetic acid); and arylmethoxycarbonyl groups, such as benzyloxycarbonyl, can be removed, for example, by catalysts such as palladium/hydrocarbonation, or by treatment with Lewis acids such as tri(trifluoroacetic acid)boron. Suitable alternative protecting groups for primary amino groups are, for example, phthalyl groups, which can be removed by treatment with alkylamines such as dimethylaminopropylamine or with hydrazine.

Suitable protecting groups for hydroxyl groups are, for example, acyl groups, such as alkanoyl groups, such as acetyl groups, aromatic acyl groups, such as benzoyl groups, or arylmethyl groups, such as benzyl groups. The deprotection conditions for these protecting groups will necessarily vary depending on the choice of protecting group. Therefore, for example, acyl groups such as alkanoyl or aromatic acyl groups can be removed by hydrolysis with a suitable base, such as an alkali metal hydroxide, such as lithium hydroxide, sodium hydroxide, or ammonia. Alternatively, arylmethyl groups such as benzyl groups can be removed, for example, by catalysts such as palladium/hydrocarbonation.

Suitable protecting groups for the carboxyl group are, for example, esterification groups, such as methyl or ethyl, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, tert-butyl, which can be removed, for example, by treatment with an acid such as an organic acid such as trifluoroacetic acid, or, for example, benzyl, which can be removed, for example, by a catalyst such as palladium/hydrocarbonation.

Once a compound of formula (I) has been synthesized by any of the methods defined herein, the method may then further include the following additional steps: (i) removing any protecting groups present; (ii) converting a compound of formula (I) into another compound of formula (I); (iii) forming a pharmaceutically acceptable salt, hydrate, or solvate thereof; and/or (iv) forming a prodrug thereof.

The resulting compound of formula (I) can be separated and purified using techniques well known in the art.

Conveniently, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the respective reaction conditions. Examples of suitable solvents include, but are not limited to, hydrocarbons such as hexane, petroleum ether, benzene, toluene, or xylene; chlorinated hydrocarbons such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane, chloroform, or dichloromethane; alcohols such as methanol, ethanol, isopropanol, n-propanol, n-butanol, or tert-butanol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF), 2-methyltetrahydrofuran, cyclopentylmethyl ether (CPME), methyl tert-butyl ether (MTBE), or dioxane; and glycol ethers such as ethylene glycol. Alcohol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diethylene glycol dimethyl ether); ketone, such as acetone, methyl isobutyl ketone (MIBK) or butanone; amide, such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidone (NMP); nitrile, such as acetonitrile; sulfoxide, such as dimethyl sulfoxide (DMSO); nitro compound, such as nitromethane or nitrobenzene; ester, such as ethyl acetate or methyl acetate, or a mixture of said solvents or a mixture with water.

Depending on the reaction steps and conditions used, the reaction temperature is appropriately between approximately -100°C and 300°C.

Reaction times typically range from a fraction of a minute to several days, depending on the reactivity of the individual compounds and the specific reaction conditions. A suitable reaction time can be readily determined using methods known in the art, such as reaction monitoring. Based on the reaction temperatures given above, suitable reaction times are generally in the range of 10 minutes to 48 hours.

Furthermore, other compounds of this disclosure can be readily prepared using the procedures described herein in conjunction with techniques common in the art. Those skilled in the art will readily understand that these compounds can be prepared using known variations of the conditions and methods of the following preparation procedures.

As will be understood by those skilled in the art of organic synthesis, the compounds of this disclosure are readily obtained by a variety of synthetic routes, some of which are illustrated by way of example in the appended examples. Those skilled in the art will readily recognize which types of reagents and reaction conditions will be used and how they will be applied and modified (where necessary or useful) in any particular case to obtain the compounds of this disclosure. Furthermore, some compounds of this disclosure can be readily synthesized by reacting other compounds of this disclosure under suitable conditions, for example, by converting one particular functional group present in a compound of this disclosure or a suitable precursor molecule of it into another, said conversion being achieved by applying standard synthetic methods, such as reduction, oxidation, addition, or substitution reactions; those methods are well known to those skilled in the art. Likewise, those skilled in the art will apply synthetic protecting (or protecting) groups whenever necessary or useful; suitable protecting groups and methods for introducing and removing them are well known to those skilled in the art of chemical synthesis and are described in more detail, for example, in P.G.M. Wuts, T.W. Greene, “Greene’s Protective Groups in Organic Synthesis”, 4th edition (2006) (John Wiley & Sons).

The general routes for preparing the compounds of this application are described in Schemes 1-5 of this document.

Option 1

Compound 1a and compound 1b react in the presence of a base (e.g., triethylamine) in a solvent (e.g., acetonitrile), and optionally at an elevated temperature, to give compound 1c.

Option 2

Compound 1a and compound 1b are reacted in the presence of a metal catalyst (e.g., copper chloride) in a solvent (e.g., dimethylformamide) and optionally at an elevated temperature to give compound 1c.

Option 3

Compound 2a is reacted with compound 2b in the presence of a base (e.g., sodium bis(trimethylsilyl)amino) in a solvent (e.g., tetrahydrofuran) and optionally at a reduced temperature (e.g., -78°C) to produce compound 2c. Compound 2c is then reacted in a solvent (e.g., ethyl acetate) in the presence of a metal catalyst for hydrogenation (e.g., 10% Pd/C) and optionally at an elevated temperature to give compound 2d.

Option 4

Compound 3a and compound 3b are reacted in the presence of thionyl chloride, and optionally at a reduced temperature (e.g., 0°C), to give compound 3c.

It should be understood that, in the descriptions and formulas shown above, unless otherwise stated, various groups such as _R1 - _R4 and R are as defined herein. Furthermore, for synthetic purposes, the compounds in the schemes are merely representative with selected substituents to illustrate the general synthetic methods of the compounds disclosed herein.

Bioassay

Once compounds designed, selected, and/or optimized using the methods described above are generated, they can be characterized using a variety of assays known to those skilled in the art to determine whether the compounds possess biological activity. For example, molecules can be characterized using conventional assays (including, but not limited to, those described below) to determine whether they possess predicted activity, binding activity, and/or binding specificity.

Furthermore, high-throughput screening can be used to accelerate analyses using such assays. As a result, molecules described herein can be rapidly screened for activity using techniques known in the art. General methods for performing high-throughput screening are described, for example, in Devlin (1998) High Throughput Screening, Marcel Dekker; and U.S. Patent No. 5,763,263. High-throughput assays can utilize one or more different assay techniques, including but not limited to those described below.

Various in vitro or in vivo biological assays may be suitable for detecting the effects of the compounds disclosed herein. These in vitro or in vivo biological assays may include, but are not limited to, enzyme activity assays, electrophoretic mobility variation assays, reporter gene assays, in vitro cell viability assays, and the assays described herein.

Pharmaceutical Composition

In some aspects, this disclosure provides pharmaceutical compositions comprising a compound of the disclosed type as an active ingredient. In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound of the various types described herein, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers or excipients. In some embodiments, this disclosure provides pharmaceutical compositions comprising at least one compound selected from Table 1.

As used herein, the term "composition" is intended to cover a product comprising a specified amount of a specified ingredient, and any product produced directly or indirectly from a combination of the specified amounts of the specified ingredients.

The compounds of this disclosure can be formulated into forms for oral administration, such as tablets, capsules (each including sustained-release or timed-release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. The compounds of this disclosure can also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (e.g., patch) administration, using forms well known to those skilled in the pharmaceutical art.

The formulations disclosed herein may be in the form of an aqueous solution comprising an aqueous medium. The aqueous medium component may comprise water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include those selected from: solubility enhancers, chelating agents, preservatives, tensioning agents, viscosity/suspending agents, buffers, and pH adjusters, and mixtures thereof.

Any suitable solubility enhancer can be used. Examples of solubility enhancers include cyclodextrins, such as those selected from the following: hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, atactic methylated-β-cyclodextrin, ethylated-β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated-β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylamino)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated-β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin, β-cyclodextrin sulfonyl ether, branched-chain β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, atactic methylated-γ-cyclodextrin, and trimethyl-γ-cyclodextrin, and mixtures thereof.

Any suitable chelating agent can be used. Examples of suitable chelating agents include those selected from the following: ethylenediaminetetraacetic acid (EDTA) and its metal salts, disodium EDTA, trisodium EDTA, and tetrasodium EDTA and mixtures thereof.

Any suitable preservative may be used. Examples of preservatives include those selected from the following: quaternary ammonium salts such as benzalkonium halide (preferably benzalkonium chloride), chlorhexidine gluconate, benzyl chloride, hexadecylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, thimerosal, methylparaben, propylparaben, sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethylparaben, propylaminopropyl biguanide, and butylparaben, and mixtures thereof.

The aqueous medium may also contain a tensioning agent to adjust the tension (osmotic pressure). The tensioning agent may be selected from glycols (e.g., propylene glycol, diethylene glycol, triethylene glycol), glycerol, dextrose, glycerol, mannitol, potassium chloride and sodium chloride, and mixtures thereof.

Aqueous media may also contain viscosity/suspension agents. Suitable viscosity/suspension agents include those selected from: cellulose derivatives, such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycol (e.g., polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose, and crosslinked acrylic polymers (carbopols), such as acrylic polymers crosslinked with polyolefin ethers or divinyl glycol (Carbopols – e.g., Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974, and Carbopol 974P), and mixtures thereof.

To adjust the formulation to an acceptable pH (typically a pH range of about 5.0 to about 9.0, more preferably about 5.5 to about 8.5, particularly about 6.0 to about 8.5, about 7.0 to about 8.5, about 7.2 to about 7.7, about 7.1 to about 7.9, or about 7.5 to about 8.0), the formulation may contain a pH adjuster. The pH adjuster is typically an inorganic acid or a metal hydroxide base, selected from potassium hydroxide, sodium hydroxide, and hydrochloric acid, and mixtures thereof, preferably sodium hydroxide and/or hydrochloric acid. These acidic and/or basic pH adjusters are added to adjust the formulation to a target acceptable pH range. Therefore, it may not be necessary to use both an acid and a base simultaneously—depending on the formulation, adding either an acid or a base may be sufficient to bring the mixture to the desired pH range.

Aqueous media may also contain buffers to stabilize pH. When used, buffers are selected from phosphate buffers (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), borate buffers (such as boric acid or its salts, including disodium tetraborate), citrate buffers (such as citric acid or its salts, including sodium citrate), and ε-aminocaproic acid and mixtures thereof.

The formulation may further include a wetting agent. Suitable wetting agents include those selected from the following: polyoxypropylene-polyoxyethylene block copolymers (poloxam), polyethoxylated ethers of castor oil, polyoxyethylene-modified sorbitol esters (polysorbates), oxyethylated octylphenol polymers (Tyloxapol), polyoxyethylene 40 stearate, fatty acid diol esters, fatty acid glycerides, sucrose fatty acid esters, and polyoxyethylene fatty acid esters and mixtures thereof.

Oral compositions typically contain an inert diluent or an edible, pharmaceutically acceptable carrier. They may be encapsulated in gelatin capsules or compressed into tablets. For oral therapeutic administration, the active compound may be combined with excipients and administered in tablet, lozenge, or capsule form. Oral compositions may also be prepared using fluid carriers for use as mouthwashes, wherein the compound in the fluid carrier is administered orally, gargled, and spat out or swallowed. Pharmaceutically compatible binder and/or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc., may contain any of the following components or compounds of similar nature: binders, such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients, such as starch or lactose; disintegrants, such as alginic acid, Primogel, or corn starch; lubricants, such as magnesium stearate or sterotes; gliding agents, such as colloidal silica; sweeteners, such as sucrose or saccharin; or flavoring agents, such as peppermint, methyl salicylate, or orange flavoring.

According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure as defined above, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutically acceptable diluent or carrier.

The compositions disclosed herein may be in forms suitable for oral administration (e.g., tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), topical administration (e.g., creams, ointments, gels or aqueous or oily solutions or suspensions), inhalation administration (e.g., as fine powders or liquid aerosols), inhalation administration (e.g., as fine powders), or parenteral administration (e.g., as sterile aqueous or oily solutions for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular administration, or as suppositories for rectal administration).

The compositions disclosed herein can be obtained using conventional pharmaceutical excipients well known in the art through routine procedures. Therefore, compositions intended for oral use may contain, for example, one or more colorants, sweeteners, flavorings, and/or preservatives.

An effective amount of the compound disclosed herein for treatment is sufficient to treat or prevent the inflammasome-related condition referred to herein, slow its progression, and/or reduce the amount of symptoms associated with the condition.

According to well-known medical principles, the dosage of a Formula I compound for therapeutic or preventative purposes will naturally vary depending on the nature and severity of the condition, the age and sex of the animal or patient, and the route of administration.

How to use

In some aspects, this disclosure provides a method for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo), which includes contacting cells with an effective amount of the compound of this disclosure or a pharmaceutically acceptable salt thereof.

In some aspects, this disclosure provides methods for treating or preventing diseases or conditions disclosed herein in a subject in need, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

In some embodiments, the disease or condition is related to inflammasome activity. In some embodiments, the disease or condition is one in which inflammasome activity is involved.

In some implementations, the disease or condition is an autoinflammatory disease, an autoimmune disease, a neurodegenerative disease, or cancer.

In some implementations, the disease or condition is an autoinflammatory condition and/or an autoimmune condition.

In some embodiments, the disease or condition is selected from: cold pyridine-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and joint (CINCA) syndrome, neonatal onset of multisystem inflammatory disease (NOMID), familial Mediterranean fever and nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammatory diseases occurring in protein misfolding diseases (e.g., prion diseases).

In some implementations, the disease or condition is a neurodegenerative disease.

In some implementations, the disease or condition is Parkinson's disease or Alzheimer's disease.

In some implementations, the disease or condition is cancer.

In some implementation schemes, the cancer is metastatic cancer, gastrointestinal cancer, skin cancer, non-small cell lung cancer, or colorectal adenocarcinoma.

In some aspects, this disclosure provides methods for treating or preventing autoinflammatory conditions, autoimmune diseases, neurodegenerative diseases, or cancer in subjects in need, comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of this disclosure.

In some aspects, this disclosure provides methods for treating or preventing autoinflammatory and/or autoimmune conditions selected from cold pyridine-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and joint (CINCA) syndrome, neonatal onset of multisystem inflammatory disease (NOMID), familial Mediterranean fever and nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammatory diseases occurring in protein misfolding diseases (e.g., prion diseases), said methods comprising administering to said subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

In some aspects, this disclosure provides methods for treating or preventing neurodegenerative diseases (such as Parkinson's disease or Alzheimer's disease) in subjects in need, the methods comprising administering to the subject a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present disclosure.

In some aspects, this disclosure provides a method for treating or preventing cancer in a subject in need, the method comprising administering to the subject a therapeutically effective amount of a compound of this disclosure or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of this disclosure.

In some aspects, this disclosure provides compounds of the disclosure or pharmaceutical salts thereof for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome), e.g., in vitro or in vivo.

In some respects, this disclosure provides compounds of this disclosure or pharmaceutical salts thereof for the treatment or prevention of diseases or conditions disclosed herein.

In some respects, this disclosure provides compounds of the disclosure or pharmaceutical salts thereof for use in treating or preventing autoinflammatory conditions, autoimmune diseases, neurodegenerative diseases or cancer in subjects in need.

In some aspects, this disclosure provides compounds of the disclosure or pharmaceutical salts thereof for the treatment or prevention of autoinflammatory and/or autoimmune conditions selected from the following in subjects of need: cold pyridine-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and joint (CINCA) syndrome/neonatal onset of multisystem inflammatory disease (NOMID), familial Mediterranean fever and nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammatory diseases occurring in protein misfolding diseases (e.g., prion diseases).

In some respects, this disclosure provides compounds of this disclosure or pharmaceutical salts thereof for the treatment or prevention of neurodegenerative diseases (such as Parkinson's disease or Alzheimer's disease) in subjects in need.

In some respects, this disclosure provides compounds of the disclosure or pharmaceutical salts thereof for the treatment or prevention of cancer in a subject in need.

In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for inhibiting the activity of inflammasomes (e.g., NLRP3 inflammasome) (e.g., in vitro or in vivo).

In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for the treatment or prevention of the diseases or conditions disclosed herein.

In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for the treatment or prevention of autoinflammatory conditions, autoimmune conditions, neurodegenerative diseases or cancer in subjects of need.

In some aspects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for the treatment or prevention of a subject in need of a subject selected from the following autoinflammatory and/or autoimmune conditions: cold pyridine-associated autoinflammatory syndromes (CAPS; e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and joint (CINCA) syndrome/neonatal onset of multisystem inflammatory disease (NOMID), familial Mediterranean fever and nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammatory diseases occurring in protein misfolding diseases (e.g., prion diseases).

In some aspects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of medicaments for the treatment or prevention of neurodegenerative diseases (e.g., Parkinson's disease or Alzheimer's disease) in subjects of need.

In some respects, this disclosure provides for the use of the compounds of this disclosure or pharmaceutical salts thereof in the preparation of a medicament for the treatment or prevention of cancer in a subject of need.

This disclosure provides compounds that act as inhibitors of inflammasome activity. Therefore, this disclosure provides methods for inhibiting inflammasome activity in vitro or in vivo, said methods comprising contacting cells with an effective amount of the compound as defined herein or a pharmaceutically acceptable salt thereof.

The effectiveness of the compounds disclosed herein can be determined by industrially accepted assays/disease models based on standard practices described in the art and found in current common sense.

This disclosure also provides a method for treating a disease or condition involving inflammasome activity in a patient requiring such treatment, the method comprising administering to the patient a therapeutically effective amount of a compound as defined herein or a pharmaceutically acceptable salt or pharmaceutical composition thereof.

Generally speaking, the compounds disclosed herein that inhibit the maturation of IL-1 family cytokines are effective in all therapeutic indications mediated or associated with elevated levels of active forms of cytokines belonging to the IL-1 family (Sims J. et al., Nature Reviews Immunology 10, 89-102 (February 2010)).

Exemplary diseases and corresponding references will be given below: autoinflammatory and autoimmune diseases such as CAPS (Dinarello CA. Immunity. 2004 Mar; 20(3):243-4; Hoffman HM. al. Reumatología 2005; 21(3)), gout, rheumatoid arthritis (Gabay C et al. Arthritis Research & Therapy 2009, 11:230; Schett et al.). G. et al. Nat Rev Rheumatol. 2016 Jan; 12(1):14-24.), Crohn's disease (JungMogg Kim Korean J Gastroenterol Vol.58 No.6, 300-310), COPD (Mortaz E. et al. Tanaffos. 2011; 10(2):9–14.), fibrosis (Gasse P. et al. Am J Respir Crit Care M ed. May 15, 2009; 179(10):903-13), obesity, type 2 diabetes (Dinarello CA. et al. Curr Opin Endocrinol Diabetes Obes. 2010 Aug; 17(4):314-21), multiple sclerosis (see EAE-model in Coll RC. et al. Nat Med. 2015 Mar; 21(3):248-55) and many other diseases (Martin (e.g., Immunol. 2009.27:229–65) such as Parkinson's disease or Alzheimer's disease (Michael T. et al. Nature 493,674–678 (January 31, 2013); Halle A. et al., Nat Immunol. 2008 Aug; 9(8):857-65; Saresella M. et al. Mol Neurodegener. 2016 Mar 3; 11:23) and even some tumors.

Suitably, the compounds according to this disclosure can be used to treat diseases selected from: autoinflammatory diseases, autoimmune diseases, neurodegenerative diseases, and cancer. The autoinflammatory and autoimmune diseases are suitably selected from cold pyridine-associated autoinflammatory syndromes (CAPS) such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and arthritic (CINCA) syndrome/neonatal onset multisystem inflammatory disease (NOMID), familial Mediterranean fever and nonalcoholic fatty liver disease (NAFLD), gout, rheumatoid arthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammatory diseases occurring in protein misfolding diseases (e.g., prion diseases). The neurodegenerative diseases are suitably selected from Parkinson's disease and Alzheimer's disease.

Therefore, the compounds disclosed herein can be used to treat diseases selected from: cold pyridine-associated autoinflammatory syndromes (CAPS) such as familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurocutaneous and arthritic (CINCA) syndrome/neonatal onset of multisystem inflammatory disease (NOMID), familial Mediterranean fever, gout, rheumatoid arthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, neuroinflammation occurring in protein misfolding diseases (e.g., prion diseases), Parkinson's disease, Alzheimer's disease, and oncological diseases.

Cancer treatment; association with inflammasomes

Chronic inflammatory responses have long been observed to be associated with various types of cancer. During malignant transformation or cancer treatment, inflammasomes may be activated in response to danger signals, and this activation can be both beneficial and harmful in cancer.

IL-1β expression is elevated in a variety of cancers, including breast cancer, prostate cancer, colon cancer, lung cancer, head and neck cancer, and melanoma, and patients with tumors that generate IL-1β generally have a poor prognosis (Lewis, Anne M., et al. "Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment." Journal of Translational Medicine 4.1 (2006):48).

Cancers originating from epithelial cells (carcinoma) or glandular epithelium (adenocarcinoma) are heterogeneous; they are composed of many different cell types. These may include fibroblasts, immune cells, adipocytes, endothelial cells, and pericytes, all of which may secrete cytokines/chemokines (Grivennikov, Sergei I., Florian R. Greten, and Michael Karin. "Immunity, inflammation, and cancer." Cell 140.6 (2010):883-899). This can lead to cancer-related inflammation through immune cell infiltration. The presence of leukocytes in tumors is known, but it has only recently become apparent that the inflammatory microenvironment is an important component of all tumors. Most tumors (>90%) are the result of somatic mutations or environmental factors rather than germline mutations. Many environmental causes of cancer are related to chronic inflammation (20% of cancers are related to chronic infections, 30% to smoking/inhaling pollutants, and 35% to dietary factors (20% of all cancers are related to obesity)) (Aggarwal, Bharat B., R.V. Vijayalekshmi, and Bokyung Sung. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term friend. Clinical Cancer Research 15.2 (2009):425-430).

GI cancer

Gastrointestinal (GI) cancers are often associated with chronic inflammation. For example, Helicobacter pylori (H. pylori) infection is associated with gastric cancer (Amieva, Manuel, and Richard M. Peek. "Pathobiology of Helicobacter pylori–Induced Gastric Cancer." Gastroenterology 150.1(2016):64-78). Colorectal cancer is associated with inflammatory bowel disease (Bernstein, Charles N., et al. "Cancer risk in patients with inflammatory bowel disease." Cancer 91.4(2001):854-862). Chronic inflammation in the stomach leads to the upregulation of IL-1 and other cytokines (Basso D, et al., (1996) Helicobacter pylori infection enhances mucosal interleukin-1 beta, interleukin-6, and the soluble receptor of interleukin-2. Int J Clin Lab Res 26:207–210), and polymorphisms in the IL-1β gene increase the risk of gastric cancer (Wang P, et al., (2007) Association of interleukin-1 gene polymorphisms with gastric cancer: ameta-analysis. Int J Cancer 120:552–562).

In 19% of gastric cancer cases, caspase-1 expression was reduced, which was associated with stage, lymph node metastasis, and survival (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric cancer, and activation of its NLRP3 inflammasome may be related to its promotion of gastric cancer metastasis (Xu et al., 2013).

Skin cancer

Ultraviolet radiation is the greatest environmental risk factor for skin cancer, promoting it by causing DNA damage, immunosuppression, and inflammation. The most malignant form of skin cancer, melanoma, is characterized by the upregulation of inflammatory cytokines, all of which can be regulated by IL-1β (Lázár-Molnár, Eszter, et al., "Autocrine and paracrine regulation by cytokines and growth factors in melanoma." Cytokine 12.6(2000):547-554). Systemic inflammation induces enhanced melanoma cell metastasis and growth through an IL-1-dependent mechanism in vivo. In the B16F10 mouse melanoma model, the inhibition of metastasis by thymoquinone was shown to be dependent on the inhibition of the NLRP3 inflammasome (Ahmad, Israr, et al. "Thymoquinone suppresses metastasis of melanoma cells by inhibition of NLRP3 inflammasome." Toxicology and applied pharmacology 270.1(2013):70-76).

Glioblastoma

NLRP3 contributes to radiotherapy resistance in gliomas. Ionizing radiation can induce NLRP3 expression, and NLRP3 inhibition reduces tumor growth and prolongs survival time in mice after radiotherapy. Therefore, inhibition of the NLRP3 inflammasome could provide a therapeutic strategy for radioresistant gliomas (Li, Lianling, and Yuguang Liu. Aging-related gene signature regulated by Nlrp3 predicts glioma progression. American Journal of Cancer Research 5.1 (2015):442).

Transfer

More broadly, the applicant argues that NLRP3 promotes metastasis, and therefore, regulation of NLRP3 should potentially prevent metastasis. IL-1 is involved in tumorigenesis, tumor invasion, metastasis, tumor-host interactions (Apte, Ron N., et al. "The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions." Cancer and Metastasis Reviews 25.3 (2006):387-408) and angiogenesis (Voronov, Elena, et al. "IL-1 is required for tumor invasiveness and angiogenesis." Proceedings of the National Academy of Sciences 100.5 (2003):2645-2650).

The IL-1 gene is frequently expressed in metastatic lesions of several types of human cancer patients. For example, IL-1 mRNA is highly expressed in more than half of all tested metastatic human tumor samples (specifically including non-small cell lung cancer, colorectal adenocarcinoma, and melanoma samples) (Elaraj, Dina M., et al. "The role of interleukin 1 in growth and metastasis of human cancer xenografts." Clinical Cancer Research 12.4(2006):1088-1096), and IL-1RA inhibits the growth of xenografts in IL-1-producing tumors, but has no antiproliferative effect in vitro.

Furthermore, IL-1 signaling is a biomarker for predicting an increased risk of bone metastasis in breast cancer patients. In mouse models, IL-1β and its receptor are upregulated in breast cancer cells that have metastasized to bone compared to those that have not. In mouse models, the IL-1 receptor antagonist anakinin reduces proliferation and angiogenesis, and also has a significant impact on the tumor environment, reducing bone turnover markers IL-1β and TNFα (Holen, Ingunn, et al. "IL-1 drives breast cancer growth and bone metastasis in vivo." Oncotarget (2016).

IL-18 induces the production of MMP-9 in the human leukemia cell line HL-60, which is beneficial to the degradation of the extracellular matrix and the migration and invasion of cancer cells (Zhang, Bin, et al. "IL-18 increases invasiveness of HL-60 myeloid leukemia cells: up-regulation of matrix metalloproteinases-9 (MMP-9) expression." Leukemia research 28.1 (2004):91-95). In addition, IL-18 can support the development of tumor metastasis in the liver by inducing the expression of VCAM-1 on the sinusoidal endothelium (Carrascal, Maria Teresa, et al. "Interleukin-18 binding protein reduces b16 melanoma hepatic metastasis by neutralizing adhesiveness and growth factors of sinusoidal endothelium." Cancer Research 63.2(2003):491-497).

CD36

The fatty acid scavenger receptor CD36 plays a dual role in initiating gene transcription of pre-IL-1β and inducing the assembly of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognize oxLDL, which initiates a signaling pathway leading to the upregulation of transcription of NLRP3 and pre-IL-1β (signal 1). CD36 also mediates the internalization of oxLDL into lysosomal compartments, where crystallization occurs, inducing lysosomal rupture and activation of the NLRP3 inflammasome (signal 2) (Kagan, J. and Horng T., "NLRP3 inflammasome activation: CD36 serves double duty." Nature Immunology 14.8(2013):772-774).

A subset of human oral cancer cells expresses high levels of the fatty acid scavenger receptor CD36 and is unique in its ability to initiate metastasis. Palmitic acid or a high-fat diet enhances the metastatic potential of CD36+ cells. Neutralizing anti-CD36 antibodies block metastasis in a mouse model of human oral cancer. The presence of CD36+ metastasis initiating cells is associated with poor prognosis in multiple cancer types. Dietary lipids are proposed to promote metastasis (Pasqual, G, Avgustinova, A., Mejetta, S, Martin, M, Castellanos, A, Attolini, CS-O, Berenguer, A., Prats, N, Toll, A, Hueto, JA, Bescos, C, DiCroce, L, and Benitah, SA. 2017 “Targeting metastasis-initiating cells through the fatty acid receptor CD36” Nature 541:41-45).

In hepatocellular carcinoma, exogenous palmitic acid activates an epithelial-mesenchymal transition (EMT)-like program and induces migration, which is reduced by the CD36 inhibitor sulfonyl-N-succinimide oleate (Nath, Aritro, et al., "Elevated free fatty acid uptake via CD36 promotes epithelial-mesenchymal transition in hepatocellular carcinoma." Scientific Reports 5 (2015). Body mass index was not associated with the extent of EMT, highlighting that CD36 and free fatty acids are indeed important.

Cancer stem cells (CSCs) utilize CD36 to promote their maintenance. Oxidized phospholipids (ligands of CD36) are present in glioblastomas, and the proliferation of CSCs, but not non-CSCs, increases with exposure to oxidized LDL. CD36 is also associated with patient prognosis.

Chemotherapy resistance

In addition to their direct cytotoxic effects, chemotherapeutic agents also utilize the host immune system, which contributes to their antitumor activity. However, gemcitabine and 5-FU were shown to activate NLRP3 in bone marrow-derived suppressor cells, leading to the production of IL-1β, which reduced antitumor efficacy. Mechanistically, these agents destabilize lysosomes, releasing cathepsin B to activate NLRP3. IL-1β drives the production of IL-17 by CD4+ T cells, thereby attenuating the efficacy of chemotherapy. Greater antitumor activity of gemcitabine and 5-FU was observed when tumors were established in NLRP3 ^-/- or Caps1 ^-/- mice or in WT mice treated with IL-1RA. Therefore, activation of NLRP3 in bone marrow-derived suppressor cells limits the antitumor efficacy of gemcitabine and 5-FU (Bruchard, Mélanie, et al. "Chemotherapy-triggered cathepsin B release in myeloid-derived suppressor cells activates the Nlrp3 inflammasome and promotes tumor growth." Nature Medicine 19.1(2013):57-64.). Therefore, the compounds disclosed herein could be used in chemotherapy to treat a variety of cancers.

The compounds disclosed herein, or pharmaceutically acceptable salts thereof, may be administered alone as a single therapy, or may be administered in combination with one or more other substances and/or treatments. Such combination therapy may be achieved by administering the individual components of the treatment simultaneously, sequentially, or separately.

For example, the therapeutic effect can be enhanced by administering an adjuvant (i.e., the adjuvant itself may have only a minimal therapeutic benefit, but when combined with another therapeutic agent, the overall therapeutic benefit to the individual is enhanced). Alternatively, by way of example only, the benefit experienced by the individual can be increased by administering a compound of formula (I) together with another therapeutic agent (which also includes the treatment regimen) that also has a therapeutic benefit.

When the compounds of this disclosure are administered in combination with other therapeutic agents, the compounds of this disclosure may not need to be administered via the same route as the other therapeutic agents, and may be administered via different routes due to their different physical and chemical properties. For example, the compounds of this disclosure may be administered orally to produce and maintain their good blood levels, while other therapeutic agents may be administered intravenously. Initial dosing may be performed according to established protocols known in the art, and then, based on observed effects, a skilled clinician may modify the dosage, route of administration, and timing of administration.

The specific choice of other therapeutic agents will depend on the attending physician's diagnosis and their judgment of the individual's condition and appropriate treatment regimen. According to this aspect of the disclosure, combinations are provided for treating diseases involving inflammasome activity, comprising the compounds of the disclosure as defined above or pharmaceutically acceptable salts thereof and another suitable agent.

According to another aspect of this disclosure, a pharmaceutical composition is provided comprising a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and a suitable and pharmaceutically acceptable diluent or carrier.

In addition to their use in therapeutics, compounds of formula (I) and their pharmaceutically acceptable salts can be used as pharmacological tools for the development and standardization of in vitro and in vivo testing systems to evaluate the effects of inflammasome inhibitors in laboratory animals (such as dogs, rabbits, monkeys, rats, and mice) as part of the search for new therapeutics.

Any alternative embodiments of the macromolecules described herein in any of the pharmaceutical compositions, processes, methods, uses, pharmaceuticals, and manufacturing characteristics described herein also apply.

route of administration

The compounds disclosed herein or pharmaceutical compositions comprising these compounds may be administered to a subject via any convenient route of administration, whether systemically/peripherally or locally (i.e., at the desired site of action).

Routes of administration include, but are not limited to, oral (e.g., by ingestion); sublingual; sublingual; transdermal (e.g., by patches, ointments, etc.); transmucosal (e.g., by patches, ointments, etc.); intranasal (e.g., by nasal spray); ocular (e.g., by eye drops); pulmonary (e.g., by inhalation or blowing therapy, using, for example, by aerosols, such as through the mouth or nose); rectal (e.g., by suppositories or enemas); vaginal (e.g., by vaginal suppositories); parenteral, such as by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, intracardiac, intrasheath, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subepidermal, intra-articular, subarachnoid, and intrasternal; and by implantation of a reservoir or depository, such as subcutaneous or intramuscular.

This disclosure has been described, and the following embodiments are provided by way of example rather than limitation.

Example

Abbreviations:

ACN Acetonitrile

aq. of water

AP (Atmospheric Pressure)

Argon gas

DCM (Dichloromethane)

DMF N,N-Dimethylformamide

DMSO- _d6 hexadecimalized dimethyl sulfoxide

eq. Equivalent

MS ES ⁺ Positive Electrospray Ionization Mass Spectrometry

EtOAc (ethyl acetate)

FCC (Fast Column Chromatography)

HPLC (High Performance Liquid Chromatography)

Min

NaHMDS Sodium hexamethyldimethylsilyl azide

RM Reaction mixture

rt Room temperature

sat. Saturated

SM (Starting Material)

TEA (Triethylamine)

TFA (Trifluoroacetic acid)

THF (Tetrahydrofuran)

TLC (Thin Layer Chromatography)

Y Yield

General Procedure A

The α-hydroxy ester or α-hydroxy acid (1 equivalent) was dissolved in ACN (2 ml/mmol α-hydroxy ester or α-hydroxy acid), and the solution was cooled to 0 °C. TEA (1 equivalent) was added, followed dropwise by isocyanate (1.2 equivalent). The reaction mixture was heated to room temperature and stirred under Ar for 15 hours. The reaction mixture was diluted with DCM, and the solution was washed with 1 M HCl. The aqueous layer was extracted twice with DCM, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by FCC (DCM or EtOAc gradient in hexane) or by preparative reversed-phase HPLC (ACN in water, 0.1% formic acid buffer).

General Procedure B

An α-hydroxy ester (1 equivalent), isocyanate (1.1 equivalent), CuCl (1 equivalent), and DMF (4 ml/mmol of α-hydroxy ester, pre-degassed by bubbling with Ar for 20 min) were mixed and stirred at room temperature under Ar for 15 hours. The mixture was then poured into water, and the resulting precipitate was filtered off and washed with water. It was redissolved in MeOH and the solution was evaporated. The residue was dissolved in DCM, dried over anhydrous sodium sulfate, and filtered on an alumina pad. The filter bed was washed with EtOAc, and the filtrate was evaporated. The residue was purified by FCC (DCM or a gradient of EtOAc in hexane) to give the desired product.

General procedure C

Under an argon atmosphere, at -78°C, a 1.0 M NaHMDS solution in THF (1 equivalent) was added dropwise to a stirred solution of aldehyde (1 equivalent) and ethyl chloroacetate (1 equivalent) in anhydrous THF (3 mL/mmol aldehyde). The reaction was stirred at -78°C for 30 min, then heated to 0°C, quenched with water, and concentrated. The residue was partitioned between diethyl ether and water, and the aqueous layer was extracted twice with diethyl ether. The combined organic fractions were washed with brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was used for the next step without further purification.

General Procedure D

Ethylene oxide (1 equivalent) was dissolved in EtOAc (10 mL/mmol ethylene oxide), and 10% Pd/C (10% by weight relative to ethylene oxide) was added. The reaction mixture was stirred overnight at room temperature under a hydrogen atmosphere (AP). The reaction mixture was filtered through a Celite pad, the filter bed was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The crude product was used for the next step without further purification.

General Procedure E

The carboxylic acid (1 equivalent) was dissolved in alcohol R_³-OH (6 mL/mmol acid), and the solution was cooled to 0 °C under Ar. Thionyl chloride (1.5 equivalent) was added dropwise at 0 °C, and the reaction mixture was stirred under Ar at room temperature for 15 h. It was then evaporated to dryness and co-evaporated with cyclohexane (twice). The residue was purified by grinding in Et _₂ O/hexane or by FCC (0 to 20% Et_OAc/hexane).

Example 1. Synthesis of intermediates

4-Isocyanate-1,2,3,5,6,7-hexahydro-s-indara (Intermediate A)

Step 1. 3-Chloro-1-(2,3-dihydro-1H-inden-5-yl)prop-1-one. A suspension of aluminum chloride (12.4 g, 93 mmol, 1 equivalent) in DCM (50 ml) was cooled to -10 °C under an argon atmosphere with vigorous stirring. A solution of 3-chloropropionyl chloride (11 g, 93 mmol, 1 equivalent) and indenman (10 g, 85 mmol, 0.9 equivalent) in DCM (15 ml) was added dropwise over 0.5 hours, maintaining the temperature between -15 °C and -5 °C. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was added dropwise to cold (0 °C) 2 M HCl over 30 minutes, maintaining the temperature between 0 °C and 10 °C. The layers were separated, and the aqueous phase was extracted with DCM (3 × 30 ml). The combined organic layers were washed successively with water, saturated sodium bicarbonate, and brine. The organic phase was dried over _Na₂SO₄ , filtered, and evaporated _under reduced pressure to approximately 30 ml. Hexane (50 ml) was added, and evaporation continued; this process was repeated twice. After further addition of hexane (50 ml), the slurry was filtered and dried to give 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)prop-1-one, a brownish-yellow solid. Y = 81%. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 7.84 (d, 1H), 7.78–7.76 (m, 1H), 7.37 (d, J = 8 Hz, 1H), 3.92 (t, J = 6 Hz, 2H), 3.51 (t, J = 6 Hz, 2H), 2.92 (t, J = 8 Hz, 4H), 2.09–2.01 (m, 2H).

Step 2. 8-Nitro-1,2,3,5,6,7-Hexahydro-s-indarsen-1-one and 4-nitro-1,2,3,5,6,7-Hexahydro-s-indarsen-1-one. 3-Chloro-1-(2,3-dihydro-1H-indene-5-yl)prop-1-one (82 g, 0.39 mol, 1 equivalent) was added in portions to concentrated sulfuric acid (71 ml, 1.34 mol, 3.4 equivalent). The resulting mixture was heated to 60°C for 2 days. The RM was cooled to 0°C, and a mixture of nitric acid (26 ml, 0.59 mol, 1.5 equivalent) and concentrated sulfuric acid (26 ml, 0.49 mol, 1.25 equivalent) was added dropwise. The RM was stirred for 1 h, maintaining the temperature between 0°C and 5°C. The RM was slowly added to a mixture of water and DCM under ice bath cooling. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were washed sequentially with brine and saturated sodium bicarbonate. The organic layers were dried _{over Na₂SO₄} and filtered. The crude mixture was purified by FCC (hexane/ethyl acetate). The desired product was further purified by crystallization from MeOH. 8-Nitro-1,2,3,5,6,7-Hexahydro-s-indargen-1-one: Y = 36%. MS ES ⁺ : 218. ^1H NMR (400MHz, DMSO- _d6 ) δ 7.67 (s, 1H), 3.15–3.08 (m, 2H), 3.04 (t, J = 8Hz, 2H), 2.90 (t, J = 8Hz, 2H), 2.77–2.71 (m, 2H), 2.17–2.10 (m, 2H). 4-Nitro-1,2,3,5,6,7-Hexahydro-s-indargen-1-one: Y = 5%. MS ES ⁺ : 218. ^1H NMR (400MHz, DMSO- _d6) )δ7.82(s,1H),3.41–3.36(m,2H),3.34–3.29(m,3H),3.02(t,J=8Hz,2H),2.77–2.69(m,2H),2.17–2.10(m,2H).

Step 3. 1,2,3,5,6,7-Hexahydro-s-indargen-4-amine. A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-s-indargen-1-one and 4-nitro-1,2,3,5,6,7-hexahydro-s-indargen-1-one (7.00 g, 32 mmol, 1 equivalent) was suspended in MeOH (70 mL). The solution was treated with 20% palladium hydroxide/carbon (1.72 g, 12 mmol, 0.4 equivalent) and methanesulfonic acid (3.41 g, 35 mmol, 1.1 equivalent). The mixture was hydrogenated at 35 psi for 5 h. The catalyst was removed by filtration on a Celite pad, and the filter bed was washed with MeOH. The filtrate was diluted with water (350 mL) and the pH was adjusted to 11 with 2 M NaOH. The slurry was filtered, and the crude solid was recrystallized from MeOH/water (9:1) to give 1,2,3,5,6,7-hexahydro-s-indargen-4-amine, as a colorless needle-like substance. Y = 73%. MS ES ⁺ : 174.1. ^1H NMR (400MHz, DMSO- _d6 ) δ 6.35 (s, 1H), 4.52 (s, 2H), 2.72 (t, J = 7Hz, 4H), 2.59 (t, J = 7Hz, 4H), 2.00-1.93 (m, 4H).

Step 4. 4-Isocyanate-1,2,3,5,6,7-Hexahydro-s-indargen (Intermediate A). Triphosgene (0.64 g, 2.16 mmol, 3 equivalents) was added in a single batch to a stirred solution of 1,2,3,5,6,7-hexahydro-s-indargen-4-amine (1.1 g, 6.35 mmol, 1 equivalent) and TEA (0.973 mL, 6.98 mmol, 1.1 equivalents) in THF (20 mL). The mixture was heated to reflux for 4 hours and cooled to room temperature. The THF was evaporated, and the residue was absorbed in pentane and filtered through a silica gel stopper. The solvent was evaporated under vacuum to give 4-isocyanate-1,2,3,5,6,7-hexahydro-s-indargen as a white solid. Y = 71%. ^¹H NMR (400 MHz, chloroform-d) δ 6.96 (s, ¹H), 2.94–2.89 (m, ⁸H), 2.22–2.03 (m, ⁴H).

2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid (intermediate B)

Step 1: 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}tert-butyl acetate

The title compound was prepared using tert-butyl glycolate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% DCM/hexane). Y = 65%. MS ES ⁺ ([M+Na] ⁺ ): 354.4. ^1H NMR (400MHz, DMSO- _d6 ) δ 9.13 (s, 1H), 6.95 (s, 1H), 4.48 (s, 2H), 2.81 (t, J = 7Hz, 4H), 2.72 (t, J = 7Hz, 4H), 2.03–1.91 (m, 4H), 1.43 (s, 9H).

Step 2: 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid. Dissolve tert-butyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid (1.75 g, 5.28 mmol) in a 20% solution of TFA in DCM (100 ml). Stir the reaction mixture at room temperature for 2 h and evaporate to dryness. Co-evaporate the residue twice with cyclohexane and grind with hexane. Filter the resulting white powder, wash with hexane, and dry under vacuum. Y＝96%.MS ES ⁺ :276.1. ¹ H NMR (300MHz, DMSO-d ₆ )δ12.88(s,1H),9.09(s,1H),6.95(s,1H),4.52(s,2H),2.81(t,J＝7Hz,4H),2.71(t,J＝7Hz,4H),2.04–1.89(m,4H).

Example 2. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

The title compound was prepared using ethyl 2-hydroxyacetate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% DCM/hexane). Y = 40%. MS ES ⁺ ([M+Na] ⁺ ): 326.2. ^1H NMR (300MHz, DMSO-d ₆ ) δ 9.19 (s, 1H), 6.95 (s, 1H), 4.62 (s, 2H), 4.18–4.11 (m, 2H), 2.80 (t, J = 7Hz, 4H), 2.70 (t, J = 7Hz, 4H), 2.05–1.88 (m, 4H), 1.21 (t, J = 7Hz, 3H).

Example 3. Ethyl 2-{[((2,6-difluorophenyl)carbamoyl]oxy}acetate

The title compound was prepared using ethyl 2-hydroxyacetate and 1,3-difluoro-2-isocyanophenyl as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% DCM/hexane). Y = 28%. MS ES ⁺ ([M+Na] ⁺ ): 282.0. ^1H NMR (400MHz, chloroform-d) δ 7.28–7.19 (m, 1H), 7.03–6.94 (m, 2H), 6.34 (s, 1H), 4.72 (s, 2H), 4.30–4.25 (m, 2H), 1.32 (t, J = 7Hz, 3H).

Example 4. Ethyl 2-{[(2,6-dichlorophenyl)carbamoyl]oxy}acetate

The title compound was prepared using ethyl 2-hydroxyacetate and 1,3-dichloro-2-isocyanophenyl as starting materials according to general procedure A. The crude product was purified by FCC (0 to 25% EtOAc/hexane). Y = 65%. MS ES ⁺ ([M+Na] ⁺ ): 314.5. ^1H NMR (400MHz, chloroform-d) δ 7.40 (d, J = 8Hz, 2H), 7.21 (t, J = 7Hz, 1H), 6.54 (s, 1H), 4.72 (s, 2H), 4.30–4.25 (m, 2H), 1.32 (t, J = 7Hz, 3H).

Example 5. Ethyl 2-{[(naphthyl-1-yl)carbamoyl]oxy}

The title compound was prepared using ethyl 2-hydroxyacetate and 1-isocyanonaphthalene as starting materials according to general procedure A. The crude product was purified by FCC (0 to 25% EtOAc/hexane). Y = 96%. MS ES ⁺ ([M+Na] ⁺ ): 296.1. ^1H NMR (400MHz, chloroform-d) δ 7.95 (d, J = 8Hz, 1H), 7.92–7.83 (m, 2H), 7.73 (d, J = 8Hz, 1H), 7.61–7.47 (m, 3H), 7.15 (s, 1H), 4.76 (s, 2H), 4.33–4.28 (m, 2H), 1.34 (t, J = 7Hz, 3H).

Example 6. Ethyl 2-{[(2,2-dimethyl-2,3-dihydro-1-benzofuran-7-yl)carbamoyl]oxy}

The title compound was prepared using ethyl 2-hydroxyacetate and 7-isocyano-2,2-dimethyl-2,3-dihydro-1-benzofuran as starting materials according to general procedure A. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y = 74%. MS ES ⁺ ([M+Na] ⁺ ): 316.2. ^1H NMR (400MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 7.21 (d, J = 8Hz, 1H), 6.99–6.94 (m, 1H), 6.75 (t, J = 8Hz, 1H), 4.63 (s, 2H), 4.18–4.12 (m, 2H), 3.02 (s, 2H), 1.43 (s, 6H), 1.21 (t, J = 7Hz, 3H).

Example 7. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionate

The title compound was prepared according to general procedure A using ethyl 2-hydroxy-3-methoxypropionate and intermediate A as starting materials. The crude product was purified by FCC (0 to 25% EtOAc/hexane). Y = 54%. MS ES ⁺ ([M+Na] ⁺ ): 370.6

¹ H NMR (400MHz, DMSO-d ₆ )δ9.26(s,1H),6.95(s,1H),5.15–5.00(m,1H),4.22–4.09(m,2H),3.87–3.62(m,2H),3.31(d ,J＝4Hz,3H),2.81(t,J＝7Hz,4H),2.71(t,J＝7Hz,4H),2.03–1.92(m,4H),1.21(t,J＝7Hz,3H).

Example 8. Ethyl 2-({[2-fluoro-5-(trifluoromethyl)phenyl]carbamoyl}oxy)acetate

The title compound was prepared using ethyl 2-hydroxyacetate and 2-fluoro-5-(trifluoromethyl)phenyl isocyanate as starting materials according to general procedure A. The crude product was purified by preparative TLC (20% EtOAc/hexane). Y = 14%. MS ES ⁺ ([M+Na] ⁺ ): 332.5. ^1H NMR (400MHz, DMSO-d ₆ ) δ 10.12 (s, 1H), 8.11–8.09 (m, 1H), 7.68–7.38 (m, 2H), 4.74 (s, 2H), 4.20–4.15 (m, 2H), 1.22 (t, J = 7Hz, 3H).

Example 9. Ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}acetate

The title compound was prepared using ethyl 2-hydroxyacetate and 2,6-dimethylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y = 38%. MS ES ⁺ ([M+Na] ⁺ ): 274.1

^1H NMR (400MHz, chloroform-d) δ 7.11 (s, 3H), 6.26 (s, 1H), 4.70 (s, 2H), 4.30–4.25 (m, 2H), 2.32 (s, 6H), 1.32 (t, J = 7Hz, 3H).

Example 10. Ethyl 2-{[(2,6-diethylphenyl)carbamoyl]oxy}acetate

The title compound was prepared using ethyl 2-hydroxyacetate and 2,6-diethylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% DCM/hexane). Y = 57%. MS ES ⁺ ([M+Na] ⁺ ): 302.5. ^1H NMR (400MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 7.20–7.16 (m, 1H), 7.09 (d, J = 7Hz, 2H), 4.63 (s, 2H), 4.18–4.12 (m, 2H), 2.62–2.53 (m, 4H), 1.22 (t, J = 7Hz, 3H), 1.12 (t, J = 8Hz, 6H).

Example 11. Ethyl 2-({[2-(chloro-6-methylphenyl)carbamoyl]oxy}acetate

The title compound was prepared from ethyl 2-hydroxyacetate and 2-chloro-6-methylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% DCM/hexane). Y = 33%. MS ES ⁺ ([M+Na] ⁺ ): 294.2. ^1H NMR (400MHz, DMSO- _d6 ) δ 9.33 (s, 1H), 7.36–7.34 (m, 1H), 7.28–7.19 (m, 2H), 4.66 (s, 2H), 4.18–4.13 (m, 2H), 2.23 (s, 3H), 1.21 (t, J = 7Hz, 4H).

Example 12. Ethyl 2-{[(2-cyanophenyl)carbamoyl]oxy}acetate

The title compound was prepared using ethyl 2-hydroxyacetate and 2-isocyanatobenzyl nitrile as starting materials according to general procedure A. The crude product was purified by FCC (0 to 30% EtOAc/hexane). Y = 21%. MS ES ⁺ ([M+Na] ⁺ ): 271.0. ¹ ¹H NMR (400MHz, chloroform-d) δ 8.25 (d, J = 8 Hz, 1H), 7.63–7.59 (m, 2H), 7.36 (s, 1H), 7.18 (t, J = 8 Hz, 1H), 4.74 (s, 2H), 4.33–4.27 (m, 2H), 1.34 (t, J = 7 Hz, 3H).

Example 13. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyridin-3-yl)propionate

Step 1: Ethyl 3-(pyridin-3-yl)ethylene oxide-2-carboxylate. The title compound was prepared using 3-pyridinecarboxaldehyde as the starting material according to general procedure C. Y = 41%. MS ES ⁺ : 194.1. ^1H NMR (300MHz, chloroform-d) δ 8.67–8.59 (m, 2H), 7.63–7.54 (m, 1H), 7.39–7.28 (m, 1H), 4.44–4.24 (m, 2H), 4.16 (d, J = 2Hz, 1H), 3.55 (d, J = 2Hz, 1H), 1.36 (t, J = 7Hz, 3H).

Step 2: Ethyl 2-hydroxy-3-(pyridin-3-yl)propionate. The title compound was prepared using ethyl 3-(pyridin-3-yl)ethylene oxide-2-carboxylate as the starting material according to general procedure D. Y = 70%. MS ES ⁺ : 196.2. ^1H NMR (300MHz, chloroform-d) δ 8.50 (d, J = 6Hz, 2H), 7.62 (d, J = 8Hz, 1H), 7.36–7.16 (m, 1H), 4.52–4.39 (m, 1H), 4.29–4.23 (m, 2H), 3.18–3.10 (m, 1H), 3.03–2.96 (m, 1H), 1.31 (t, J = 7Hz, 3H).

Step 3: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyridin-3-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(pyridin-3-yl)propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by reversed-phase preparative HPLC. Y＝5%.MS ES ⁺ :395.4. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.15(s,1H),8.52(s,1H),8.46(s,1H),7.75(s,1H),7.36(s,1H),6.95(s,1H),5.31–5.05(m,1H),4.13–4. 06(m,2H),3.24–3.08(m,2H),2.80(t,J＝7Hz,4H),2.71–2.56(m,4H),2.09–1.78(m,4H),1.14(t,J＝7Hz,3H).

Example 14. Ethyl 2-{[(2-tert-butylphenyl)carbamoyl]oxy}acetate

2-tert-butylaniline (200 mg, 1.34 mmol, 1 equivalent) was dissolved in anhydrous THF (10 mL), and TEA (0.224 mL, 1.61 mmol, 1.2 equivalent) was added. The solution was treated with triphosgene (0.159 mg, 0.54 mmol, 0.4 equivalent), and the resulting mixture was stirred at 60 °C for 4 h. The reaction mixture was cooled to 0 °C, and ethyl glycolate (0.167 mL, 1.61 mmol, 1.2 equivalent) and TEA (0.163 mg, 1.61 mmol, 1.2 equivalent) were added. The reaction mixture was stirred at room temperature for 15 h, filtered through a Celite filter, and the filter bed was washed with EtOAc. The filtrate was concentrated under reduced pressure, and the residue was purified by FCC (0 to 20% EtOAc/hexane). Y＝47%.MS ES ⁺ ([M + Na] ⁺ ): 302.6. ¹ H NMR (300MHz, DMSO-d ₆ )δ8.94(s,1H),7.42–7.37(m,1H),7.26–7.15(m,2H),7.13–6.97(m,1H),4.62(s,2H),4.18–4.12(m,2H),1.34(s,9H),1.21(t,J＝7Hz,3H).

Example 15. Ethyl 2-((2,4,6-trimethylmethylcarbamoyl)oxy)ethyl acetate

The title compound was prepared using ethyl glycolate and 2,4,6-trimethylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by preparative TLC (20% EtOAc/hexane) and FCC (0 to 100% DCM/hexane). Y = 57%. MS ES ⁺ ([M+Na] ⁺ ): 288.1. ^1H NMR (400MHz, chloroform-d) δ 6.92 (s, 2H), 6.19 (s, 1H), 4.70 (s, 2H), 4.30–4.24 (m, 2H), 2.29 (s, 9H), 1.32 (t, J = 7Hz, 3H).

Example 16. Ethyl 2-(((2-isopropylphenyl)carbamoyl)oxy)ethyl acetate

The title compound was prepared using ethyl glycolate and 2-isopropylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y = 49%. MS ES ⁺ ([M+Na] ⁺ ): 288.2. ^1H NMR (400MHz, chloroform-d) δ 7.73–7.63 (m, 1H), 7.32–7.29 (m, 1H), 7.25–7.17 (m, 2H), 6.64 (s, 1H), 4.71 (s, 2H), 4.31–4.25 (m, 2H), 3.17–3.03 (m, 1H), 1.33 (t, J = 7Hz, 3H), 1.28 (d, J = 7Hz, 6H)

Example 17. Ethyl 2-(((2-ethyl-6-methylphenyl)carbamoyl)oxy)ethyl acetate

The title compound was prepared using ethyl glycolate and 2-ethyl-6-methylphenyl isocyanate as starting materials according to general procedure A. The crude product was subjected to FCC (0 to 20% EtOAc/hexane) followed by preparative TLC (100% DCM). Y = 35%. MS ES ⁺ ([M+Na] ⁺ ): 288.2. ^1H NMR (400MHz, DMSO-d ₆ ) Major conformational isomers: δ 9.00 (s, 1H), 7.16–7.10 (m, 1H), 7.10–7.06 (m, 2H), 4.64 (s, 2H), 4.18–4.12 (m, 2H), 2.59–2.52 (m, 2H), 2.17 (s, 3H), 1.21 (t, J = 7Hz, 3H), 1.11 (t, J = 7Hz, 3H).

Example 18. Ethyl 2-(((1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl)oxy)-3-phenylpropionate

Step 1: Ethyl 3-phenylethylene oxide-2-carboxylate. The title compound was prepared using ethyl chloroacetate and benzaldehyde as starting materials according to general procedure C. The crude product was purified by FCC (0 to 10% EtOAc/hexane). Y = 45%. MS ES ⁺ ([M+Na] ⁺ ): 234.1. ^1H NMR (400MHz, DMSO-d ₆ ) δ 7.38 (s, 5H), 4.24–4.18 (m, 2H), 4.16 (d, J = 2Hz, 1H), 3.81 (d, J = 2Hz, 1H), 1.25 (t, J = 7Hz, 3H).

Step 2: Ethyl 2-hydroxy-3-phenylpropionate. The title compound was prepared using ethyl 3-phenylethylene oxide-2-carboxylate as the starting material according to general procedure D. Y = 96%. MS ES ⁺ : 195.2. ^1H NMR (400MHz, DMSO- _d6 ) δ 7.30–7.24 (m, 2H), 7.24–7.17 (m, 3H), 5.53 (d, J = 6Hz, 1H), 4.26–4.19 (m, 1H), 4.09–4.03 (m, 2H), 2.98–2.90 (m, 1H), 2.87–2.79 (m, 1H), 1.14 (t, J = 7Hz, 3H).

Step 3: Ethyl 2-(((1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl)oxy)-3-phenylpropionate.

The title compound was prepared using ethyl 2-hydroxy-3-phenylpropionate and intermediate A as starting materials according to general procedure A. The crude product was purified by two consecutive FCC purifications (0 to 100% DCM/hexane and 0 to 20% EtOAc/hexane). Y = 21%. MS ES ⁺ ([M+Na] ⁺ ): 416.8. ^1H NMR (400MHz, methanol- _d4 ) δ 7.40–7.03 (m, 5H), 6.97 (s, 1H), 5.26–5.09 (m, 1H), 4.21–4.15 (m, 2H), 3.28–3.09 (m, 2H), 2.97–2.82 (m, 4H), 2.80–2.53 (m, 4H), 2.12–1.94 (m, 4H), 1.23 (t, J = 7Hz, 3H).

Example 19. Ethyl 2-(((1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl)oxy)-3-(pyridin-2-yl)propionate

Step 1: Ethyl 3-(pyridin-2-yl)ethylene oxide-2-carboxylate. The title compound was prepared using ethyl chloroacetate and 2-pyridinecarboxaldehyde as starting materials according to general procedure C. The crude product was purified by FCC (0 to 50% EtOAc gradient in hexane). Y = 67%, a mixture of diastereomers (75/25). MS ES ⁺ : 194.1. Diastereomer 1 (major): ^¹H NMR (400MHz, DMSO- _d₆ ) δ 8.59–8.56 (m, 1H), 7.88–7.83 (m, 1H), 7.50–7.45 (m, 1H), 7.44–7.39 (m, 1H), 4.25–4.18 (m, 3H), 3.98–3.96 (m, 1H), 1.25 (t, J = 7Hz, 3H). Diastereomer 2 (minor): ^¹H NMR (400MHz, DMSO- _d₆) )δ8.54–8.51(m,1H),7.82–7.78(m,1H),7.39–7.33(m,2H),4.40(d,J＝5Hz,1H),4.10(d,J＝5Hz,1H),3.95–3.92(m,2H),0.95(t,J＝7Hz,3H).

Step 2: Ethyl 2-hydroxy-3-(pyridin-2-yl)propionate. The title compound was prepared using ethyl 3-(pyridin-2-yl)ethylene oxide-2-carboxylate (a mixture of two diastereomers) as the starting material, according to general procedure D. Y＝85%.MS ES ⁺ :196.1. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.51–8.46(m,1H),7.71–7.67(m,1H),7.26(d,J＝8Hz,1H),7.24–7.20(m,1H),5.60–5.54(m,1H) ,4.49–4.41(m,1H),4.10–4.04(m,2H),3.10–3.05(m,1H),2.99–2.94(m,1H),1.14(t,J＝7Hz,3H).

Step 3: Ethyl 2-(((1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl)oxy)-3-(pyridin-2-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(pyridin-2-yl)propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y＝16%.MS ES ⁺ :395.4. ¹ HNMR (400MHz, DMSO-d ₆ )δ9.08(s,1H),8.52(d,J＝4Hz,1H),7.81–7.69(m,1H),7.42–7.33(m,1H),7.31–7.24(m,1H),6.93(s,1H),5.41–5.33(m, 1H), 4.14–4.09 (m, 2H), 3.31–3.20 (m, 2H), 2.78 (t, J = 7Hz, 4H), 2.67–2.55 (m, 4H), 2.01–1.83 (m, 4H), 1.15 (t, J = 7Hz, 3H).

Example 20. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-propionate

The title compound was prepared using ethyl (2R)-2-hydroxypropionate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y = 24%. MS ES ⁺ ([M+Na] ⁺ ): 340.3. ^1H NMR (400MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 6.95 (s, 1H), 4.94–4.89 (m, 1H), 4.16–4.11 (m, 2H), 2.81 (t, J = 7Hz, 4H), 2.70 (t, J = 7Hz, 4H), 2.02–1.91 (m, 4H), 1.43 (d, J = 5Hz, 3H), 1.21 (t, J = 7Hz, 3H).

Example 21. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propyl-2-yl acetate

The title compound was prepared using propyl-2-hydroxyacetate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% DCM/hexane). Y = 56%. MS ES ⁺ ([M+Na] ⁺ ): 340.3. ^1H NMR (400MHz, DMSO- _d6 ) δ 9.16 (s, 1H), 6.95 (s, 1H), 5.04–4.91 (m, 1H), 4.58 (s, 2H), 2.81 (t, J = 7Hz, 4H), 2.76–2.66 (m, 4H), 2.11–1.86 (m, 4H), 1.21 (d, J = 6Hz, 6H).

Example 22. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetate

2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid (intermediate B, 200 mg, 0.73 mmol, 1 equivalent) was suspended in acetone (2 mL), and TEA (152 μl, 1.09 mmol, 1.5 equivalent) was added. 1-Iodopropane (78 μl, 0.8 mmol, 1.1 equivalent) was added to the resulting solution, and RM was stirred at room temperature under Ar for 15 h. RM was diluted with DCM, and the solution was washed with 1 M HCl. The aqueous layer was extracted twice with DCM. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by grinding in hexane to give the title compound. Y＝15%.MS ES ⁺ ([M + Na] ⁺ ): 340.4. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.17(s,1H),6.95(s,1H),4.63(s,2H),4.07(t,J＝7Hz,2H),2.81(t,J＝6Hz,4H ), 2.71 (t, J = 7Hz, 4H), 2.06–1.89 (m, 4H), 1.66–1.55 (m, 2H), 0.90 (t, J = 7Hz, 3H).

Example 23. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}cyclopropyl methyl acetate

The title compound was prepared using intermediate B and cyclopropylmethanol as starting materials according to general procedure E. The crude product was purified by grinding in Et ₂ O/hexane. Y = 69%. MS ES ⁺ ([M+Na] ⁺ ): 352.4. ^1H NMR (400MHz, DMSO-d ₆ ) δ 9.18(s,1H), 6.95(s,1H), 4.64(s,2H), 3.95(d,J＝7Hz,2H), 2.81(t,J＝7Hz,4H), 2.77–2.66(m,4H), 2.09–1.87(m,4H), 1.16–1.03(m,1H), 0.56–0.49(m,2H), 0.32–0.26(m,2H).

Example 24. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}cyclobutyl acetate

The title compound was prepared using intermediate B and cyclobutanol as starting materials according to general procedure E. The crude product was purified by grinding with _Et₂O /hexane. Y = 61%. MS ^ES⁺ ([M+Na] ^⁺ ): 352.3. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.17 (s, 1H), 6.95 (s, 1H), 5.04–4.92 (m, 1H), 4.60 (s, 2H), 2.81 (t, J = 7Hz, 4H), 2.71 (t, J = 7Hz, 4H), 2.35–2.23 (m, 2H), 2.09–2.00 (m, 2H), 2.00–1.92 (m, 4H), 1.81–1.70 (m, 1H), 1.68–1.54 (m, 1H).

Example 25. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid 2-methylpropyl ester

The title compound was prepared using intermediate B and 2-methylprop-1-ol as starting materials according to general procedure E. The crude product was purified by grinding with _Et₂O /hexane. Y = 56%. MS ^ES⁺ ([M+Na] ^⁺ ): 354.4. ^¹H NMR (400MHz, DMSO- _d₆ ) δ 9.18 (s, 1H), 6.95 (s, 1H), 4.65 (s, 2H), 3.91 (d, J = 7Hz, 2H), 2.81 (t, J = 7Hz, 4H), 2.77–2.64 (m, 4H), 2.01–1.93 (m, 4H), 1.92–1.83 (m, 1H), 0.90 (d, J = 7Hz, 6H).

Example 26. Ethyl propionate of (2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

Step 1: (2R)-3-(4-cyanophenyl)-2-hydroxypropionic acid. Dissolve (2R)-2-amino-3-(4-cyanophenyl)propionic acid (500 mg, 2.63 mmol, 1 equivalent) in a 4:1 deionized water:acetic acid (30 ml) solution, and slowly add sodium nitrite (544 mg, 7.89 mmol, 3 equivalent) in water (5 ml) over 10 minutes at 0 °C. Heat the mixture to room temperature and stir for 15 hours. Quench the reaction with 2 M methylamine/THF (2 ml) and evaporate the resulting mixture under reduced pressure to about one-third of its volume. Basicilerate the mixture to pH 9 with a saturated aqueous solution _{of NaHCO3} and wash with EtOAc. Then acidify the aqueous layer to pH 3 with 2 M HCl. Extract the mixture four times with DCM, and dry the combined organic layers with anhydrous sodium sulfate and evaporate to dryness. Purify the residue by grinding with _Et2O /hexane. Y＝43%.MS ^ES- :190.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ12.60(s,1H),7.75(d,J＝8Hz,2H),7.45(d,J＝8Hz,2H),5.41(s,1H),4.20(m,1H),3.06(m,1H),2.88(m,1H).

Step 2: (2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}propionic acid. The title compound was prepared using (2R)-3-(4-cyanophenyl)-2-hydroxypropionic acid and intermediate A as starting materials according to general procedure A. The crude product was purified by grinding with _Et₂O . Y = 55%. MS ^ES⁺ : 391.0.

Step 3: Ethyl (2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. (2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate (200 mg, 0.51 mmol, 1 equivalent) was suspended in acetone (2 ml) and treated with TEA (107 μl, 0.77 mmol, 1.5 equivalent). Iodoethane (49 μl, 0.61 mmol, 1.2 equivalent) was added to the resulting solution, and RM was stirred at room temperature under Ar for 15 h. The reaction mixture was diluted with DCM, and the solution was washed with 1 M HCl. The aqueous layer was extracted twice with DCM, and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by FCC (0 to 40% EtOAc/hexane). Y=22%.MS ES ⁺ ([M+Na] ⁺ ): 442.1. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.13(s,1H),7.90–7.70(m,2H),7.62–7.42(m,2H),6.94(s,1H),5.31–5.11(m,1H),4.13–4.07(m,2 H), 3.30–3.10 (m, 2H), 2.80 (t, J = 7Hz, 4H), 2.66–2.57 (m, 4H), 2.00–1.85 (m, 4H), 1.14 (t, J = 7Hz, 3H).

Example 27. Ethyl 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)ethyl acetate-5Z

The title compound was prepared using ethyl glycolate and 2-isopropyl-6-methylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 20% EtOAc gradient in hexane). Y = 66%. MS ES ⁺ ([M+Na] ⁺ ): 302.3. ^1H NMR (300MHz, DMSO-d ₆ ) δ 8.98 (s, 1H), 7.20–7.12 (m, 2H), 7.11–7.01 (m, 1H), 4.63 (s, 2H), 4.17–4.09 (m, 2H), 3.21–3.09 (m, 1H), 2.16 (s, 3H), 1.20 (t, J = 7Hz, 3H), 1.11 (d, J = 7Hz, 6H).

Example 28. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetic acid

The title compound was prepared using glycolic acid and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 10% MeOH/DCM). Y = 17%. MS ES ⁺ ([M+Na] ⁺ ): 298.3. ^1H NMR (300MHz, DMSO- _d6 ) δ 12.88 (s, 1H), 9.09 (s, 1H), 6.95 (s, 1H), 4.52 (s, 2H), 2.81 (t, J = 7Hz, 4H), 2.71 (t, J = 7Hz, 4H), 2.04–1.89 (m, 4H).

Example 29. Ethyl 2-{[(2,6-diethyl-4-methylphenyl)carbamoyl]oxy}acetate

Step 1: 2,6-Diethyl-4-methylphenyl isocyanate. A mixture of di-tert-butyl dicarbonate (702 mg, 3.22 mmol, 1.5 equivalents) and DMAP (131 mg, 0.11 mmol, 0.5 equivalents) in anhydrous ACN (5 ml) was stirred at room temperature for 5 minutes. Then, a solution of 2,6-diethyl-4-methylaniline (350 mg, 2.14 mmol, 1 equivalent) in anhydrous ACN (2 ml) was added dropwise. After 30 minutes at room temperature, the mixture was concentrated under reduced pressure, dissolved in anhydrous hexane, and filtered through a silica gel stopper. The filtrate was evaporated, and the residue was used for the next step without further purification. Y = 40%. ^¹H NMR (400 MHz, chloroform-d) δ 6.90 (s, 2H), 2.70–2.63 (m, 4H), 2.32 (s, 3H), 1.26 (t, J = 8 Hz, 6H).

Step 2: Ethyl 2-{[(2,6-diethyl-4-methylphenyl)carbamoyl]oxy}. The title compound was prepared using ethyl glycolate and 2,6-diethyl-4-methylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by reversed-phase preparative HPLC (0.1% formic acid buffer). Y = 50%. MS ES ⁺ ([M+Na] ⁺ ): 316.3. ^1H NMR (400MHz, DMSO-d ₆ ) 8.86(s,1H), 6.89(s,2H), 4.62(s,2H), 4.18–4.10(m,2H), 2.60–2.44(m,4H), 2.26(s,3H), 1.21(t,J=7Hz,3H), 1.10(t,J=7Hz,6H).

Example 30. Methyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}acetate

The title compound was prepared according to general procedure A, using methyl glycolate and intermediate A as starting materials and THF as the reaction solvent. Purification was performed by FCC (0 to 25% EtOAc/hexane). Y = 66%. MS ES ⁺ ([M+Na] ⁺ ): 312.3. ^1H NMR (400MHz, DMSO- _d6 ) δ 9.17 (s, 1H), 6.95 (s, 1H), 4.64 (s, 2H), 3.69 (s, 3H), 2.81 (t, J = 7Hz, 4H), 2.71 (t, J = 7Hz, 4H), 2.02–1.93 (m, 4H).

Example 31. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-4-phenylbutyrate

The title compound was prepared according to general procedure A, using ethyl (R)-2-hydroxy-4-phenylbutyrate and intermediate A as starting materials and THF as the reaction solvent. The crude product was purified by preparative TLC (100% DCM). Y=9%.MS ES ⁺ ([M+Na] ⁺ ): 430.6. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.22(s,1H),7.36–7.17(m,5H),6.96(s,1H),4.79–4.72(m,1H),4.17–4.08(m,2H),2.82(t,J＝7Hz, 4H), 2.86–2.66 (m, 2H), 2.78–2.69 (m, 4H), 2.09–2.07 (m, 2H), 2.03–1.93 (m, 4H), 1.20 (t, J = 7Hz, 3H).

Example 32. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate. Pyrazole (293 mg, 4.30 mmol, 2.5 equivalents) and ethyl 2,3-epoxypropionate (200 mg, 1.72 mmol, 1 equivalent) were loaded into a microwave-safe vial. The substrate was dissolved in anhydrous EtOH (3 mL) under argon atmosphere, and the vial was sealed. The reaction was heated at 90 °C (oil bath) for 3 days and monitored by TLC. The solvent was removed under vacuum, and the residue was purified by FCC (0 to 15% EtOAc/hexane). Y＝96%.MS ES ⁺ :185.4. ¹ HNMR (400MHz, DMSO-d ₆ )δ7.68–7.65(m,1H),7.45–7.41(m,1H),6.21(t,J＝2Hz,1H),5.85–5.81(m,1H) ,4.43–4.33(m,2H),4.31–4.23(m,1H),4.13–4.07(m,2H),1.18(t,J＝7Hz,3H).

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. Following general procedure A, the title compound was prepared using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate and intermediate A as starting materials, with THF as the reaction solvent. The crude product was purified by preparative TLC (DCM:EtOAc 9:1). Y＝18%.MS ES ⁺ :384.4. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s,1H),7.78(s,1H),7.47(s,1H),6.95(s,1H),6.28(s,1H),5.27(s,1H),4.61(s,2H),4. 15–4.10(m,2H),2.80(t,J＝7Hz,4H),2.66(t,J＝8Hz,4H),2.01–1.89(m,4H),1.18(t,J＝7Hz,3H).

Example 33. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}cyclopentyl acetate

Step 1: 2-(Benzyloxy)acetic acid cyclopentyl ester. Cyclopentanol (735 mg, 8.53 mmol, 1.05 equivalents) was dissolved in anhydrous DCM (8 mL) under Ar conditions, and the solution was cooled to 0 °C. Anhydrous pyridine (0.723 mL, 8.94 mmol, 1.1 equivalents) was added, followed by dropwise addition of benzyloxyacetyl chloride (1.5 mg, 8.12 mmol, 1 equivalent). The mixture was stirred under Ar conditions at room temperature for 16 hours. The reaction was quenched with water at 0 °C, and the layers were separated. The organic layer was washed with a saturated aqueous solution of _NaHCO3 , dried over _{anhydrous Na2SO4} , and concentrated. The residue was purified by FCC (0 to 10% EtOAc/hexane). Y = 97%. ^¹H NMR (400 MHz, chloroform-d) δ 7.42–7.30 (m, 5H), 5.32–5.26 (m, 1H), 4.65 (s, 2H), 4.08 (s, 2H), 1.97–1.85 (m, 2H), 1.81–1.68 (m, 4H), 1.68–1.56 (m, 2H).

Step 2: Cyclopentyl 2-hydroxyacetate. 2-(benzyloxy)cyclopentyl acetate (1.93 g, 8.25 mmol, 1 equivalent) was dissolved in anhydrous MeOH (40 mL). Air was removed using a vacuum pump, and the flask was purged with argon. Pd/C (10% w/w, 190 mg) was added, and a _H₂ atmosphere was used instead of an Ar atmosphere. The reaction mixture was stirred at room temperature and atmospheric pressure for 16 hours. The reaction mixture was filtered through a Celite pad, the filter bed was washed with MeOH, and the filtrate was evaporated under vacuum. The crude product was used for the next step without further purification. Y = 57%. ^¹H NMR (400 MHz, chloroform-d) δ 5.34–5.27 (m, 1H), 4.12 (s, 2H), 1.99–1.85 (m, 2H), 1.85–1.68 (m, 4H), 1.68–1.53 (m, 2H).

Step 3: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}cyclopentyl acetate. The title compound was prepared using 2-hydroxyacetic acid cyclopentyl acetate and intermediate A as starting materials, with THF as the reaction solvent, according to general procedure A. The crude product was purified by FCC (0 to 80% DCM/hexane). Y=24%.MS ES ⁺ ([M+Na] ⁺ ): 366.5. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.17(s,1H),6.95(s,1H),5.18–5.12(m,1H),4.57(s,2H),2.81(t,J＝7Hz,4H ),2.76–2.66(m,4H),2.02–1.91(m,4H),1.90–1.78(m,2H),1.70–1.49(m,6H).

Example 34. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(1H-imidazol-1-yl)propionate. In a microwave-safe vial, 1H-imidazolium (176 mg, 2.58 mmol, 1 equivalent) and ethyl 2,3-epoxypropionate (300 mg, 2.58 mmol, 1 equivalent) were added, and the substrate was dissolved in anhydrous EtOH (3 mL) under Ar conditions. The vial was sealed, and the mixture was heated at 90 °C (oil bath) for 16 hours. The solvent was removed under vacuum, and the residue was purified by FCC (0 to 10% MeOH/DCM) to give the title compound. Y＝33%.MS ES ⁺ :185.2. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.58–7.53(m,1H),7.15–7.10(m,1H),6.88–6.83(m,1H),5.94(d,J＝6Hz,1H),4.28–4.18(m,1H),4.18–4.06(m,4H),1.19(t,J＝7Hz,3H).

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionate. Following general procedure A, the title compound was prepared using ethyl 2-hydroxy-3-(1H-imidazol-1-yl)propionate and intermediate A as starting materials, with THF as the reaction solvent. The crude product was purified by reversed-phase preparative HPLC (0.1% formate buffer). Y＝26%.MS ES ⁺ :384.4. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.24(s,1H),7.67(s,1H),7.22(s,1H),6.97(s,1H),6.91(s,1H),5.30–5.21(m,1H),4.49(s,2H) ,4.15–4.08(m,2H),2.81(t,J＝7Hz,4H),2.72–2.60(m,4H),2.03–1.90(m,4H),1.17(t,J＝7Hz,3H).

Example 35. Ethyl 2-({[2,6-bis(prop-2-yl)phenyl]carbamoyl}oxy)acetate

The title compound was prepared using ethyl glycolate and 2,6-diisopropylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (4:1 hexane/EtOAc). Y = 42%. MS ES ⁺ : 308.3. ^1H NMR (400MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.32–7.22 (m, 1H), 7.15 (d, J = 8Hz, 2H), 4.63 (s, 2H), 4.17–4.10 (m, 2H), 3.21–3.11 (m, 2H), 1.23–1.20 (m, 3H), 1.18–1.06 (m, 12H).

Example 36. Ethyl 2-({[2-chloro-5-(trifluoromethyl)phenyl]carbamoyl}oxy)acetate

The title compound was prepared using ethyl glycolate and 2-chloro-5-(trifluoromethyl)phenyl isocyanate as starting materials according to general procedure A. The crude product was purified twice by FCC (hexane/DCM). Y = 6%. MS ES ⁺ : 348.6. ^1H NMR (400MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 7.96 (d, J = 2Hz, 1H), 7.76 (d, J = 8Hz, 1H), 7.57 (dd, J = 2, 8Hz, 1H), 4.73 (s, 2H), 4.17 (q, J = 7Hz, 2H), 1.22 (t, J = 7Hz, 3H).

Example 37. Ethyl 2-{[(2-tert-butyl-6-methylphenyl)carbamoyl]oxy}

The title compound was prepared using ethyl glycolate and 2-tert-butyl-6-methylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (4:1 hexane/EtOAc). Y = 22%. MS ES ⁺ 316.2[M+Na] ⁺ . ¹ H NMR (400MHz, chloroform-d) δ 7.33–7.29 (m, 1H), 7.22–7.16 (m, 2H), 6.33 (s, 1H), 4.72 (s, 2H), 4.28 (q, J = 7Hz, 2H), 2.32 (s, 3H), 1.43 (s, 9H), 1.32 (t, J = 7Hz, 3H).

Example 38. Ethyl 2-{[(2,5-dimethylphenyl)carbamoyl]oxy}acetate

The title compound was prepared using ethyl glycolate and 2,5-dimethylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified twice by FCC (hexane/EtOAc, then hexane/DCM). Y = 22%. MS ES ⁺ 274.2 [M+Na] ⁺ . ¹ H NMR (400MHz, chloroform-d) δ 7.62 (s, 1H), 7.07 (d, J = 8Hz, 1H), 6.89 (d, J = 8Hz, 1H), 6.56 (s, 1H), 4.70 (s, 2H), 4.29 (q, J = 7Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1.33 (t, J = 7Hz, 3H).

Example 39. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionic acid

Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionate (Example 5F) (51 mg, 0.15 mmol) was dissolved in a 1:1 THF/water mixture (1.5 mL) and cooled to 0 °C. Lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added, and the reaction was stirred for 30 min. THF was removed under vacuum. RM was acidified to pH 3 with 1 M HCl and extracted with EtOAc. The organic phase was dried over _Na₂SO₄ and concentrated. A precipitate formed, which was filtered off and purified by preparative TLC elution with 9:1 DCM/MeOH. The product spot was extracted with THF and evaporated to give the title compound as _a white solid. Y＝60%.MS ES ⁺ :320. ¹ H NMR (400MHz, DMSO-d ₆ )δ11.74(s,1H),8.69(s,1H),6.89(s,1H),4.81–4.75(m,1H),3.85–3.73(m,1H),3.73 –3.65(m,1H),3.24(s,3H),2.79(t,J＝7Hz,4H),2.72(t,J＝7Hz,4H),2.00–1.88(m,4H).

Example 40. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}cyclopropyl acetate

Step 1: 2-(benzyloxy)acetic acid cyclopropyl ester. Cyclopropanol (108 μl, 1.71 mmol) was dissolved in anhydrous DCM (8 mL) and cooled to 0 °C. Triethylamine (294 μl, 2.11 mmol) was added, followed by dropwise addition of 2-benzyloxyacetyl chloride (256 μl, 1.62 mmol). The mixture was stirred at room temperature for 18 hours and then concentrated. The precipitate was filtered off, and the filtrate was evaporated to dryness to give the title compound as a yellow oil. Y = 100%. ^¹H NMR (400 MHz, chloroform-d) δ 7.41–7.30 (m, 5H), 4.65 (s, 2H), 4.27–4.21 (m, 1H), 4.09 (s, 2H), 0.81–0.70 (m, 4H).

Step 2: Cyclopropyl 2-hydroxyacetate. Cyclopropyl 2-(benzyloxy)acetate (0.375 g, 1.82 mmol) was dissolved in THF (18 mL) and purged with argon. 10% Pd/C (40 mg) was added, and the RM (argon/vacuum circulation) was purged, followed by stirring under a hydrogen atmosphere for 18 h. The RM was filtered through Celite, washed with ACN, and evaporated to dryness to give the title compound. Y = 67%. ^¹H NMR (300 MHz, DMSO- _d⁶ ) δ 5.32 (t, J = 7 Hz, 1H), 4.13–4.05 (m, 1H), 3.97 (d, J = 7 Hz, 2H), 0.74–0.56 (m, 4H).

Step 3: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}cyclopropyl acetate. The title compound was prepared using 2-(benzyloxy)cyclopropyl acetate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 15% EtOAc/hexane) followed by preparative TLC (silica, 100% DCM). Y＝2%.MS ES ⁺ :315.4. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.18(s,1H),6.96(s,1H),4.60(s,2H),4.20–4.12(m,1H),2.81(t,J＝7Hz,4H),2.71(t,J＝8Hz,4H),1.98(q,J＝7Hz,4H),0.76–0.61(m,4H).

Example 41. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid

Step 1: 2-Hydroxy-3-(1H-pyrazol-1-yl)propionate tert-butyl ester. 10 g (69.4 mmol) of ethylene oxide-2-carboxylate tert-butyl ester was dissolved in anhydrous EtOH (210 mL). Pyrazole (11.8 g, 174.4 mmol) was added, and the reaction was heated at 80 °C for 16 hours. The reaction mixture was concentrated under vacuum and co-evaporated twice with toluene. The crude product was purified by FCC (0-40% EtOAc/DCM) followed by reverse-phase FCC (C18, 5-90% ACN/ _H₂O ) to give the title compound as a white solid. Y=19%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.66(dd,J＝2,1Hz,1H),7.43(dd,J＝2,1Hz,1H),6.21(t,J＝2Hz,1H),5.69–5.65(m,1H),4.37–4.18(m,3H),1.39(s,9H).

Step 2: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)tert-butyl propionate. The title compound was prepared using tert-butyl ethylene oxide-2-carboxylate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 40% EtOAc/hexane). Y = 22%. MS ES ⁺ : 412.

Step 3: 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid tert-butyl ester (30 mg, 0.073 mmol) was dissolved in anhydrous 1,4-dioxane (0.3 mL) and cooled to 0 °C. 4 M HCl (0.5 mL, 2 mmol) was added, and RM was stirred at 0 °C for 16 h. The reaction was incomplete, so the solvent was removed under vacuum, 20% TFA/DCM (0.7 mL) was added, and the reaction was stirred at 0 °C for 16 h. RM was concentrated, co-evaporated with hexane, and then co-evaporated three times with _Et₂O . The filtered solid was washed with _Et₂O and dried to give the title product, a gray solid. Y = 46%. ^{MS ES⁺} : 356. ^¹H NMR (300MHz, DMSO- _d₆ ) δ 13.26 (s, 1H), 9.08 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 6.94 (s, 1H), 6.27 (s, 1H), 5.22 (t, J = 6Hz, 1H), 4.58 (s, 2H), 2.80 (t, J = 7Hz, 4H), 2.63 (t, J = 7Hz, 4H), 2.03–1.86 (m, 4H).

Example 41. Ethyl propionate (2R)-3-(3-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

Step 1: (2R)-3-(3-cyanophenyl)-2-hydroxypropionic acid. Dissolve a solution of D-3-cyanophenylalanine (0.30 g, 1.58 mmol) in water (1.6 ml) and AcOH (0.4 ml) and cool to 0 °C. Slowly add 1 M sodium nitrite (aq.) (2.4 ml, 3.16 mmol). Heat RM to room temperature and stir for 16 hours. Add methylamine (40%/ _H₂O , 0.285 ml, 4.73 mmol) to quench the reaction, then acidify with 1 M HCl to pH ~ ₃ . Extract the mixture with EtOAc, dry the organic phase ( _Na₂SO₄ ) and concentrate to give an orange liquid. Add 60% ACN (+0.1% TFA)/water and lyophilize the mixture to give the title product. Y = 29%. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 12.54 (s, ¹H), 7.77–7.64 (m, 2H), 7.60 (d, J = 8Hz, ¹H), 7.50 (t, J = 8Hz, ¹H), 4.26–4.14 (m, ¹H), 3.04 (dd, J = 14, 4Hz, ¹H), 2.86 (dd, J = 14, 8Hz, ¹H). No OH protons were observed.

Step 2: Ethyl (2R)-3-(3-cyanophenyl)-2-hydroxypropanoate. Thionyl chloride (48 μl, 1.38 mmol) was added dropwise to a solution of (2R)-3-(3-cyanophenyl)-2-hydroxypropanoic acid (0.22 g, 1.15 mmol) cooled to 0 °C in EtOH (16 mL). RM was stirred at room temperature for 1 h, then evaporated under vacuum. The crude product was purified by FCC (silica, hexane/EtOAc) to give the title compound as a pale yellow oil. Y=59%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.72–7.66(m,2H),7.63–7.55(m,1H),7.54–7.45(m,1H),5.63(d,J=6Hz,1H),4.34–4.22(m, 1H), 4.08 (q, J = 7Hz, 2H), 3.02 (dd, J = 14, 5Hz, 1H), 2.89 (dd, J = 14, 8Hz, 1H), 1.15 (t, J = 7Hz, 3H).

Step 3: Ethyl (2R)-3-(3-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}propionate. The title compound was prepared using ethyl (2R)-3-(3-cyanophenyl)-2-hydroxypropionate and intermediate A as starting materials according to general procedure B. The crude product was purified by FCC (EtOAc/hexane) followed by preparative HPLC. Y＝30%.MS ES ⁺ :419. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.14(s,1H),7.87–7.62(m,3H),7.62–7.29(m,1H),6.95(s,1H),5.21–5.17(m,1H),4.11(q,J＝7Hz, 2H),3.25–3.10(m,2H),2.83-2.78(m,4H),2.73–2.51(m,4H),1.99–1.90(m,4H),1.14(t,J＝7Hz,3H).

Example 42. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazol-1-yl)phenyl]propionate

Step 1: Ethyl 3-[3-(1H-pyrazol-1-yl)phenyl]ethylene oxide-2-carboxylate. 3-(1H-pyrazol-1-yl)benzaldehyde (0.50 g, 2.90 mmol) and ethyl chloroacetate (0.31 mL, 2.90 mmol) were dissolved in anhydrous THF (12 mL) under argon atmosphere and cooled to -78 °C. 1.0 M sodium hexamethyldisilazane/THF (2.90 mL, 2.90 mmol) was added dropwise. The RM was stirred at -78 °C for 30 min, then heated to 0 °C and quenched with water. The RM was concentrated, partitioned, and separated between water and _Et₂O . The organic phase was washed with brine, dried over _Na₂SO₄ , filtered, and concentrated to give the title compound. Y = 39%. _MS ^ES⁺ : 259.1.

Step 2: Ethyl 2-hydroxy-3-[3-(1H-pyrazol-1-yl)phenyl]propionate. In a hydrogenation flask, a solution of ethyl 3-[3-(1H-pyrazol-1-yl)phenyl]ethylene oxide-2-carboxylate (0.35 g, 1.36 mmol) in EtOAc (15 mL) was treated with 10% Pd/carbon (14 mg). The RM was purged, and then stirred at room temperature and pressure for 16 hours under a hydrogen atmosphere. The RM was filtered through Celite, washed with EtOAc, and concentrated to give the title compound as a yellow oil. Y = 83%. MS ES ⁺ : 261.1.

Step 3: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazol-1-yl)phenyl]propionate. The title compound was prepared using ethyl 2-hydroxy-3-[3-(1H-pyrazol-1-yl)phenyl]propionate and intermediate A as starting materials according to general procedure B. The crude product was purified by FCC (EtOAc/hexane). Y＝48%.MS ES ⁺ :460.6. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.13(s,1H),8.49(s,1H),7.96–7.63(m,3H),7.43(s,1H),7.25(s,1H),6.92(s,1H),6.65–6.44(m,1H),5.23–5.18( m,1H),4.12(q,J＝7Hz,2H),3.21(s,2H),2.81-2.74(m,4H),2.64–2.58(m,4H),1.94–1.88(m,4H),1.15(t,J＝7Hz,3H).

Example 43. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazol-1-yl)phenyl]propionate ethyl ester

Step 1: (2R)-3-(3-bromophenyl)-2-hydroxypropionic acid. Dissolve (2R)-2-amino-3-(3-bromophenyl)propionic acid (1.0 g, 4.10 mmol) in a 4:1 water/AcOH solution (40 mL) and cool to 0 °C. Slowly add 1 M sodium nitrite (8.2 mL, 8.2 mmol). Stir the reaction at room temperature for 16 _h , treat with 40% aqueous methylamine solution (0.48 mL, 12.3 mmol), and stir for another 10 min. Acidify the reaction to pH 3 with 1 M HCl and extract with EtOAc. Dry the organic phase in _Na₂SO₄ and concentrate to give the title compound as a yellow oil. Y = 54%. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 7.54–7.35 (m, 2H), 7.34–7.16 (m, 2H), 5.76 (s, 1H), 4.16 (dd, J = 8, 4Hz, 1H), 2.97 (dd, J = 14, 4Hz, 1H), 2.79 (dd, J = 14, 8Hz, 1H). No _CO₂H protons were observed.

Step 2: Ethyl (2R)-3-(3-bromophenyl)-2-hydroxypropanoate. A solution of (2R)-3-(3-bromophenyl)-2-hydroxypropanoic acid (0.93 g, 3.80 mmol) in EtOH (16 mL) was cooled to 0 °C and treated dropwise with thionyl chloride (0.16 mL, 4.55 mmol). The solution was heated to room temperature and stirred for 1 h, then evaporated to dryness. The crude product was purified by FCC (EtOAc/hexane) to give the title compound as a pale yellow oil. Y=75%. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.51–7.35(m,2H),7.24(d,J＝2Hz,2H),5.59(d,J＝6Hz,1H),4.33–4.18(m,1H),4.1 4–3.97(m,2H),2.95(dd,J＝14,5Hz,1H),2.83(dd,J＝14,8Hz,1H),1.15(t,J＝7Hz,3H)

Step 3: Ethyl (2R)-3-(3-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propionate. A solution of ethyl (2R)-3-(3-bromophenyl)-2-hydroxypropionate (0.75 g, 3.06 mmol) and imidazole (0.42 g, 6.12 mmol) in DMF (16 ml) was treated with tert-butyldimethylchlorosilane (0.55 g, 3.67 mmol). RM was stirred at room temperature for 16 h, then diluted with water and extracted twice with EtOAc. The combined organic matter was washed with brine, dried over _{anhydrous Na₂SO₄} , and concentrated. The crude product was purified by FCC (EtOAc/hexane) to give the title compound as a colorless oil. Y=98%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.48–7.38(m,2H),7.28–7.20(m,2H),4.40(dd,J＝9,4Hz,1H),4.18–4.05(m,2H),3.02(dd,J＝1 3,4Hz,1H),2.81(dd,J＝13,9Hz,1H),1.19(t,J＝7Hz,3H),0.76(s,9H),-0.10(s,3H),-0.23(s,3H)

Step 4: Ethyl (2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[3-(1H-pyrazol-1-yl)phenyl]propionate. A sealed container containing ethyl (2R)-3-(3-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propionate (0.30 g, 0.77 mmol), pyrazole (79 mg, 1.16 mmol), copper iodide (I) (15 mg, 0.077 mmol), (S,S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (22 mg, 0.16 mmol), and potassium carbonate (225 mg, 1.63 mmol)/1,4-dioxane (15 ml) was degassed and backfilled with argon. The reaction was stirred at 100 °C for 16 hours. RM was filtered through a Celite filter, washed with EtOAc, and concentrated. The residue was partitioned between water and EtOAc, and the organic phase was then dried ( _Na₂SO₄ ), filtered, and concentrated. The crude product was purified by FCC (EtOAc/hexane) to give the title compound as a yellow oil. _Y = 14%. MS ES ⁺ : 375.1

Step 5: Ethyl (2R)-2-hydroxy-3-[3-(1H-pyrazol-1-yl)phenyl]propionate. Add triethylamine trifluoride (0.52 ml, 3.2 mmol) to an anhydrous THF (1 ml) solution of ethyl (2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[3-(1H-pyrazol-1-yl)phenyl]propionate (0.10 g, 0.27 mmol). Stir the RM at room temperature for 16 h, dilute with EtOAc, and wash with dilute sodium bicarbonate solution. Extract the aqueous phase with EtAOc, and wash the combined organic matter successively with water and brine. Dry over _Na₂SO₄ , filter, and concentrate under vacuum to give the title compound as a yellow oil. _Y = 57%. MS ES ⁺ : 261.3

Step 6: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazol-1-yl)phenyl]propionate. The title compound was prepared using ethyl (2R)-2-hydroxy-3-[3-(1H-pyrazol-1-yl)phenyl]propionate and intermediate A as starting materials, according to general procedure B. The crude product was purified by FCC (EtOAc/hexane). Y＝12%.MS ES ⁺ :460.6. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.12(s,1H),8.49(s,1H),7.88–7.63(m,3H),7.50–7.34(m,1H),7.29–7.15(m,1H),6.92(s,1H),6.65–6.44(m,1H),5.23– 5.18(m,1H),4.12(q,J＝7Hz,2H),3.21(s,2H),2.81-2.74(m,4H),2.64–2.58(m,4H),1.99–1.81(m,4H),1.15(t,J＝7Hz,3H).

Example 44. Ethyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-1H-pyrazol-1-yl)propionate

Step 1: tert-butyl ethylene oxide-2-carboxylate. Dissolve tert-butyl acrylate (30 g, 234 mmol) in DCM (300 ml). Add a solution of m-chloroperoxybenzoic acid (50.5 g, 293 mmol) in DCM ( ₄₂₀ ml) and heat RM under reflux for 2 days. Add more m-chloroperoxybenzoic acid (67 g, 388 mmol) and heat the reaction under reflux for another 4 days. RM is filtered. The filtrate is cooled on an ice-water bath and allowed to stand. Carefully add _{Na₂S₂O₃} . Separate the _layers . Filter the organic phase, wash with saturated sodium bicarbonate solution, and filter again. Wash the organic phase with brine and filter. Dry the filtrate with _Na₂SO₄ , filter, and concentrate under vacuum. Suspend the resulting residue in hexane, filter _, and concentrate the filtrate under vacuum to give the title compound as a yellow oil. Y＝47%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ3.34 (dd, J＝4, 3Hz, 1H), 2.95-2.87 (m, 2H), 1.52 (s, 9H)

Step 2: 2-Hydroxy-3-(1H-pyrazol-1-yl)propionate tert-butyl ester. 10.0 g (69.4 mmol) of ethylene oxide-2-carboxylate tert-butyl ester was dissolved in anhydrous EtOH (210 mL) and treated with pyrazole (11.8 g, 173 mmol). RM was heated at 80 °C for 18 hours. The solvent was removed under vacuum, and then the mixture was co-evaporated with toluene. Purification was achieved by FCC (0–40% EtOAc/DCM), followed by reverse-phase FCC (C18, 5–90% ACN/ _H₂O ), yielding the title compound as a white solid. Y=19%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ7.66 (dd, J=2, 1Hz), 7.43 (dd, J=2, 1Hz), 6.21 (t, J=2Hz, 1H), 5.69–5.65 (m, 1H), 4.37–4.18 (m, 3H), 1.39 (s, 9H)

Step 3: 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)tert-butyl propionate. The title compound was prepared from 2-hydroxy-3-(1H-pyrazol-1-yl)tert-butyl propionate and 2,6-difluorophenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 10% MeOH/DCM). Y = 69%. MS ES ⁺ : 368

Step 4: Ethyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-1H-pyrazol-1-yl)propionate. A solution of tert-butyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate (0.10 g, 0.27 mmol) in EtOH (2.0 mL) was treated with 4 M HCl/dioxane (0.10 mL, 0.4 mmol) and heated to reflux for 3 h. RM was evaporated to dryness and purified by FCC (0-10% MeOH/DCM) to give the title compound as a white solid. Y＝22%.MS ES ⁺ :340.3. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.55(s,1H),7.78(s,1H),7.46(s,1H),7.43–7.32(m,1H),7.22–7.12(m,2H) ,6.27(s,1H),5.29(s,1H),4.62(s,2H),4.12(q,J＝7Hz,2H),1.17(t,J＝7Hz,3H)

Example 45. Ethyl 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate

Step 1: 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate tert-butyl ester. The title compound was prepared using 2-hydroxy-3-(1H-pyrazol-1-yl)propionate and phenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 40% EtOAc/hexane). Y=65%. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.89(s,1H),7.79(dd,J＝2,1Hz,1H),7.47(dd,J＝2,1Hz,1H),7.46–7.37(m,2H),7.34–7.24(m ,2H),7.04–7.00(m,1H),6.28(t,J＝2Hz,1H),5.26–5.21(m,1H),4.63–4.57(m,2H),1.39(s,9H)

Step 2: 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionic acid. A solution of tert-butyl 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionic acid (218 mg, 0.66 mmol) in a 4:1 DCM/TFA (5 mL) solution was stirred at room temperature for 12 hours. RM was evaporated and co-evaporated with hexane, followed by purification by reversed-phase HPLC to give the title compound as a grayish-white solid. Y = 14%. MS ES ⁺ : 276.1

Step 3: Ethyl 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate. The title compound was prepared using 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionic acid and EtOH as starting materials according to general procedure E. The crude product was purified by FCC (0-40% EtOAc/hexane) followed by preparative TLC (40% EtOAc/hexane). Y＝18%.MS ES ⁺ :304.3. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.94(s,1H),7.78(d,J＝2Hz,1H),7.47(dd,J＝2,1Hz,1H),7.46–7.37(m,2H),7.33–7.24(m,2H),7.06–6. 98(m,1H),6.30–6.26(m,1H),5.37(t,J＝5Hz,1H),4.65–4.62(m,2H),4.18–4.11(m,2H),1.18(t,J＝7Hz,3H)

Example 46. Ethyl 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate tert-butyl ester. The title compound was prepared from 2-hydroxy-3-(1H-pyrazol-1-yl)propionate and 1-ethyl-2-isocyano-3-methylbenzene according to general procedure A. The crude product was purified by FCC (0 to 40% EtOAc/hexane). Y=50%. ¹ H NMR (300MHz, DMSO-d ₆ )δ8.96(s,1H),7.80(d,J＝2Hz,1H),7.48(d,J＝1Hz,1H),7.14–7.02(m,3H),6.29(t,J＝2Hz,1H) ,5.16(t,J＝6Hz,1H),4.59(d,J＝6Hz,2H),2.12(s,3H),1.40–1.36(m,11H),1.07(t,J＝8Hz,3H)

Step 2: 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid. A solution of tert-butyl 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid (0.22 g, 0.59 mmol) in 4:1 DCM/TFA (5 mL) was stirred at room temperature for 2 h. RM was evaporated, and then co-evaporated with hexane, followed by purification by reversed-phase HPLC to give the title compound as a grayish-white solid. Y = 11%. MS ES ⁺ : 318.4

Step 3: Ethyl 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. The title compound was prepared using 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate and EtOH as starting materials according to general procedure E. The crude product was purified by FCC (0-40% EtOAc/hexane). Y＝25%.MS ES ⁺ :346.4. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.00(s,1H),7.79(d,J＝2Hz,1H),7.48(d,J＝1Hz,1H),7.14–7.04(m,3H),6.29(t,J＝2Hz,1H),5.31(t,J＝6Hz,1 H),4.65–4.62(m,2H),4.17–4.10(m,2H),2.54–2.52(m,2H),2.11(s,3H),1.18(t,J＝7Hz,3H),1.07(t,J＝8Hz,3H)

Example 47. Ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)tert-butyl propionate. The title compound was prepared from 2-hydroxy-3-(1H-pyrazol-1-yl)tert-butyl propionate and 2,6-dimethylphenyl isocyanate as starting materials according to general procedure A. The crude product was purified by FCC (0 to 40% EtOAc/hexane). Y＝56%. ¹ HNMR (300MHz, DMSO-d ₆ )δ8.98(s,1H),7.80(d,J＝2Hz,1H),7.48(d,J＝2Hz,1H),7.09–7.02(m,3H),6.29( t, J＝2Hz, 1H), 5.17 (t, J＝6Hz, 1H), 4.60 (d, J＝6Hz, 2H), 2.13 (s, 6H), 1.38 (s, 9H).

Step 2: 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid. A solution of tert-butyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid (0.36 g, 1.00 mmol) in 4:1 DCM/TFA (5 ml) was stirred at room temperature for 5 hours. The RM was evaporated and co-evaporated with hexane three times, followed by purification by preparative TLC (10% MeOH, 2% AcOH, 88% DCM) to give the title compound as a grayish-white solid. Y = 7%, MSES ⁺ : 304.2.

Step 3: Ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. The title compound was prepared using 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate and EtOH as starting materials according to general procedure E. The crude product was purified by FCC (0-40% EtOAc/hexane). Y＝34%.MSES ⁺ :332.6. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.01(s,1H),7.79(d,J＝2Hz,1H),7.48(d,J＝2Hz,1H),7.10–7.03(m,3H),6.29(t,J＝2Hz,1H ), 5.30 (t, J = 6Hz, 1H), 4.65–4.62 (m, 2H), 4.16–4.09 (m, 2H), 2.12 (s, 6H), 1.18 (t, J = 7Hz, 3H).

Example 48. The following compounds were synthesized using a synthetic route similar to that of Example 47, according to the following scheme:

2-{[(2,6-diethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate ethyl ester

MS ES ⁺ :360.4. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.98(s,1H),7.79(d,J＝2Hz,1H),7.49(d,J＝1Hz,1H),7.13–7.04(m,3H),6.30(t,J＝2Hz,1H),5.31(t,J＝6Hz,1H ), 4.63 (d, J = 6Hz, 2H), 4.17–4.09 (m, 2H), 2.49–2.43 (m, 4H), 2.12 (s, 6H), 1.18 (t, J = 7Hz, 3H), 1.13–1.03 (m, 6H).

2-{[(2-fluoro-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate ethyl ester

MS ES ⁺ :336.5. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.24(s,1H),7.78(s,1H),7.47(s,1H),7.29–7.14(m,1H),7.13–6.97(m,2H),6.28(s,1H) ,5.38–5.20(m,1H),4.75–4.52(m,2H),4.12(q,J＝7Hz,2H),2.17(s,3H),1.17(t,J＝7Hz,3H).

2-{[(2-chloro-6-fluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate ethyl ester

MS ES ⁺ :356.5. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.59(s,1H),7.78(s,1H),7.47(s,1H),7.41–7.24(m,3H),6.28(s,1H),5.29(s,1H),4.63(s,2H),4.12(q,J＝7Hz,2H),1.17(t,J＝7Hz,3H).

2-{[(2-chloro-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate ethyl ester

MS ES ⁺ :352.5. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.34(s,1H),7.79(d,J＝2Hz,1H),7.48(d,J＝1Hz,1H),7.36–7.31(m,1H),7.27–7.19(m,2H),6.32–6.2 6(m,1H),5.31(t,J＝6Hz,1H),4.64(d,J＝5Hz,2H),4.13(q,J＝7Hz,2H),2.18(s,3H),1.18(t,J＝7Hz,3H).

2-{[(2,6-dichlorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate ethyl ester

MS ES ⁺ :372.8. ¹ H NMR (300MHz, chloroform-d) δ7.54(s,1H),7.42–7.36(m,2H),7.26–7.17(m,1H),6.26(s,1H),5.52–5.44(m,1H),4.74–4.62(m,2H),4.27(q,J＝7Hz,2H),1.30(t,J＝7Hz,3H).

Example 49. Ethyl 2-[(cyclohexylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(1H-pyrazole-1-yl)propionate. Pyrazole (1.17 g, 17.2 mmol) was added to a stirred solution of ethyl-2,3-epoxypropionate (2 g, 17.2 mmol) in ethanol (20 mL) at room temperature. The reaction mixture was heated at 80 °C for 16 hours. The reaction mixture was cooled to room temperature and concentrated under vacuum. The resulting crude product was poured into water (100 mL) and extracted with ethyl acetate (3 × 70 mL). The combined organic phases were washed with water (5 × 70 mL) to remove excess pyrazole. The organic phases were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum to give the title compound. Y = 35%. MS ES ⁺ : 185.2.

Step 2: Ethyl 2-[(cyclohexylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate. Ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (0.1 g, 0.54 mmol) and copper(I) chloride (0.058 g, 5.90 mmol) were added to a solution of cyclohexyl isocyanate (0.067 g, 0.54 mmol) in DMF (1.5 mL) at room temperature. The reaction mixture was stirred at room temperature for 10 minutes. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (2 × 30 mL). The combined organic phases were washed with cold water (5 × 30 mL), then with brine (30 mL), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The crude material was purified by FCC (20% ethyl acetate/hexane) to give the title compound as a colorless liquid. Y＝55%.MS ES ⁺ :310.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.73-7.72(m,1H),7.44-7.41(m,2H),6.25(t,J＝4Hz,1H),5.16(t,J＝5Hz,1H),4.57-4 .51(m,2H),4.10–4.05(m,2H),3.20-3.15(m,1H),1.73-1.51(m,5H),1.28–1.19(m,8H).

Example 50. Ethyl 2-[(cyclopentylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthesis route similar to that of Example 49. MS ES ⁺ : 296.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.72 (d, J = 2Hz, 1H), 7.50–7.44 (m, 2H), 6.25 (t, J = 2Hz, 1H), 5.16 (t, J = 5Hz, 1H), 4.56–4.51 (m, 2H), 4.12–4.06 (m, 2H), 3.74–3.69 (m, 1H), 1.77–1.71 (m, 2H), 1.69–1.58 (m, 2H), 1.48–1.38 (m, 4H), 1.30–1.26 (m, 3H).

Example 51. Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate

Step 1: Ethyl 3-(4-cyano-1H-pyrazole-1-yl)-2-hydroxypropionate. Add 4-cyanopyrazole (0.30 g, 3.22 mmol) to a solution of ethyl-2,3-epoxypropionate (0.75 g, 6.45 mmol) in anhydrous EtOH (5 mL). Heat RM in a sealed tube at 90 °C for 16 hours. Evaporate RM to give the title compound as a yellow liquid, which was used directly without further purification. MS ES ⁺ : 210.1

Step 2: Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}propionate. The title compound was prepared using ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropionate and intermediate A as starting materials according to general procedure B. The crude product was purified by FCC (0-30% EtOAc/hexane). Y＝10%.MS ES ⁺ :409.2. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.17(s,1H),8.68–8.61(m,1H),8.10(s,1H),6.96(s,1H),5.35(br.s,1H),4.71(br.s,2H),4 .14(q,J＝7Hz,2H),2.89-2.79(m,4H),2.73–2.58(m,4H),2.03–1.89(m,4H),1.19(t,J＝7Hz,3H).

Example 52. Ethyl 2-[(cycloheptylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthesis route similar to that of Example 49. MS ES ⁺ : 324.3. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.72 (d, J = 2Hz, 1H), 7.46–7.44 (m, 2H), 6.25 (t, J = 2Hz, 1H), 5.15 (t, J = 5Hz, 1H), 4.52–4.51 (m, 2H), 4.11–4.06 (m, 2H), 3.42–3.39 (m, 1H), 1.74–1.72 (m, 2H), 1.59–1.24 (m, 9H), 1.17–1.13 (m, 3H).

Example 53. Ethyl 2-{[(2-cyano-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate. Pyrazole (16.1 g, 236 mmol) was added to a solution of ethyl-2,3-epoxypropionate (11 g, 94.7 mmol) in anhydrous EtOH (190 ml). The RM was heated in a sealed reactor at 90 °C for 3 days. The RM was evaporated. The crude product was purified by FCC (0-100% DCM/hexane, then 0-30% EtOAc/DCM), followed by evaporation (55 °C, <4 mbar) to give the title compound as a yellow oil. Y=31%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.66(dd,J＝2,1Hz,1H),7.43(dd,J＝2,1Hz,1H),6.21(t,J＝2Hz,1H),5.82(d,J＝6Hz,1H),4.45–4.20(m,3H),4.10(q,J＝7Hz,2H),1.18(t,J＝7Hz,3H).

Step 2: 2-Amino-3-methylbenzylnitrile. Triethylamine (0.99 mL, 7.1 mmol) was added to a solution of 2-amino-3-methylbenzylnitrile (0.85 g, 6.4 mmol) in THF (17 mL), followed by the addition of phosgene (20%, in toluene, 3.41 mL, 6.4 mmol). The mixture was heated under reflux for 4 hours and then cooled to room temperature. THF was evaporated under vacuum, and the residue was precipitated with cold pentane. The resulting mixture was filtered, and the filtrate was evaporated to give the title compound as a yellow oil. Y = 74%. MS ES ⁺ : 232.0 (The compound was analyzed in diethylamine to produce diethylurea).

Step 3: Ethyl 2-{[(2-cyano-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. The title compound was prepared from ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate and 2-isocyano-3-methylbenzyl nitrile as starting materials according to general procedure A. The crude product was purified by FCC (0 to 60% EtOAc/hexane) followed by preparative HPLC. Y = 14%. MS ES ⁺ : 343. ¹ H NMR (300MHz, chloroform-d) δ 7.58–7.46 (m, 4H), 7.33 (d, J = 8Hz, 1H), 6.93 (s, 1H), 6.28 (s, 1H), 5.53–5.45 (m, 1H), 4.69 (s, 2H), 4.28 (q, J = 7Hz, 2H), 2.32 (s, 3H), 1.31 (t, J = 7Hz, 3H).

Example 54. Ethyl 2-{[(2-cyano-6-ethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthetic route similar to that of Example 53. MS ES ⁺ :357

Example 55. Ethyl 2-{[(2-chloro-6-cyanophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthetic route similar to that of Example 53. MS ES ⁺ : 363.0. ¹ H NMR (300MHz, chloroform-d) δ 7.69 (dd, J = 8, 1Hz, 1H), 7.64 (dd, J = 8, 1Hz, 1H), 7.55 (d, J = 2Hz, 1H), 7.49–7.45 (m 1H), 7.34 (t, J = 8Hz, 1H), 7.08 (s, 1H), 6.31–6.24 (m, 1H), 5.52 (dd, J = 6, 5Hz, 1H), 4.76–4.71 (m, 2H), 4.36–4.19 (m, 2H), 1.73 (s, 1H), 1.30 (t, J = 7Hz, 3H).

Example 56. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionate

Step 1: Ethyl 2-oxo-3-(pyrazin-2-yl)propionate. Methylpyrazine (0.40 g, 4.25 mmol) was added under an inert atmosphere to a 2 M LDA solution of THF/hexane/ethylbenzene (4.3 ml, 8.60 mmol) in anhydrous THF (5 ml) cooled to -78 °C. The mixture was stirred for 15 min, followed by the addition of ethyl 2,2,2-triethoxyethyl acetate (1.03 ml, 4.68 mmol). The solution was warmed to room temperature and stirred for 16 h. The mixture was then poured into 1 M HCl and stirred for 1 h. The mixture was neutralized with _NaHCO3 solution and extracted three times with DCM. The combined organic matter was washed with brine, _dried over _Na2SO4 , filtered, and evaporated. The crude product was purified by FCC (0-90% EtOAc/DCM) to give the title compound as an orange solid. Y = 87%. ^¹H NMR (300 MHz, chloroform-d) δ 13.01 (s, ¹H), 8.60 (d, J = 2 Hz, ¹H), 8.49 (d, J = 3 Hz, ¹H), 8.45–8.41 (m, ¹H), 6.66 (s, ¹H), 4.40 (q, J = 7 Hz, 2H), 1.42 (t, J = 7 Hz, 3H)

Step 2: Ethyl 2-hydroxy-3-(pyrazin-2-yl)propionate. A solution of ethyl 2-oxo-3-(pyrazin-2-yl)propionate (0.20 g, 1.03 mmol) in EtOH (40 mL) was cooled to -78 °C and treated with NaBH4 (0.16 g, 4.1 mmol). The RM was stirred at -78 °C for 1 h, then heated to room temperature and stirred for another 1 h. The RM was poured onto ice, acidified to pH 2 with 1 M HCl, and extracted with DCM. The organic phase was dried over _Na₂SO₄ , filtered, and concentrated under vacuum. The crude product was purified by FCC (EtOAc/hexane) to give the title compound as a yellow oil. _Y = 30%. MS ES ⁺ : 197.

Step 3: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(pyrazin-2-yl)propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 60% EtOAc/hexane) followed by preparative HPLC. Y=7%.MS ES ⁺ : ^396.1.1H NMR (300MHz, acetonitrile- _d3 )δ8.60–8.48(m,3H),7.00(s,1H),5.36(dd,J＝8,5Hz,1H),4.20(q,J＝7Hz,2H),3.40–3.30 (br.s,2H),2.87(t,J＝7Hz,4H),2.74–2.63(m4H),2.09–2.01(m,4H),1.24(t,J＝7Hz,3H).

Example 57. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid

Step 1: (2S)-2-Bromo-3-hydroxypropionic acid. L-serine (52.5 g, 0.50 mol) and potassium bromide (202 g, 1.70 mol) were dissolved in water (400 ml). Hydrobromic acid (48%, 123 ml, 1.0 mol) was added, and the solution was cooled to -13°C under an Ar atmosphere. Sodium nitrite (43 g, 0.63 mol) was slowly added in portions (approximately 5 g every 15 min). After each addition, the solution turned brown, and then the color slowly faded, but the solution was not completely decolorized. After the complete addition (approximately 2.5 h), the solution was heated to 0°C, Ar purging was stopped, and the solution was stirred for 6 h. Excess nitrogen oxides were removed by bubbling Ar through the mixture for 1 h. The solution was extracted with diethyl ether (6 × 300 ml). The combined organic compounds were concentrated to 0.51 under vacuum, dried over anhydrous _MgSO4 , filtered, and evaporated to dryness to give the title compound as a pale yellow oil, which was used without further purification. Y = 88%. ^¹H NMR (400 MHz, DMSO- _d⁶ ) δ 4.25–4.22 (dd, J = 8, 6 Hz, 1H), 3.82–3.76 (m, 1H), 3.70–3.64 (dd, J = 11, 6 Hz, 1H).

Step 2: Potassium (2R)-ethylene oxide-2-carboxylate. Dissolve (2S)-2-bromo-3-hydroxypropionic acid (74.5 g, 0.45 mol) in anhydrous ethanol (300 ml) and cool to -20 °C under nitrogen. Slowly add the filtrate of KOH (50 g, 0.89 mol) in anhydrous ethanol (300 ml). After 2 hours, heat the mixture to 0 °C and stir at this temperature for 14 hours. Filter the solution and further concentrate the filtrate to about half its volume. Filter the mixture again. Dry the combined filtered solids under vacuum to give the title compound as a white solid. Y=95%. ¹ H NMR (400MHz, D ₂ O) δ 3.34-3.33 (dd, J=5, 3Hz, 1H), 2.93-2.90 (dd, J=6, 5Hz, 1H), 2.76-2.74 (dd, J=6, 3Hz, 1H).

Step 3: (2R)-Ethylene oxide-2-carboxylate. A suspension of potassium (4.0 g, 32 mmol), benzyl triethylammonium chloride (7.3 g, 32 mmol), and benzyl bromide (11.4 ml, 96 mmol) in dichloromethane (230 ml) was heated under reflux for 16 hours. The solvent was removed under vacuum. The resulting solid was ground three times with diethyl ether. The combined ether extracts were filtered, dried ( _MgSO₄ ), and evaporated under vacuum. The crude product was purified by FCC (10-50% EtOAc/petroleum ether) to give the title compound as a colorless oil. Y=46%. ¹ H NMR (400MHz, CDCl ₃ ) δ7.43-7.32 (m, 5H), 5.28-5.18 (m, 2H), 3.49-3.48 (dd, J=4, 2Hz, 1H), 3.02-2.92 (m, 2H).

Step 4: (2R)-2-hydroxy-3-(1H-pyrazol-1-yl)propionate benzyl ester. (2R)-ethylene oxide-2-carboxylate benzyl ester (3.00 g, 16.8 mmol) was dissolved in anhydrous ethanol (32 ml), and the resulting solution was treated with pyrazole (2.87 g, 42 mmol). RM was stirred at 90 °C for 16 h, and then concentrated under vacuum. The crude product was purified by FCC (0-70% EtOAc/hexane) and then dried under high vacuum (<3 mbar, 63 °C) to remove residual pyrazole. The title compound was obtained as a yellow oil. Y＝60%. ¹ HNMR (400MHz, DMSO-d ₆ )δ7.65(d,J＝2Hz,1H),7.46–7.42(m,1H),7.39-7.32(m,5H),6.21(d,J＝2Hz,1H),5.92(d ,J＝6Hz,1H),5.17-5.10(m,2H),4.51-4.46(m,1H),4.43-4.39(m,1H),4.34-4.28(m,1H).

Step 5: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)benzyl propionate. The title compound was prepared using (2R)-2-hydroxy-3-(1H-pyrazol-1-yl)benzyl propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 50% EtOAc/hexane). Y=78%. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.17(s,1H),7.78(s,1H),7.48(s,1H),7.35(s,5H),6.93(s,1H),6.28(s,1H),5.38(s,1H ),5.19-5.10(m,2H),4.66(s,2H),2.78(t,J＝7Hz,4H),2.66–2.52(m,4H),2.01–1.84(m,4H).

Step 6: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid. A mixture of (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid benzyl ester (1.4 g, 3.14 mmol), 10% Pd/C (163 mg, 0.14 mmol), and THF (3 ml) was purged and then stirred under a hydrogen atmosphere for 16 hours. The solution was filtered through a Quadrasil stopper. The filtered solid was extracted successively with acetonitrile, ethanol, and hexane washings. The combined filtrates were evaporated to give the title compound as a white solid. Y=99%.MS ES ⁺ : ^356.2.1H NMR(400MHz,DMSO-d6)δ9.10(s,1H),7.77(s,1H),7.46(s,1H),6.93(s,1H),6.27(s ,1H),5.22(s,1H),4.59(s,2H),2.79(t,J=7Hz,4H),2.65(d,4H),1.97-1.90(m,4H).

Example 58. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyridazin-3-yl)propionate

Step 1: Ethyl 2-oxo-3-(pyridazin-3-yl)propionate. 2-Methylpyridazine (0.20 g, 2.1 mmol) was added to a 2M LDA solution of THF/hexane/ethylbenzene (2.2 ml, 4.4 mmol) in anhydrous THF (2.5 ml) cooled to -78 °C. The mixture was stirred for 15 min, followed by the addition of ethyl 2,2,2-triethoxyethyl acetate (0.51 ml, 2.3 mmol). The solution was warmed to room temperature and stirred for 16 h. The mixture was then poured into 1M HCl and stirred for 1 h. The mixture was neutralized with _NaHCO3 solution and extracted three times with DCM. The combined organic matter was washed with brine, dried over _Na2SO4 , filtered, and evaporated. The crude product was purified by FCC (0-90% EtOAc/DCM) to give the title compound as _a green solid. Y = 51%. ^1H NMR (300MHz, chloroform-d) δ 15.03 (s, 1H), 8.60 (dd, J = 4, 2Hz, 1H), 7.42–7.31 (m, 2H), 6.33 (s, 1H), 4.38 (q, J = 7Hz, 2H), 1.42 (t, J = 7Hz, 3H).

Step 2: Ethyl 2-hydroxy-3-(pyridazin-3-yl)propionate. A solution of ethyl 2-oxo-3-(pyridazin-3-yl)propionate (0.22 g, 1.12 mmol) in EtOH (40 mL) was cooled to -78 °C and treated with NaBH4 (0.17 g, 4.48 mmol). RM was stirred at -78 °C for 1 h, then heated to room temperature and stirred for another 1.5 h. RM was poured onto ice, acidified to pH 2 with 1 M HCl, and extracted with DCM. The organic phase was dried over _Na₂SO₄ , filtered, and concentrated under vacuum. The crude product was purified by FCC (MeOH/DCM) to give the title compound as a yellow oil. _Y = 11%. MS ES ⁺ : 197

Step 3: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyridazin-3-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(pyridazin-3-yl)propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by preparative HPLC. Y＝10%.MS ES ⁺ : ^396.1.1H NMR (300MHz, chloroform-d) δ9.13(s,1H),7.59–7.36(m,1H),7.02(s,1H),6.54–6.19(m,1H),5.65–5.47(m,1H),4.26(q ,J＝7Hz,2H),3.79–3.46(m,2H),2.89(t,J＝7Hz,4H),2.80–2.66(m,4H),2.11–2.00(m,4H),1.29(t,J＝7Hz,3H).

Example 59. Ethyl 3-(1H-pyrazol-1-yl)-2-{[(2,3,6-trifluorophenyl)carbamoyl]oxy}-propionate

2,3-6-trifluorophenylaniline (0.072 mL, 0.68 mmol) and ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (0.15 g, 0.82 mmol) (synthesis see Example 49) were dissolved in THF (8 mL) and treated with triethylamine (0.11 mL, 0.82 mmol). The solution was treated with triphosgene, and the resulting mixture was stirred at 60 °C for 4 hours. RM was evaporated, and then co-evaporated three times with DCM. The crude product was purified by FCC (0-5% MeOH/DCM) and then by preparative HPLC to give the title compound as a white solid. Y = 24%. MS ES ⁺ : 358.4.

¹ H NMR (400MHz, DMSO-d ₆ )δ9.78(s,1H),7.85–7.62(m,1H),7.53–7.38(m,2H),7.28–7.16(m,1H),6.26(s,1 H), 5.31 (t, J = 6Hz, 1H), 4.62 (d, J = 4Hz, 2H), 4.17–4.09 (m, 2H), 1.18 (t, J = 7Hz, 3H).

Example 60. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)benzyl propionate

The title compound was synthesized according to the procedure described in Example 57.

Example 61. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionic acid (0.20 g, 0.56 mmol) (synthesis see Example 57) was dissolved in EtOH (5 mL) and cooled to 0 °C. Thionyl chloride (82 μl, 1.13 mmol) was added, and RM was stirred at room temperature for 16 h. RM was concentrated under vacuum, and the residue was diluted with saturated _NaHCO3 solution and extracted with DCM. The organic phase was dried over _Na2SO4 and concentrated under vacuum. The resulting solid was suspended in _hexane , filtered, thoroughly washed with hexane, and dried under vacuum to give the title compound as a white solid. Y＝66%.MS ES ⁺ : ^384.3.1H NMR (300MHz, chloroform-d) δ7.55(s,1H),7.49(s,1H),7.03(s,1H),6.43(s,1H),6.28(s,1H),5.45(s,1H),4.66( s,2H),4.27(q,J＝7Hz,2H),2.90(t,J＝8Hz,4H),2.79(t,J＝7Hz,4H),2.18-1.98(m,4H),1.31(t,J＝7Hz,3H)

Example 62. Ethyl 2-{[(2-ethyl-6-fluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthetic route similar to that of Example 53.

Y = 63%

MS ES ⁺ :350

¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(s,1H),7.78(s,1H),7.48(s,1H),7.32–7.20(m,1H),7.13–7.06(m,2H),6.29(s,1H),5.35–5.25( m,1H),4.69–4.57(m,2H),4.17–4.06(m,2H),2.62–2.52(m,2H),1.17(t,J＝7Hz,3H),1.09(t,J＝7Hz,3H).

Example 63. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionate

Step 1: Ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propionate. A mixture of (2R)-ethylene oxide-2-carboxylic acid benzyl ester (3.00 g, 16.8 mmol) (synthesis see Example 5AJ), imidazole (2.87 g, 42.1 mmol), and ethanol (32 ml) was heated at 90 °C for 16 hours. The RM was concentrated under vacuum and purified by FCC (0-10% MeOH/DCM) to give the title compound as a yellow oil. Y = 31%. MS ES ⁺ : 185.

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionate. The title compound was prepared using ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0 to 100% (95:5 EtOAc/EtOH)/hexane). Y＝32%.MS ES ⁺ : ^384.3.1H NMR (300MHz, chloroform-d) δ7.55(s,1H),7.22-6.85(m,3H),6.57(s,1H),5.35(s,1H),4.47(s,2H),4.2 5(q,J＝7Hz,2H),2.91(t,J＝7Hz,4H),2.81(t,J＝7Hz,4H),2.16–2.02(m,4H),1.29(t,J＝7Hz,3H)

Example 64. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionate

Step 1: (2R)-2-hydroxy-3-methoxypropionate benzyl ester. A mixture of (2R)-ethylene oxide-2-carboxylate (1.36 g, 7.6 mmol) (synthesis see Example 5AJ), magnesium perchlorate (0.43 g, 1.9 mmol), and methanol (0.37 ml, 9.2 mmol) was stirred at -10 °C for 10 min, and then heated at 45 °C for 20 h. RM was purified by FCC (20-50% EtOAc/hexane) to give the title compound as a colorless oil. Y = 60%. ^¹H NMR (300 MHz, chloroform-d) δ 7.43–7.35 (m, 5H), 5.36–5.21 (m, 2H), 4.41–4.33 (m, 1H), 3.72 (dd, J = 3, 2Hz, 2H), 3.38 (s, 3H), 3.06 (d, J = 3, 2Hz, 1H)

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-methoxypropionate benzyl ester. The title compound was prepared using (2R)-2-hydroxy-3-methoxypropionate benzyl ester and intermediate A as starting materials according to general procedure B. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y = 64%. MS ES ⁺ : 410.1.

Step 3: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionic acid. A mixture of (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionic acid benzyl ester (0.89 g, 2.17 mmol), 10% Pd/C (0.1 g), and THF (50 ml) was purged and then stirred under a hydrogen atmosphere for 16 hours. The solution was filtered through Celite and concentrated. The crude product was diluted with EtOAc and extracted with 1 M NaOH. The aqueous phase was acidified to pH 5 and extracted with EtOAc. The organic phase was dried over _Na₂SO₄ , filtered, and evaporated to give the title compound. Y = 63%. _MS ^ES⁺ : 342.1 [M + Na] ^⁺ .

Step 4: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionic acid. The title compound was prepared from (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionic acid and ethanol as starting materials according to general procedure E. The crude product was purified by FCC (0 to 20% EtOAc/hexane). Y = 71%. MS ES ⁺ : 348.2. ¹ H NMR (300MHz, chloroform-d) δ 7.03 (s, 1H), 6.46 (s, 1H), 5.32–5.27 (m, 1H), 4.35–4.23 (m, 2H), 3.97–3.88 (m, 1H), 3.87–3.77 (m, 1H), 3.45 (s, 3H), 2.94–2.82 (m, 8H), 2.15–2.03 (m, 4H), 1.33 (t, J = 7Hz, 3H)

Example 65. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-methoxypropionic acid

The title compound was synthesized according to the procedure described in Example 64.

Example 66. Ethyl 2-({[2-chloro-3-(trifluoromethyl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthetic route similar to that of Example 59. Y = 45%. MS ES ⁺ : 406.0. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 7.79–7.68 (m, 3H), 7.58–7.50 (m, 1H), 7.49–7.46 (m, 1H), 6.27 (t, J = 2Hz, 1H), 5.35 (t, J = 5Hz, 1H), 4.63 (d, J = 5Hz, 2H), 4.14 (q, J = 7Hz, 2H), 1.19 (t, J = 7Hz, 3H).

Example 67. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionate. A solution of 1,2,4-triazole (0.10 g, 1.45 mmol) in anhydrous DMF (1 ml) was treated with NaH (60%, mineral oil, 58 mg, 1.45 mmol). A solution of ethylene oxide-2-carboxylate in DMF (1 ml) was added. The mixture was stirred at 60 °C for 4 hours. The resulting mixture was diluted with EtOAc to obtain a solution, washed with saturated _NH₄Cl solution, dried over _{Na₂SO₄ ,} filtered, and evaporated to dryness. The crude product was purified by FCC (0-5% MeOH/DCM) to give the title compound as an orange oil. Y＝30%.MS ES ⁺ :185.8. ¹ H NMR (300MHz, DMSO-d ₆ )δ8.44(s,1H),7.96(s,1H),5.97–5.92(m,1H),4.49–4.35(m,3H),4.12(q,J＝7Hz,2H),1.20(t,J＝7Hz,3H)

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionate and intermediate A as starting materials according to general procedure B. The crude product was purified by preparative HPLC. Y＝41%.MS ES ⁺ :385.2. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.19(s,1H),8.57(s,1H),8.00(s,1H),6.95(s,1H),5.32(s,1H),4.73(s,2H),4.14(q, J＝7Hz,2H),2.80(t,J＝7Hz,4H),2.71–2.59(m,4H),1.90–1.80(m,4H),1.19(t,J＝7Hz,3H).

Example 68. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(3-methyl-1H-pyrazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(3-methyl-1H-pyrazole-1-yl)propionate. In a sealed tube, 3-methyl-1H-pyrazole (0.50 g, 6.09 mmol), ethylene oxide-2-carboxylate (1.41 g, 12.2 mmol), and anhydrous ethanol (6 ml) were loaded. RM was heated at 90 °C for 16 hours, followed by vacuum concentration. The crude product was purified by FCC (0-100% DCM/hexane) to obtain the desired product at a ratio of 2:1 with ethyl 2-hydroxy-3-(5-methyl-1H-pyrazole-1-yl)propionate. It was used directly for the next step without further purification. Y = 98%. MS ES ⁺ : 199.4

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(3-methyl-1H-pyrazol-1-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(3-methyl-1H-pyrazol-1-yl)propionate and intermediate A as starting materials according to general procedure B. The crude product was purified by preparative HPLC followed by crystallization (hexane and diethyl ether). Y＝13%.MS ES ⁺ : ^398.1.1H NMR (300MHz, chloroform-d) δ7.03(s,1H),6.40(s,1H),6.03(s,1H),5.42(s,1H),4.68–4.42(m,2H),4.33–4. 20(m,2H),2.90(t,J＝8Hz,4H),2.79(t,J＝7Hz,4H),2.28(s,3H),2.15–2.00(m,4H),1.36-1.26(m,3H)

Example 69. Ethyl 3-(1H-pyrazol-1-yl)-2-{[(2,4,6-trifluorophenyl)carbamoyl]oxy}-propionate

The title compound was prepared using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate and 1,3,5-trifluoro-2-isocyanophenyl as starting materials according to general procedure B. The crude product was purified by FCC (0–5% MeOH/DCM) followed by preparative HPLC. Y = 2%. MS ES ⁺ : 358.1. ^1H NMR (300MHz, DMSO-d ₆ ) δ 9.52 (s, 1H), 7.77 (s, 1H), 7.46 (s, 1H), 7.34–7.24 (m, 2H), 6.28 (s, 1H), 5.30 (s, 1H), 4.67–4.57 (m, 2H), 4.12 (q, J = 7Hz, 2H), 1.17 (t, J = 7Hz, 3H).

Example 70. Ethyl 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionate

Step 1: tert-butyl ethylene oxide-2-carboxylate. Dissolve tert-butyl acrylate (34.3 ml, 234 mmol) in DCM (300 ml). Add a solution of mCPBA (50.5 g, 293 mmol) in DCM (420 ml) and reflux the mixture for 2 days. Add more mCPBA (67 g, 375 mmol) and reflux the mixture for another 4 days. Filter the mixture and cool the filtrate to 0° _C . Add saturated _{Na₂S₂O₃} dropwise, then separate the layers. Filter the organic phase, wash with saturated sodium _bicarbonate , filter, wash with brine, filter, dry with anhydrous sodium sulfate, and concentrate under vacuum. Grind the residue with cold hexane, filter, and evaporate the filtrate to dryness to give the title compound as a yellow oil. Y = 47%. ^1H NMR (300MHz, chloroform-d) δ 3.34 (dd, J = 4, 3Hz, 1H), 2.95–2.87 (m, 2H), 1.52 (s, 9H).

Step 2: 2-Hydroxy-3-(1H-pyrazol-1-yl)propionate tert-butyl ester. Pyrazole (5.67 g, 83 mmol) was added to an anhydrous EtOH (100 mL) solution of tert-butyl ethylene oxide-2-carboxylate (4.80 g, 33 mmol). The RM was heated at 80 °C for 18 hours, concentrated, and co-evaporated with toluene. The crude product was purified by FCC (0-30% EtOAc/hexane) followed by reverse-phase FCC (5-40% MeCN/ _H₂O ) to give the title compound as a white solid. Y=64%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.66(dd,J＝2,1Hz,1H),7.43(dd,J＝2,1Hz,1H),6.21(t,J＝2Hz,1H),5.72–5.61(m,1H),4.37–4.16(m,3H),1.39(s,9H)

Step 3: 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionate tert-butyl ester. The title compound was prepared from 2-hydroxy-3-(1H-pyrazol-1-yl)propionate and 2-isocyano-1-methyl-3-(prop-2-yl)benzene as starting materials according to general procedure A. The crude product was purified by FCC (0 to 50% EtOAc/hexane). Y = 78%. MS ES ⁺ : 388.3

Step 4: 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionic acid. 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionic acid tert-butyl ester (0.36 g, 0.92 mmol) was dissolved in a 1:4 TFA/DCM mixture (10 ml) and stirred at room temperature for 18 h. The RM was concentrated and co-evaporated with hexane. The crude product was suspended in water, alkalized with _NaHCO3 , and washed with EtOAc. The aqueous phase was acidified to pH 5 with 1 M HCl and extracted with EtOAc. The organic phase was dried over sodium sulfate and evaporated. The crude product was purified by FCC (0-20% EtOAc/(hexane + 1% AcOH)) and then purified by preparative HPLC to give the title compound as a white solid. Y = 23%. MS ES ⁺ :332.3

Step 5: Ethyl 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionate. The title compound was prepared from 2-({[2-methyl-6-(prop-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionic acid and ethanol as starting materials according to general procedure E. The crude product was purified by preparative HPLC. Y = 18%. MS ES ⁺ : 360.0. ¹ H NMR (400MHz, chloroform-d) δ 7.54 (s, 1H), 7.40 (s, 1H), 7.27–7.18 (m, 2H), 7.14–7.02 (m, 1H), 6.53 (s, 1H), 6.26 (s, 1H), 5.40–5.30 (m, 1H), 4.72–4.56 (m, 2H), 1.47 (s, 9H)

Example 71. Ethyl 2-{[(3-chloro-2,6-difluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Synthesized using a synthetic route similar to that of Example 59. Y = 2%. MS ES ⁺ : 373.9

^1H NMR (300MHz, methanol- _d4 ) δ 7.77–7.66 (m, 1H), 7.57–7.51 (m, 1H), 7.49–7.39 (m, 1H), 7.12–7.03 (m, 1H), 6.38–6.28 (m, 1H), 5.38 (t, J = 5Hz, 1H), 4.69 (d, J = 5Hz, 2H), 4.22 (q, J = 7Hz, 2H), 1.27 (t, J = 7Hz, 3H).

Example 72. Ethyl propionate (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

Step 1: Ethyl (2R)-ethylene oxide-2-carboxylate. Potassium (2R)-ethylene oxide-2-carboxylate (50.0 g, 396 mmol) (synthesis see Example 5AJ) was added in a single batch at 25°C under _N₂ to a mixture of dichloromethane (250 ml) and bromoethane (172 g, 1.59 mol) and benzyl (triethyl)ammonium chloride (90.2 g, 396 mmol). The mixture was stirred at 45°C for 16 h. The mixture was cooled to room temperature. The residue was poured into _H₂O (300 ml) and stirred for 5 min. The aqueous phase was extracted with dichloromethane (150 ml). The combined organic phases were washed with brine (100 ml), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The crude product was purified by FCC (0-50% EtOAc/petroleum ether) to give the title compound as a yellow oil. Y = 9%. ^1H NMR (400MHz, chloroform-d) δ 4.23-4.28 (m, 2H), 3.42-3.44 (m, 1H), 2.93-2.98 (m, 2H), 1.31 (t, J = 7Hz, 3H).

Step 2: Ethyl (2R)-3-(4-cyano-1H-pyrazole-1-yl)-2-hydroxypropionate. In a sealed tube, 1H-pyrazole-4-carboxynitrile (2.00 g, 21.5 mmol) and ethyl (2R)-ethylene oxide-2-carboxylate (1.00 g, 8.61 mmol) were dissolved in EtOH (7 ml). The solution was heated in a microwave irradiation at 100 °C for 180 min. The solution was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%, 20 min) to give the title compound as a yellow oil. Y = 42%. ^¹H NMR (400 MHz, chloroform-d) δ 7.95 (s, ¹H), 7.79 (s, ¹H), 4.50–4.54 (m, ³H), 4.25–4.30 (m, ²H), 1.31 (t, J = 7 Hz, ³H)

Step 3: Ethyl (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. The title compound was prepared using ethyl (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropionate and intermediate A as starting materials according to general procedure A. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 50%-80%, 20min) to obtain the title compound as a white solid. Y＝18%.MS ES ⁺ :409.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.17(s,1H),8.61(s,1H),8.10(s,1H),6.95(s,1H),5.34(s,1H),4.71(s,2H ), 4.05-4.16 (m, 2H), 2.65-2.80 (m, 8H), 1.94-1.99 (m, 4H), 1.18 (t, J = 7Hz, 3H).

Example 73. (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}benzyl propionate

Step 1: (2R)-3-(4-cyano-1H-pyrazole-1-yl)-2-hydroxypropanoate benzyl ester. A mixture of (2R)-ethylene oxide-2-carboxylate (0.50 g, 2.81 mmol) and 4-cyanopyrazole (0.52 g, 5.62 mmol) in EtOH (1 ml) was heated at 120 °C under microwave irradiation in a sealed tube for 1 hour. RM was concentrated and purified by FCC (EtOAc/hexane) to give the title compound. Y = 20%. MS ES ⁺ : 272.2

Step 2: (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}benzyl propionate. The title compound was prepared using (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropionate and intermediate A as starting materials according to general procedure B. The crude product was purified by FCC to obtain the title compound as a white solid. Y＝50%.MS ES ⁺ : ^471.1H NMR (300MHz, chloroform-d) δ7.78(s,2H),7.44–7.33(m,5H),7.06(s,1H),6.37(s,1H),5.55(s,1H) ),5.30–5.16(m,2H),4.69(s,2H),2.99–2.86(m,4H),2.80–2.68(m,4H),2.12–2.02(m,4H)

Example 74. Ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionate

Step 1: Ethyl 2-oxo-3-(pyrimidin-2-yl)propionate. 2-M methylpyrimidine (0.60 g, 6.4 mmol) was added to a 2M LDA solution in THF/hexane/ethylbenzene (6.4 ml, 12.8 mmol) in anhydrous THF (15 ml) cooled to -78 °C. The RM was stirred for 1 h, then ethyl 2,2,2-triethoxyacetate (1.31 ml, 7.0 mmol) was added. The solution was warmed to room temperature and stirred for 3 days. The RM was poured into 1M HCl and stirred for 1 h. The mixture was neutralized with _NaHCO3 solution and extracted three times with EtOAc. The combined organic matter was washed with brine, _dried over _Na2SO4 , filtered, and evaporated. The crude product was purified by FCC (0-50% EtOAc/hexane) to give the title compound as a yellow solid. Y=35%. ¹ H NMR (300MHz, DMSO-d ₆ ) δ 13.63 (s, 1H), 8.89 (d, J = 5Hz, 2H), 7.43 (t, J = 5Hz, 1H), 6.52 (s, 1H), 4.29 (q, J = 7Hz, 2H), 1.30 (t, J = 7Hz, 3H).

Step 2: Ethyl 2-hydroxy-3-(pyrimidin-2-yl)propionate. A solution of ethyl 2-oxo-3-(pyrimidin-2-yl)propionate (0.42 g, 2.16 mmol) in EtOH (20 mL) was cooled to -78 °C and treated with _NaBH₄ (0.33 g, 8.65 mmol). RM was stirred at -78 °C for 1 h, then heated to room temperature and stirred for another 1.5 h. RM was poured onto ice, acidified to pH 2 with 1 M HCl, and extracted sequentially with EtOAc, nBuOH, and a 4: ₁ iPrOH/DCM mixture. The combined organic phases were dried over _Na₂SO₄ , filtered, and concentrated under vacuum to give the title compound as a yellow oil. Y = 41%. MS ^ES⁺ : 197.0

Step 3: Ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionate. Following general procedure B, the title compound was prepared using ethyl 2-hydroxy-3-(pyrimidin-2-yl)propionate and 2,6-dimethylphenyl isocyanate as starting materials. The crude product was purified by FCC (0-20% MeOH/DCM) to obtain the title compound as a colorless oil. Y=2%.MS ES ⁺ : ^344.0.1H NMR (300MHz, methanol- _d4 )δ8.78(d,J＝5Hz,2H),8.74–8.61(m,1H),7.41(t,J＝5Hz,1H),7.13–7.01(m,3H),5.73 –5.63(m,1H),4.24(q,J＝7Hz,2H),3.63–3.44(m,2H),2.20(s,6H),1.28(t,J＝7Hz,3H)

Example 75. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionic acid

Step 1: Ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propionate. Benzyl (2R)-ethylene oxide-2-carboxylate (3.00 g, 16.8 mmol) (synthesis see Example 5AJ) was dissolved in EtOH (32 ml). Imidazole (2.87 g, 42.1 mmol) was added, and RM was heated in a sealed tube at 90 °C for 16 hours. RM was concentrated and purified by FCC (0-10% MeOH/DCM) to give the title compound as a yellow oil. Y=31%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.56(d,J＝1Hz,1H),7.12(t,J＝1Hz,1H),6.85(t,J＝1Hz,1H),5.96(d,J＝5Hz,1H),4.40–4.30(m,1H),4.29–4.05(m,4H),1.19(t,J＝7Hz,3H).

Step 2: (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propionate. Ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propionate (0.97 g, 5.3 mmol) was dissolved in a 1:1 THF/water solution (20 ml) and cooled to 0 °C. Lithium hydroxide monohydrate (0.23 g, 5.5 mmol) was added, and RM was stirred at 0 °C for 30 min, then at room temperature for 1 h. THF was removed under vacuum, and RM was acidified with 2 M HCl to pH ~3. The solution was washed with EtOAc and then lyophilized to give the title compound as a white solid. Y = 93%. MS ES ⁺ : 157.

Step 3: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl)propionic acid. A solution of (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propionate (96 mg, 0.50 mmol), triethylamine (0.154 mL, 0.11 mmol), and DMSO (3 mL) was treated with intermediate A (0.10 g, 0.50 mmol) and stirred for 16 hours. The crude product was purified by preparative HPLC to give the title compound as a white solid. Y＝17%.MS ES ⁺ :356. ¹ HNMR (300MHz, DMSO-d ₆ )δ13.38(s,1H),9.14(s,1H),7.70(s,1H),7.24(s,1H),6.96(s,1H),6.91(s,1H),5.22–5 .12(m,1H),4.56–4.35(m,2H),2.81(t,J＝7Hz,4H),2.69(t,J＝8Hz,4H),2.02–1.89(m,4H).

Example 76. Ethyl 3-(4-fluoro-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate

Step 1: Ethyl 3-(4-fluoro-1H-pyrazole-1-yl)-2-hydroxypropionate. Ethyl ethylene oxide-2-carboxylate (0.15 g, 1.3 mmol) was dissolved in EtOH (3 ml). Pyrazole (0.28 g, 3.2 mmol) was added, and RM was heated in a sealed tube at 90 °C for 16 hours. RM was evaporated under low pressure to remove excess pyrazole and give the title compound. MS ES ⁺ : 203.1.

Step 2: Ethyl 3-(4-fluoro-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. The title compound was prepared using ethyl 3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxypropionate and intermediate A as starting materials according to general procedure B. The crude product was purified by preparative HPLC to obtain the title compound as a white solid. Y＝34%.MS ES ⁺ :402. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.19(s,1H)7.94(s,1H),7.56–7.45(m,1H),6.96(s,1H),5.32–5.21(m,1H),4.54(s,2H),4.1 3(q,J＝7Hz,2H),2.81(t,J＝7Hz,4H),2.73–2.59(m,4H),2.01–1.91(m,4H),1.19(t,J＝7Hz,3H).

Example 77. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H-imidazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(5-methyl-1H-imidazol-1-yl)propionate. Ethyl ethylene oxide-2-carboxylate (0.10 g, 0.86 mmol) was dissolved in EtOH (1 ml). 5-methyl-1H-imidazolium (71 mg, 0.86 mmol) was added, and RM was heated in a microwave reactor at 120 °C for 1 h. RM was evaporated to dryness and partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate and evaporated. The crude product was purified by FCC (0-7% MeOH/DCM) to give the title compound as a colorless oil. Y = 52%. MS ES ⁺ : 199.

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H-imidazol-1-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(5-methyl-1H-imidazol-1-yl)propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by FCC (0-7% MeOH/DCM) to give the title compound as a white solid. Y＝23%.MS ES ⁺ :398.1. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.22(s,1H)7.08(s,1H),6.96(s,1H),6.79–6.63(m,1H),5.33–5.13(m,1H),4.38(s,2H),4.18–4.0 9(m,2H),2.81(t,J＝6Hz,4H),2.75–2.59(m,4H),2.33(s,3H),2.01–1.91(m,4H),1.19(t,J＝7Hz,3H).

Example 78. (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid

To a mixture of (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid propionate (400 mg, 0.95 mmol) (synthesis see Example 5CI) in dioxane (5 mL), 6 M HCl (5 mL) was added in a single addition at 20 °C. The mixture was stirred at 20 °C for 48 hours. The RM was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 45%-80%, 20 min) to give the title compound as a white solid. Y＝28%.MS ES ⁺ :381.0. ¹ H NMR (400MHz, DMSO-d ₆ )δ13.40(s,1H),9.09(s,1H),8.60(s,1H),8.10(s,1H),6.95(s,1H),5.28(s,1H),4.69(s,2H),2.80-2.64(m,8H),1.98-1.91(m,4H).

Example 79. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionate

Step 1: Ethyl (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionate. In a sealed tube, ethyl (2R)-ethylene oxide-2-carboxylate (1.00 g, 8.61 mmol) (synthesis see Example 5AY) and 1,2,4-triazole (1.49 g, 21.5 mmol) were dissolved in EtOH (10 ml). RM was heated in a microwave reactor at 100 °C for 3 hours. RM was concentrated under vacuum and purified by preparative HPLC (column: Agela Innoval ODS-2250*80 mm; mobile phase: [water (0.1% TFA)-ACN]; B%: 0%-20%, 20 min) to give the title compound as a yellow oil. Y = 27%. MS ES ⁺ : 186.1. ¹ H NMR (400MHz, methanol-d ₄ ) δ 8.66 (s, 1H), 8.11 (s, 1H), 4.62-4.54 (m, 3H), 4.25-4.20 (m, 2H), 1.28 (t, J = 7Hz, 3H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionate. Following general procedure A, the title compound was prepared using ethyl (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionate and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.225% TFA)-ACN]; B%: 25-55%, 20 min) to obtain the title compound as a white solid. Y = 26%. MS ES ⁺ : 385.3. ¹ H NMR (400MHz, methanol-d ₄ ) δ 8.66 (s, 1H), 8.08 (s, 1H), 6.96 (s, 1H), 5.42 (s, 1H), 4.86–4.81 (m, 2H), 4.26–4.21 (m, 2H), 2.87–2.72 (m, 8H), 2.07–1.99 (m, 4H), 1.28 (t, J = 7Hz, 3H).

Example 80. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(2-methyl-1H-imidazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propionate. In a sealed tube, ethyl ethylene oxide-2-carboxylate (212 mg, 1.83 mmol) and 2-methylimidazolium (150 mg, 1.83 mmol) were dissolved in EtOH (1 ml). RM was heated in a microwave reactor at 120 °C for 1 hour. RM was concentrated under vacuum and purified by FCC (0-10% MeOH/DCM) to give the title compound as an orange oil. Y = 58%. MS ES ⁺ : 199.2.

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(2-methyl-1H-imidazol-1-yl)propionate. Following general procedure B, ethyl 2-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propionate and intermediate A were used as starting materials to prepare the title compound. The crude product was purified by FCC (0-10% MeOH/DCM) and then further purified by preparative HPLC to obtain the title compound as a white solid. MS ES ⁺ :398.6. ¹ H NMR (300MHz, DMSO-d ₆ )δ9.21(s,1H),7.08(s,1H),6.97(s,1H),6.74(s,1H),5.34–5.21(m,1H),4.49-4.26(m,2H),4.19–4. 10(m,2H),2.81(t,J＝7Hz,4H),2.75–2.55(m,4H),2.33(s,3H),2.01–1.91(m,4H),1.19(t,J＝7Hz,3H).

Example 81. Ethyl 2-{[(2-chloro-6-ethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: 1-Chloro-3-ethyl-2-isocyanophenyl. Triethylamine (0.246 ml, 1.77 mmol) was added to a THF (10 ml) solution of 2-chloro-6-ethylaniline (0.25 g, 1.61 mmol), followed by phosgene (20%/toluene, 0.85 ml, 1.61 mmol). The mixture was heated at 60 °C for 4 h, then cooled to room temperature. The THF was evaporated under vacuum, and the residue was precipitated with cold pentane. The resulting mixture was filtered, and the filtrate was evaporated to give the title compound as a red oil. Y = 93%. MS ES ⁺ : 227 (The compound was analyzed in diethylamine, yielding diethylurea).

Step 2: Ethyl 2-{[(2-chloro-6-ethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. Following general procedure B, the title compound was prepared using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (synthesis see Example 49) and 1-chloro-3-ethyl-2-isocyanophenyl as starting materials. The crude product was purified by FCC (0-10% MeOH/DCM) and then further purified by preparative TLC to obtain the title compound as a grayish-white solid. MS ES ⁺ :366. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.33(s,1H),7.79(d,J＝2Hz,1H),7.48(d,J＝2Hz,1H),7.36–7.33(m,1H),7.29–7.21(m,2H),6.29(t,J＝2Hz,1H),5 .31(t,J＝6Hz,1H),4.66–4.62(m,2H),4.17–4.05(m,2H),2.58–2.52(m,2H),1.18(t,J＝7Hz,3H),1.09(t,J＝8Hz,3H).

Example 82. Ethyl 2-{[(2-methylnaphth-1-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: 1-Amino-2-methylnaphthalene. Triphosgene (0.47 g, 1.59 mmol) was added dropwise to a mixture of 1-amino-2-methylnaphthalene (0.5 g, 3.18 mmol) and triethylamine (0.353 g, 3.49 mmol) in THF (6 ml) at room temperature. The mixture was heated to reflux for 4 hours. The reaction mixture was cooled to room temperature, evaporated to dryness, and the resulting residue was filtered and washed with pentane (25 ml). The filtrate was evaporated under vacuum to give the title compound as a yellow liquid. This substance was used directly without any further purification. Y=89%. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.08(d,J＝8Hz,1H)7.83(d,J＝8Hz,1H),7.65(d,J＝8Hz,1H),7.58-7.56(m,1H),7.52-7.50(m,1H),7.34(d,J＝8Hz,1H),2.55(s,3H).

Step 2: Ethyl 2-{[(2-methylnaphth-1-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. The title compound was prepared from ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (synthesis see Example 49) and 1-isocyano-2-methylnaphthalene as starting materials according to general procedure B. The crude product was purified by FCC (0-30% EtOAc/hexane) to give the title compound as a colorless oil. MS ES ⁺ :368.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.53(s,1H),7.91-7.78(m,4H),7.52-7.40(m,4H),6.34(s,1H),5.35(t,J＝6Hz, 1H), 4.69 (d, J = 6Hz, 2H), 4.16-4.14 (m, 2H), 2.46-2.31 (m, 3H), 1.22-1.18 (m, 3H).

Example 83. Ethyl 2-{[(2-methylcyclohexyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: ₁ -Isocyano-2-methylcyclohexane. To a solution of 2-methylcyclohexane-1-amine (0.2 g, 1.77 mmol) in toluene (3 ml), 20% phosgene/toluene (1 ml, 2.12 mmol) was added. The reaction mixture was heated at 80 °C for 4 hours. The reaction mixture was concentrated under vacuum to give the title compound, which was used directly in the next step. Y = 100%.

Step 2: Ethyl 2-{[(2-methylcyclohexyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. Following general procedure B, the title compound was prepared using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (synthesis see Example 49) and 1-isocyano-2-methylcyclohexane as starting materials. The crude product was purified by FCC (0-25% EtOAc/hexane) to obtain the title compound as a colorless oil. Y＝10%.MS ES ⁺ :324.1. ¹ H NMR (400MHz, DMSO-d ₆ )δ7.72-7.71(m,1H),7.45-7.43(m,1H),7.35-7.31(m,1H),6.26-6.24(m,1H),5.18-5.15(m,1H),4.54-4. 56(m,2H),4.11-4.05(m,2H),2.92-2.80(m,1H),1.67-1.55(m,4H),1.45-1.09(m,8H),0.98-0.81(m,3H).

Example 84. Ethyl propionate of (2R)-3-(4-chloro-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

Step 1: Ethyl (2R)-3-(4-chloro-1H-pyrazol-1-yl)-2-hydroxypropionate. 4-chloro-1H-pyrazole (1.10 g, 10.77 mmol) was added in a single step to a solution of (2R)-ethylene oxide-2-carboxylate (0.5 g, 4.31 mmol) in EtOH (5 ml) at 80 °C under _N₂ . The mixture was stirred at 80 °C for 1 h, then filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (30% EtOAc/petroleum ether) to give the title compound as a colorless oil. Y = 21%. ^¹H NMR (400MHz, methanol- _d⁴ ) δ 7.71 (s, ¹H), 7.69 (s, ¹H), 7.49 (s, ¹H), 4.51–4.43 (m, ¹H), 4.41 (d, J = 4Hz, ¹H), 4.36–4.28 (m, ¹H), 4.22–4.15 (m, 2H), 1.28–1.22 (m, 3H).

Step 2: Ethyl (2R)-3-(4-chloro-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. Following general procedure B, the title compound was prepared using ethyl (2R)-3-(4-chloro-1H-pyrazol-1-yl)-2-hydroxypropionate and intermediate A as starting materials. The crude product was purified by preparative TLC (1:2 EtOAc/hexane) to obtain the title compound as a white solid. Y = 18%. MS ES ⁺ : 418.1. ¹ H NMR (400MHz, chloroform-d) δ 7.52-7.38 (m, 1H), 7.02 (s, 1H), 6.41 (s, 1H), 5.43 (br. s, 1H), 4.58 (s, 2H), 4.25 (q, J = 7Hz, 2H), 2.99-2.65 (m, 8H), 2.10-2.03 (m, 4H), 1.29 (t, J = 7Hz, 3H).

Example 85. Ethyl propionate of (2R)-3-(4-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy} and ethyl propionate of (2R)-3-(5-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

Step 1: A mixture of ethyl (2R)-3-(4-cyano-1H-imidazol-1-yl)-2-hydroxypropionate and ethyl (2R)-3-(5-cyano-1H-imidazol-1-yl)-2-hydroxypropionate was added in portions to a solution of 4H-imidazol-5-carboxynitrile (2.00 g, 21.53 mmol) in EtOH (10 ml) under _N2 conditions (see Example 5AY for synthesis). The mixture was stirred at 95 °C for 0.5 h, and then concentrated under reduced pressure to obtain the residue. The residue was purified by FCC (1:2 EtOAc/petroleum ether) to give a mixture of (R)-3-(4-cyano-1H-imidazol-1-yl)-2-hydroxypropionate ethyl ester (28% yield) and (R)-3-(5-cyano-1H-imidazol-1-yl)-2-hydroxypropionate ethyl ester (28% yield) as a yellow oil.

Step 2: Ethyl propionate of (2R)-3-(4-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy} and ethyl propionate of (2R)-3-(5-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}. Dissolve a mixture (200 mg, 0.96 mmol) of (2S)-3-(4-cyanoimidazol-1-yl)-2-hydroxy-propionate and (2R)-3-(5-cyanoimidazol-1-yl)-2-hydroxy-propionate in anhydrous THF (2 ml) and cool to 0 °C. CuCl (47 mg, 478 μmol) was added, and the mixture was stirred for 30 minutes. Then, 4-isocyano-1,2,3,5,6,7-hexahydro-s-indane (200 mg, 1.00 mmol) was slowly added. The reaction mixture was heated to room temperature and stirred for 10 hours. The reaction mixture was diluted with _H₂O (5 mL) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (10 mL), dried over _Na₂SO₄ , filtered, and concentrated under reduced pressure to obtain the residue. _The residue was purified by preparative TLC (1:2 EtOAc/petroleum ether) to give the desired product as a white solid. The mixture was further separated by SFC (column: OD (250 mm × 30 mm, 5 μm); mobile phase: EtOH; B%: 35%, 12 min). Ethyl propionate (2R)-3-(5-cyanoimidazol-1-yl)-2-(1,2,3,5,6,7-hexahydro-s-indarsen-4-ylcarbamoyloxy)propionate (5 mg, 2% yield) and ethyl propionate (2R)-3-(4-cyanoimidazol-1-yl)-2-(1,2,3,5,6,7-hexahydro-s-indarsen-4-ylcarbamoyloxy)propionate (5 mg, 2% yield) were obtained as white solids. Analysis of ethyl propionate (2R)-3-(4-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate: MS ES ⁺ : 409.1. ^1H NMR (400 MHz, acetonitrile-d ₃₎ δ 7.81(s,1H), 7.67(s,1H), 7.53(s,1H), 7.00(s,1H), 5.30(s,1H), 4.51(s,2H), 4.20-4.15(m,2H), 2.87(s,4H), 2.73(s,4H), 2.04-1.93(m,4H), 1.22(t,J＝7Hz,3H). Ethyl propionate analysis: MS ES ⁺ : 409.1. ^1H NMR (400MHz, acetonitrile- _d3) )δ7.85(s,1H),7.66(s,1H),7.46(s,1H),7.00(s,1H),5.32(s,1H),4.59(s,2H),4 .25-4.18(m,2H),2.86(s,4H),2.72(s,4H),2.06-1.98(m,4H),1.25(t,J＝7Hz,3H).

Example 86. Ethyl 2-({[2,6-dimethyl-4-(trifluoromethyl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propionate

The synthesis was performed using a synthetic route similar to that of Example 59, using 2,6-dimethyl-4-(trifluoromethyl)aniline and ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (synthesis see Example 49). Y = 26%. MS ES ⁺ : 400. ¹ ¹H NMR (300 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 7.80 (s, 1H), 7.52–7.31 (m, 3H), 6.29 (s, 1H), 5.38–5.15 (m, 1H), 4.70–4.32 (m, 2H), 4.14 (q, J = 7 Hz, 2H), 2.27–2.03 (m, 6H), 1.18 (t, J = 7 Hz, 3H).

Example 87. Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(4-methoxy-1H-pyrazol-1-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(4-methoxy-1H-pyrazole-1-yl)propionate. In a sealed tube, a mixture of 4-methoxy-1H-pyrazole (0.150 g, 1.53 mmol) and ethylene oxide-2-carboxylate (0.178 g, 1.53 mmol) in EtOH (1 ml) was heated at 120 °C for 1 h in a microwave reactor. Another equivalent of ethylene oxide-2-carboxylate (0.178 g, 1.53 mmol) was added, and RM was heated at 120 °C for 1 h in a microwave reactor. RM was evaporated to dryness and purified by FCC (0-10% MeOH/DCM) to give the title compound as a yellow oil. Y=96%. ¹ H NMR (300MHz, DMSO-d ₆ )δ7.41(d,J＝1Hz,1H),7.19(d,J＝1Hz,1H),5.82(d,J＝6Hz,1H),4.40–4.33(m,1H),4.18–4.05(m,4H),3.64(s,3H),1.18(t,J＝7Hz,3H).

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(4-methoxy-1H-pyrazol-1-yl)propionate. Following general procedure B, the title compound was prepared using ethyl 2-hydroxy-3-(4-methoxy-1H-pyrazol-1-yl)propionate and intermediate A as starting materials. The crude product was purified by FCC (EtOAc/hexane) and then further purified by preparative HPLC to obtain the title compound. Y＝1%.MS ES ⁺ : ^414.5.1H NMR (300MHz, chloroform-d) δ7.14(s,1H),7.03(s,1H),6.42(s,1H),5.43(s,1H),4.53(s,2H),4.27(q,J＝7H z, 2H), 3.74 (s, 3H), 2.90 (t, J = 7Hz, 4H), 2.81 (t, J = 7Hz, 4H), 2.14–2.04 (m, 4H), 1.31 (t, J = 7Hz, 3H).

Example 88. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(pyrimidin-2-yl)propionate. Iron diacetoxy (3.88 g, 22 mmol) was added in a single step to a solution of 2-methylpyrimidine (42.0 g, 446 mmol) and ethyl 2-oxoacetate (118 g, 580 mmol) in 1,4-dioxane (290 mL) at 10–20 °C. The mixture was heated to 101 °C and stirred for 48 hours. The mixture was filtered through an RM filter and concentrated under vacuum. The resulting residue was purified by FCC (0–50% EtOAc/petroleum ether) to give the title compound as a yellow solid. Y = 74%. ^1H NMR (400MHz, chloroform-d) δ 8.70 (d, J = 5Hz, 2H), 7.22 (t, J = 5Hz, 1H), 5.77–5.44 (m, 1H), 4.80–4.69 (m, 1H), 4.26 (q, J = 7Hz, 2H), 3.47–3.56 (m, 1H), 3.36–3.46 (m, 1H), 1.24 (t, J = 7Hz, 3H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionate. The title compound was prepared using ethyl 2-hydroxy-3-(pyrimidin-2-yl)propionate and intermediate A as starting materials, following general procedure B. The crude product was purified by FCC (0-60% EtOAc/hexane) to give a racemic product as a white solid. This was separated by a chiral SFC (column: DAICL CHIRALPAK IC (250 mm * 30 mm, 5 μm); mobile phase: EtOH; B%: 22%, 3.9 min). Peak 1 contains the title compound. Y=9%.MS ES ⁺ : ^396.1.1H NMR (400MHz, chloroform-d) δ8.70 (d, J = 5Hz, 2H), 7.21–7.17 (m, 1H), 6.98 (s, 1H), 6.27 (br.s, 1H), 5.80–5.75 (m, 1H), 4.2 6(q,J＝7Hz,2H),3.65–3.49(m,2H),2.89–2.83(m,4H),2.79–2.74(m,4H),2.09–1.99(m,4H),1.28(t,J＝7Hz,3H).

Example 89. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionate

Step 1: Ethyl 2-hydroxy-3-(pyrazin-2-yl)propionate. Under _N2 , ethyl 2-oxoacetate (56.4 g, 276 mmol) and iron diacetoxyacetate (0.99 g, 6.4 mmol) were added to a solution of 2-methylpyrazine (20.0 g, 212 mmol) in 1,4-dioxane (140 mL). The reaction was heated at 140 °C for 48 h. The mixture was concentrated under reduced pressure. The residue was purified by FCC (0-10% EtOAc/petroleum ether) to give the title compound. Y = 30%. ^1H NMR (400MHz, chloroform-d) δ 8.54–8.48 (m, 3H), 4.70–4.64 (m, 1H), 4.26 (q, J = 8Hz, 2H), 3.38–3.33 (m, 1H), 3.25–3.19 (m, 1H), 1.26 (t, J = 7Hz, 3H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionate. Following general procedure B, the title compound (a racemic mixture) was prepared using ethyl 2-hydroxy-3-(pyrazin-2-yl)propionate and intermediate A as starting materials. The crude mixture was purified by FCC (0-50% EtOAc/hexane) to give the racemic product as a white solid. This was separated by a chiral SFC (column: Daicel Chiralpak AD-H (250 mm * 30 mm, 5 μm); mobile phase: EtOH; B%: 24%, 5.5 min). Peak 2 contains the title compound. Y＝34%.MS ES ⁺ :396.1. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.22–9.15(br.s,1H),8.68–8.55(m,3H),6.93(s,1H),5.40–5.32(m,1H),4.13(q,J＝7Hz,2H), 3.41–3.29(m,2H),2.82–2.74(m,4H),2.69–2.55(m,4H),1.98–1.88(m,4H),1.16(t,J=7Hz,3H).

Example 90. Ethyl (2R)-3-ethoxy-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate

Step 1: Ethyl (2R)-3-ethoxy-2-hydroxypropionate. Ethanol (0.35 ml, 6.0 mmol) was added to a solution of ethyl (2R)-ethylene oxide-2-carboxylate (100 mg, 0.86 mmol) in EtOAc (1 ml), followed by magnesium trifluoromethanesulfonate (444 mg, 1.38 mmol). The mixture was stirred at 60 °C for 24 hours. The residue was purified by FCC (5-20% EtOAc/petroleum ether) to give the title compound as a colorless oil. Y = 72%. ^¹H NMR (400 MHz, chloroform-d) δ 4.36–4.20 (m, 3H), 3.73 (d, J = 4 Hz, 2H), 3.64–3.46 (m, 2H), 3.05 (d, J = 6 Hz, 1H), 1.31 (t, J = 7 Hz, 3H), 1.19 (t, J = 7 Hz, 3H).

Step 2: Ethyl (2R)-3-ethoxy-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. The title compound was prepared using ethyl (2R)-3-ethoxy-2-hydroxypropionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by preparative TLC (25% EtOAc/hexane) to give the title compound as a white solid. Y = 10%. MS ES ⁺ : 362.1. ¹ H NMR (400MHz, chloroform-d) δ 7.01 (s, 1H), 6.48 (s, 1H), 5.28 (s, 1H), 4.43–4.13 (m, 2H), 4.01–3.84 (m, 2H), 3.70–3.45 (m, 2H), 3.01–2.76 (m, 8H), 2.17–1.98 (m, 4H), 1.31 (t, J = 7Hz, 3H), 1.27–1.19 (m, 3H).

Example 91. Ethyl propionate (2R)-3-(3-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}

Step 1: Ethyl (2R)-3-(3-cyano-1H-pyrazol-1-yl)-2-hydroxypropionate. Ethyl (2R)-ethylene oxide-2-carboxylate (1.0 g, 8.61 mmol) was added in portions to a solution of 1H-pyrazol-3-carboxynitrile (2.00 g, 21.5 mmol) in EtOH (3 mL) (see Example 5AY for synthesis). The mixture was then stirred at 90 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by FCC (1:2 EtOAc/gasoline) to give the title compound as a colorless oil. Y = 14%. ^1H NMR (400MHz, chloroform-d) δ 7.59 (d, J = 3Hz, 1H), 6.65 (d, J = 3Hz, 1H), 4.56-4.47 (m, 3H), 4.33-4.25 (m, 2H), 1.35-1.29 (m, 3H).

Step 2: Ethyl (2R)-3-(3-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. The title compound was prepared from (2R)-3-(3-cyano-1H-pyrazol-1-yl)-2-hydroxypropionate and intermediate A, following general procedure B. The crude mixture was purified by preparative TLC (33% EtOAc/hexane) to give the title compound as a white solid. Y = 10%. MS ES ⁺ : 409.2

¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(s,1H),8.11(s,1H),7.04(s,1H),6.96(s,1H),5.38(s,1H),4.77(s,2H),4.18-4 .12(m,2H),2.87-2.74(m,4H),2.73-2.62(m,4H),2.02-1.89(m,4H),1.19(t,J＝7Hz,3H).

Example 92. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-[4-(trifluoromethyl)-1H-pyrazol-1-yl]propionate ethyl ester

Step 1: Ethyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)-1H-pyrazol-1-yl]propionate. Add 4-trifluoromethylpyrazole (586 mg, 4.31 mmol) to a solution of ethyl (2R)-ethylene oxide-2-carboxylate (0.20 g, 1.72 mmol) (synthesis see Example 5AY) in EtOH (2 ml). Stir the solution at 90 °C for 16 hours. Concentrate the reaction mixture, dilute with _H₂O (20 ml), and extract with EtOAc (3 × 15 ml). Wash the combined organic layers with brine (10 ml), _dry to _Na₂SO₄ , filter, and concentrate under reduced pressure to give the residue. Purify the residue by FCC (0-9% MeOH/DCM) to give the title compound as a yellow oil. Y=58%. ¹ H NMR (400MHz, DMSO-d ₆ )δ13.65–13.55(br.s,1H),8.39(s,1H),7.90(s,1H),5.94(d,J＝6Hz,1H),4.46-4.40(m,2H),4.13-4.08(m,2H),1.17(t,J＝7Hz,3H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-[4-(trifluoromethyl)-1H-pyrazol-1-yl]propionate. Following general procedure B, the title compound was prepared using ethyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)-1H-pyrazol-1-yl]propionate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (33% EtOAc/hexane) to obtain the title compound as a white solid. Y = 12%. MS ES ⁺ : 452.2. ¹ H NMR (400MHz, chloroform-d) δ 7.80–7.70 (m, 2H), 7.00 (s, 1H), 6.42 (s, 1H), 5.48 (s, 1H), 4.72–4.62 (m, 2H), 4.29–4.18 (m, 2H), 2.93–2.85 (m, 4H), 2.82–2.72 (m, 4H), 2.11–2.03 (m, 4H), 1.30 (m, 3H).

Example 93. (2R)-3-{4-[(dimethylamino)methyl]-1H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate

Step 1: (2R)-3-{4-[(dimethylamino)methyl]-1H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}benzyl propionate. Add N,N-dimethylmethylene ammonium iodide (0.33 g, 1.80 mmol) to a solution of (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate (0.20 g, 0.45 mmol) (synthesis see Example 5AM) in acetonitrile (2 ml) and DMF (1 ml). RM was purged with argon and sealed in a tube. RM was heated at 90 °C for 16 hours, then concentrated under vacuum. The residue was purified by FCC (40% EtOAc/hexane, then 0-10% MeOH/DCM) to give the title compound as a green solid. Y = 20%. MS ES ⁺ : 504.

Step 2: (2R)-3-{4-[(dimethylamino)methyl]-1H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionate. Benzyl propionate (31 mg, 0.06 mmol) was dissolved in MeOH (5 mL) in a Parr reactor. 1,1,2-Trichloroethane (6 μl, 0.07 mmol) and palladium/carbon (10%, 0.05 g) were added. The RM was stirred under a hydrogen atmosphere for 16 hours. The RM was filtered through a Celite filter, washed with MeOH, and the filtrate was concentrated under vacuum. The resulting residue was dissolved in a minimum volume of MeOH, precipitated with diethyl ether, and the resulting solid was filtered off to give the title compound as a yellow solid. MS ES ⁺ : 413. ^1H NMR (300MHz, DMSO- _d6 ) δ 8.88 (s, 1H), 8.20 (s, 1H), 7.76–7.70 (m, 1H), 7.38 (s, 1H), 6.91 (s, 1H), 5.11–5.05 (m, 1H), 4.65–4.55 (m, 1H), 4.42–4.32 (m, 1H), 2.87–2.76 (m, 4H), 2.74–2.62 (m, 4H), 2.24 (s, 6H), 2.00–1.86 (m, 4H).

Example 94. Ethyl 2-{[(2,4-dimethylthiophen-3-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate

Step 1: 2,4-Dimethylthiophene-3-carboxylic acid. Under a nitrogen atmosphere at -78°C, n _- butyllithium (1.6 M/hexane, 5 mL, 8.0 mmol) was added dropwise to a solution of 4-methylthiophene-3-carboxylic acid (0.5 g, 3.5 mmol) in THF (20 mL). The resulting reaction mixture was stirred at -78°C for 30 min. A solution of methyl iodide (0.24 mL, 3.8 mmol) in THF (20 mL) was added dropwise to the reaction mixture. The resulting reaction mixture was stirred at -78°C for 30 min, then allowed to warm to room temperature. The reaction mixture was poured into saturated ammonium chloride (50 mL), and the resulting solution/suspension was concentrated under vacuum. The aqueous layer was extracted with DCM (70 mL) and filtered under reduced pressure. The filtrate was concentrated under vacuum. The crude product was purified by grinding with diethyl ether (2 × 20 mL), followed by vacuum concentration to give the title compound as a grayish-white solid. Y = 74%. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 6.93 (d, J = 1Hz, 1H), 2.58 (s, 3H), 2.28 (s, 3H).

Step 2: Ethyl 2-{[(2,4-dimethylthiophen-3-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propionate. Diphenylphosphoazide (0.38 g, 1.41 mmol) was added to a solution of 2,4-dimethylthiophen-3-carboxylic acid (0.2 g, 1.28 mmol) in toluene (10 mL) under _a nitrogen atmosphere at 0 °C, followed by the addition of N,N-diisopropylethylamine (0.20 g, 1.53 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was cooled to 0 °C and ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (0.20 g, 1.28 mmol) was added to toluene (5 mL) (see Example 49 for synthesis). 1-(isocyanomethyl)-2-methylbenzene (0.94 g, 5.12 mmol) was added at 0 °C, and RM was heated at 120 °C for 5 h, then cooled to room temperature. RM was concentrated under vacuum, ground with diethyl ether (2 × 20 ml), and the resulting solid was filtered. Further purification by preparative HPLC yielded the title compound as a yellow solid. Y＝9%.MS ES ⁺ :338.1. ¹ H NMR (400MHz, DMSO-d ₆ )δ8.98(s,1H),7.78(d,J＝2Hz,1H),7.47(s,1H),6.86(s,1H),6.28(s,1H),5.32–5.24(m,1 H), 4.62 (d, J = 6Hz, 2H), 4.11 (t, J = 7Hz, 2H), 2.12 (s, 3H), 1.96 (s, 3H), 1.15 (t, J = 7Hz, 3H).

Example 95. Ethyl 2-[({4,10-dioxatricyclo[ ^7.3.0.03,7 ]dodecane-1(9),2,7-trien-2-yl}-carbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate

Step 1: 4,10-Dioxatricyclo[7.3.0.0 ^3,7 ]dodecane-1(9),2,7-triene-2-carboxaldehyde. Add stannous chloride (IV) (1.11 g, 4.27 mmol) to a stirred solution of 4,10-dioxatricyclo[7.3.0.0 ^3,7 ]dodecane-1,3(7),8-triene (0.55 g, 3.39 mmol) in anhydrous DCM (11.5 ml), and stir for 5 minutes with RM. Add dichloromethyl methyl ether (0.39 g, 3.39 mmol) in DCM (0.6 ml) at 0 °C under a _N2 atmosphere. Stir with RM at 0 °C for 15 minutes, then pour into water (25 ml). Extract the aqueous layer with DCM (2 × 30 ml) and wash the combined organic phases with 3M HCl (15 ml). Dry the organic phases over _{anhydrous Na2SO4} , filter, and evaporate under reduced pressure. The crude product was purified by FCC (0.5% ethyl acetate/hexane) to give the title compound as a yellow solid. Y = 49%. ^¹H NMR (400 MHz, chloroform-d) δ 10.31 (s, 1H), 6.89 (s, 1H), 4.70 (t, J = 9 Hz, 2H), 4.61 (t, J = 9 Hz, 2H), 3.50–3.45 (m, 2H), 3.22–3.17 (m, 2H).

Step 2: 4,10-Dioxatricyclo[ ^7.3.0.03,7 ]dodecane-1(9),2,7-trien-2-carboxylic acid. At 0 °C, sulfamic acid (0.245 g, 2.52 mmol) was added to a stirred solution of 4,10-dioxatricyclo[7.3.0.03,7]dodecane-1(9),2,7-trien-2-carboxaldehyde (0.32 g, 1.68 mmol) in acetone (3 ml). A solution of sodium chlorite (0.196 g, 2.17 mmol) in water (0.5 ml) was added dropwise, and the RM was stirred at 0 °C for 30 minutes. The RM was poured into cold water (20 ml) and extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under reduced pressure. The crude product was ground together with pentane (3 × 30 ml), filtered, and dried under vacuum to give the title compound as a brown solid. Y = 77%. MS ES ⁺ : 207.0.

Step 3: Ethyl 2-[({4,10-dioxatricyclo[ ^7.3.0.03,7 ]dodecane-1(9),2,7-trien-2-yl}carbamoyl)oxy]-3-(1H-pyrazol-1-yl)propionate. Triethylamine (0.50 ml, 4.07 mmol) and ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propionate (0.250 g, 1.35 mmol) were added to a stirred solution of 4,10-dioxatricyclo[7.3.0.03,7]dodecane-1(9),2,7-trien-2-carboxylic acid (0.280 g, 1.35 mmol) in toluene (5 ml) (see Example 49 for synthesis). After stirring for 5 minutes, diphenylphosphoazide (1.11 g, 4.07 mmol) was added, and RM was heated in a microwave reactor at 100 °C. The reaction mixture was cooled to room temperature, poured into cold water (25 ml), and extracted with ethyl acetate (3 × 30 ml). The combined organic layers were dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The crude product was purified by FCC (50% ethyl acetate/hexane) and further purified by preparative HPLC to give the title compound as a grayish-white solid. Y = 2%. MS ES ⁺ : 388.2. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 7.88–7.82 (m, 1H), 7.45 (s, 1H), 7.26 (s, 1H), 7.14–7.13 (m, 1H), 6.27 (s, 1H), 5.21 (s, 1H), 4.58 (s, 2H), 4.48–4.41 (m, 2H), 4.11–4.09 (m, 2H), 3.14–3.06 (m, 2H), 2.95–2.86 (m, 2H), 1.23–1.15 (m, 3H). 2H peaks were masked by solvent.

Example 96. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(2-methoxyethoxy)propionate

Step 1: Ethyl (2R)-2-hydroxy-3-(2-methoxyethoxy)propionate. Add 2-methoxyethanol (475 μl, 6.0 mmol) and magnesium trifluoromethanesulfonate (444 mg, 1.38 mmol) to a solution of ethyl (2R)-ethylene oxide-2-carboxylate (100 mg, 0.86 mmol) (synthesis see Example 5AY) in EtOAc (1 ml). Stir the mixture at 60 °C for 12 h. Purify the residue by FCC (9-25% EtOAc/gasoline) to give the title compound as a colorless oil. Y = 42%. ^1H NMR (400MHz, chloroform-d) δ 4.32 (t, J = 4Hz, 1H), 4.27 (t, J = 7Hz, 2H), 3.82 (d, J = 4Hz, 2H), 3.73–3.66 (m, 2H), 3.58–3.51 (m, 2H), 3.38 (s, 3H), 1.31 (t, J = 7Hz, 3H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(2-methoxyethoxy)propionate. The title compound was prepared using ethyl (2R)-2-hydroxy-3-(2-methoxyethoxy)propionate and intermediate A as starting materials, according to general procedure B. The crude mixture was purified by preparative TLC (33% EtOAc/hexane) to give the title compound as a white solid. Y = 17%. MS ES ⁺ : 392.1. ¹ H NMR (400MHz, chloroform-d) δ 7.01 (s, 1H), 6.50–6.42 (br.s, 1H), 5.28 (s, 1H), 4.34–4.20 (m, 2H), 4.06–3.89 (m, 2H), 3.78–3.51 (m, 4H), 3.38 (s, 3H), 2.95–2.81 (m, 8H), 2.08 (m, 4H), 1.31 (t, J = 7Hz, 3H).

Example 97. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(oxacyclohexane-4-yloxy)propionate

Step 1: Ethyl (2R)-2-hydroxy-3-(oxacyclohexane-4-yloxy)propionate. Tetrahydropyran-4-ol (155 μl, 1.55 mmol) and magnesium trifluoromethanesulfonate (666 mg, 2.07 mmol) were added to a solution of ethyl (2R)-ethylene oxide-2-carboxylate (150 mg, 1.29 mmol) in EtOAc (1 ml). The mixture was stirred at 60 °C for 36 hours. The residue was purified by FCC (5-10% EtOAc/gasoline) to give the title compound as a colorless oil. Y = 14%. ^1H NMR (400MHz, chloroform-d) δ 4.34-4.18 (m, 3H), 3.96-3.83 (m, 2H), 3.81-3.71 (m, 2H), 3.59-3.49 (m, 1H), 3.48-3.37 (m, 2H), 3.05 (d, J = 7Hz, 1H), 1.93-1.81 (m, 2H), 1.62-1.52 (m, 2H), 1.30 (t, J = 7Hz, 3H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(oxecyclohexane-4-yloxy)propionate. The title compound was prepared using ethyl (2R)-2-hydroxy-3-(oxecyclohexane-4-yloxy)propionate and intermediate A as starting materials, according to general procedure B. The crude mixture was purified by preparative TLC (50% EtOAc/hexane) to give the title compound as a white solid. Y = 10%. MS ES ⁺ : 418.3. ¹ H NMR (400MHz, chloroform-d) δ 7.01 (s, 1H), 6.50–6.46 (br.s, 1H), 5.28 (s, 1H), 4.32–4.20 (m, 2H), 4.02–3.83 (m, 4H), 3.65–3.33 (m, 3H), 2.93–2.80 (m, 8H), 2.13–2.02 (m, 4H), 1.93–1.75 (m, 2H), 1.70–1.50 (m, 2H), 1.31 (t, J = 7Hz, 3H).

Example 98. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H-1,2,4-triazol-1-yl)propionate and ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(3-methyl-1H-1,2,4-triazol-1-yl)propionate

Step 1: Ethyl (2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)propionate and ethyl (2R)-2-hydroxy-3-(5-methyl-1H-1,2,4-triazol-1-yl)propionate. Add 5-methyl-1H-1,2,4-triazole (2.68 g, 32.3 mmol) and DIPEA (5.40 ml, 31.00 mmol) to a solution of ethyl (2R)-ethylene oxide-2-carboxylate (1.50 g, 12.9 mmol) (synthesis see Example 5AY) in EtOH (15 ml). Stir the mixture at room temperature for 3 hours, then concentrate. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10um; liquid phase: [A-TFA/H ₂ O＝0.075％v/v; B-ACN] B％:1％-20％, 20min) to obtain ethyl (2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)propionate as yellow oil (12% yield) and ethyl (2R)-2-hydroxy-3-(5-methyl-1H-1,2,4-triazol-1-yl)propionate as yellow oil (10% yield). Ethyl (2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)propionate analysis: ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.57 (s, 1H), 5.70–5.30 (br.s, 1H), 4.43–4.31 (m, 3H), 4.13 (q, J＝7Hz, 2H), 2.27 (s, 3H), 1.19 (t, J＝7Hz, 3H). Ethyl (2R)-2-hydroxy-3-(5-methyl-1H-1,2,4-triazol-1-yl)propionate analysis: ^¹H NMR (400MHz, DMSO- _d⁶) )δ8.11(s,1H),6.45–6.10(br.s,1H),4.45-4.31(m,3H),4.11(q,J＝7Hz,2H),2.46(s,3H),1.19(t,J＝7Hz,3H).

Step 2a: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(3-methyl-1H-1,2,4-triazol-1-yl)propionate. The title compound was prepared using ethyl (2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)propionate and intermediate A as starting materials, according to general procedure B. The crude mixture was purified by FCC (0-17% EtOAc/hexane) and then by preparative HPLC (column: Agela Durashell C18 150*25, 5μm; liquid phase: [A- _{10mM NH4HCO3/H2O ; B} -ACN] B%: 39%-69%, 10min) to obtain the title compound as a white solid. Y＝1%.MS ES ⁺ : ^399.2.1H NMR (400MHz, chloroform-d) δ8.26(s,1H),7.03(s,1H),6.47(s,1H),5.46(s,1H),4.65(s,2H),4.28(q,J＝7 Hz,2H),2.93–2.85(m,4H),2.83–2.74(m,4H),2.43(s,3H),2.11-2.04(m,4H),1.32(t,J＝7Hz,3H).

Step 2b: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H-1,2,4-triazol-1-yl)propionate. Following general procedure B, the title compound was prepared using ethyl (2R)-2-hydroxy-3-(5-methyl-1H-1,2,4-triazol-1-yl)propionate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (9% MeOH/DCM) to give the title compound as a pale yellow solid. Y＝1%.MS ES ⁺ : ^399.2.1 HNMR (400MHz, chloroform-d) δ7.73(s,1H),6.95(s,1H),6.33(s,1H),5.41(s,1H),4.53(s,2H),4.19-4.12(m ,2H),2.86–2.75(m,4H),2.73-2.63(br.s,4H),2.02-1.95(m,4H),1.51(s,3H),1.25(t,J＝7Hz,3H).

Example 99. Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(prop-2-yloxy)propionate

Step 1: Ethyl (2R)-2-hydroxy-3-(prop-2-yloxy)propionate. Propanol (462 μl, 6.03 mmol) and magnesium trifluoromethanesulfonate (444 mg, 1.38 mmol) were added to a solution of ethyl (2R)-ethylene oxide-2-carboxylate (100 mg, 0.86 mmol) (synthesis see Example 5AY) in EtOAc (1 ml). The mixture was stirred at 60 °C for 24 hours. The residue was purified by FCC (5-17% EtOAc/gasoline) to give the title compound as a colorless oil. Y = 69%. ^1H NMR (400MHz, chloroform-d) δ 4.35-4.16 (m, 3H), 3.77-3.65 (m, 2H), 3.61-3.57 (m, 1H), 1.29 (t, J = 7Hz, 3H), 1.18-1.06 (m, 6H).

Step 2: Ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(prop-2-yloxy)propionate. The title compound was prepared using ethyl (2R)-2-hydroxy-3-(prop-2-yloxy)propionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by preparative TLC (25% EtOAc/gasoline) to give the title compound as a white solid. Y＝10%.MS ES ⁺ : ^376.3.1H NMR (400MHz, chloroform-d) δ7.00(s,1H),6.50–6.42(br.s,1H),5.26(s,1H),4.34-4.16(m,2H),3.87(s,2 H),3.65(s,1H),2.91-2.81(m,8H),2.12-2.01(m,4H),1.31(t,J＝7Hz,3H),1.21–1.12(br.s,6H).

Example 100. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid

Step 1: 2-Hydroxy-3-(pyrimidin-2-yl)propionic acid. LiOH·H₂O (7.31 g, 174 mmol) was added in a single addition to a mixture of ethyl _2- hydroxy-3-(pyrimidin-2-yl)propionic acid (26.0 g, 133 mmol) (synthesis see Example 5BP) in THF (180 ml) and _H₂O (180 ml) at 10–20 °C. The mixture was stirred at 10–20 °C for 16 hours. The mixture was concentrated under vacuum to remove THF, yielding an aqueous solution. This solution was washed with EtOAc (3 × 40 ml). The aqueous phase was acidified to pH ~3 with 1 M HCl and then concentrated under vacuum to give the title compound as a yellow solid. Y = quantitative. ^¹H NMR (400MHz, DMSO- _d⁶ ) δ 8.70 (d, J = 6Hz, 2H), 7.32 (t, J = 5Hz, 1H), 4.44–4.35 (m, 1H), 3.31 (dd, J = 14, 4Hz, 1H), 2.90 (dd, J = 14, 10Hz, 1H). No exchangeable protons were observed.

Step 2: Benzyl 2-hydroxy-3-(pyrimidin-2-yl)propionate. H₂SO₄ (317 μl, 5.9 mmol) was added in a single batch to a mixture of 2 _- hydroxy- _3- (pyrimidin-2-yl)propionic acid (10.0 g, 59 mmol) and benzyl alcohol (70 mL) at a temperature between 10 and 20 °C. The mixture was heated to 45 °C and stirred for 16 h. The mixture was concentrated and purified by FCC (0-60% ethyl acetate/petroleum ether) to give the title compound as a white solid. Y = 19%. ^¹H NMR (400 MHz, chloroform-d) δ 8.62 (d, J = 5 Hz, 2H), 7.36–7.28 (m, 4H), 7.15 (t, J = 5 Hz, 1H), 5.20 (s, 2H), 4.83–4.76 (m, 1H), 4.42 (s, 1H), 3.58–3.51 (m, 1H), 3.50–3.43 (m, 1H).

Step 3: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)benzyl propionate. The title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)benzyl propionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by FCC (0-60% EtOAc/gasoline) to give the title compound as a white solid. Y=27%.MS ES ⁺ : ^458.1.1H NMR (400MHz, chloroform-d) δ8.64(d,J＝4Hz,2H),7.34(s,4H),7.15(t,J＝5Hz,1H),6.98(s,1H),6.25(s,1H),5.85(t ,J＝6Hz,1H),5.30–5.17(m,2H),3.63–3.55(m,2H),2.90–2.81(m,4H),2.75–2.65(m,4H),2.11–1.93(m,4H).

Step 4: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid. Under _N2 , add 10% Pd/C (1.73 mmol) to a solution of benzyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid benzyl ester (790 mg, 1.73 mmol) in MeOH (20 mL). Stir the mixture at 15 °C for 2 h under _H2 (15 psi). Filter the mixture through a Celite filter and concentrate under vacuum to obtain the residue. The residue was purified by reversed-phase chromatography (column: Waters Xbridge 150*25, 5μm; mobile phase: [water (10mM _NH₄HCO₃ ) _-ACN ]; B%: 14%-44%, 12min) to give the racemic product. This was then separated by chiral SFC (column: Daicel Chiralpak IC (250mm*30mm, 5μm); mobile phase: [0.1% _NH₃ · _H₂O /EtOH]; B%: 45%, 6min) to give the title compound as a white solid. The desired (R)-enantiomer is peak 1. Y = 15%. MS ES ⁺ : 368.1. ¹ H NMR (400MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.75 (d, J = 5Hz, 2H), 7.38 (t, J = 5Hz, 1H), 6.89 (s, 1H), 5.52–5.45 (m, 1H), 3.58–3.38 (m, 2H), 2.82–2.72 (m, 4H), 2.69–2.53 (m, 4H), 1.97–1.85 (m, 4H). No CO ₂ H observed.

Example 101. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: Propyl-2-yl 2-hydroxy-3-(pyrimidin-2-yl)propionic acid. H₂SO₄ (317 μl, 5.95 mmol) was added in a single addition to a mixture of 2 _- hydroxy- _3- (pyrimidin-2-yl)propionic acid (10.0 g, 59.5 mmol) (synthesis see Example 5CC) in isopropanol (70 mL) at 10–20 °C. RM was heated at 45 °C for 16 h. RM was alkalized to pH ~8 with an aqueous solution _{of NaHCO₃} , and then concentrated under vacuum. The resulting aqueous/suspension was extracted with EtOAc (3 × 50 mL). The combined organic phases were concentrated under vacuum to give the residue. The residue was purified by FCC (0–50% EtOAc/petroleum ether) to give the title compound as a white solid. Y=23% ^.1H NMR(400MHz, chloroform-d)8.68(d,J＝5Hz,2H),7.20(t,J＝5Hz,1H),5.14–5.03(m,1H),4.71(br.s,1H), 4.27(br.s,1H),3.55–3.48(m,1H),3.46–3.38(m,1H),1.25(d,J＝6Hz,3H),1.19(d,J＝6Hz,3H).

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester. The title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester and intermediate A as starting materials according to general procedure B. The crude mixture was purified by FCC (0-60% EtOAc/gasoline) to give a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AY-H (250mm*30mm, 5μm); mobile phase: EtOH; B%: 45%, 8min) to give the title compound as a white solid. The desired (R)-enantiomer is peak 1. Y=8%.MS ES ⁺ : ^410.2.1H NMR(400MHz, chloroform-d)8.70(s,2H),7.19(s,1H),6.98(s,1H),6.26(br.s,1H),5.78–5.70(m,1H),5.18-5.06(m,1H), 3.56(br.s,2H),2.91–2.81(m,4H),2.80–2.70(m,4H),2.10–1.98(m,4H),1.27(d,J＝6Hz,3H),1.24(d,J＝6Hz,3H).

Example 102. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)cyclopentyl propionate

Step 1: Cyclopentyl 2-hydroxy-3-(pyrimidin-2-yl)propionate. H₂SO₄ (317 μl, 5.95 mmol) was added in a single addition to a mixture of 2 _- hydroxy- _3- (pyrimidin-2-yl)propionate (10.0 g, 59.5 mmol) (synthesis see Example 5CC) in cyclopentanol (70 mL) at 10–20 °C. RM was heated at 45 °C for 16 h. RM was alkalized to pH ~8 with an aqueous solution _{of NaHCO₃} , and then concentrated under vacuum. The resulting aqueous/suspension was extracted with EtOAc (3 × 50 mL). The combined organic phases were concentrated under vacuum to give the residue. The residue was purified by FCC (0–60% EtOAc/petroleum ether) to give the title compound as a white solid. Y = 15%. ^¹H NMR (400 MHz, chloroform-d) 8.67 (d, J = 5 Hz, 2H), 7.19 (t, J = 5 Hz, 1H), 5.26–5.19 (m, 1H), 4.72–4.66 (m, 1H), 4.41–4.11 (m, 1H), 3.53–3.44 (m, 1H), 3.43–3.35 (m, 1H), 1.89–1.73 (m, 2H), 1.73–1.46 (m, 6H).

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2-yl)cyclopentyl propionate. The title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)cyclopentyl propionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by FCC (0-60% EtOAc/gasoline) to give a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AY-H (250mm*30mm, 5μm); mobile phase: IPA; B%: 45%, 20min) to give the title compound as a white solid. The desired (R)-enantiomer is peak 1. Y＝5%.MS ES ⁺ :436.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.07(br.s,1H),8.77(d,J＝4Hz,2H),7.41(t,J＝5Hz,1H),6.91(s,1H),5.54–5.44(m,1H),5.15–5.10(m,1H ),3.40(br.s,2H),2.82–2.72(m,4H),2.62(br.s,4H),1.93(br.s,4H),1.85-1.69(m,2H),1.66–1.44(m,6H).

Example 103. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionic acid

Step 1: 2-Hydroxy-3-(pyrazin-2-yl)propionic acid. Add 2M NaOH (18.3 ml, 36.6 mmol) to a solution of ethyl 2-hydroxy-3-(pyrazin-2-yl)propionic acid (6.00 g, 30.5 mmol) (synthesis see Example 5BQ) in EtOH (42 ml), and stir the mixture at room temperature for 1 hour. Concentrate the reaction mixture under vacuum to obtain an aqueous solution. Wash the solution with ethyl acetate (2 × 20 ml), adjust the pH of the aqueous phase to ~2, and concentrate under vacuum to give the title compound as a brown solid, which is used directly without purification. Y = quantitative. ^1H NMR (400MHz, _D₂O ) δ 8.54–8.53 (m, 2H), 8.47 (d, J = 2Hz, 1H), 4.50–4.44 (m, 1H), 3.33–3.26 (m, 1H), 3.17–3.09 (m, 1H). No exchangeable protons were observed.

Step 2: Benzyl 2-hydroxy-3-(pyrazin-2-yl)propionate. H₂SO₄ (317 μl, 5.9 mmol) was added in a single batch to a mixture of 2 _- hydroxy- _3- (pyrazin-2-yl)propionic acid (10.0 g, 59 mmol) and benzyl alcohol (70 mL) at a temperature between 10 and 20 °C. The mixture was heated to 45 °C and stirred for 16 hours. The mixture was concentrated and purified by FCC (0-60% ethyl acetate/petroleum ether) to give the title compound as a white solid.

Step 3: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)benzyl propionate. The title compound was prepared using 2-hydroxy-3-(pyrazin-2-yl)benzyl propionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by FCC (0-50% EtOAc/gasoline) to give the title compound as a white solid. Y = 22%. MS ES ⁺ : 458.1. ¹ H NMR (400MHz, chloroform-d) δ 8.50–8.42 (m, 3H), 7.35 (s, 5H), 7.00 (s, 1H), 5.62 (br.s, 1H), 5.29–5.16 (m, 2H), 3.42 (br.s, 2H), 2.90–2.84 (m, 4H), 2.75–2.65 (m, 3H), 2.09–2.00 (m, 4H). NH4+ not observed.

Step 4: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionic acid. Add 10% Pd/C (0.87 mmol) to a solution of benzyl 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionic acid (400 mg, 0.87 mmol) in MeOH (8 mL) under _N2 atmosphere. Stir the mixture at room temperature under _H2 atmosphere for 25 min. Filter the mixture through Celite and concentrate under vacuum to give the racemic product. The title compound was obtained as a white solid by chiral SFC (column: Daicel Chiralpak IC (250 mm * 30 mm, 5 μm); mobile phase: [0.1% _NH3 · _H2O /EtOH]; B%: 35%, 8 min). The desired (R)-enantiomer is peak 2. Y = 45%. MS ES ⁺ : 368.1. ^1H NMR (400 MHz, DMSO- _d6 ) δ 8.88 (br. s, 1H), 8.65–8.50 (m, 3H), 6.89 (s, 1H), 5.27–5.19 (m, 1H), 3.34–3.21 (m, 2H), 2.81–2.73 (m, 4H), 2.65–2.52 (m, 4H), 1.97–1.82 (m, 4H).

Example 104. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionate prop-2-ester

Step 1: Propyl-2-yl 2-hydroxy-3-(pyrazin-2-yl)propionate. 4-(dimethylamino)pyridine (290 mg, 2.38 mmol) was added to a solution of 2-hydroxy-3-(pyrazin-2-yl)propionate (4.00 g, 23.8 mmol, 1.0 equivalent) in isopropanol (28 mL), followed by dropwise addition of oxaloyl chloride (2.29 mL, 26.2 mmol). The mixture was stirred at room temperature for 12 h, then concentrated under reduced pressure. The residue was purified by FCC (0 to 15% EtOAc/petroleum ether) to give the title compound as a brown oil. Y = 24%. ^¹H NMR (400 MHz, chloroform-d) δ 8.53–8.49 (m, 2H), 8.46 (d, J = 2 Hz, 1H), 5.14–5.02 (m, 1H), 4.64–4.58 (m, 1H), 3.38–3.28 (m, 1H), 3.22–3.16 (m, 1H), 1.27–1.20 (m, 6H).

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propionic acid prop-2-yl ester. The title compound was prepared using 2-hydroxy-3-(pyrazin-2-yl)propionic acid prop-2-yl ester and intermediate A as starting materials according to general procedure B. The crude mixture was purified by FCC (0-50% EtOAc/gasoline) to give a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AD-H (250mm*30mm, 5μm); mobile phase: EtOH; B%: 30%, 6min) to give the title compound as a white solid. The desired (R)-enantiomer is peak 1. Y＝31%.MS ES ⁺ :410.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.12(br.s,1H),8.72–8.51(m,3H),6.92(s,1H),5.34–5.26(m,1H),4.98–4.85(m,1H),3.33–3.30(m ,2H),2.82–2.74(m,4H),2.69–2.56(m,4H),1.98–1.88(m,4H),1.16(d,J＝6Hz,3H),1.12(d,J＝6Hz,3H).

Example 105. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)cyclopentyl propionate

Step 1: Cyclopentyl 2-hydroxy-3-(pyrazin-2-yl)propionate. DMAP (290 mg, 2.38 mmol) was added to a solution of 2-hydroxy-3-(pyrazin-2-yl)propionate (4.00 g, 23.7 mmol) (synthesis see Example 5CF) in cyclopentanol (28 mL), followed by dropwise addition of oxaloyl chloride (2.29 mL, 26.1 mmol). The mixture was stirred at room temperature for 12 h, then concentrated under reduced pressure. The residue was purified by FCC (0 to 15% EtOAc/petroleum ether) to give the title compound as a brown oil. Y = 28%. ^¹H NMR (400 MHz, chloroform-d) δ 8.52–8.50 (m, 2H), 8.47 (d, J = 2 Hz, 1H), 5.30–5.23 (m, 1H), 4.64–4.59 (m, 1H), 3.39–3.26 (m, 1H), 3.24–3.15 (m, 1H), 1.90–1.55 (m, 8H).

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)cyclopentyl propionate. The title compound was prepared using 2-hydroxy-3-(pyrazin-2-yl)cyclopentyl propionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by FCC (0-50% EtOAc/gasoline) to give a racemic mixture of the product as a white solid. The enantiomers were separated by chiral SFC (column: Daicel Chiralpak AD-H (250mm*30mm, 5μm); mobile phase: [0.1% _NH3 · _H2O /MeOH]; B%: 26%, 20min) to give the title compound as a white solid. The desired (R)-enantiomer is peak 2. Y＝35%.MS ES ⁺ :436.2. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.14–9.06(br.s,1H),8.73–8.66(br.s,1H),8.59(s,1H),8.54(s,1H),6.92(s,1H),5.34–5.26(m,1H),5.14–5.05(m ,1H),3.40–3.28(m,2H),2.82–2.76(m,4H),2.66–2.59(m,4H),2.00–1.88(m,4H),1.86–1.71(m,2H),1.58–1.51(m,6H).

Example 108. (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid propyl-2-yl ester

Step 1: (2R)-Ethylene oxide-2-propane-2-yl ester. In a mixture of potassium (2R)-ethylene oxide-2-carboxylate (30.0 g, 237 mmol) (synthesis see Example 5AJ) in a DCM (150 ml), benzyltriethylammonium chloride (54.2 g, 238 mmol) and 2-bromopropane (117 g, 951 mmol) were added in a single step at room temperature under _N2 . The mixture was stirred at 45 °C for 16 h. The RM was cooled, poured into _H2O (500 ml), and stirred for 5 min. The aqueous phase was extracted with dichloromethane (100 ml). The organic phase was washed with brine (200 ml), dried over _{anhydrous Na2SO4} , filtered, and concentrated under vacuum. The residue was purified by FCC (0 to 50% EtOAc/gasoline) to give the title compound as a yellow oil. ^1H NMR (400MHz, chloroform-d) δ 5.16–5.04 (m, 1H), 3.39–3.37 (m, 1H), 2.96–2.89 (m, 2H), 1.30–1.24 (m, 6H).

Step 2: (2R)-3-(4-cyano-1H-pyrazole-1-yl)-2-hydroxypropanoate prop-2-yl ester. In a microwave tube, (2R)-ethylene oxide-2-carboxylic acid prop-2-yl ester (2.00 g, 15.4 mmol) and 4-cyanopyrazole (3.58 g, 38.4 mmol) were dissolved in isopropanol (10 ml). RM was heated in a microwave reactor at 100 °C for 3 hours. RM was concentrated under vacuum and then purified by preparative HPLC: (column: Agela Innoval ODS-2 100 mm * 350 mm; mobile phase: [water (0.1% TFA)-ACN]; B%: 5%-25%, 20 min) to obtain the title compound as a yellow oil. MS ES ⁺ : 224.2. ¹ H NMR (400MHz, chloroform-d) δ 7.94 (s, 1H), 7.78 (s, 1H), 5.13–5.06 (m, 1H), 4.51–4.48 (m, 2H), 3.72 (s, 1H), 1.32–1.26 (m, 6H).

Step 3: Propyl-2-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid ester. The title compound was prepared using (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropionic acid ester and intermediate A as starting materials, according to general procedure A. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 50%-80%, 20min) to obtain the title compound as a white solid. Y＝26%.MS ES ⁺ :423.3. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.16(s,1H),8.61(s,1H),8.10(s,1H),6.95(s,1H),5.29(s,1H),4.98–4.88(m,2H),4 .70(s,2H),2.85–2.77(m,4H),2.74–2.60(m,4H),1.99–1.92(m,4H),1.23–1.16(m,6H).

Example 109. (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}cyclopentyl propionate

Step 1: (2R)-Ethylene oxide-2-carboxylate cyclopentyl ester. Benzyltriethylammonium chloride (90.3 g, 396 mmol) was added in a single batch at room temperature under _N₂ to a mixture of potassium (50.0 g, 396 mmol) of (2R)-ethylene oxide-2-carboxylate (see Example 5AJ for synthesis) and cyclopropyl bromide (236 g, 1.59 mol) in dichloromethane (250 ml). The mixture was stirred at 45 °C for 16 h. The mixture was cooled, poured into water (1500 ml), and stirred for 5 min. The aqueous phase was extracted with dichloromethane (200 ml). The organic phase was washed with brine (200 ml), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The residue was purified by FCC (0 to 50% EtOAc/gasoline) to give the title compound as a yellow oil. Y = 22%. ^1H NMR (400MHz, chloroform-d) δ 5.29–5.22 (m, 1H), 3.40–3.34 (m, 1H), 2.95–2.85 (m, 2H), 1.89–1.58 (m, 8H).

Step 2: (2R)-3-(4-cyano-1H-pyrazole-1-yl)-2-hydroxypropanoate cyclopentyl ester. In a microwave tube, (2R)-ethylene oxide-2-carboxylic acid cyclopentyl ester (1.50 g, 9.60 mmol) and 4-cyanopyrazole (2.24 g, 24.0 mmol) were dissolved in cyclopentanol (10 ml). The RM was heated in a microwave reactor at 100 °C for 2 hours. The mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC (column: Agela Innoval ODS-2250*80 mm; mobile phase: [water (0.1% TFA)-ACN]; B%: 12%-42%, 30 min) to give the title compound as a yellow oil. MS ES ⁺ : 250.2. ¹ H NMR (400MHz, chloroform-d) δ 7.93 (s, 1H), 7.79 (s, 1H), 5.30–5.24 (m, 1H), 4.51–4.48 (m, 2H), 3.79–3.73 (m, 1H), 1.95–1.55 (m, 8H).

Step 3: (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}cyclopentyl propionate. The title compound was prepared using (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxycyclopentyl propionate and intermediate A as starting materials, according to general procedure A. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 50%-80%, 20min) to obtain the title compound as a white solid. Y＝5%.MS ES ⁺ :449.4. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.17(s,1H),8.62(s,1H),8.10(s,1H),6.95(s,1H),5.29(s,1H),5.13–5.08(m,2H),4.7 3–4.67(m,2H),2.90–2.77(m,4H),2.73–2.62(m,4H),1.99–1.94(m,4H),1.77–1.54(m,8H).

Example 110. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionic acid and (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionic acid prop-2-yl ester

Step 1: (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionic acid propionate. In a microwave tube, (2R)-ethylene oxide-2-carboxylic acid propionate (2.00 g, 15.4 mmol) (synthesis see Example 5CI) and 1H-1,2,4-triazole (2.65 g, 38.4 mmol) were dissolved in isopropanol (10 ml). The RM was heated in a microwave reactor at 100 °C for 3 hours. The mixture was concentrated under vacuum, and the residue was purified by preparative HPLC (column: Agela Innoval ODS-2250*80 mm; mobile phase: [water (0.1% TFA)-ACN]; B%: 0%-21%, 30 min) to give the title compound as a yellow oil. MS ES ⁺ : 200.1. ¹ H NMR (400MHz, chloroform-d) δ 8.58 (s, 1H), 8.04 (s, 1H), 5.10–5.05 (m, 1H), 4.62–4.51 (m, 3H), 1.29–1.23 (m, 6H).

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionate prop-2-yl ester. Following general procedure A, the title compound was prepared using (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propionate prop-2-yl ester and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 45%-75%, 20 min) to obtain the title compound as a white solid. Y＝25%.MS ES ⁺ :399.3. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.19(s,1H),8.60(s,1H),8.02(s,1H),6.95(s,1H),5.32–5.24(m,1H),4.99–4.90(m,1H),4 .72–4.66(m,2H),2.85–2.80(m,4H),2.70–2.61(m,4H),2.00–1.90(m,4H),1.24–1.17(m,6H).

Step 3: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionic acid. Add 4M HCl (5 ml) in a single step to a mixture of (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)propionic acid propionate (400 mg, 1.00 mmol) in 1,4-dioxane (5 ml). Stir the mixture at room temperature for 48 hours. The RM was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 200*40mm*10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 20%-55%, 10min) to give the title compound as a white solid. Y＝28%.MS ES ⁺ :357.0. ¹ H NMR (400MHz, DMSO-d ₆ )δ13.46–13.28(br.s,1H),9.11(s,1H),8.56(s,1H),7.99(s,1H),6.94(s,1H),5.26 (s,1H),4.74–4.66(m,2H),2.90–2.84(m,4H),2.82–2.78(m,4H),1.98–1.92(m,4H).

Example 111. (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)cyclopentyl propionate

Step 1: (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)cyclopentyl propionate. In a microwave tube, (2R)-ethylene oxide-2-carboxylic acid cyclopentyl ester (1.00 g, 6.40 mmol) (synthesis see Example 5CJ) and 1H-1,2,4-triazole (1.11 g, 16.0 mmol) were dissolved in cyclopentanol (7 ml). RM was heated in a microwave reactor at 100 °C for 3 hours. RM was concentrated under reduced pressure to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 10%-40%, 20 min) to obtain the title compound as a colorless oil. Y = 46%. ^1H NMR (400MHz, methanol- _d4 ) δ 8.68 (s, 1H), 8.13 (s, 1H), 5.25–5.21 (m, 1H), 4.62–4.49 (m, 3H), 1.89–1.61 (m, 8H).

Step 2: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol-1-yl)cyclopentyl propionate. The title compound was prepared using (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)cyclopentyl propionate and intermediate A as starting materials according to general procedure A. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250*50mm*10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 50%-80%, 20min) to obtain the title compound as a white solid. Y=5%.MS ES ⁺ :425.1. ¹ H NMR (400MHz, methanol- _{d 4} )δ8.62(s,1H),8.05(s,1H),6.96(s,1H),5.36(s,1H),5.25–5.20(m,1H),4.83–4.75 (m,2H),2.90–2.82(m,4H),2.80–2.71(m,4H),2.06–2.00(m,4H),1.87–1.61(m,8H).

Example 112. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(6-methylpyrazin-2-yl)propionic acid prop-2-yl ester

Step 1: Propyl-2-yl 2-hydroxy-3-(6-methylpyrazine-2-yl)propionate. Under _N2 , 2,6-dimethylpyrazine (1.0 g, 9.25 mmol) and iron diacetoxy (80 mg, 462 μmol) were added to a solution of isopropyl 2-oxoacetate (1.13 g, 9.71 mmol) in dioxane (8 mL). The reaction mixture was heated at 120 °C for 42 h. The reaction mixture was concentrated under vacuum, and the resulting residue was purified by FCC (0-10% MeOH/DCM) to give the title compound as a brown oil. Y = 9%. ^1H NMR (400MHz, chloroform-d) δ 8.34 (s, 1H), 8.31 (s, 1H), 5.18–4.99 (m, 1H), 4.67–4.52 (m, 1H), 3.82 (d, J = 6Hz, 1H), 3.33–3.23 (m, 1H), 3.20–3.11 (m, 1H), 2.54 (s, 3H), 1.27–1.24 (m, 6H).

Step 2: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(6-methylpyrazin-2-yl)propionate prop-2-yl ester. The title compound was prepared using 2-hydroxy-3-(6-methylpyrazin-2-yl)propionate prop-2-yl ester and intermediate A as starting materials according to general procedure B. The crude mixture was purified by preparative TLC (50% EtOAc/gasoline) to give the title compound as a white solid. Y＝14%.MS ES ⁺ : ^424.4.1H NMR (400MHz, chloroform-d) δ8.38–8.30(br.s,2H),7.00(s,1H),6.29–6.19(br.s,1H),5.53–5.45(m,1H),5.15-5.06(m,1H), 3.39–3.29(m,2H),2.87(t,J＝7Hz,4H),2.80–2.70(t,J＝7Hz,4H),2.55(s,3H),2.10–1.99(m,4H),1.29-1.25(m,6H).

Example 113. 2-{[(3-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: 1-Isocyano-3-methylcyclohexane. Add 3-methylcyclohexylamine (250 mg, 2.21 mmol) and triethylamine (655 μl, 4.64 mmol) to a solution of triphosgene (655 mg, 2.21 mmol) in DCM (3 mL). Stir the mixture at room temperature for 1 h, then concentrate to give the title compound as a yellow solid. This compound is used directly in the next step.

Step 2: 2-Methylpyrimidine. 10% Pd/C (240 g) and MgO (240 g, 5.95 mol) were added to a solution of 4,6-dichloro-2-methylpyrimidine (240 g, 1.47 mol) in methanol (1.32 L) and _H₂O (1.10 L). RM was stirred at room temperature under a _H₂ atmosphere (30 psi) for 1 h. The mixture was filtered through a Celite filter. The filtrate was extracted with DCM (4 × 1 L). The combined organic phases were distilled at 1 atm to remove DCM at 39 °C and methanol at 65 °C, giving the title compound as a brown liquid. Y = 28%. ^¹H NMR (400 MHz, methanol- _d⁴ ) δ 8.66 (d, J = 5 Hz, 2H), 7.29 (t, J = 5 Hz, 1H), 2.65 (s, 3H).

Step 3: Propyl-2-hydroxy-3-(pyrimidin-2-yl)propionate. Iron diacetoxy (924 mg, 5.3 mmol) was added in a single step to a solution of 2-methylpyrimidine (10 g, 106 mmol) and isopropyl 2-oxoacetate (24.7 g, 212 mmol) in dioxane (100 ml) at 10 to 20 °C. The mixture was heated at 140 °C for 48 hours. The reaction mixture was concentrated under vacuum to give a residue. This residue was purified by FCC (10 to 50% EtOAc/gasoline) to give the title compound as a yellow solid. Y = 22%. ^1H NMR (400MHz, chloroform-d) δ 8.70 (d, J = 5Hz, 2H), 7.22 (t, J = 5Hz, 1H) 5.20-5.07 (m, 1H), 4.73-4.71 (m, 1H), 3.55-3.40 (m, 2H), 1.26 (d, J = 6Hz, 3H), 1.21 (d, J = 6Hz, 3H).

Step 4: 2-{[(3-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester. Following general procedure B, the title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester and 1-isocyano-3-methylcyclohexane as starting materials. The crude mixture was purified by preparative TLC (2:1 EtOAc/gasoline, Rf = 0.3) to obtain the title compound as a white solid. Y＝52%.MS ES ⁺ : ^350.2.1H NMR (400MHz, chloroform-d) δ8.69 (d, J = 5Hz, 2H), 7.17 (t, J = 5Hz, 1H) 5.68-5.58 (m ,1H),5.14-5.07(m,1H),4.69–4.63(m,1H),3.51-3.37(m,2H),2.06-1.8 3(m,2H),1.78-1.63(m,2H),1.55-1.31(m,2H),1.27(d,J＝6Hz,3H),1.22 (d,J＝6Hz,3H),0.94-0.89(m,1H),0.88(d,J＝3Hz,3H),0.87-0.69(m,2H)

Example 114. 3-(5-cyanopyrazin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid propionate-2-yl ester

Step 1: 3-(5-cyanopyrazin-2-yl)-2-hydroxypropanoate prop-2-yl ester. Under a _nitrogen atmosphere, 2-oxoacetic acid isopropyl ester (1.17 g, 10.07 mmol) and iron diacetoxy (73 mg, 419 μmol) were added to a solution of 5-methylpyrazin-2-carboxynitrile (1.0 g, 8.39 mmol) in dioxane (7 mL). The RM was heated at 120 °C for 48 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 5-35, 20 min) to give the title compound as a pale yellow oil. Y = 23%. ^1H NMR (400MHz, chloroform-d) δ 8.83 (s, 1H), 8.65 (s, 1H), 5.19–5.05 (m, 1H), 4.65–4.59 (m, 1H), 3.45–3.40 (m, 1H), 3.30–3.23 (m, 1H), 1.29 (t, J = 6Hz, 6H).

Step 2: Propyl-2-yl 3-(5-cyanopyrazin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}propionic acid propionate. The title compound was prepared using 3-(5-cyanopyrazin-2-yl)-2-hydroxypropionic acid propionate and intermediate A as starting materials according to general procedure B. The crude mixture was purified by preparative HPLC (column: Nano-MicroUnisil 8-120 C18 Ultra Plus 250*50mm; mobile phase: [water ( _10mMNH4HCO3 ) _-ACN ]; B%: 47-70, 20min) to obtain the title compound as a yellow solid. Y = 8%. MS ES ⁺ : 435.3

¹ H NMR (400MHz, methanol-d ₄ )δ8.99(s,1H),8.80(s,1H),6.96(s,1H),5.48–5.42(m,1H),5.11–5.01(m,1H),3.57–3 .45(m,2H),2.90–2.80(m,4H),2.76–2.68(m,4H),2.07–1.95(m,4H),1.29–1.23(m,6H).

Example 115. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(2-methylpyrimidin-4-yl)propionic acid prop-2-yl ester

Step 1: Propyl-2-hydroxy-3-(2-methylpyrimidin-4-yl)propionate. Under a nitrogen atmosphere, isopropyl 2-oxoacetate (1.18 g, 10.17 mmol) and iron diacetoxy (80 mg, 0.46 mmol) were added to a solution of 2,4-dimethylpyrimidin (1.00 g, 9.25 mmol) in dioxane (7 mL). The mixture was stirred under nitrogen at 120 °C for 48 hours. The solvent was removed under reduced pressure. The residue was purified by FCC (33-100% EtOAc/gasoline) to give the title compound as a light brown oil. Y = 14%. ^1H NMR (400MHz, chloroform-d) δppm 8.53 (d, J = 5Hz, 1H), 7.04 (d, J = 5Hz, 1H), 5.14–5.01 (m, 1H), 4.62–4.57 (m, 1H), 3.27–3.04 (m, 2H), 2.70 (s, 3H), 1.26–1.20 (m, 6H).

Step 2: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(2-methylpyrimidin-4-yl)propionic acid prop-2-yl ester. The title compound was prepared using 2-hydroxy-3-(2-methylpyrimidin-4-yl)propionic acid prop-2-yl ester and intermediate A as starting materials according to general procedure B. The crude mixture was purified by preparative HPLC (column: Ultimate C18 10μm 250mm*50mm; mobile phase: [water (10mM _NH₄HCO₃ ) _-ACN ]; B%: 40-60, 25min) to obtain the title compound as a white solid. Y=2%.MS ES ⁺ :424.3. ¹ H NMR (400MHz, methanol- _{d 4} )δ8.58(br.s,1H),7.32(br.s,1H),6.90(s,1H),5.45(br.s,1H),5.10-5.00(m, 1H),2.88–2.82(m,4H),2.77-2.61(m,9H),2.09–1.95(m,4H),1.27-1.23(m,6H).

Example 116. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(5-methylpyrazine-2-yl)propionic acid prop-2-yl ester

Step 1: Propyl-2-yl 2-hydroxy-3-(5-methylpyrazine-2-yl)propionate. Under _N2 , 2,5-dimethylpyrazine (0.50 g, 4.62 mmol) and iron diacetoxy (24 mg, 0.14 mmol) were added to a solution of isopropyl 2-oxoacetate (564 mg, 4.85 mmol) in dioxane (5 mL). The reaction mixture was stirred at 140 °C for 48 h. The reaction mixture was concentrated under vacuum, purified by preparative HPLC, and then purified by FCC (9% MeOH/DCM) to give the title compound as a yellow oil. Y = 17%. ^1H NMR (400MHz, chloroform-d) δppm 8.38(s, 1H), 8.37(s, 1H), 5.14–5.04(m, 1H), 4.61–4.56(m, 1H), 3.67(d, J = 6Hz, 1H), 3.35–3.09(m, 2H), 2.55(s, 3H), 1.27–1.24(m, 6H).

Step 2: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(5-methylpyrazin-2-yl)propionate prop-2-yl ester. The title compound was prepared using 2-hydroxy-3-(5-methylpyrazin-2-yl)propionate prop-2-yl ester and intermediate A as starting materials according to general procedure B. The crude mixture was purified by preparative TLC (1:1 EtOAc/gasoline) to give the title compound as a white solid. Y＝18%.MS ES ⁺ :424.2. ¹ H NMR (400MHz, chloroform-d) δppm 8.43(br.s,2H),7.00(s,1H),6.27(br.s,1H)5.50–5.42(m,1H),5.15–5.06(m,1H),3.40–3.25( m,2H),2.91–2.83(m,4H),2.75–2.62(m,4H),2.57(s,3H),2.14-1.94(m,4H),1.28–1.24(m,6H).

Example 117. 2-{[(1-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: 1-Isocyano-1-methylcyclohexane. Add 1-methylcyclohexylamine (150 mg, 1.33 mmol) and triethylamine (369 μl, 2.65 mmol) to a mixture of triphosgene (393 mg, 1.33 mmol) in DCM (2 ml) cooled to 0 °C under nitrogen. Stir the mixture at room temperature for 2 hours. Remove the solvent under reduced pressure to give the title compound as a white solid, which is used directly in the next step. Y = 100%.

Step 2: 2-{[(1-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester. Following general procedure B, the title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester (synthesis see Example 5CO) and 1-isocyano-1-methylcyclohexane as starting materials. The crude mixture was purified by preparative TLC (2:1 EtOAc/gasoline) to obtain the title compound as a colorless gel. Y=9%.MS ES ⁺ : ^350.1.1H NMR (400MHz, chloroform-d) δ8.69(d,J＝5Hz,2H),7.17(t,J＝5Hz,1H),5.63–5.57(m,1H),5.14-5.07(m,1H),4. 68(s,1H),3.49(s,2H),1.95-1.78(m,2H),1.52-1.33(m,8H),1.29-1.25(m,6H),1.22(d,J＝6Hz,3H).

Example 118. 2-{[(2-chloro-6-fluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: 1-Chloro-3-fluoro-2-isocyanophenyl. Add 2-chloro-6-fluoroaniline (200 mg, 1.37 mmol) to a solution of triphosgene (408 mg, 1.37 mmol) in DCM (3 mL). Cool the RM to 0 °C and treat with triethylamine (402 μl, 2.89 mmol). Stir the RM at room temperature for 1 hour. Remove the solvent under reduced pressure to obtain the desired product as a white solid, which was used for the next step without further purification. MS ES ⁺ : 204.2 (in methanol).

Step 2: 2-{[(2-chloro-6-fluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester. The title compound was prepared from 2-hydroxy-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester (synthesis see Example 5CO) and 1-chloro-3-fluoro-2-isocyanophenyl as starting materials according to general procedure B. The crude mixture was purified by preparative TLC (1:1 EtOAc/gasoline, Rf = 0.4) to obtain the title compound as a colorless gel. Y = 28%. MS ES ⁺ : 382.1. ¹ H NMR (400MHz, chloroform-d) δ 8.70 (d, J = 5Hz, 2H), 7.22–7.14 (m, 3H), 7.08–6.99 (m, 1H), 6.34 (s, 1H), 5.79–5.75 (m, 1H), 5.17–5.08 (m, 1H), 3.62–3.52 (m, 2H), 1.28 (d, J = 6Hz, 3H), 1.25 (d, J = 6Hz, 3H).

Example 119. 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: 1,3-Difluoro-2-isocyanophenyl. Add 2,6-difluoroaniline (200 mg, 1.55 mmol) to a solution of triphosgene (460 mg, 1.55 mmol) in DCM (3 mL). Cool the RM to 0 °C and treat with triethylamine (453 μl, 3.25 mmol). Stir the RM at room temperature for 1 hour. Remove the solvent under reduced pressure to obtain the desired product as a white solid, which was used for the next step without further purification. MS ES ⁺ : 188.3 (in methanol).

Step 2: 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester. Following general procedure B, the title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester (synthesis see Example 5CO) and 1,3-difluoro-2-isocyanophenyl as starting materials. The crude mixture was purified by preparative TLC (1:1 EtOAc/gasoline, Rf = 0.4) to obtain the title compound as a colorless gel. Y＝12%.MS ES ⁺ : ^366.1.1H NMR (400MHz, chloroform-d) δ8.70 (d, J = 5Hz, 2H), 7.23-7.12 (m, 2H), 6.97-6.86 (m, 2H), 6.24 (s, 1H), 5. 78–5.72(m,1H),5.17-5.07(m,1H),3.62-3.49(m,2H),1.28(d,J＝6Hz,3H),1.25(d,J＝6Hz,3H).

Example 120. 2-{[(2,6-dichlorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: 1,3-Dichloro-2-isocyanophenyl. Add 2,6-dichloroaniline (200 mg, 1.23 mmol) to a solution of triphosgene (366 mg, 1.23 mmol) in DCM (3 mL). Cool the RM to 0 °C and treat with triethylamine (361 μl, 2.59 mmol). Stir the RM at room temperature for 1 hour. Remove the solvent under reduced pressure to obtain the desired product as a white solid, which was used for the next step without further purification. MS ES ⁺ : 220.2 (in methanol)

Step 2: 2-{[(2,6-dichlorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester. Following general procedure B, the title compound was prepared using 2-hydroxy-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester (synthesis see Example 5CO) and 1,3-dichloro-2-isocyanophenyl as starting materials. The crude mixture was purified by preparative TLC (1:1 EtOAc/gasoline, Rf = 0.4) to obtain the title compound as a colorless gel. Y=28%.MS ES ⁺ : ^398.1.1H NMR (400MHz, chloroform-d) δ8.70(d,J＝5Hz,2H),7.34(d,J＝8Hz,2H),7.22-7.11(m,2H),6.48–6.35(br.s,1H) ),5.82–5.76(m,1H),5.18-5.07(m,1H),3.70-3.43(m,2H),1.28(d,J＝6Hz,3H),1.25(d,J＝6Hz,3H).

Example 121. (2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid propionate-2-yl ester

Step 1: Propyl-2-yl (2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-hydroxypropionic acid. To a solution of isopropyl (2R)-ethylene oxide-2-carboxylate (0.4 g, 3.07 mmol) (synthesis see Example 5CI) in EtOH (10 mL), 1H-1,2,4-triazol-3-carboxynitrile (723 mg, 7.68 mmol) and DIPEA (1.28 mL, 7.38 mmol) were added. The mixture was stirred at room temperature for 16 hours, then concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 5-35, 20 min) to give the title compound as a white solid. Y = 27%. ^1H NMR (400MHz, methanol- _d4 ) δ 8.60 (s, 1H), 5.11-5.03 (m, 1H), 4.68-4.50 (m, 3H), 1.36-1.26 (m, 6H).

Step 2: Propyl-2-yl propionate (2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid ester. The title compound was prepared using (2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-hydroxypropionic acid ester and intermediate A as starting materials, according to general procedure B. The crude product was purified by preparative HPLC (column: Waters Xbridge 150*5010μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 47-67, 12 min) to obtain the title compound as a white solid. Y=8%.MS ES ⁺ : ^424.1.1H NMR (400MHz, chloroform-d) δ8.25(s,1H),7.04(s,1H),6.42(s,1H),5.46(s,1H),5.16-5.10(m,1H) ,4.80(s,1H),2.98–2.82(m,4H),2.80–2.70(m,4H),2.12-2.04(m,4H),1.29(t,J＝6Hz,6H).

Example 122. 2-[({bicyclo[2.2.2]oct-1-yl}carbamoyl)oxy]-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: 1-Isocyanobicyclo[2.2.2]octane. Bicyclo[2.2.2]oct-4-amine (50 mg, 399 μmol) was added to a solution of triphosgene (119 mg, 399 μmol) cooled to 0 °C in DCM (2 mL), followed by Et ₃ N (0.167 mL, 1.20 mmol). The mixture was stirred at room temperature for 1 h, and then the solvent was removed under reduced pressure to give the title compound as a white solid. This product was used directly for the next step. Y = 99%. MS ES ⁺ : 184.1 (in methanol).

Step 2: 2-[({bicyclo[2.2.2]oct-1-yl}carbamoyl)oxy]-3-(pyrimidin-2-yl)propionate prop-2-yl ester. The title compound was prepared from 2-hydroxy-3-(pyrimidin-2-yl)propionate prop-2-yl ester (synthesis see Example 5CO) and 1-isocyano-bicyclo[2.2.2]octane as starting materials, according to general procedure B. The crude mixture was purified by preparative TLC (1:1 EtOAc/gasoline, Rf = 0.35) to give the title compound as a white solid. Y = 19%. MS ES ⁺ : 362.2. ¹ H NMR (400MHz, methanol- _d⁴⁺D₂O ) δ 8.72 (d, J = 5Hz, _2H ), 7.36 (t, J = 5Hz, 1H), 5.40–5.32 (m, 1H), 5.06–4.99 (m, 1H), 3.47–3.35 (m, 2H), 1.76–1.50 (m, 13H), 1.26–1.17 (m, 6H).

Example 123. 2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}-3-(pyridazin-4-yl)propionate prop-2-yl ester

Step 1: Propyl-2-hydroxy-3-(pyridazin-4-yl)propionate. Isopropyl ₂ -oxoacetate (1.23 g, 10.62 mmol) and iron diacetoxy (46 mg, 0.27 mmol) were added to a solution of 4-methylpyridazine (500 mg, 5.31 mmol) in dioxane (5 mL) under a nitrogen atmosphere. The reaction mixture was heated at 100 °C for 24 hours. The reaction mixture was filtered, and the filtrate was directly purified by preparative HPLC (column: Phenomenex Luna C18 250*50 mm*10 μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 1-20, 20 min) to give the title compound as a pink oil. Y = 38%. ^¹H NMR (400MHz, chloroform-d) δ 9.28–9.20 (m, 2H), 7.78–7.72 (m, 1H), 5.16–5.06 (m, 1H), 4.49–4.46 (m, 1H), 3.30–3.24 (m, 1H), 3.09–3.01 (m, 1H), 1.31–1.28 (m, 6H).

Step 2: 2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}-3-(pyridazin-4-yl)propionate prop-2-yl ester. Following general procedure B, the title compound was prepared using 2-hydroxy-3-(pyridazin-4-yl)propionate prop-2-yl ester and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Nano-micro Kromasil C18100*30mm 5μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 40-55, 10min) to obtain the title compound as a brown solid. Y = 1%. MS ES ⁺ :410.2. ¹ H NMR (400MHz, chloroform-d) δ 9.24–9.12 (m, 2H), 7.47 (s, 1H), 7.05–6.95 (m, 1H), 6.34 (s, 1H), 5.40–5.30 (m, 1H), 5.08–5.02 (m, 1H), 3.35–3.10 (m, 2H), 2.95–2.48 (m, 8H), 2.07–2.00 (m, 4H), 1.95–1.12 (m, 6H).

Example 124. 2-{[(trans-2-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionic acid prop-2-yl ester

Step 1: trans-1-isocyano-2-methylcyclohexane. Under a nitrogen atmosphere at ₀ °C, trans-2-methylcyclohexylamine (50 mg, 0.44 mmol) and _Et3N (89 mg, 0.88 mmol) were added in portions to a mixture of triphosgene (131 mg, 0.44 mmol) in DCM (1 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give the title compound as a white solid. Y = 100%.

Step 2: 2-{[(trans-2-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propionate prop-2-yl ester. The title compound was prepared from 2-hydroxy-3-(pyrimidin-2-yl)propionate prop-2-yl ester (synthesis see Example 5CO) and trans-1-isocyano-2-methylcyclohexane as starting materials, according to general procedure B. The crude mixture was purified by preparative HPLC (column: Waters Xbridge 150*50mm, 10μm; mobile phase: [water (0.1% TFA)-ACN]; B%: 30-60, 12min) to obtain the title compound as a white solid. Y＝5%.MS ES ⁺ : ^350.2.1H NMR (400MHz, chloroform-d) δ8.70 (d, J = 5Hz, 2H), 7.20-7.17 (m, 1H), 5.66-5.60 (m, 1H), 5.15-5.01 (m, 1H), 4.58 (d, J = 9Hz, 1H), 3.53-3 .44(m,2H),3.14-3.10(m,1H),2.00-1.88(m,2H),1.65-1.62(m,2H),1.28-1.20(m,6H),1.21-1.02(m,5H),0.99-0.88(m,3H).

Example 125. 3-(5-cyanopyrimidin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarsen-4-yl)carbamoyl]oxy}propionic acid propionate-2-yl ester

Step 1: Propyl-2-(5-cyanopyrimidin-2-yl)-2-hydroxypropanoate. Iron diacetoxy (29 mg, 0.17 mmol) was added in a single batch to a mixture of 2-methylpyrimidin-5-carboxynitrile (200 mg, 1.68 mmol) and isopropyl 2-oxoacetate (585 mg, 5.04 mmol) in dioxane (3 mL) under _N₂ . The mixture was stirred at 100 °C for 48 hours. The mixture was poured into _H₂O (25 mL), and the resulting mixture was extracted with ethyl acetate (3 × 20 mL). The combined organic phases were washed with brine (10 mL), dried over _{anhydrous Na₂SO₄} , filtered, and concentrated under vacuum. The residue was purified by FCC (0-100% EtOAc/gasoline) to give the title compound as a white solid. Y=30%. ¹ H NMR (400MHz, DMSO-d ₆ )δ9.24(s,1H),5.66(d,J=6Hz,1H),4.95-4.85(m,1H),4.64-4.55(m,1H),3.38-3.32(m,1H),3.29-3.20(m,1H),1.21–1.10(m,6H).

Step 2: Propyl-2-yl 3-(5-cyanopyrimidin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indarin-4-yl)carbamoyl]oxy}propionic acid propionate. The title compound was prepared using 3-(5-cyanopyrimidin-2-yl)-2-hydroxypropionic acid propionate and intermediate A as starting materials according to general procedure B. The crude product was purified by preparative TLC ( _SiO₂ , 1:1 EtOAc/gasoline) to obtain the title compound as a colorless oil. Y = 34%. MS ES ⁺ : 435.2

¹ H NMR(400MHz, chloroform-d)δ8.95(s,2H),7.00(s,1H),6.27–6.17(br.s,1H),5.79–5.71(m,1H),5.20-5.05(m ,1H),3.71–3.61(m,2H),2.93–2.83(m,4H),2.82-2.70(m,4H),2.11-1.98(m,4H),1.30-1.21(m,6H).

Example 126. Bioactivity of the compounds disclosed herein

The bioactivity of the compounds disclosed herein was determined using the assays described herein.

PBMC IC50 Determinative Assay

The inhibitory activity of the compounds disclosed herein on IL-1β release following NLRP3 activation in peripheral blood mononuclear cells (PBMCs) was tested.

PBMCs were separated from the erythrocyte sedimentation rate (ESR) layer by density gradient centrifugation on a Histopaque-1077 (Sigma, catalog number 10771). The separated cells were seeded into the wells of 96-well plates and incubated with lipopolysaccharide (LPS) for 3 hours. After medium exchange, the compounds disclosed herein (one compound per well) were added, and the cells were incubated for 30 minutes. Next, the cells were stimulated with ATP (5 mM) or nigericin (10 μM) for 1 hour, and the cell culture medium from the wells was collected for further analysis.

The release of IL-1β into the culture medium was determined by quantifying IL-1β in the medium using the IL-1β enzyme-linked immunosorbent assay (ELISA) Ready-SET-Go! (eBioscience catalog number 88-7261-88). In brief, in the first step, a high-affinity binding plate (Corning, Costa 9018, or NUNC Maxisorp catalog number 44-2404) was coated overnight at 4°C with the specific capture antibody (anti-human IL-1β ref. 14-7018-68) included in the kit. Subsequently, the plate was blocked at room temperature (rt) with blocking buffer for 1 hour and incubated with protein standards and culture medium after washing with buffer (PBS containing 0.05% Tween-20). After incubation at room temperature for 2 hours, the plate was washed and incubated at room temperature for 1 hour with the biotinylated detection antibody (anti-human IL-1β biotin ref. 33-7110-68) included in the kit. The plate was washed and incubated with HRP-streptolysin at room temperature for 30 minutes, followed by another wash. A signal was generated upon addition of 3,3,5,5-tetramethylbenzidine-peroxidase (TMB), and the reaction was stopped until color appeared, with 2M _H₂SO₄ used to _terminate the reaction. The signal at 450 nm was detected using a microplate spectrophotometer (BioTek). The detection range of IL-1β ELISA is 2–150 ng/ml.

_IC50 values were determined using Graph Pad Prism software, and the measured _IC50 values of the compounds disclosed herein are shown in Table 2 below (“A” indicates _IC50 < 10 nM; “B” indicates _IC50 range between 10 nM and 100 nM; “C” indicates _IC50 range between 100 nM and 1 μM; “D” indicates _IC50 range between > 1 μM and 10 μM; “E” indicates _IC50 > 10 μM). These results indicate that the compounds disclosed herein can inhibit the release of IL-1β following inflammasome activation.

Table 2

equivalent

Details of one or more embodiments of this disclosure are set forth in the description appended above. While any methods and materials similar to or equivalent to those described herein may be used in the practice or testing of this disclosure, preferred methods and materials are now described. Other features, objects, and advantages of this disclosure will be apparent from the specification and claims. In the specification and appended claims, the singular form includes the plural object unless the context clearly indicates otherwise. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. All patents and publications referenced in this specification are incorporated herein by reference.

The foregoing description is given for illustrative purposes only and is not intended to limit this disclosure to the precise form disclosed, but is defined by the appended claims.

Claims (76)

1. Compounds of formula (I): Or its pharmaceutically acceptable salt, wherein: _R1 is: (a) where n and _na are each independently 0, 1, 2 or 3; (b) benzofuranyl or dihydrobenzofuranyl, wherein the benzofuranyl or dihydrobenzofuranyl is optionally substituted with one or more _R6 ; (c) (d) or (e) _R3 is H or a _C1 - _C4 alkyl group optionally substituted with one or more _R7s ; _R4 is H, _C1 - _C6 alkyl, -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl), or -( _CH2 ) _O-3 - _C6 aryl; _R6 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C1 - _C6 alkoxy, _C3 - _C8 cycloalkyl, halogen, -OH, -CN, _-NH2 , -NH( _C1 - _C6 alkyl), -N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 ; _R7 is _-OR8 , _C5 - _C10 aryl, or 5- to 10-membered heteroaryl, wherein the _C5 - _C10 aryl or 5- to 10-membered heteroaryl is optionally substituted by one or more _R7S , wherein each _R7S is independently _C1 - _C6 alkyl, _C1 - _C6 alkoxy, 5- to 10-membered heteroaryl, halogen, -OH, -CN, -( _CH2 ) _{O-3- NH2} , -( _CH2 ) _O-3- NH( _C1 - _C6 alkyl), -( _CH2 ) _O-3- N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 , or _-CF3 ; and _R8 is a _C1 - _C6 alkyl or a 5- to 7-membered heterocyclic alkyl, wherein the _C1 - _C6 alkyl or the 5- to 7-membered heterocyclic alkyl is optionally substituted by one or more _R7S . 2. The compound of claim 1, wherein _R1 is 3. The compound of claim 1, wherein _R3 is H. 4. The compound of claim 1, wherein _R3 is a _C1 - _C4 alkyl group optionally substituted with one or more _R7 . 5. The compound of claim 1, wherein _R3 is methyl or ethyl. 6. The compound of claim 1, wherein _R3 is a _C1 - _C4 alkyl group substituted with one or more _R7 . 7. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more _C1 - _C6 alkoxy groups, wherein the _C1 - _C6 alkoxy groups are optionally substituted with one or more _C1 - _C6 alkoxy groups. 8. The compound of claim 1, wherein _R3 is 9. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more -O- (5 to 7-membered heterocyclic alkyl groups). 10. The compound of claim 1, wherein _R3 is 11. The compound of claim 1, wherein _R3 is a methyl group having one or more _C5 - _C10 aryl groups, wherein the _C5 - _C10 aryl groups are optionally substituted by one or more 5- to 10-membered heteroaryl groups or -CN. 12. The compound of claim 1, wherein _R3 is 13. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more 5- to 10-membered heteroaryl groups, wherein the 5- to 10-membered heteroaryl groups are optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 . 14. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more pyridinyl groups, wherein the pyridinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _O-3- N( _C1 - _C6 alkyl) ₂ or _-CF3 . 15. The compound of claim 1, wherein _R3 is 16. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more pyrazolyl groups, wherein the pyrazolyl group is optionally substituted with one or more methyl, methoxy, F, Cl, -CN, -CH2 _- N( _CH3 ) ₂ or _-CF3 groups. 17. The compound of claim 1, wherein _R3 is 18. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more imidazole groups, wherein the imidazole groups are optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 . 19. The compound of claim 1, wherein _R3 is 20. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more pyridazinyl groups, wherein the pyridazinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3- N( _C1 - _C6 alkyl) ₂ or _-CF3 . 21. The compound of claim 1, wherein _R3 is 22. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more pyrimidinyl groups, wherein the pyrimidinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _O-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 . 23. The compound of claim 1, wherein _R3 is 24. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more pyrazinyl groups, wherein the pyrazinyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _O-3- N( _C1 - _C6 alkyl) ₂ or _-CF3 . 25. The compound of claim 1, wherein _R3 is 26. The compound of claim 1, wherein _R3 is a methyl group substituted with one or more triazolyl groups, wherein the triazolyl group is optionally substituted with one or more _C1 - _C6 alkyl, _C1 - _C6 alkoxy, halogen, -CN, -( _CH2 ) _0-3 -N( _C1 - _C6 alkyl) ₂ or _-CF3 . 27. The compound of claim 1, wherein _R3 is 28. The compound of claim 1, wherein _R3 is an ethyl group substituted with one or more _C5 - _C10 aryl groups. 29. The compound of claim 1, wherein _R3 is 30. The compound of claim 1, wherein _R4 is H. 31. The compound of claim 1, wherein _R4 is a _C1 - _C6 alkyl, -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl), or -( _CH2 ) _O-3 - _C6 aryl. 32. The compound of claim 1, wherein _R4 is a _C1 - _C6 alkyl group. 33. The compound of claim 1, wherein _R4 is methyl, ethyl, propyl or butyl. 34. The compound of claim 1, wherein _R4 is -( _CH2 ) _O-3- ( _C3 - _C6 cycloalkyl). 35. The compound of claim 1, wherein _R4 is 36. The compound of claim 1, wherein _R4 is -( _CH2 ) _O-3 - _C6 aryl. 37. The compound of claim 1, wherein _R4 is 38. The compound of claim 1, wherein at least one _R6 is a _C1 - _C6 alkyl, _C2 - _C6 alkenyl, _C1 - _C6 alkoxy, or _C3 - _C8 cycloalkyl. 39. The compound of claim 1, wherein at least one _R6 is a halogen, -OH, -CN, _-NH2 , -NH( _C1 - _C6 alkyl), -N( _C1 - _C6 alkyl) ₂ , _-CH2F , _-CHF2 or _-CF3 . 40. The compound of claim 1, wherein at least one R ₇ is -OR ₈ . 41. The compound of claim 1, wherein at least one _R7 is a _C1 - _C6 alkoxy group optionally substituted with one or more _R7S ; or at least one _R7 is an -O-(5- to 7-membered heterocyclic alkyl group optionally substituted with one or more _R7S . 42. The compound of claim 1, wherein at least one _R7 is a _C5 - _C10 aryl group optionally substituted with one or more _R7S . 43. The compound of claim 1, wherein at least one R ₇ is a 5- to 10-membered heteroaryl group optionally substituted with one or more R _7S . 44. The compound of claim 1, wherein at least one R _7S is a _C1 - _C6 alkyl, _C1 - _C6 alkoxy, or a 5- to 10-membered heteroaryl group. 45. The compound of claim 1, wherein at least one R _7S is a halogen, -OH, -CN, -(CH ₂ ) _O-3 -NH ₂ , -(CH ₂ ) _O-3 -NH (C ₁ -C ₆ alkyl), -(CH ₂ ) _O-3 -N (C ₁ -C ₆ alkyl) ₂ , -CH ₂ F, -CHF ₂ or -CF ₃ . 46. The compound of claim 1, wherein _R8 is a _C1 - _C6 alkyl group optionally substituted with one or more _R7S . 47. The compound of claim 1, wherein _R8 is a 5- to 7-membered heterocyclic alkyl group optionally substituted with one or more _R7S . 48. The compound of claim 1, wherein the compound is a compound of formula (Ib): Or its pharmaceutically acceptable salt. 49. The compound of claim 1, wherein the compound is a compound of any one of formula (II) or (IIb): Or its pharmaceutically acceptable salt. 50. The compound of claim 1, wherein the compound is a compound of any one of formula (III) or (IIIb): Or its pharmaceutically acceptable salt. 51. The compound of claim 1, wherein the compound is a compound of any one of formula (IV) or (IVb): Or its pharmaceutically acceptable salt. 52. The compound of claim 1, wherein the compound is a compound of any one of formulas (V), (Vb), (VI), and (VIb): Or its pharmaceutically acceptable salt. 53. The compound of claim 1, wherein the compound is a compound of any one of formulas (VII), (VIIb), (VIII), and (VIIIb): Or its pharmaceutically acceptable salt. 54. The compound of claim 1, wherein the compound is a compound of any one of formulas (IX), (IXb), (X), and (Xb): Or its pharmaceutically acceptable salt. 55. A compound selected from compounds numbered 1-36 and 38-130 and their pharmaceutically acceptable salts: 56. A compound selected from compounds numbered 1-36 and 38-130: 57. A method for preparing the compound of claim 1, the method comprising one or more steps described in schemes 1-2 and 4: Option 1 Option 2 Option 4 58. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier. 59. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or carrier, wherein the compound is selected from compound numbers 1-36 and 38-130: 60. Use of the compound of any one of claims 1-56 or a pharmaceutical salt thereof in the preparation of a medicament for inhibiting the activity of an inflammasome, wherein the inflammasome is the NLRP3 inflammasome. 61. The use of claim 60, wherein the activity is in vitro or in vivo. 62. Use of any compound of claims 1-56 or a pharmaceutical salt thereof in the preparation of a medicament for treating or preventing a disease or condition, wherein the disease or condition is related to the activity of an inflammasome involved, and wherein the inflammasome is an NLRP3 inflammasome. 63. The use of claim 62, wherein the disease or condition is one in which inflammasome activity is involved. 64. The use of claim 62 or 63, wherein the disease or condition is an autoinflammatory disease, an autoimmune disease, a neurodegenerative disease, or cancer. 65. The use of claim 64, wherein the disease or condition is an autoinflammatory condition or an autoimmune condition. 66. The use of claim 62 or 63, wherein the disease or condition is: cold pyridine-associated autoinflammatory syndrome, Muckle-Wells syndrome, chronic infantile neurocutaneous and joint syndrome/neonatal multisystem inflammatory disease, familial Mediterranean fever, gout, rheumatoid arthritis, osteoarthritis, Crohn's disease, chronic obstructive pulmonary disease, chronic kidney disease, fibrosis, obesity, type 2 diabetes, multiple sclerosis, or neuroinflammatory diseases occurring in protein misfolding disorders. 67. The use of claim 66, wherein the cold pyridine-associated autoinflammatory syndrome is a familial cold autoinflammatory syndrome. 68. The use of claim 66, wherein the protein misfolding disease is a prion disease. 69. The use of claim 62 or 63, wherein the disease or condition is non-alcoholic fatty liver disease. 70. The use of claim 69, wherein the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis. 71. The use of claim 64, wherein the disease or symptom is a neurodegenerative disease. 72. The use of claim 71, wherein the neurodegenerative disease is Parkinson's disease or Alzheimer's disease. 73. The use of claim 64, wherein the disease or condition is cancer. 74. The use of claim 73, wherein the cancer is metastatic cancer. 75. The use of claim 73, wherein the cancer is gastrointestinal cancer, skin cancer, or non-small cell lung cancer. 76. The use of claim 75, wherein the cancer is colorectal adenocarcinoma.