EA044707B1 - SELECTIVE INHIBITORS OF THE NLRP3 INFLAMMASOME - Google Patents

Description

Related Application

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

Field of technology to which the invention relates

The present invention relates to certain novel compounds and directly related prodrugs or pharmaceutically acceptable salt(s) that have inflammasome inhibitory activity and are accordingly useful in methods of treating a human or animal body. The present invention also relates to methods for preparing these compounds, pharmaceutical compositions containing them and their use for the treatment of disorders in which inflammasome activity is involved, such as autoinflammatory and autoimmune diseases and cancer.

Prerequisites for creating the invention

Autoimmune diseases are associated with increased production of proinflammatory 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, and is involved in a range of cell functions, including cell proliferation, differentiation and apoptosis (Seth L. et. al., Rev. Immunol., 2009, 27:621-68).

In humans, the 22 NLR proteins are classified into four NLR subfamilies according to their N-terminal domains. NLRA contains a CARD-AT domain, NLRB (NAIP) contains a BIR domain, NLRC (including NOD1 and NOD2) contains a CARD domain, and NLRP contains a pyrin domain. Multiple NLR family members are associated with 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 against pathogens, the NLRP3 inflammasome is unique in its ability to be activated in response to endogenous or exogenous non-microbial danger signals. Many such non-microbial signals have been identified, and their formation has been associated with specific disease states. For example, uric acid crystals found in patients with gout are effective triggers for NLRP3 activation. By analogy, cholesterol crystals found in patients with atherosclerosis may also enhance NLRP3 activation. Recognition of the role of non-microbial danger signals as activators of NLRP3 leads to IL-1 and IL-18 being implicated in a wide range of pathophysiological processes, including metabolic, physiological, inflammatory, hematological and immunological disorders.

The present invention is driven by the need to provide new compounds to specifically modulate NLRP3-dependent cellular processes. In particular, compounds are required with physicochemical, pharmacological and pharmaceutical properties improved over existing compounds.

The essence of the invention

In some aspects, the present invention relates to, among other things, a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein R1 is

a) C ₈ -C ₁₆ polycyclic cycloalkyl, optionally substituted by one or more R ₆ ;

b) benzofuranyl or dihydrobenzofuranyl, optionally substituted with one or more R ₆ ;

- 1 044707

R3 is H or C1- _C4 alkyl, optionally substituted by one or more _R7 ;

R ₄ represents H, C ₁ -C ₆ -alkyl, -(CH ₂ ) _0-3 -(C ₃ -C ₆ -cycloalkyl) or -(CH ₂ ) _0-3 -C ₆ -aryl;

R6 is C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkyl, halogen, oxo, -OH, -CN, -NH2, -NH (C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF3;

R ₇ is -OR8, C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl, wherein C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl is optionally substituted by one or more R _7S , wherein each R _7S is independently represents C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, 5-10-membered heteroaryl, halogen, -OH, -CN, -(CH ₂ ) _0-3 -NH ₂ , -(CH ₂ ) _0-3 -NH(C ₁ -C ₆ -alkyl), -(CH ₂ ) _0-3 -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF3; And

R8 is a C ₁ -C ₆ -alkyl or 5-7 membered heterocycloalkyl, wherein the C ₁ -C ₆ -alkyl or 5-7 membered heterocycloalkyl is optionally substituted by one or more R _7S , wherein said heterocycloalkyl rings contain from 1 to 6 heteroatoms selected from O, N, S, P and Se, and wherein said heteroaryl rings contain from 1 to 6 heteroatoms selected from N, O and S.

In some aspects, the present invention provides a pharmaceutical composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier.

In some aspects, the present invention provides a method of inhibiting the activity (eg, in vitro or in vivo) of inflammasomes (eg, the NLRP3 inflammasome), comprising contacting a cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention provides a method for treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. .

Unless otherwise specified, all technical and scientific terms used in this document

- 2 044707 mente have the same meanings as commonly understood by one of ordinary skill in the art to which the present invention belongs. Unless the context clearly requires otherwise, as used herein, singular forms also include plural forms. Although methods and substances similar or equivalent to those described herein may be used to practice or test the present invention, suitable methods and substances are described below. All publications, patent applications, patents and other references mentioned herein are incorporated herein by reference. The references cited herein are not considered to constitute prior art to the claimed invention. In the event of a conflict, this description, including definitions, will control. In addition, the substances, methods and examples are illustrative only and are not intended to be limiting. In the event of a conflict between chemical structures and the names of compounds disclosed herein, the chemical structures will control.

Other features and advantages of the present invention will become apparent from the following detailed description and claims.

Detailed Description of the Invention

Autoimmune diseases are associated with increased production of proinflammatory 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, and is involved in a range of cell functions, including cell proliferation, differentiation and apoptosis (Seth L. et. al., Rev. Immunol., 2009, 27:621-68).

IL-1 family cytokines are highly active and are associated as important mediators of inflammation, primarily in acute and chronic inflammation (Sims J. et al., Nature Reviews Immunology, 10, 89-102 (February 2010)). Increased production of IL-1 is thought to be a mediator of some autoimmune and autoinflammatory diseases. Autoinflammatory diseases are characterized by recurrent and idiopathic inflammation in the absence of autoantibodies, infection, or antigen-specific T cells.

Proinflammatory cytokines of the IL-1 superfamily include IL-1a, IL-1e, IL-18 and IL-36a, β, λ and are produced in response to pathogens and other cellular stressors as part of the host innate immune response. In contrast to many other secreted cytokines, which are formed and released through the standard cellular secretory apparatus of the endoplasmic reticulum and Golgi apparatus, members of the IL-1 family do not contain the leader sequences required for entry into the endoplasmic reticulum and are therefore retained within cells after translation. In addition, IL-1e, IL-18 and IL-36a, β, λ are synthesized as procytokines that require proteolytic activation to be converted into optimal ligands for binding to their cognate receptors on target cells.

In the case of IL-1a, ΓΕ-1β and IL-18, it is currently believed that a multimeric protein complex known as the inflammasome is responsible for the activation of the proforms of ΓΕ-1β and IL-18 and the release of these cytokines into the extracellular space. The inflammasome complex typically consists of a sensor molecule such as NLR (nucleotide-binding oligomerization domain (NOD)-like receptor), and adapter molecule ASC (apoptosis-associated Speck-like protein containing CARD (caspase recruitment domain)) and procaspase-1. In response to a variety of danger signals, including pathogen-associated molecular patterns (PAMPs) and danger-associated molecular patterns (DAMPs), inflammasome subunits oligomerize to form a supramolecular structure within the cell. PAMPs include molecules such as peptidoglycan, viral DNA or RNA, and bacterial DNA or RNA. On the other hand, DAMPs consist of a wide range of endogenous or exogenous nonmicrobial triggers, including sodium urate crystals, silica, alum, asbestos, fatty acids, ceramides, cholesterol crystals, and beta-amyloid peptide aggregates. Assembly of the inflammasome platform promotes autocatalysis of procaspase-1 to produce a highly active cysteine protease responsible for the activation and release of pro-GL-I and pro-GL-18. Thus, the release of these highly active inflammatory cytokines occurs only in response to detection of inflammasome sensors and in response to specific molecular danger signals.

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

Two other structurally distinct PYHIN domain-containing inflammasome structures (pyrin and NIH domain-containing protein), namely Absent in Melanoma 2 (AIM2) and IFNλ-inducible protein 16 (IFI16) (Latz et al., Nat. Rev. Immunol. , 2013, 13(6)397-311), serve as intracellular DNA sensors. Pyrin (encoded by the MEFV gene) is another type of inflam platform

- 3 044707 masome associated with activation of npo-IL-Ιβ (Chae et al., Immunity, 34, 755-768, 2011).

The need to assemble the inflammasome platform to achieve activation and release of IL-1e and IL-18 from monocytes and macrophages ensures careful regulation of their production through a 2-step process. First, the cell must encounter a priming ligand (such as the TLR4 receptor ligand LPS or an inflammatory cytokine such as TNFa), which leads to NFkB-dependent transcription of NLRP3, pro-IL-1β, and pro-IL-18. Newly translated procytokines remain inactive inside the cell unless the producing cell encounters a second signal leading to activation of the inflammasome platform and maturation of procaspase-1.

In addition to the proteolytic activation of pro-P1b and pro-IL-18 through the cleavage of gasdermin-D, active caspase-1 also triggers a form of inflammatory cell death known as pyroptosis. Pyroptosis allows mature forms of IL-Ιβ and IL-18 to exit cells along with the release of alarmin molecules (compounds that increase inflammation and activate innate and adaptive immunity), such as high mobility group box 1 protein, IL-33 and IL-1a .

Although inflammasome activation appears to have evolved as an important component of host immunity against pathogens, the NLRP3 inflammasome is unique in its ability to be activated in response to endogenous or exogenous non-microbial danger signals. Many such non-microbial signals have been identified, and their formation has been associated with specific disease states. For example, uric acid crystals found in patients with gout are effective triggers for NLRP3 activation. By analogy, cholesterol crystals found in patients with atherosclerosis may also enhance NLRP3 activation. Recognition of the role of non-microbial danger signals as activators of NLRP3 leads to IL-1 and IL-18 being implicated in a wide range of pathophysiological processes, including metabolic, physiological, inflammatory, hematological and immunological disorders.

The link to human disease is best illustrated by the discovery that mutations in the NLRP3 gene, which lead to gain-of-function mutations, are a condition of a range of autoinflammatory conditions commonly known as cryopyrine-associated periodic syndromes (CAPS), including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal multisystem inflammatory disease (NOMID) (Hoffman et al., Nat. Genet., 29(3), (2001) 301-305). In addition, sterile transmitter-induced activation of NLRP3 has been implicated in a wide range of disorders, including joint degeneration (gout, rheumatoid arthritis, osteoarthritis), cardiometabolic disorders (type 2 diabetes, atherosclerosis, hypertension), central nervous system diseases (Alzheimer's disease, Parkinson's disease, multiple sclerosis), diseases of the gastrointestinal tract (Crohn's disease, ulcerative colitis), lung diseases (chronic obstructive pulmonary disease, asthma) and fibrosis (non-alcoholic fatty liver, non-alcoholic hepatosteatosis, idiopathic pulmonary fibrosis). In addition, activation of NLRP3 is thought to increase kidney inflammation and therefore contribute to chronic kidney disease (CKD).

Current treatments for diseases that involve I.-1 as a pathogenic factor include the IL-1 receptor antagonist anakinra, an Fc-containing fused construct of the extracellular domains of the I.-1 receptor and the I.-1 receptor accessory protein (rilonacept). and the anti-Ι.-1β monoclonal antibody canakinumab. For example, canakinumab is licensed for CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), and gout.

Several small molecules have been reported to inhibit NLRP3 inflammasome function. Glyburide, for example, is a specific inhibitor of N.RP3 activation, even at micromolar concentrations that are difficult to achieve in vivo. Non-specific agents such as parthenolide, Bay 11-7082 and 3,4-methylenedioxy-b-nitrostyrene have been reported to disrupt NLRP3 activation but are thought to have limited therapeutic utility due to the fact that they share a common structural element. consisting of an olefin activated by substitution with an electron-withdrawing group; this may lead to the undesirable formation of covalent adducts with protein containing thiol groups. A number of naturally occurring products, such as β-hydroxybutyrate, sulforaphane, quercetin, and salvianolic acid, have also been reported to suppress N.RP3 activation. Similarly, a variety of effectors/modulators of other molecular targets have been reported to impair NLRP3 activation, including the G protein-coupled receptor TGR5 agonists, the sodium-glucose cotransport inhibitor epigliflozin, the dopamine receptor antagonist A-68930, the serotonin reuptake inhibitor fluoxetine, and the fenamates. non-steroidal anti-inflammatory drugs and the β-adrenergic receptor blocker nebivolol. The use of these molecules as therapeutic agents for the chronic treatment of NLRP3-dependent inflammatory disorders remains unapproved. A series of sulfonylurea-containing molecules have previously been identified as potent and selective inhibitors of post-translational processing of pro-1.-1b (Perregaux et al., J. Pharmacol.

- 4 044707

Exp. Ther., 299, 187-197, 2001). The exemplified 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).

The present invention provides compounds useful for specifically modulating NLRP3-dependent cellular processes. In particular, compounds with physicochemical, pharmacological and pharmaceutical properties improved over existing NLRP3-modulating compounds are required.

Definitions.

Unless otherwise specified, the following terms as used in the specification and claims have the following meanings set forth below.

It should be understood that references to administering treatment or treatment include alleviation of established symptoms of a condition. Therefore, providing treatment or treating a disease, disorder or condition involves (1) preventing or delaying the onset of clinical symptoms of the disease, disorder or condition developing in a person who may be suffering from or may be susceptible to the disease, disorder or condition, but has not yet experiences or does not demonstrate clinical or subclinical symptoms of a disease, disorder or condition;

(2) inhibition of a disease, disorder or condition, i.e. stopping, reducing or delaying the development of the disease or its relapse (in the case of maintenance treatment) or at least one of its clinical or subclinical symptoms; or (3) alleviation or weakening of the disease, i.e. leading to regression of a disease, disorder or condition, or at least one of its clinical or subclinical symptoms.

The term "therapeutically effective amount" means an amount of a compound that, when administered to a mammal to treat a disease, is sufficient for such treatment of the disease to be effective. The therapeutically effective amount will vary depending on the compound, the disease and its severity, as well as age, weight, and the like. mammal to be treated.

As used herein, the terms alkyl, C1-, C2-, _C3- , C4-, _C5 or C6 _- alkyl or _C1 - _{C6 -} alkyl are intended to include linear saturated aliphatic hydrocarbons C1, C ₂ , _C3 , _C4 , _C5 or _C6 groups and branched saturated aliphatic hydrocarbon _C3 , _C4 , _C5 or C6 groups. For example, C ₁ -C ₆ -alkyl is intended to include C1-, C ₂ -, C ₃ -, C4-, C ₅ - and C ₆ -alkyl groups. Examples of alkyl include moieties containing from one to six carbon atoms, such as, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, or n-hexyl. In some embodiments, the straight or branched alkyl contains six or fewer carbon atoms (eg, C1-C6 for straight, C3-C6 for branched), and in another embodiment, the straight or branched alkyl contains four or fewer carbon atoms.

As used herein, the term cycloalkyl refers to a saturated or partially unsaturated hydrocarbon monocyclic or polycyclic (eg, fused, bridged or spirocyclic) system containing 3-30 carbon atoms (eg, C ₃ -C ₁₂ , C ₃ -C ₁₀ or C ₃ -C ₈ ). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, 1,2,3,4-tetrahydronaphthalenyl and adamantyl. In some embodiments, the cycloalkyl is hexahydroindacenyl.

Unless otherwise specified, the term heterocycloalkyl as used herein 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) ring system containing one or more heteroatoms (such as O, N, S, P or Se), for example 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 independently selected from the group consisting of nitrogen, oxygen and sulfur. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, pyrrolidinyl, dioxanyl, tetrahydrofuranyl, isoindolinyl, indolinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, triazolidinyl, oxiranyl, azetidinyl, oxetanyl, tietanyl, 1,2,3,6-tetrahydr opyridinyl, tetrahydropyranyl, dihydropyranyl, pyranyl, morpholinyl, tetrahydrothiopyranyl, 1,4-diazepanyl, 1,4-oxazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2,5-diazabicyclo[2.2.1]heptanyl, 2-oxa- 6azaspiro[3.3]heptanyl, 2,6-diazaspiro[3.3]heptanyl, 1,4-dioxa-8-azaspiro[4.5]decanyl, 1,4-dioxaspiro[4.5]decanyl, 1-oxaspiro[4.5]decanyl, 1- azaspiro[4.5]decanyl, 3Ή-spiro[cyclohexan-1,1'-isobenzofuran]yl, 7Ή-spiro[cyclohexane-1,5'-furo[3,4-b]pyridin]-yl, 3Ή-spiro[cyclohexane -1,1'-furo[3,4-c]pyridin]yl, 3-azabicyclo[3.1.0]hexanyl, 3-azabicyclo[3.1.0]hexan-3-yl, 1,4,5,6- tetrahydropyrrolo[3,4c]pyrazolyl, 3,4,5,6,7,8-hexahydropyrido[4,3-d]pyrimidinyl, 4,5,6,7-tetrahydro-1H-pyrazolo[3,4c]pyridinyl, 5,6,7,8-tetrahydropyrido[4,3-d]pyrimidinyl, 2-azaspiro[3.3]heptanyl, 2-methyl-2- 5 044707 azaspiro[3.3]heptanyl, 2-azaspiro[3.5]nonanyl, 2- methyl-2-azaspiro[3.5]nonanyl, 2-azaspiro[4.5]decanyl,

2-methyl-2-azaspiro[4.5]decanyl, 2-oxaazaspiro[3.4]octanyl, 2-oxaazaspiro[3.4]octan-6-yl, etc. In the case of multicyclic non-aromatic rings, only one of the rings must be non-aromatic (eg 1,2,3,4-tetrahydronaphthalenyl or 2,3-dihydroindole).

As used herein, the term optionally substituted alkyl refers to unsubstituted alkyl or alkyl containing the specified substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonyl then, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro , trifluoromethyl , cyano, azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

As used herein, the term alkenyl includes unsaturated aliphatic groups similar in length and possible substitution to the alkyls described above, but containing at least one double bond. For example, the term alkenyl includes straight-chain alkenyl groups (eg, ethenyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl) and branched alkenyl groups. In certain embodiments, the straight-chain or branched alkenyl group contains six or fewer carbon atoms in its backbone (eg, C ₂ -C6 for straight-chain, C3-C6 for branched). The term C2-C6 includes alkenyl groups containing from two to six carbon atoms. The term C3-C6 includes alkenyl groups containing from three to six carbon atoms.

As used herein, the term optionally substituted alkenyl refers to unsubstituted alkenyl or alkenyl containing the specified substituents replacing one or more hydrogen atoms on one or more carbon atoms of the hydrocarbon backbone. Such substituents may include, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonyl then, phosphinato, amino (including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro , trifluoromethyl , cyano, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety.

Other optionally substituted moieties (such as optionally substituted cycloalkyl, heterocycloalkyl, aryl or heteroaryl) include both unsubstituted moieties and moieties containing one or more of these substituents. For example, substituted heterocycloalkyl includes heterocycloalkyls substituted with one or more alkyl groups, such as 2,2,6,6-tetramethylpiperidinyl and 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridinyl.

As used herein, the term aryl includes aromatic groups, including conjugated or multicyclic systems, containing one or more aromatic rings and not containing any heteroatom in the ring structure. The term aryl includes both monovalent moieties and divalent moieties. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. By way of illustration, aryl is phenyl.

As used herein, the term heteroaryl is intended to include a stable 5-, 6-, or 7-membered monocyclic or 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic aromatic heterocyclic ring that consists of carbon atoms and one or more heteroatoms, for example 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, regardless selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen atom may be substituted or unsubstituted (ie N or NR, where R represents H or other specified substituents). The nitrogen and sulfur heteroatoms may optionally be oxidized (ie 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 does not exceed 1. Examples of heteroaryl groups include pyrrole, furan, thiophene, thiazole, isothiazole, imidazole, triazole, tetrazole, pyrazole, oxazole, isoxazole, pyridine, pyrazine, pyridazine, pyrimidine and so on.

In addition, the terms aryl and heteroaryl include multicyclic aryl and heteroaryl groups, for example tricyclic, bicyclic, for example naphthalene, benzoxazole, benzodioxazole, benzothiazole, benzoimidazole, benzothiophene, quinoline, isoquinoline, naphthyridine, indole, benzofuran, purine, benzofuran, desapurine, indolizine.

A cycloalkyl, heterocycloalkyl, aryl or heteroaryl ring may be substituted at one or more positions of the ring (for example, at a ring-forming carbon atom or at a heteroatom such as N) with the substituents described above, such as, for example, alkyl, alkenyl, alkynyl, halogen, hydroxyl, alkoxy, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, alkylaminocarbonyl, aralkylaminocarbonyl, alkenylaminocarbonyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, alkenylcarbonyl, alkoxycarbonyl, aminocarbonyl, alk ylthiocarbonyl, phosphate, phosphonato, phosphinato, amino (including alkylamino , dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl , cyano, an azido, heterocyclyl, alkylaryl, or an aromatic or heteroaromatic moiety. Aryl and heteroaryl groups can also be fused or bridged to alicyclic or heterocyclic rings that are not aromatic, thereby forming a multicyclic system (e.g., tetralin, methylenedioxyphenyl, such as benzo[d][1,3]dioxol-5 -il).

As used herein, the term substituted means that one or more hydrogen atoms on a specified atom are replaced by a selection from the specified groups, provided that the normal valency of the specified atom is not exceeded and that the substitution results in a stable compound. If the substituent is oxo or keto (i.e. =O), then 2 hydrogen atoms are replaced per atom. Keto substituents are not present on aromatic moieties. As used herein, double ring bonds are double bonds that form between two adjacent ring atoms (eg, C=C, C=N, or N=N). The terms stable compound and stable structure are intended to denote a compound that is sufficiently robust to withstand purification to a suitable degree of purity from a reaction mixture and the process of incorporation into an effective therapeutic agent.

If a bond to a substituent is represented as intersecting a bond to the connecting two atoms in the ring, then the substituent can be bonded to any atom on the ring. If a substituent is described without specifying the atom through which such substituent is linked to the remainder of the compound of a given form, then such substituent may be linked through any atom in such formula. Combinations of substituents and/or variables are acceptable as long as such combinations result in stable compounds.

If a variable (for example, R) appears more than once in any part or formula of a compound, then its definition in each occurrence is independent of its definition in each other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R moieties, then the group may be optionally substituted with up to two R moieties, and in each case R is independently selected from the R variants. In addition, combinations of substituents and/or variables are acceptable , but only on the condition that such combinations lead to stable compounds.

As used herein, the term hydroxy or hydroxyl includes groups with -OH or -O ^- .

As used herein, the term halogen or halogen refers to fluorine, chlorine, bromine and iodine.

As used herein, the term alkoxy or alkoxyl includes substituted and unsubstituted alkyl, alkenyl and alkynyl groups covalently bonded to an oxygen atom. Examples of alkoxy groups or alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropyloxy, propoxy, butoxy and pentoxy groups. Examples of substituted alkoxy groups include halogenated alkoxy groups. Alkoxy groups may be substituted with groups such as alkenyl, alkynyl, halogen, hydroxyl, alkylcarbonyloxy, arylcarbonyloxy, alkoxycarbonyloxy, aryloxycarbonyloxy, carboxylate, alkylcarbonyl, arylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylthiocarbonyl, alkoxyl, phosphate, phosphonato, phosphinato, amino ( including alkylamino, dialkylamino, arylamino, diarylamino and alkylarylamino), acylamino (including alkylcarbonylamino, arylcarbonylamino, carbamoyl and ureido), amidino, imino, sulfhydryl, alkylthio, arylthio, thiocarboxylate, sulfates, alkylsulfinyl, sulfonato, sulfamoyl, sulfonamido, nitro, trifluoromethyl, cyano, azido, heterocyclyl, alkylaryl, or aromatic or heteroaromatic moieties. Examples of halogen-substituted alkoxy groups include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, dichloromethoxy and trichloromethoxy.

Unless otherwise specified, as used herein, the expressions one or more of A, B or C, one or more of A, B or C, one or more of A, B and C, one or more of 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 a selection from the group consisting of A, B and/or C, i.e. one or more A's, one or more B's, one or more C's, or any combination thereof.

It should be understood that the present invention relates to methods for synthesizing compounds according to any of the formulas described herein. The present invention also provides detailed methods for synthesizing the various disclosed compounds of the present invention in accordance with the following schemes, as well as the compounds presented in the Examples section.

It should be understood that throughout the present description, if the compositions are described as

- 7 044707 characterized by, including or containing specific components, this provides that the compositions also consist, or essentially consist, of the listed components. By analogy, if methods or processes are described as being characterized by, including or containing specific technological steps, then the processes also consist of, or essentially consist of, the listed technological steps. In addition, it should be understood that the sequence of steps or the order in which certain actions are performed is not important as long as the present invention remains usable. Moreover, two or more stages or activities may be performed simultaneously.

It should be understood that the synthetic processes of the present invention can tolerate a wide range of functional groups, so a variety of substituted starting materials can be used. The processes typically produce the desired end compound at or near the end of the overall process, although in certain cases it may be desirable to convert the compound to its pharmaceutically acceptable salt.

It should be understood that the compounds of the present invention can be prepared in a variety of ways using commercially available starting materials, compounds known from the literature, or from readily prepared intermediates, using standard synthetic methods and techniques that are either known to those skilled in the art , or will become apparent to one skilled in the art in light of the ideas set forth herein. Standard synthetic methods and techniques for preparing organic molecules, as well as transformations and operations with functional groups, can be obtained from the relevant scientific literature or from standard textbooks in the field. Without being limited to any one or more sources, classic works 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 useful and established references to organic synthesis known to those skilled in the art.

One of ordinary skill in the art will appreciate that during the reaction sequences and synthesis schemes described herein, the sequence of certain steps, such as introduction and deprotection, may be altered. One of ordinary skill in the art will be able to determine that certain groups may require protection from reaction conditions through the use of protecting groups. Protecting groups can also be used to distinguish between similar functional groups in molecules. A list of protecting groups and methods for introducing and removing such 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 indicated, any description of a method of treatment includes the use of compounds to provide such treatment or prevention as described herein, as well as the use of compounds for the preparation of a medicament for the treatment or prevention of such condition. Treatment includes treatment of humans or non-human animals, including rodents and other disease models.

As used herein, the term subject is interchangeable with the term subject in need, both terms referring to a subject having a disease or having an increased risk of developing a disease. The term subject includes a mammal. The mammal may be, for example, a human or a suitable non-human mammal such as a primate, mouse, rat, dog, cat, cow, horse, goat, camel, sheep or pig. The subject may also be a bird or poultry. In one embodiment, the mammal is a human. The subject in need thereof may be a subject who has previously been diagnosed or determined to have an imprinting disorder. The subject in need of this may also be a subject who has (eg suffers from) an imprinting disorder. Alternatively, the subject in need may be a subject who has an increased risk of developing such a disorder compared to the population as a whole (ie, a subject who is predisposed to developing such a disorder compared to the population as a whole). The subject in need thereof may have a difficult-to-treat or resistant imprinting disorder (ie, an imprinting disorder that is not or has not yet responded to treatment). The subject may be resistant at the start of treatment or may become resistant during treatment. In some embodiments, the subject in need has received all known effective drugs for the imprinting disorder and has not responded to them. In some embodiments, the subject in need has received at least one prior therapy. In a preferred embodiment, the subject has an imprinting disorder.

- 8 044707

As used herein, the term treat or treat describes the management and care of a patient to combat a disease, condition or disorder, and includes the administration of a compound of the present invention or a pharmaceutically acceptable salt thereof to relieve symptoms or complications of the disease, condition or disorder, or to eliminate diseases, conditions or disorders. The term treat may also include treatment of a cell in vitro or an animal model.

It should be understood that a compound of the present invention or a pharmaceutically acceptable salt thereof may also be used for the prevention of a corresponding disease, condition or disorder, or used to identify suitable candidates for these purposes.

As used herein, the term prevent, prevent, or protect against describes the reduction or elimination of the onset of symptoms or complications of such a disease, condition, or disorder.

It should be understood that one skilled in the art may refer to general reference literature for detailed descriptions of the known techniques discussed herein or equivalent techniques. References include Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Inc. (2005); Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd edition), 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 edition (1990). The above literature may of course be referenced in the preparation or practice of an aspect of the present invention.

It should be understood that the present invention also relates to pharmaceutical compositions containing any compound described herein in combination with at least one pharmaceutically acceptable excipient or carrier.

As used herein, the term pharmaceutical composition is a composition containing the compounds of the present invention in a form suitable for administration to a subject. In one embodiment, the pharmaceutical composition is a bulk dosage form or unit dosage form. The unit dosage form is any of a variety of forms, including, for example, a capsule, an intravenous bag, a tablet, a single pump on an aerosol inhaler, or a vial. The amount of active ingredient (eg, a compound of the present invention or a pharmaceutically acceptable salt thereof) in a unit dose of the composition is an effective amount and will vary according to the particular treatment being used. One skilled in the art will understand that routine dosage adjustments may sometimes need to be prepared depending on the age and condition of the patient. The dosage will also depend on the route of administration. A variety of routes of administration are available, including oral, pulmonary, rectal, parenteral, transdermal, subcutaneous, intravenous, intramuscular, intraperitoneal, inhalation, buccal, sublingual, intrapleural, intrathecal, intranasal, and the like. Dosage forms for topical or transdermal administration of a compound of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. In one embodiment, the active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives, buffers, or propellants.

As used herein, the term pharmaceutically acceptable refers to those compounds, anions, cations, substances, compositions, carriers and/or dosage forms that, within the bounds of sound medical judgment, are suitable for use in contact with tissues of humans and animals without causing excessive toxicity, irritation , allergic response or other problems or complications, commensurate with an acceptable benefit/risk ratio.

As used herein, the term pharmaceutically acceptable excipient means an excipient that is useful for the preparation of a pharmaceutical composition that is generally safe, non-toxic, and not biologically or otherwise objectionable, and includes an excipient that is acceptable for veterinary use, as well as for pharmaceutical use in humans. As used herein and in the claims, the term pharmaceutically acceptable excipient includes one or more such excipients.

It should be understood that the pharmaceutical composition according to the present invention is formulated so that it is compatible with the intended route of administration. Examples of the route of administration include parenteral, eg, intravenous, intradermal, subcutaneous, oral (eg, inhalation), transdermal (topical), and transmucosal. Solutions or suspensions used for parenteral, intradermal or subcutaneous use may include the following components: a sterile diluent such as water for injection, saline, fatty oils, polyethylene glycols, glycerin, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid;

- 9 044707 buffer agents such as acetates, citrates or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. The pH value can be adjusted using acids or bases such as hydrochloric acid or sodium hydroxide. The parenteral drug may be placed in ampoules, single-use syringes, or multi-dose vials made of glass or plastic.

It should be understood that the compound or pharmaceutical composition of the present invention can be administered to a subject by many well known methods used today for chemotherapy treatment. For example, the compound of the present invention can be administered by injection into the bloodstream or body cavities, or taken orally, or applied to the skin through patches. The dose chosen should be sufficient to provide effective treatment, but not so high as to cause unacceptable side effects. The status of the disease state (eg, imprinting disorders, etc.) and the patient's health status should preferably be closely monitored during treatment and for a reasonable period after treatment.

As used herein, the term therapeutically effective amount refers to an amount of a pharmaceutical agent to treat, alleviate, or prevent a specified disease or condition, or to produce a detectable therapeutic or inhibitory effect. The effect can be determined by any method of analysis known in the art. The exact effective amount for a subject will depend on the subject's body weight, size and medical condition; on the nature and degree of the condition; and on the therapeutic agent or combination of therapeutic agents selected for administration. Therapeutically effective amounts in a given situation can be determined by routine experimentation within the bounds of the experience and judgment of the attending physician. In a preferred aspect, the disease or condition being treated is an imprinting disorder.

It should be understood that for any compound, the therapeutically effective amount can be assessed initially both in cell culture assays, such as neoplastic cells, and in animal models, typically rats, mice, rabbits, dogs or pigs. The animal model can also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine applicable doses and routes of administration in humans. Therapeutic/prophylactic efficacy and toxicity can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example ED5 ₀ (dose therapeutically effective in 50% of the population) and LD ₅₀ (dose lethal in 50% of the population). The dose ratio between toxic and therapeutic effects represents the therapeutic index, and it can be expressed as the ratio LD ₅₀ /ED ₅₀ . Pharmaceutical compositions that exhibit high therapeutic indices are preferred. The dosage may vary within these limits depending on the dosage form used, the sensitivity of the patient and the route of administration.

Dosage and administration are adjusted to provide sufficient levels of the active ingredient(s) or to maintain the desired effect. Factors that may be taken into account include the severity of the disease state, the general health of the subject, the age, weight and sex of the subject, diet, timing and frequency of administration, drug combination(s), sensitivity response and tolerance/response to therapy. Long-acting pharmaceutical compositions can be administered every 3-4 days, every week, or once every two weeks, depending on the half-life and elimination rate of the particular composition.

Pharmaceutical compositions containing the active compounds of the present invention can be produced by a generally known method, for example, by conventional processes of mixing, dissolving, granulating, dragee preparation, trituration, emulsification, encapsulation, encapsulation or lyophilization. Pharmaceutical compositions can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers containing excipients and/or auxiliaries to facilitate processing of the active compounds into preparations that can be used pharmaceutically. Of course, the appropriate formulation depends on the route of administration chosen.

Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (in the case of water-soluble) or dispersions and sterile powders for the immediate preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable vehicles include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). In all cases, the composition must be sterile and must be fluid to such an extent that it can be easily administered by syringe. It must be stable under the conditions of production and storage, and must be protected from the contaminating action of microorganisms such as bacteria and fungi. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, a polyol (eg, glycerin, propylene glycol and liquid polyethylene glycol, etc.), and suitable mixtures thereof. Suitable fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the desired particle size in the case of a dispersion, and by the use of surfactants. Prevention of the action of microorganisms can be achieved through various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, etc. In many cases it will be preferable to include isotonic agents such as sugars, polyalcohols such as mannitol and sorbitol, and sodium chloride in the composition. Prolonged absorption of injectable compositions can be achieved by including in the composition an agent that delays absorption, for example, aluminum monostearate and gelatin.

Sterile injection solutions can be prepared by introducing the active compound in the required amount into a suitable diluent with one or a combination of the ingredients listed above, if necessary, followed by sterilization by filtration. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains the basic dispersion medium and other necessary ingredients from those listed above. In the case of sterile powders for the preparation of sterile injectable solutions, the preparation methods are vacuum drying and lyophilization, whereby a powder of the active ingredient plus any additional desired ingredient is obtained from its solution previously sterilized by filtration.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be formulated together with excipients and may be used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouth rinse, in which the compound in the liquid carrier is administered orally and rinsed and spit out or swallowed. Pharmaceutically acceptable binders and/or excipients may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose; a leavening agent such as alginic acid, Primogel or cornstarch; a lubricant such as magnesium stearate or Sterotes; a glidant such as fumed silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

For administration by inhalation, the compounds are delivered in the form of an aerosol spray from a pressurized container or dispenser that contains a suitable propellant, for example a gas such as carbon dioxide, or a nebulizer.

Systemic administration can also be transmucosal or transdermal. For transmucosal or percutaneous administration, the composition uses penetrants suitable for overcoming the relevant barrier. Such penetrants are well known in the art and include, for example, detergents, bile salts and fusidic acid derivatives for transmucosal administration. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated as ointments, balms, gels or creams, which are generally known in the art.

The active compounds can be formulated together with pharmaceutically acceptable carriers that will protect the compound from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters and polylactic acid can be used. Methods for preparing such compositions will be apparent to one skilled in the art. These substances can also be purchased commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeting infected cells with monoclonal antibodies to viral antigens) can also be used as pharmaceutically acceptable carriers. They can be prepared in accordance with methods known to one skilled in the art, for example, as described in US Pat. No. 4,522,811.

It is particularly advantageous to formulate oral or parenteral compositions in unit dosage form for ease of administration and versatility in dosage. As used herein, the term unit dosage form refers to physically discrete units corresponding to unit dosages for the subject to be treated; each unit contains a predetermined amount of active compound calculated to produce the desired therapeutic effect, together with the required pharmaceutical carrier. The specification for unit dosage forms according to the present invention is dictated by and directly depends on the unique characteristics of the active compound and the particular therapeutic effect achieved.

For therapeutic applications, among other factors influencing the chosen dosage,

- 11 044707 dosages of the pharmaceutical compositions used in accordance with the present invention vary depending on the agent, age, weight and clinical condition of the recipient patient, and on the experience and judgment of the clinician or practitioner administering the therapy. Typically, the dose will be sufficient to cause a delay and preferably a regression of the symptoms of the imprinting disorder, and also preferably causing complete regression of the imprinting disorder. Dosages may vary from approximately 0.01 mg/kg per day to approximately 5000 mg/kg per day. In preferred aspects, dosages can range from about 1 mg/kg per day to about 1000 mg/kg per day. In one aspect, dosages may range from about 0.1 mg per day to about 50 g per day; about 0.1 mg per day to about 25 g per day; about 0.1 mg per day to about 10 g per day; about 0.1 mg per day to about 3 g per day; or about 0.1 mg per day to about 1 g per day, given as single, divided, or continuous doses (which dose may be adjusted based on the patient's body weight in kg, body surface area in m ² and age in years). An effective amount of a pharmaceutical agent is that amount that produces an objectively measurable improvement as noted by a clinician or other qualified observer. Improvement in survival and growth indicates regression. As used herein, the term effective dosing method refers to the amount of active compound to produce the desired biological effect in a subject or cell.

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

It should be understood that for compounds of the present invention that are capable of further forming salts, all of these forms also fall within the scope of the claimed invention.

As used herein, the term pharmaceutically acceptable salts refers to derivatives of the compounds of the present invention wherein the parent compound is modified by preparing salts thereof with acids or bases. Examples of pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of basic moieties such as amines, alkali or organic salts of acid moieties such as carboxylic acids, and the like. Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, salts derived from inorganic or organic acids selected from 2-acetoxybenzoic, 2-hydroxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarboxylic, carboxylic, citric, ethylenediaminetetraacetic, ethanedisulfonic, 1,2- ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycol, glycoliarsanilic, hexylresorcinolic, hydrabamic, hydrobromic, hydrochloric, hydroiodic, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl sulfonic, maleic, malic, almond, methanesulf onic acid, naphthalene sulfonic acid, nitric acid, oxalic acid, pamic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, salicylic, stearic, succinic, aminosulfonic, sulfanilic, sulfuric, tannic, tartaric, toluenesulfonic acids or commonly used amino acids such as glycine, alanine, phenylalanine, arginine and the like.

Other examples of pharmaceutically acceptable salts include caproic 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, tertiary butylacetic acid, muconic acid and the like. The present invention also covers salts formed when the acid proton present in the parent compound is either replaced by a metal ion, for example an alkali metal ion, an alkaline earth metal ion or an aluminum ion; or coordinated with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine and the like. With respect to salt forms, it is understood that the ratio of the compound to the cation or anion of the salt may 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 references to pharmaceutically acceptable salts include solvent added forms (solvates) or crystalline forms (polymorphs) of the same salt as defined herein.

It should be understood that the compounds of the present invention may also be formulated as esters, such as pharmaceutically acceptable esters. For example, the carboxylic acid functionality in a compound can be converted to its corresponding ester, such as a methyl, ethyl or other ester. Additionally, the alcohol group in a compound can be converted to its corresponding ester, such as an acetate, propionate, or other ester.

The compounds or pharmaceutically acceptable salts thereof are administered orally, nasally, transdermally, pulmonaryly, inhalation, buccally, sublingually, intraperitoneally, subcutaneously, intramuscularly,

- 12 044707 intravenously, rectally, intrapleurally, intrathecally and parenterally. In one embodiment, the compound is administered orally. One skilled in the art will determine the advantages of certain routes of administration.

The dosage regimen of the compounds used is selected according to a number of factors including the type, species, age, weight, sex and medical condition of the patient; the severity of the condition being treated; route of administration; the patient's kidney and liver function; and the particular compound or salt thereof used. A qualified physician or veterinarian can easily determine and prescribe the effective amount of medication required to prevent, counteract, or stop the progression of the condition.

Methods for formulation and administration of the disclosed compounds of the present invention 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 used in pharmaceutical preparations in combination with a pharmaceutically acceptable carrier or diluent. 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 quantities sufficient to provide the desired dosage size within the limits described herein.

Unless otherwise noted, all percentages and ratios used herein are by weight. Other features and advantages of the present invention are apparent from various examples. The accompanying examples illustrate various components and methodology suitable for practice of the present invention. The examples do not limit the claims. Based on the present invention, one skilled in the art will be able to identify and use various components and methodology suitable for practicing the present invention.

In the synthesis schemes described herein, the compounds may be depicted in one specific configuration for simplicity. Such specific configurations should not be construed as limiting the present invention to any one isomer, tautomer, regioisomer or stereoisomer, and should not exclude mixtures of isomers, tautomers, regioisomers or stereoisomers; however, it should be understood that a given isomer, tautomer, regioisomer or stereoisomer may have a higher level of activity than another isomer, tautomer, regioisomer or stereoisomer.

All publications and patent documents cited herein are incorporated herein by reference as if each publication or document individually were expressly stated to be incorporated herein by reference. Citation of publications and patent documents is not intended to imply that any or any of them constitute relevant prior art, nor does it provide a basis for such an assumption as to their content or date. Having taken into account the present invention as disclosed by way of description, one skilled in the art will recognize that the present invention may be practiced in a variety of embodiments and that the foregoing description and the following examples are presented for illustrative purposes and not for the purpose of limitation of the following claims.

As used herein, the expression compound of the present invention refers to compounds that are disclosed herein, both generally and more specifically.

Compounds according to the present invention.

In some aspects, the present invention provides a compound of formula (I)

or a pharmaceutically acceptable salt thereof, wherein R ₁ is

a) C8-C16 polycyclic cycloalkyl, optionally substituted with one or more R6;

b) benzofuranyl or dihydrobenzofuranyl, optionally substituted with one or more R ₆ ;

- 13 044707

R3 is H or C1- _C4 alkyl, optionally substituted by one or more R7;

R4 represents H, C ₁ -C ₆ alkyl, -(CH ₂ ) ₀ . ₃ -(C ₃ -C ₆ -cycloalkyl) or -(CH ₂ ) ₀ . ₃ -C ₆ -aryl;

R6 is C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkyl, halogen, oxo, -OH, -CN, -NH2, -NH (C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF3;

R7 is -OR8, C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl, wherein C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl is optionally substituted by one or more R7S, wherein each R7S is independently C ₁ -C ₆ -alkyl, C ₁ -C ₆ -alkoxy, 5-10-membered heteroaryl, halogen, -OH, -CN, -(CH ₂ ) _0-3 -NH ₂ , -(CH ₂ ) _0-3 -NH(C ₁ -C ₆ -alkyl), -(CH ₂ ) _0-3 -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF3; And

R8 is a C ₁ -C ₆ -alkyl or 5-7 membered heterocycloalkyl, wherein the C ₁ -C ₆ -alkyl or 5-7 membered heterocycloalkyl is optionally substituted by one or more R7S, wherein said heterocycloalkyl rings contain from 1 to 6 heteroatoms , selected from O, N, S,

- 14 044707

P and Se, and wherein said heteroaryl rings contain from 1 to 6 heteroatoms selected from N, O and S.

For a compound of formula (I), it is intended that each R1, R3, _R4 , _R6 , _R7 , _R7S and R8 may be selected, as applicable, from the groups described herein, and any group described herein document for any of R1, R3, R4, _R6 , _R7 , _R7S and R8, may be combined, when applicable, with any group described herein for one or more of the remaining of Ri, R3, R4, R6, R7, R7S and R8.

In some embodiments, R1 is C ₈ -C ₁₆ -cycloalkyl, polycyclic cycloalkyl, optionally substituted with one or more C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₃ groups -C ₈ -cycloalkyl, halogen, oxo, -OH, -CN, -NH ₂ , -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF ₃ .

In some embodiments, R1 is

In some embodiments, R3 is C1- _C4 alkyl, optionally substituted with one or more groups selected from -OR8, _C5 - _C1 o-aryl, and 5-10 membered heteroaryl.

In some embodiments, R3 is methyl substituted with one or more 5-10 membered heteroaryls, wherein the 5-10 membered heteroaryl is optionally substituted with one or more _C1 - _C6 alkyls, _C1 - _C6 alkoxy, halogens, -CN, -(CH ₂ ) _0-3 -N(C ₁ -C ₆ -alkyl) ₂ or -CF3.

In some embodiments, R3 is

- 15 044707

In some embodiments, R4 is H.

In some embodiments, R4 is C ₁ -C ₆ alkyl, -(CH ₂ ) ₀ . ₃ -(C ₃ -C ₆ cycloalkyl) or -(CH ₂ ) ₀ . ₃ -C ₅ -C ₆ -aryl.

In some embodiments, R ₄ is methyl, ethyl, propyl, butyl,

In some embodiments, at least one R ₇ is a 5-10 membered heteroaryl, optionally substituted with one or more groups selected from halogen, -OH, -CN, -(CH ₂ ) ₀ . ₃ -NH2, -(CH ₂ ) ₀ - ₃ -NH(C ₁ -C ₆ -alkyl), -(CH ₂ ) ₀ . ₃ -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF3.

In some embodiments, the compound is a compound of formulas (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), ( IVb), (V), (Va), (Vb), (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIII), (VIIIa), (VIIIb) , (IX), (IXa), (IXb), (X), (Xa) or (Xb):

- 16 044707

- 17 044707

- 18 044707

or a pharmaceutically acceptable salt thereof.

It is intended that for a compound according to any one of formulas (I)-(X), (Ia)-(Xa) and (Ib)-(Xb), each of R1, R3, R4, R6, R7, R7S and R8 can be selected , when applicable, from the groups described herein, and any group described herein for any of R1, R3, R4, R6, R7, R7S, and R8 may be combined, as applicable, with any group described herein for one or more of the remainder of R1, R3, _R4 , R6, R7, R7S and R8.

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

Table 1

Connection No. Structure Name 1 ΓΆ A/o /¾. A J o x- / А- N '0' γ VJ n g Ethyl-2 - {[(1,2,3,5,6,7 - hexahydro-sind acen-4-yl)carbamoyl]oxy} acetate % OZO _ 7 ΐ °’ t Ethyl-2-{ [(2,6- difluorophenyl)carbamoyl]oxy}acetate 3 Zh'Zh' ^{and ΰ} 1. A . O . -γ Ν O' A Cl ^rf 0 Ethyl-2-{[(2,6- d ichlorophenyl)carbamoyl ] oxy } acetate 4 . ii; . ,- n π - Ethyl 2-{[(naphthalene-1 yl)carbamoyl]oxy} acetate

- 19 044707

$ .. ¹ _μ 0 Ι -Χ,Ν Ο,>. U 2 ⁰ ' Ethyl 2-{[(2,2-dimethyl-2,3-dihydro-1 benzofuran-7-yl)carbamoyl]oxy} acetate 6 o ^H y - h O ¹ * ZX QV H\ M ] Ethyl 2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy}-3 methoxypropanoate 7 _ W A / IZ\/ O-C / \ Ethyl 2-({[2-fluoro-5(trifluoromethyl)phenyl]carbamoyl}oxy)acetate 8 GHD. .... O . t If °' T'“ Ethyl-2-{[(2,6- dimethylphenyl)carbamoyl]oxy}acetate 9 C1 .1 ..... .o.... ζ . -O j -.- Ethyl-2-{[(2,6- diethylphenyl)carbamoyl] oxy} acetate 10 Il O Ά O T and V y - CI 0 Ethyl 2-({ [2-(chloro-6methylphenyl)carbamoyl] oxy } acetate eleven Ch d l o ..· T · «°' Ύ ~ CN ^p O Ethyl-2-{[(2- cyanophenyl)carbamoyl] oxy } acetate 12 GL ' „ ..-:· ,Ν ιι. .eleven.; g g N O' ΑΧ. / N l ‘ Ί Ethyl 2-{[(1,2,3,5,6,7-hekcahydro-syndacen-4-yl)carbamoyl]oxy}-3(pyr idin-3-yl)propanoate 13 0.,.1, .0. , γ m _n 1 ⁿ η Ethyl-2-{\(2-tert- butylphenyl)carbamoyl]oxy} acetate 14 11 i. s , Ν''Ν''O''< I ⁿ d Ethyl 2-((mesitylcarbamoyl)oxy)acetate 15 Ρ^ ⁴ Ί ^and L ⁿ o Ethyl-2-(((2- isopropylphenyl)carbamoyl)oxy)acetate 16 L d ν. „ J ⁿ 0 Ethyl-2-(((2-ethyl-6- methylphenyl)carbamoyl)oxy)acetate 17 ...o ,0 ί d $.;.; vJ' n ^s g Ethyl 2-(((1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl)oxy)-3 phenylpropanoate

- 20 044707

18 Г, 1 Ί Il Ϊ Г □ J Ή Ethyl 2-(((1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl)oxy)-3 (pyridin-2-yl)propanoate 19 t\ XSf ⁰ : U-, K k ,< o _h ( G Y ^ϋ G V- ^{J po} Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4yl)carbamoyl]oxy}propanoate 20 ,g>f-. Ϊ. Ϊ -..O. , \J Ή ⁰ ί 'Г Propan-2-yl-2-{ [(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy } acetate 21 1 .ί-=ΖΓ·< V \\ Χ-Ο ο Α G / 2-{[(1,2,3,5,6,7-G hexahydro-3-indacen-4yl)carbamoyl]oxy} acetate 22 ί 7—\ / \ □ ο 4 ό /b ¥ Cyclopropylmethyl-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy} acetate 23 /Ϊ I - ,0, <Χ η °' ι X/ Cyclobutyl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy} acetate 24 /d '>=ο / ( ο Ο“< ,, ΖΙ g >, - ί Μ χ. '^—4 1 2-methylpropyl-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy} acetate 25 G 7¾ ... \ // v, ' </ 7 Q ρ .... Μ 4.. Ethyl 3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate 26 rf^ ο Ν ,5 U ο V'ν'·o''y 1 ^Η Ω -X χ. Ethyl 2-({ [2-methyl-6-(propan-2yl)phenyl] carbamoyl} oke i)acetate

- 21 044707

27 Γ”λ Λ > Г 0 1. And he \ Ύ И '° Г VJ ^π ο 2-{[(1,2,3,5,6,7-G hexahydro-3-indacen-4yl)carbamoyl]oxy}acetic acid 28 ο Vo\ ρ o V -------------------.. \___/ CH/ Ethyl 2-{[(2, b-diethyl-4methylphenyl)carbamoyl]oxy}acetate 29 Γ>I l . _ο Ο 4 °' X Methyl-2-{[(1,2,3,5,6,7-hexahydro-8- indacen-4-yl)carbamoyl]oxy}acetate thirty \ν \ - '' ^Ί Χ~\ j ΊΣΖ JPD \ 4 \ Ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl]oxy}-4phenylbutanoate 31 Μ' ν _Ί ,ν< ,j τζ d \ Α Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 -(1Hpyrazol-1 -yl)propanoate 32 ,^Ο 0 A A l ο \J η 'θ’ ϊ X? Cyclopentyl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy} acetate 33 X / _(! dJ ^N 1 ί. ί 1 0 XX ь '°' к '' Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 -(1Nimidazol-1-yl)propanoate 34 A- O X o Ethyl 2-({ [2,6-bis(propan-2yl)phenyl] carbamoyl} oke i)acetate 35 F MV sdl^ Cl ⁿ 0 Ethyl 2-({[2-chloro-5-(trifluoromethyl)phenyl]carbamoyl}oxy)acetate

- 22 044707

36 TH o o Ethyl 2-{[(2-tert-butyl-6methylphenyl)carbamoyl]oxy} acetate 37 AL a H g Ethyl-2-{[(2.5- dimethylphenyl)carbamoyl]oxy}acetate 38 Έ О — ^=O о °=< ^ZI 2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy}-3- methoxypropanoic acid 39 IZ >°o cyclopropyl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy } acetate 40 θΛ ^Λ Α ^ΟΗ μ ⁿ o 2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy}-3 -(1H-pyrazol-1yl)propanoic acid 41 _Ζ3 __ΛΛ \=/ \=O о °к Ethyl-(2C)-3 -(3-cyanophenyl)-2{[(1,2,3,5,6,7-hexahydro-z-indacen-4yl)carbamoyl]oxy}propanoate 42 -D N Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy} -3 - [3 -(1Hpyrazol-1-yl)phenyl]propanoate 43 N Ethyl-(2H)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy} -3 - [3 -(1Hpyrazol-1-yl)phenyl ]propanoate 44 M-nN'Q ⁰ -/ F ^H 0 Ethyl 2-{[(2,6difluorophenyl)carbamoyl]oxy}-3-111pyrazol-1-yl)propanoate

- 23 044707

45 P IZ o Ethyl 2-[(phenylcarbamoyl)oxy]-3-(1Hpyrazol-1-yl)propanoate 46 0# Ethyl-2-{[(2-ethyl-6- methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 47 -Ζ~Λ >° O o=/Z—, ABOUT Ethyl 2-{[(2,6dimethylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 48 Ethyl-2-{[(2,6- diethylphenyl)carbamoyl]oxy} -3 -(1Hpyrazol-1 -yl)propanoate 49 Cq ₀ o °P h ZT V/ Ethyl-2-{[(2-fluoro-6- methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 50 p> IZ Q )-° o O=/ Z —. C ^g 0 Ethyl 2-{[(2-chloro-6fluorophenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 51 -^θ· IZ ^Z Q >o О о=/ z—. ζ =0 Ethyl-2-{[(2-chloro-6- methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 52 cq «о °=( Ο ζτ V/ ^δ Ethyl 2-{[(2,6dichlorophenyl)carbamoyl]oxy}-3 -(1Hpyrazol-1-yl)propanoate 53 L * °\_ L-Z Y=O ABOUT °K Ethyl 2-[(cyclohexylcarbamoyl)oxy]-3(1H-pyrazol-1-yl)propanoate 54 /-η 0 ^H 0 Ethyl 2-[(cyclopentylcarbamoyl)oxy]3 -(1H-pyrazol-1-yl)propanoate

- 24 044707

55 Ν Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2{[(1,2,3,5,6,7-hexahydro-8-ind acen-4yl)carbamoyl]oxy}propanoate 56 0 I ζ >° ο Ο=( Ζ—, ο Ethyl 2-[(cycloheptylcarbamoyl)oxy]-3(1H-pyrazol-1-yl)propanoate 57 Ν Ethyl-2-{[(2-cyano-6- methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 58 Ν Ethyl 2-{[(2-cyano-6ethylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 59 ^ζ ^Ο ΐζ' Q >° ο Ο=( Ζ -. Ο ^ζ χ3 Ethyl-2-{[(2-chloro-6- cyanophenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 60 ζ ζ >° ο ο=^~~^=\ Ο Ethyl 2-{[(1,2,3,5,6,7-hexahydrosindacen-4-yl)carbamoyl]oxy}-3(pyrazin-2-yl)propanoate 61 ^AoV VJ ^no (2R)-2-{[(1,2,3,5,6,7-heκcahydro-syndacen-4-yl)carbamoyl]oxy}-3-(lHπyrazol-l-yl)πpoπanoic acid 62 С=/ \=о о °к ZZ Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8indacen-4-yl)carbamoyl]oxy}-3(pyridazin-3-yl)propanoate 63 fSA^-' F ^H 0 Ethyl-3-(1H-pyrazol-1-yl)-2-{[(2,3,6trifluorophenyl)carbamoyl]oxy} propanoate

- 25 044707

64 A tf v o °=< .. ^{z T} Benzyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]-oxy}-3 -(1Hpyrazol-1 -yl)propanoate 65 i? +~Z 2=0 О °4 ^{H x} Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy}-3 -(1Hpyrazol-1-yl)propanoate 66 Cq= _o o °=< LL. ZT Ethyl 2-{[(2-ethyl-bfluorophenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 67 Iz >° o °fb Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy}-3 -(1Nimidazol-1-yl)propanoate 68 o - ^=Q o °4. ² - ¹ v^q Ethyl-(2I)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl]oxy}-3methoxypropanoate 69 o —o b °4 ^Z - ¹¹ (2R)-2-{[(1,2,3,5,6,7-hexahydro-syndacen-4-yl)carbamoyl]oxy}-3methooxypropanoic acid 70 CQo o °=< 4: LL LL Ethyl 2-({ [2-chloro-3(trifluoromethyl)phenyl]carbamoyl } oxy)3 -(1H-pyrazol-1-yl)propanoate 71 ΟΎί IZ >° °Ъ _?Ч s Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 -(1H1,2,4-triazol-1 -yl)propanoate 72 λΎί tz >° O □ =/ z—. ° O r Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8indacen-4-yl)carbamoyl]oxy}-3-(3 methyl-1H-pyrazol-1-yl)propanoate

- 26 044707

73 “Π ιζ -π >° ο o=/Z—, (= ο Ethyl 3-(1H-pyrazol-1-yl)-2-{[(2,4,6trifluorophenyl)carbamoyl]oxy} propanoate 74 ο ° *3 { Ethyl 2-({ [2-methyl-6-(propan-2yl)phenyl]carbamoyl}oxy)-3-(1Hpyrazol-1 -yl)propanoate 75 ο ΰ Ζ Ζ -π >° ο ο=/ζ—. ο Ethyl-2-{[(3 -chloro-2,6- difluorophenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 76 ^ζ *<^ / 4>° ο °4 .. ^ΗΖ Ethyl-(2C)-3 -(4-cyano-1H-pyrazol-1-yl)2-{ [(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy }propanoate 77 Ν /g/o Benzyl-(2C)-3 -(4-cyano-1H-pyrazol-1 yl)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4yl)carbamoyl]oxy}propanoate 78 —ΛΛ ΙΖ ' >° ο Ο=^ Ethyl-2-{[(2,6- dimethylphenyl)carbamoyl]oxy}-3 (pyrimidin-2-yl)propanoate 79 g\ /^L<Х ^ОН V/ ⁿ J (2R)-2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 -(1Nimidazol-1-yl)propanoic acid 80 IZ >° o o=< Z-, Ethyl 3 -(4-fluoro-1H-pyrazol-1-yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate

- 27 044707

81 ΙΖ >° ο ο=/ ζ-/ Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8indacen-4-yl)carbamoyl]oxy}-3-(5methyl-1H-imidazol-1-yl)propanoate 82 ^ζ \=ο ο °=< .. ζτ ъп (2R)-3 -(4-cyano-1 H-pyrazol-1 -yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy}propane acid 83 Γ\ ΡΎ ° Λ ^Ν 6¼ ύ°^ λ—' ^Η 0 Ethyl-(2H)-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy} -3 -(1H1,2,4-triazol-1 - yl)propanoate 84 ΙΖ >° ο °=^ ^ζ Υ Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8indacen-4-yl)carbamoyl]oxy}-3-(2methyl-1H-imidazol-1-yl)propanoate 85 ΙΖ Ο >° ο °^3 { Ethyl 2-{[(2-chloro-6ethylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 86 ') ί ? \ '—ζ γο ο °4 /=\ 21 4X4 Ethyl 2-{[(2-methylnaphthalene-1yl)carbamoyl]oxy}-3-(1H-pyrazol-1yl)propanoate 87 Y^oV^ Ethyl-2-{[(2- methylcyclohexyl)carbamoyl]oxy } -3 (1 H-pyrazol-1 -yl)propanoate 88 ΙΖ >° ο Ο=/ Ζ—, Ο ζ ^ζ /L ; - Ethyl-(2C)-3 -(4-chloro-1H-pyrazol-1-yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy }propanoate

- 28 044707

89 Ν η 6V°'V- Ethyl-(2C)-3 -(4-cyano-1 H-imide azol-1 yl)-2-{[(1,2,3,5,6,7-hexahydro-8indacen-4yl)carbamoyl]oxy} propanoate 90 IZ >° Ethyl-(2C)-3 -(5-cyano-1H-imide azol-1 yl)-2-{[(1,2,3,5,6,7-hexahydro-8indacen-4yl)carbamoyl]oxy}propanoate 91 F ρ=\ ^F ^L / Ν ^Γ >'Vw 1 ^Η ΰ Ethyl-2-({ [2,6-dimethyl-4- (trifluoromethyl)phenyl]carbamoyl}oxy)3 -(1H-pyrazol-1 -yl)propanoate 92 ΙΖ >° ο o=/ Ζ —. Ο ζ / (vt _o Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy }-3 -(4methoxy-1H-pyrazol-1-yl)propanoate 93 ΙΖ > ^ο ο 0==^ η Ethyl-(2K)-2-{ [(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy } -3 (pyrimidin-2-yl)propanoate 94 L-Ul^ ΙΖ >° □ ο =^ ^=\ Ο ζ, ζ Ethyl-(2K)-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy } -3 (pyrazin-2-yl)propanoate 95 Ethyl-(2H)-3-ethoxy-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate 96 ,Ν 7 Mr. D No. nr ° Ethyl-(2C)-3 -(3-cyano-1H-pyrazol-1-yl)2-{ [(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy }propanoate

- 29 044707

97 Iz >° Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy} -3 - [4(trifluoromethyl)-1H-pyrazol-1 yl]propanoate 98 o ^Ό ν 1 z 2=o o °=< .. ^ZI: (2R)-3 - {4-[(dimethylamino)methyl]-1Hpyrazol-1-yl}-2-{[(1,2,3,5,6,7hexahydro-8-indacene-4- yl)carbamoyl]oxy}propanoic acid hydrochloride 99 /=< О < N yV ₀ X^ ^{1 H} 0 Ethyl 2-{[(2,4-dimethylthiophen-3yl)carbamoyl]oxy}-3-(1H-pyrazol-1yl)propanoate 100 Ozy® TZ o O=/ Z —. o ^z \ Ethyl-2-[({4,10-dioxatricyclo[7.3.0.0 ³ ' ⁷ ]dodeca-1,3 (7), 8-trien-2-yl} carbamoyl)oxy]-3 (1 H-pyrazol-1 -yl)propanoate 101 Ethyl-(2K)-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy } -3 -(2methoxyethoxy)propanoate 102 I z >O q o=/ o—( o O \-/ Ethyl-(2K)-2-{ [(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy } -3 -(oxan4-yloxy)propanoate 103 rU L-Z 2=° about zx Ethyl-(2K)-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 -(5methyl-1 Η-1,2,4 -triazol-1-yl)propanoate 104 λΎί ZZ >=° q o=/ ο—ς o ' Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy}-3 (propan-2-yloxy)propanoate

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105 Λ ο S.Ts ,, ^ΖΤ - Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydrosindacen-4-yl)carbamoyl]oxy}-3-(3 methyl-1 H-1,2,4 -triazol-1-yl)propanoate 106 δ ζ=<^ \=ο ο °=κ ζι (2C)-2-{[(1,2,3,5,6,7-hexahydrosindacen-4-yl)carbamoyl]oxy}-3(pyrimidin-2-yl)propanoic acid 107 ΙΖ >° ο Ο ν7 Propan-2-yl-(2К)-2-{[(1,2,3,5,6,7hexahydro-8-indacene-4- yl)carbamoyl]oxy} -3 -(pyrimidin-2yl)propanoate 108 CXv ΙΖ >° ο ο=^ \=ζ 6' ^J Cyclopentyl-(2K)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}-3 -(pyrimidin-2yl)propanoate 109 iUl^ ΙΖ >° ο ο=^ ^=\ Ο ^Ζ , , ^{Ζ 1} VA (2R)-2-{ [(1,2,3,5,6,7-hexahydrosindacen-4-yl)carbamoyl]oxy}-3(pyrazin-2-yl)propanoic acid 110 'XX^V ΙΖ >° ο Ο ==^ У=\ ο ζ\ ζ Propan-2-yl-(2К)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}-3 -(pyrazin-2yl)propanoate 111 λΛ-1 ΙΖ > _ο □ Jb Cyclopentyl-(2K)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}-3 -(pyrazin-2yl)propanoate 112 Ν η A Γϊί ° Γ ^Ν ΑίΛοΝν \J » 5 1 Propan-2-yl-(2K)-3 -(4-cyano-1Hpyrazol-1-yl)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy }propanoate

- 31 044707

FROM ν Cyclopentyl-(2C)-3-(4-cyano-1Hpyrazol-1-yl)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate 114 ζ \=ο ο °=< , _χ (2R)-2- {[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy } -3 -(1H- 1,2,4-triazol-1-yl)propanoic acid 115 GU <> ° G' O^Y ^L ° τ°Υ VJ ^{no 1} Proπan-2-yl-(2R)-2-{[(1,2,3,5,6,7hexahydro-8-indacene-4- yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol1-yl)propanoate 116 SUA ΣΣ >° Ο Ο=/ Ζ-, ο Ζ ό Cyclopentyl-(2E)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol1-yl)propanoate 117 ΙΖ >° ο ο=^ У=\ Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro8-indacen-4-yl)carbamoyl]oxy} -3 -(6methylpyrazin-2-yl)propanoate 118 ⁿ about 1 Propan-2-yl-2-{[(3methylcyclohexyl)carbamoyl]oxy}-3 (pyrimidin-2-yl)propanoate 119 ΣΣ >° Ο QΟ Ζ ζ -<h ζ Propan-2-yl-3 -(5-cyanopyrazin-2-yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate 120 ζ=^Vq. _o ο °=< ^{ζ τ} V^Q Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydros-indacen-4-yl)carbamoyl]oxy}-3-(2methylpyrimidin-4-yl)propanoate 121 ^4^=° ο °+ ^z:L α_<Ί Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy} -3 -(5 methylpyrazin-2-yl)propanoate

- 32 044707

122 oDoH ⁿ 3 7 Propan-2-yl-2-{[(1 methylcyclohexyl)carbamoyl]oxy}-3 (pyrimidin-2-yl)propanoate 123 -i IZ L >° O o=^Z Propan-2-yl-2-{[(2-chloro-6fluorophenyl)carbamoyl]oxy}-3(pyrimidin-2-yl)propanoate 124 νΎ ΦΥ F O ¹ Propan-2-yl-2-{ [(2,6difluorophenyl)carbamoyl]oxy}-3 (pyrimidin-2-yl)propanoate 125 γ iz' Q >° o o z Propan-2-yl-2-{[(2,6dichlorophenyl)carbamoyl]oxy}-3(pyrimidin-2-yl)propanoate 126 IZ >=° q z—, ,° o ill Propan-2-yl-(2К)-3 -(3-cyano-1 Η-1,2,4triazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydros- indacen-4yl)carbamoyl]oxy}propanoate 127 ZYV: _O 0 ^o= K ZI A Propan-2-yl-2-[({bicyclo[2.2.2]octan-1yl} carbamoyl)oxy]-3 -(pyrimidin-2 yl)propanoate 128 1\II Jl / A. .n YY o /ΥΥοΥθγо 1 Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy}-3 (pyridazin-4-yl)propanoate 129 1 O γ 1 and ^H ( o N γ./ D 1 Propan-2-yl-2-{ [(trans-2methylcyclohexyl)carbamoyl]oxy}-3 (pyrimidin-2-yl)propanoate 130 ζγ to a °=< _ ^ZT Propan-2-yl-3 -(5-cyanopyrimidin-2yl)-2-{[(1,2,3,5,6,7-hexahydro-8indacen-4yl)carbamoyl]oxy}propanoate

In some aspects, the present invention provides a compound that is an isotope-labeled derivative (eg, an isotope-labeled compound) of any of the compounds of formulas (I)-(X), (Ia)-(Xa), and (Ib)-(Xb).

In some embodiments, the compound is an isotopically labeled derivative of any of the compounds described in Table. 1, and pharmaceutically acceptable salts.

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

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

The deuterium-labeled compound is understood to contain a deuterium atom with a relative abundance that is substantially higher than the relative abundance of deuterium in nature, which is 0.015%.

In some embodiments, the deuterium-labeled compound has a deuterium enrichment factor of at least 3500 (52.5% deuterium inclusion in each specified deuterium atom), at least 4000 (60% deuterium inclusion), at least 4500 (67 deuterium inclusion .5%), at least 5000 (deuterium inclusion 75%), at least 5500

- 33 044707 (deuterium inclusion 82.5%), at least 6000 (deuterium inclusion 90%), at least 6333.3 (deuterium inclusion 95%), at least 6466.7 (deuterium inclusion 97%), according at least 6600 (99% deuterium inclusion) or at least 6633.3 (99.5% deuterium inclusion). As used herein, the term deuterium enrichment factor means the relationship between the relative abundance of deuterium and the relative abundance of deuterium in nature.

It is understood that the deuterium-labeled compound can be prepared using any of a wide variety of techniques known in the art. For example, a deuterium-labeled derivative can generally be prepared by following the procedures disclosed in the Schemes and/or Examples described herein by replacing a non-deuterium-labeled reagent with a deuterium-labeled reagent.

The compound of the present invention or a pharmaceutically acceptable salt thereof which contains said deuterium atom(s) falls within the scope of the present invention. In addition, substitution with heavier deuterium (ie, ² H) may provide certain therapeutic benefits resulting from greater metabolic stability, such as increased in vivo half-life, or reduced dosage requirements.

For the avoidance of doubt, it is understood that if a group is cited herein with the qualification described herein, then said group includes the first and broadest definition encountered, as well as any and all specific definitions for that group.

Specific compounds according to the present invention include, for example, compounds according to any of formulas (I)-(X), (Ia)-(Xa) and (Ib)-(Xb) or a pharmaceutically acceptable salt thereof, where unless otherwise indicated, each of R1, _R3 , R4 and associated substituents has any of the meanings defined above herein.

The various functional groups and substituents forming the compounds of formula (I) are generally selected such that the molecular weight of the compound does not exceed 1000 daltons (Da). More often, the molecular weight of the compound will be less than 900 Da, such as less than 800 Da, or less than 750 Da, or less than 700 Da, or less than 650 Da. More conveniently, the molecular weight is less than 600 Da and, for example, is 550 Da or less.

A suitable pharmaceutically acceptable salt of a compound of the present invention is, for example, an acid addition salt of a compound of the present invention that is sufficiently basic, for example an acid addition salt with an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric, methanesulfonic or maleic acid. In addition, a suitable pharmaceutically acceptable salt of the compound of the present invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or an organic base salt which provides a pharmaceutically acceptable cation, for example, a salt of methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris(2-hydroxyethyl)amine.

It should be understood that the compounds of any of the formulas described herein include both the compounds themselves and their salts, as applicable. A salt may be formed, for example, between an anion and a positively charged group (eg amino) on a substituted benzene compound. Suitable anions include chloride, bromide, iodide, sulfate, bisulfate, sulfamate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, glutamate, glucuronate, glutarate, malate, maleate, succinate, fumarate, tartrate, tosylate, salicylate, lactate, naphthalene sulfonate and acetate (eg trifluoroacetate).

As used herein, the term pharmaceutically acceptable anion refers to an anion suitable for forming a pharmaceutically acceptable salt. By analogy, a salt can also be formed between a cation and a negatively charged group (such as a carboxylate) on a substituted benzene compound. Suitable cations include sodium ion, potassium ion, magnesium ion, calcium ion and ammonium cation such as tetramethylammonium ion. Substituted benzene compounds also include salts containing quaternary nitrogen atoms.

It should also be understood that certain compounds according to any of formulas (I)-(X), (Ia)-(Xa) and (Ib)-(Xb) may exhibit polymorphism, and that the present invention covers all such or mixtures thereof that have inhibitory activity against inflammosomes. It is well known that crystalline substances can be analyzed using well-established techniques such as X-ray powder diffractometry, differential scanning calorimetry, thermogravimetric analysis, diffuse reflectance Fourier transform (DRIFT) spectroscopy, near-infrared (NIR) spectroscopy, nuclear magnetic resonance spectroscopy. solution and/or solid phase. The water content of such crystalline substances can be determined by Karl Fischer analysis.

The effects of a compound according to any of formulas (I)-(X), (Ia)-(Xa) and (Ib)-(Xb) in vivo may be due in part to one or more metabolites that are formed in the human or animal body after administration of the compound according to any of formulas (I)-(X), (Ia)-(Xa) and (Ib)-(Xb). As noted

- 34 044707 supra herein, the in vivo effects of a compound according to any of formulas (I)-(X), (Ia)-(Xa) and (Ib)-(Xb) may also occur through metabolism of the precursor compound (prodrug) .

Although the present invention may relate to any compound or specific group of compounds defined herein by optional, preferred or suitable features or otherwise through specific embodiments, the present invention may also relate to any compound or specific group of compounds that specifically exclude those mentioned optional, preferred or suitable features or embodiments. A feature of the present invention relates to specific structural groups in R ₁ that are relevant to the scope of the claims presented herein. In some cases, specific groups define structures that are not relevant to the present invention and therefore may be disclaimed. Such structures may be disclaimed in which R ₁ refers to phenyl directly substituted by at least 2 groups, including: 1 halogen group and 1 methyl group; 2 or more halogen groups; or 2 methyl groups.

Accordingly, the present invention excludes any individual compounds that do not have biological activity as defined herein.

Methods of synthesis.

In some aspects, the present invention relates to a method for preparing a compound of the present invention.

In some aspects, the present invention relates to a method for preparing a compound, comprising one or more of the steps described herein.

In some aspects, the present invention relates to a compound obtained or obtained, or directly obtained, by the method for preparing the compound described herein.

In some aspects, the present invention provides an intermediate described herein suitable for use in a method for preparing the compound described herein.

The compounds of the present invention can be prepared by any suitable technique known in the art. Specific processes for preparing these compounds are described below in the accompanying examples.

When describing the synthetic methods described herein and any referenced synthetic methods that are used to prepare the starting materials, it is understood that all proposed reaction conditions, including the choice of solvent, reaction atmosphere, reaction temperature, experimental duration and product isolation procedures reactions can be selected by one skilled in the art.

It is understood by one skilled in the art of organic synthesis that the functional groups present in the various parts of the molecule must be compatible with the reagents and reaction conditions used.

It will be appreciated that during the synthesis of the compounds of the present invention, either through the processes defined herein or during the synthesis of certain starting materials, it may be desirable to protect certain substituents to prevent them from reacting undesirably. A qualified chemist will be able to appreciate when such protection is required and how such protecting groups can be introduced and subsequently removed. For examples of protective groups, see one of the many general textbooks on the subject, such as 'Protective Groups in Organic Synthesis' by Theodora Green (publisher: John Wiley & Sons). The protecting groups may be deprotected by any convenient method described in the literature or known to the skilled chemist as suitable for deprotection of the particular protecting group taken, such methods being selected to provide deprotection with minimal effect on groups elsewhere in the molecule. Thus, if the reactants contain, for example, groups such as amino, carboxy or hydroxy, then it may be desirable to protect the group in some of the reactions mentioned herein.

By way of example, a suitable protecting group for an amino group or alkylamino group is, for example, an acyl group, for example an alkanoyl group, such as acetyl, an alkoxycarbonyl group, for example, a methoxycarbonyl, ethoxycarbonyl or tert-butoxycarbonyl group, an arylmethoxycarbonyl group, such as benzyloxycarbonyl, or an aroyl group, for example benzoyl. The conditions for deprotection presented above generally vary depending on the choice of protecting group. Thus, for example, an acyl group, such as an alkanolyl or alkoxycarbonyl group, or an aroyl group, can be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively, an acyl group such as a tert-butoxycarbonyl group may be removed, for example by treatment with a suitable acid such as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid, and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example , by hydrogenation with a catalyst such as palladium carbon, or

- 35 044707 by treatment with a Lewis acid, for example boron tris(trifluoroacetate). A suitable alternative protecting group for the primary amino group is, for example, a phthayl group, which can be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or hydrazine.

A suitable protecting group for the hydroxy group is, for example, an acyl group, eg an alkanoyl group such as acetyl, an aroyl group such as benzoyl, or an arylmethyl group such as benzyl. The conditions for deprotection presented above will necessarily vary depending on the choice of protecting group. Thus, for example, an acyl group, such as an alkanoyl or aroyl group, can be removed, for example, by hydrolysis with a base such as an alkali metal hydroxide, eg lithium hydroxide, sodium hydroxide or ammonia. Alternatively, an arylmethyl group, such as a benzyl group, can be removed, for example, by hydrogenation with a catalyst such as palladium carbon.

A suitable protecting group for the carboxy group is, for example, an esterifying group, for example a methyl or ethyl group, which can be removed, for example, by hydrolysis with a base such as sodium hydroxide, or, for example, a tert-butyl group, which can be removed, for example , by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or, for example, a benzyl group, which can be removed, for example, by hydrogenation with a catalyst such as palladium carbon.

Once a compound of formula (I) has been synthesized by any of the processes defined herein, subsequent processes may further include the additional steps of (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 thereof.

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

For convenience, the reaction of the compounds is carried out in the presence of a suitable solvent, which is preferably inert under the appropriate 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 trichlorethylene, 1,2-dichloroethane, carbon tetrachloride, 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, cyclopentyl methyl ether (CPME), methyl tert-butyl ether (MTBE) or dioxane; glycol ethers such as ethylene glycol monomethyl or monoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones such as acetone, methyl isobutyl ketone (MIBK) or butanone; amides such as acetamide, dimethylacetamide, dimethylformamide (DMF) or N-methylpyrrolidinone (NMP); nitriles such as acetonitrile; sulfoxides such as dimethyl sulfoxide (DMSO); nitro compounds such as nitromethane or nitrobenzene; esters such as ethyl acetate or methyl acetate, or mixtures of the mentioned solvents or mixtures with water.

The reaction temperature is suitably from about -100 to 300°C depending on the reaction step and conditions used.

Reaction times typically range from a fraction of a minute to several days, depending on the reactivity of the compounds involved and the corresponding reaction conditions. Suitable reaction times are easily determined by methods known in the art, for example by monitoring the reactions. Based on the reaction temperatures presented above, suitable reaction times are generally in the range of 10 minutes to 48 hours.

Moreover, by using the techniques described herein, in combination with average skill in the art, additional compounds of the present invention can be easily prepared. It will be readily apparent to those skilled in the art that a variety of conditions and processes of subsequent preparation techniques can be used to prepare the compounds.

As will be appreciated by one skilled in the art of organic synthesis, the compounds of the present invention are readily obtainable by a variety of synthetic routes, some of which are illustrated in the accompanying Examples. One skilled in the art will readily recognize what type of reagents and reaction conditions are to be used and how they must be applied and adapted in any particular case - wherever necessary or useful - for the purpose of preparing the compounds of the present invention. In addition, some of the compounds of the present invention can be easily synthesized by reacting other compounds of the present invention under suitable conditions, for example, by converting one particular functional group present on a compound of the present invention, or a suitable precursor molecule thereof, to another group by using standard methods of synthesis, such as reduction, oxidation, addition or substitution reactions; These methods are well known to those skilled in the art. By analogy, one skilled in the art can use - wherever necessary or useful - synthetic protecting (or protecting) groups; suitable protecting groups, as well as methods for introducing or removing them, are well known to one 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).

General routes for preparing the compounds of this application are described herein in Schemes 1-4.

base 9

Rr-NCO + la o ⁿ o

W 1с

Scheme 1

Compound 1a is reacted with compound 1b in the presence of a base (eg triethylamine) in a solvent (eg acetonitrile) and optionally at elevated temperature to obtain compound 1c.

metal θ ^R 3

R _r NCO - but ^L y% _;! ^t™or

1a o ^no

1b ic

Scheme 2

Compound 1a is reacted with compound 1b in the presence of a metal catalyst (eg copper chloride) in a solvent (eg dimethylformamide) and optionally at elevated temperature to obtain compound 1c.

Scheme 3

React compound 2a with compound 2b in the presence of a base (eg, sodium bis(trimethylsilyl)amide) in a solvent (eg, tetrahydrofuran) and optionally at reduced temperature (eg, -78°C) to obtain compound 2c. React compound 2c in the presence of a metal hydrogenation catalyst (eg, 10% Pd/C) in a solvent (eg, ethyl acetate) and optionally at elevated temperature to produce compound 2d.

Scheme 4

Compound 3a is reacted with compound 3b in the presence of thionyl chloride and optionally at reduced temperature (eg 0°C) to obtain compound 3c.

It should be understood that in the above description and formulas, the meanings of various groups, such as R1-R4 and R, are defined herein except as otherwise indicated. In addition, for purposes of synthesis, the compounds in the diagrams are only representative of the substituents selected to illustrate the general methodology for the synthesis of the compound disclosed herein.

Biological methods of analysis.

Once the compounds developed, selected and/or optimized by the methods described above are obtained, they can be characterized using a variety of analytical techniques known to one of ordinary skill in the art to determine whether the compounds have biological activity. For example, molecules can be characterized by conventional assays, including but not limited to those described below, to determine whether they have predicted activity, binding activity, and/or binding specificity.

Additionally, high-throughput screening can be used to speed up analysis using such methods. As a result, the molecules described herein can be rapidly screened for activity using techniques known in the art. General methodologies for conducting high throughput screening are described, for example, in Devlin (1998), High Throughput Screening, Marcel Dekker; and US Patent No. 5,763,263. High-throughput analysis methods may employ one or more different analysis techniques, including, without limitation, the techniques described below.

Various in vitro or in vivo biological assays may be suitable for determining the effect of the compounds of the present invention. Such biological methods of analysis in vitro or

- 37 044707 in vivo may include, without limitation, enzyme activity assay methods, electrophoretic activity change assay methods, reporter gene assay methods, in vitro cell viability assay methods, and assay methods described herein.

Pharmaceutical compositions.

In some aspects, the present invention relates to a pharmaceutical composition containing a compound of the present invention as an active ingredient. In some embodiments, the present invention provides a pharmaceutical composition comprising at least one compound of each of the formulas described herein, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or excipients. According to some embodiments, the present invention relates to a pharmaceutical composition containing at least one compound selected from table. 1.

As used herein, the term composition is intended to include a product containing certain ingredients in certain amounts, as well as any product that is obtained, directly or indirectly, from a combination of certain ingredients in certain amounts.

The compounds of the present invention may be formulated for oral administration in forms such as tablets, capsules (each of which includes sustained release or time controlled release formulations), pills, powders, granules, elixirs, tinctures, suspensions, syrups and emulsions. The compounds of the present invention may also be formulated for intravenous (bolus or infusion), intraperitoneal, topical, subcutaneous, intramuscular, or transdermal (eg, patch) administration, all forms of use being well known to one skilled in the art of pharmaceutical technology.

The composition according to the present invention may be in the form of an aqueous solution containing an aqueous base. The aqueous base component may include water and at least one pharmaceutically acceptable excipient. Suitable acceptable excipients include excipients selected from the group consisting of a solubility enhancer, a chelating agent, a preservative, a tonicity agent, a viscosity control/suspension agent, a buffer and a pH modifier, and mixtures thereof.

Any suitable solubility enhancing agent may be used. Examples of the solubility enhancer include a cyclodextrin such as one selected from the group consisting of hydroxypropyl-β-cyclodextrin, methyl-β-cyclodextrin, randomly methylated β-cyclodextrin, ethylated β-cyclodextrin, triacetyl-β-cyclodextrin, peracetylated β-cyclodextrin, carboxymethyl-β-cyclodextrin, hydroxyethyl-β-cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-β-cyclodextrin, glucosyl-β-cyclodextrin, sulfated β-cyclodextrin (S-β-CD), maltosyl-β-cyclodextrin , β-cyclodextrin-sulfobutyl ether, branched β-cyclodextrin, hydroxypropyl-γ-cyclodextrin, randomly methylated γ-cyclodextrin and trimethyl-γ-cyclodextrin and mixtures thereof.

Any suitable chelating agent may be used. Examples of suitable chelating agents include those selected from the group consisting of ethylenediaminetetraacetic acid and its metal salts, disodium edetate, trisodium edetate and tetrasodium edetate, and mixtures thereof.

Any suitable preservative may be used. Examples of the preservative include preservatives selected from the group consisting of quaternary ammonium salts such as benzalkonium halides (preferably benzalkonium chloride), chlorhexidine gluconate, benzethonium chloride, cetylpyridinium chloride, benzyl bromide, phenylmercuric nitrate, phenylmercuric acetate, phenylmercuric neodecanoate, merthiol ta, methylparaben, propylparaben , sorbic acid, potassium sorbate, sodium benzoate, sodium propionate, ethyl para-hydroxybenzoate, propylaminopropyl biguanide and butyl para-hydroxybenzoate and sorbic acid and mixtures thereof.

The aqueous base may also include an agent to regulate tonicity (osmotic pressure). The tonicity adjusting agent may be selected from the group consisting of glycol (such as propylene glycol, diethylene glycol, triethylene glycol), glycerin, dextrose, glycerin, mannitol, potassium chloride and sodium chloride, and mixtures thereof.

The aqueous base may also contain a viscosity control/suspension agent. Suitable viscosity control/suspending agents include those selected from the group consisting of cellulose derivatives such as methylcellulose, ethylcellulose, hydroxyethylcellulose, polyethylene glycols (such as polyethylene glycol 300, polyethylene glycol 400), carboxymethylcellulose, hydroxypropyl methylcellulose and cross-linked acrylic acid polymers (carbomers) such as polymers of acrylic acid cross-linked with polyalkenyl ethers or divinyl glycol (Carbopols - such as Carbopol 934, Carbopol 934P, Carbopol 971, Carbopol 974 and Carbopol 974P) and mixtures thereof.

- 38 044707

To adjust the composition to an acceptable pH value (typically a pH range of from about 5.0 to about 9.0, more preferably from about 5.5 to about 8.5, in particular from about 6.0 to about 8.5, from 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 modifying agent . The pH modifying agent is typically a mineral acid or a metal hydroxide base selected from the group consisting of potassium hydroxide, sodium hydroxide and hydrochloric acid and mixtures thereof, and preferably sodium hydroxide and/or hydrochloric acid. Such acidic and/or basic pH modifying agents are added to adjust the formulation to the target acceptable pH range. Based on this, it is not always necessary to use both an acid and a base - depending on the composition, adding only an acid or only a base may be sufficient to obtain a mixture with the desired pH range.

The aqueous base may also contain a buffering agent to stabilize the pH values. When used, the buffer is selected from the group consisting of a phosphate buffer (such as sodium dihydrogen phosphate and disodium hydrogen phosphate), a borate buffer (such as boric acid or its salts, including disodium tetraborate), a citrate buffer (such as citric acid or its salts, including citrate sodium) and ε-aminocaproic acid and mixtures thereof.

The composition may additionally contain a humectant. Suitable classes of humectants include humectants selected from the group consisting of polyoxypropylene-polyoxyethylene block copolymers (poloxamers), polyethoxylated castor ethers, polyoxyethylene sorbitan esters (polysorbates), polymers of oxyethylated octylphenol (Tyloxapol), polyoxyl 40 stearate, fatty esters acid and glycol, fatty acid esters of glycerol, sucrose fatty esters and polyoxyethylene fatty esters and mixtures thereof.

Oral compositions typically include an inert diluent or an edible pharmaceutically acceptable carrier. They may be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound may be formulated together with excipients and may be used in the form of tablets, lozenges or capsules. Oral compositions can also be prepared using a liquid carrier for use as a mouth rinse, in which the compound in the liquid carrier is administered orally and rinsed and spit out or swallowed. Pharmaceutically acceptable binders and/or excipients may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may contain any of the following ingredients or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; a filler such as starch or lactose; a leavening agent such as alginic acid, Primogel or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as fumed silica; a sweetener such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

In accordance with a further aspect of the present invention, there is provided a pharmaceutical composition that contains a compound of the present invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The compositions of the present invention may be in a form suitable for oral administration (for example, tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical application (for example, as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (eg, as a fine powder or liquid aerosol), for administration by insufflation (eg, as a fine powder), or for parenteral administration (eg, as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

The compositions of the present invention can be prepared by conventional techniques using conventional pharmaceutical excipients well known in the art. Thus, compositions intended for oral administration may contain, for example, one or more coloring agents, sweeteners, flavoring agents and/or preservatives.

An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent an inflammasome-related condition referred to herein, slow its progression, and/or reduce symptoms associated with the condition.

The dose level for therapeutic or prophylactic purposes of a compound of formula I will naturally vary according to the nature and severity of the conditions, age and sex.

- 39 044707 animal or patient, and by administration, in accordance with well known principles of medicine.

Methods of application.

In some aspects, the present invention provides a method of inhibiting the activity of an inflammasome (eg, the NLRP3 inflammasome) (eg, in vitro or in vivo), comprising contacting a cell with an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.

In some aspects, the present invention provides a method for treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. .

In some embodiments, the disease or disorder is associated with the activity of the inflammasomes involved. In some embodiments, the disease or disorder is a disease or disorder that involves inflammasome activity.

In some embodiments, the disease or disorder is an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a malignancy.

In some embodiments, the disease or disorder is an autoinflammatory disorder and/or an autoimmune disorder.

In some embodiments, the disease or disorder is selected from cryopyrin-associated periodic syndrome (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous articular syndrome (CINCA), multisystem inflammatory disease neonatal age (NOMID), familial Mediterranean fever and non-alcoholic fatty liver disease (NAFLD), non-alcoholic 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 neuroinflammation that occurs in protein misfolding diseases (eg, prion diseases).

In some embodiments, the disease and disorder is a neurodegenerative disease.

In some embodiments, the disease and disorder is Parkinson's disease or Alzheimer's disease.

In some embodiments, the disease and disorder is a cancer.

In some embodiments, the cancer is a metastatic cancer, a gastrointestinal cancer, a skin cancer, a non-small cell lung carcinoma, or a colorectal adenocarcinoma.

In some aspects, the present invention provides a method for treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention. .

In some embodiments, the present invention provides a method for treating or preventing an autoinflammatory disorder and/or an autoimmune disorder selected from cryopyrin-associated autoinflammatory syndrome (CAPS, e.g., familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic Infantile Neurological Cutaneous Articular Syndrome (CINCA), Neonatal Multisystem Inflammatory Disease (NOMID), Familial Mediterranean Fever and Non-Alcoholic Fatty Liver Disease (NAFLD), Non-Alcoholic Steatohepatitis (NASH), Gout, Rheumatoid Arthritis, Osteoarthritis, Crohn's Disease, Chronic Obstructive Disease lung disease (COPD), chronic kidney disease (CKD), fibrosis, obesity, type 2 diabetes, multiple sclerosis, and neuroinflammation arising from protein misfolding diseases (eg, prion diseases), in a subject in need thereof, comprising administering to the subject therapeutically an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention.

In some aspects, the present invention provides a method for treating or preventing a neurodegenerative disease (eg, Parkinson's disease or Alzheimer's disease) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt or pharmaceutical composition thereof. according to the present invention.

In some aspects, the present invention provides a method for treating or preventing cancer in a subject in need thereof, the method comprising administering

- 40 044707 to the subject a therapeutically effective amount of a compound according to the present invention or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to the present invention.

The present invention relates to compounds that act as inhibitors of inflammasome activity. Therefore, the present invention provides a method of inhibiting inflammasome activity in vitro or in vivo, the method comprising contacting a cell with an effective amount of a compound or a pharmaceutically acceptable salt thereof as defined herein.

The effectiveness of the compounds of the present invention can be determined by assays used in industry/disease models, in accordance with standard practice for efficacy studies described in the art, which can be found in the currently publicly available information.

The present invention also provides a method of treating a disease or disorder involving inflammasome activity in a patient in need of such treatment, the method comprising administering to said patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined herein.

In general, compounds of the present invention that inhibit the maturation of IL-1 family cytokines are effective in all therapeutic indications that are mediated by or associated with increased levels of active forms of cytokines belonging to the IL-1 family of cytokines (Sims J. et al ., Nature Reviews Immunology, 10, 89-102 (February 2010).

Illustrative diseases and corresponding references will be presented in the following documents: autoinflammatory and autoimmune diseases of the CAPS type (Dinarello C.A., Immunity, 2004 Mar, 20(3):243-4; Hoffman H.M. et al., Reumatologia, 2005, 21(3)) , gout, rheumatoid arthritis (Gabay C. et al., Arthritis Research & Therapy, 2009, 11:230; Schett G. et al., Nat. Rev. Rheumatol., 2016 Jan, 12(1):14-24) , Crohn's disease (Jung Mogg 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 Med., 2009 May 15, 179(10):903-13), obesity, type 2 diabetes (Dinarello C.A. et al., Curr. Opin Endocrinol. Diabetes Obes., 2010 Aug, 17(4):314-21), multiple sclerosis (see EAE model in Coll R.C. et al., Nat. Med., 2015 Mar, 21(3):248-55 ) and many others (Martinon F. et al., Immunol., 2009, 27:229-65) like Parkinson's disease or Alzheimer's disease (Michael T. et al., Nature, 493, 674-678 (31 January 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 oncological disorders.

Accordingly, the compounds of the present invention can be used to treat a disease selected from the group consisting of an autoinflammatory disease, an autoimmune disease, a neurodegenerative disease and a malignant tumor. Said autoinflammatory and autoimmune disease is suitably selected from the group consisting of cryopyrine-associated autoinflammatory syndrome (CAPS), such as, for example, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous-articular syndrome (CINCA), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever and non-alcoholic fatty liver disease (NAFLD), gout, rheumatoid arthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis and neuroinflammation arising from protein misfolding diseases such as prion diseases. Said neurodegenerative disease is suitably selected from Parkinson's disease and Alzheimer's disease.

Accordingly, the compounds of the present invention can be used to treat a disease selected from the group consisting of cryopyrin-associated autoinflammatory syndrome (CAPS), such as, for example, familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous articular syndrome (CINCA), neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever, gout, rheumatoid arthritis, Crohn's disease, COPD, fibrosis, obesity, type 2 diabetes, multiple sclerosis, neuroinflammation arising from diseases with impaired protein folding such as prion diseases, Parkinson's disease, Alzheimer's disease and cancer disorders.

Treatment of a malignant tumor; connections with the inflammasome.

It has long been noted that chronic inflammatory responses are associated with various types of malignancies. During malignant transformation or anticancer therapy, inflammasomes can be activated in response to danger signals, and in malignant tumors this activation can be either beneficial or harmful.

IL-1e expression is increased in a number of malignant tumors (including breast, prostate, colon, lung, head and neck, and melanoma).

- 41 044707 and patients with IL-Ιβ-producing tumors tend to have a worse 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).

Malignant tumors of epithelial cells (carcinoma) or glandular epithelium (adenocarcinoma) are heterogeneous and consist of many different types of cells. These may include, among others, fibroblasts, immune cells, adipocytes, endothelial cells and pericytes, which can all secrete cytokine/chemokine (Grivennikov, Sergei I., Florian R. Greten, Michael Karin, Immunity, inflammation, and cancer, Cell, 140.6(2010):883-899). This may lead to inflammation associated with malignancy through infiltration of immune cells. Leukocytes are known to be present in tumors, but only recently has it become apparent that the inflammatory microenvironment is a critical component of all tumors. Most tumors (>90%) are the result of somatic or environmental mutations rather than generative mutations, and many environmental causes of malignancy are associated with chronic inflammation (20% of malignancies associated with chronic infection, 30% with smoking /inhalation of toxic contaminants and 35% with dietary factors (20% of all malignant tumors are associated with obesity)) (Aggarwal, Bharat B., R.V. Vijayalekshmi, Bokyung Sung, Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long -term foe, Clinical Cancer Research, 15.2(2009):425-430).

Malignant tumor of the gastrointestinal tract.

Tumors of the gastrointestinal (GI) tract are often associated with chronic inflammation. For example, H. pylori infection is associated with gastric malignancy (Amieva, Manuel, Richard M. Peek, Pathobiology of Helicobacter pylori-Induced Gastric Cancer, Gastroenterology, 150.1(2016):64-78). Colorectal malignancy 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 increased levels 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-1e gene may increase the risk of gastric cancer (Wang P. et al. (2007), Association of interleukin-1 gene polymorphisms with gastric cancer : a meta-analysis, Int. J. Cancer, 120:552-562).

In 19% of gastric malignancies, caspase-1 expression is reduced, which correlates with stage, lymph node metastasis and survival (Jee et al., 2005). Mycoplasma hyorhinis is associated with the development of gastric malignancy, and activation of the NLRP3 inflammasome may be associated with increased metastasis of gastric malignancy (Xu et al., 2013).

Malignant skin tumors.

Ultraviolet exposure represents the greatest environmental risk for the development of skin cancer, which is enhanced by damage, immunosuppression, and inflammation. The most malignant skin tumor, melanoma, is characterized by increased levels of inflammatory cytokines, each of which can be regulated by IL-1e (Lazar-Molnar, Eszter et al., Autocrine and paracrine regulation by cytokines and growth factors in melanoma, Cytokine, 12.6 (2000): 547-554). Systemic inflammation induces increased metastasis and growth of melanoma cells through IL-1-dependent mechanisms in vivo. Thymoquinone inhibition of metastasis in the B16F10 mouse model of melanoma has been shown to depend on 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 promotes radiotherapy resistance in glioma. Ionizing radiation can induce NLRP3 expression, whereas NLRP3 inhibition reduced tumor growth and prolonged the survival of mice after radiotherapy. Therefore, inhibition of the NLRP3 inflammasome may provide a treatment strategy for radiation-resistant glioma (Li, Lianling, and Yuguang Liu, Aging-related gene signature regulated by Nlrp3 predicts glioma progression, American journal of cancer research, 5.1(2015):442).

Metastasis.

More broadly, applicants believe that NLRP3 is involved in enhancing metastasis and, therefore, modulation of NLRP3 is likely to block it. IL-1 is involved in tumorigenesis, tumor invasiveness, metastasis, tumor-host interactions (Apte, Ron N. et al., The involvement of IL-1 in tumorigenesis, tumor invasiveness, metastasis and tumor-host interactions, Cancer & 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 during metastasis in patients with certain types of human malignancies. For example, IL-1mRNA was highly expressed in more than half of all human metastatic tumor types tested, specifically including tumor samples from non-small cell lung carcinoma, colorectal adenocarcinoma, and melanoma (Elaraj,

- 42 044707

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 xenograft growth in IL-1-producing tumors, but without antiproliferative effects in vitro.

In addition, IL-1 signaling is a biomarker for predicting breast cancer patients at increased risk of developing bone metastases. In mouse models, breast cancer cells that metastasize to bone have increased levels of IL-1e and its receptor compared to cells that do not metastasize. In a mouse model, the IL-1 receptor antagonist anakinra reduced proliferation and angiogenesis in addition to exerting profound effects on the tumor environment, reducing markers of bone turnover, IL-1e and TNF alpha (Holen, Ingunn, et al., IL-1 drives breast cancer growth and bone metastasis in vivo, Oncotarget (2016)).

IL-18 induced MMP-9 production in the human leukemia cell line HL-60, thereby promoting extracellular matrix degradation and migration and invasiveness of malignant tumor 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 may promote the development of tumor metastases in the liver by inducing VCAM1 expression in sinusoidal liver endothelial cells (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 phagocytic fatty acid receptor CD36 plays a dual role in initiating pro-IL-1β gene transcription and inducing assembly of the NLRP3 inflammasome complex. CD36 and the TLR4-TLR6 heterodimer recognize oxLDL, which initiates a signaling pathway leading to increased transcription levels of NLRP3 and pro-IL-1β (signal 1). CD36 also mediates the internalization of oxLDL into the lysosomal compartment, where crystals form, inducing lysosomal rupture and activation of the NLRP3 inflammasome (signal 2) (Kagan, J., Horng T., NLRP3 inflammasome activation: CD36 serves double duty, Nature Immunology, 14.8 (2013) :772-774).

A subpopulation of human oral carcinoma cells express high levels of the phagocytic fatty acid receptor CD36 and are unique in their ability to initiate metastasis. Palmitic acid or a high-fat diet enhances the metastatic capacity of CD36+ cells. Neutralization of anti-CD36 antibodies blocked metastasis in orthotopic mouse models of human oral cancer. The presence of metastasis-initiating CD36+ cells correlates with poor prognosis in multiple types of carcinomas. It has been suggested that dietary lipids may enhance metastasis (Pasqual, G., Avgustinova, A., Mejetta, S., Martin, M., Castellanos, A., Attolini, CS-O, Berenguer, A., Prats, N., Toll, A., Hueto, J.A., Bescos, C., Di Croce, L., Benitah, S.A., 2017, Targeting metastasis-initiating cells through the fatty acid receptor CD36, Nature, 541:41-45).

In hepatocellular carcinoma, exogenous palmitic acid activated an epithelial-mesenchymal transition (EMT)-like program and induced migration, which was reduced by the CD36 inhibitor, sulfo-N-succinimidyl 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 severity of EMT, as CD36 and free fatty acids are essentially important.

Cancer stem cells (CSCs) use CD36 to enhance their own supply. Oxidized phospholipids, ligands of CD36, were present in glioblastoma, and oxidized LDL increased proliferation of CSCs but not other cells. CD36 also correlated with patient prognosis.

Resistance to chemotherapy.

In addition to direct cytotoxic effects, chemotherapeutic agents target the host immune system, which promotes antitumor activity. However, gemcitabine and 5-FU have been shown to activate NLRP3 in myeloid-derived suppressor cells, leading to the production of IL-1e, which reduces antitumor efficacy. Mechanistically, these agents disrupted the lysosome to release cathepsin B with activation of NLRP3. IL-1e stimulated the production of IL-17 from CD4+ T cells, which in turn attenuated the effectiveness of chemotherapy. Greater antitumor effects for both gemcitabine and 5-FU were observed when tumors formed in NLRP3' ^/ ' or Caps1 ^-/ ' mice, or in wild-type mice treated with IL-1RA. Thus, activation of NLRP3 in myeloid-derived suppressor cells limits the antitumor efficacy of gemcitabine and 5-FU (Bruchard, Melanie, 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.). In this regard, the compounds of the present invention may be useful in chemotherapy for the treatment of a number of malignant

- 43 044707 tumors.

The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be administered alone as monotherapy, or they may be administered in combination with one or more other agents and/or treatments. Such combination treatment can be achieved through simultaneous, sequential or separate administration of the individual treatment components.

For example, therapeutic efficacy may be enhanced by administration of an adjuvant (ie, the adjuvant alone may have only minimal therapeutic efficacy, but when combined with another therapeutic agent, the overall therapeutic efficacy for the individual will be enhanced). Alternatively, and by way of example only, efficacy in a subject may be enhanced by administering a compound of formula (I) with another therapeutic agent (which also includes a treatment regimen) that also has therapeutic efficacy.

In cases where the compound of the present invention is administered in combination with other therapeutic agents, the compound of the present invention need not be administered through the same route as the other therapeutic agents and may be administered through a different route of administration due to different physical and chemical characteristics. For example, a compound of the present invention may be administered orally to establish and maintain good blood levels, while another therapeutic agent may be administered intravenously. Initial administration can be carried out in accordance with established protocols known in the art, and then, based on the effects obtained, the methods of administration and timing of administration can be modified by a qualified physician.

The specific choice of other therapeutic agent will depend on the diagnosis of the treating physicians and their judgment of the individual's condition, and on the appropriate treatment protocol. In accordance with this aspect of the invention, there is provided a combination for use in the treatment of a disease in which inflammasome activity is involved, comprising a compound of the present invention as defined hereinbefore, or a pharmaceutically acceptable salt thereof, and another suitable agent.

In accordance with a further aspect of the invention, there is provided a pharmaceutical composition that contains a compound of the present invention or a pharmaceutically acceptable salt thereof in combination with a suitable pharmaceutically acceptable diluent or carrier.

In addition to its use in therapeutic medicine, the compounds of formula (I) and their pharmaceutically acceptable salts are also useful as pharmacological tools for the development and standardization of in vitro and in vivo test systems for assessing the effects of inflammasome inhibitors in laboratory animals such as dogs, rabbits, monkeys, rats and mice as part of the search for new therapeutic agents.

For any of the pharmaceutical composition, process, method, use, drug and manufacturing features of the present invention mentioned above, any of the alternative embodiments of the macromolecules of the present invention described herein are also applicable.

Routes of administration.

The compounds of the present invention, or pharmaceutical compositions containing such compounds, can be administered to a subject through any conventional route of administration, either systemically/peripherally or locally (ie, to the area of desired effect).

Routes of administration include, but are not limited to, oral (eg, by oral administration); buccal; sublingual; transdermal (including, for example, by film, patch, etc.); transmucosal (including, for example, by film, patch, etc.); intranasal (for example, through a nasal spray); ocular (for example, through eye drops); pulmonary (for example, through inhalation or insufflation therapy using, for example, an aerosol, for example, through the mouth or nose); rectal (for example, through a suppository or enema); vaginal (for example, through a pessary); parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid and intrasternal; by implanting a depot or reservoir, for example, subcutaneously or intramuscularly.

In view of the invention described, the following examples are presented by way of illustration and not by way of limitation.

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Examples

Abbreviations. ACN acetonitrile aq. water AR Atmosphere pressure Ag argon DCM dichloromethane DMF N,N-dimethylformamide DMSO-iC hexadeuterodimethyl sulfoxide eq. equivalents MSES+ electrospray ionization mass spectrometry positive charged ions EtOAc ethyl acetate FCC flash column chromatography HPLC high performance liquid chromatography min minutes NaHMDS sodium hexamethyldisilazide R.M. reaction mixture k.t. room temperature us. saturated S.M. starting material TEA triethylamine T.F.A. trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography Y exit General technique A. Ri R- TECH ° ^R ° «O - no- ^L _G 'H '' G ^H O

The α-hydroxyester or α-hydroxy acid (1 eq.) was dissolved in ACN (2 ml/mmol α-hydroxyester or α-hydroxy acid), and the solution was cooled to 0°C. TEA (1 eq) was added followed by isocyanate (1.2 eq) added dropwise. The reaction mixture was allowed to warm to room temperature and stirring was continued for 15 hours under Ar atmosphere. The reaction mixture was diluted with DCM and washed with 1 M HCl solution. 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 preparative reverse phase HPLC (ACN-water, 0.1% formic acid buffer).

General technique B.

Rj O R ₃

CUC' II I ⁺ Ηθ-''γ·% ₄ --- ^r '-n- V

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

General technique C.

To a stirred solution of aldehyde (1 equiv.) and ethyl chloroacetate (1 equiv.) in anhydrous THF (3 ml/mmol

- 45 044707 aldehyde) in an argon atmosphere at -78°C, a 1.0 M solution of NaHMDS in THF (1 eq.) was added dropwise.

The reaction mixture was stirred at -78°C for 30 minutes, warmed to 0°C, quenched by adding 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 in the next step without further purification.

General technique D.

⁰ ?

't-г· о А .....► ^R ) ^J ·

AND HE

Oxirane (1 eq.) was dissolved in EtOAc (10 ml/mmol oxirane), and 10% Pd/C (10 wt.% relative to oxirane) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (AP) overnight. The reaction mixture was filtered through a pad of Celite, the filter pad was washed with EtOAc, and the filtrate was concentrated under reduced pressure. The crude product was used in the next step without further purification.

General technique E.

V

Carboxylic acid (1 equiv.) was dissolved in alcohol R ₄ -OH (6 ml/mmol acid), and the solution was cooled to 0°C in an Ar atmosphere. At 0°C, thionyl chloride (1.5 eq.) was added dropwise and the reaction mixture was stirred at room temperature for 15 h under Ar atmosphere. The mixture was then evaporated to dryness and co-evaporated with cyclohexane (twice). The residue was purified by trituration in Et ₂ O/hexane or by FCC (0-20% EtOAc in hexane).

Example 1. Synthesis of intermediate compounds.

4-Isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A).

Step 1: 3-chloro-1-(2,3-dihydro-1H-inden-5-yl)propan-1-one.

A suspension of aluminum chloride (12.4 g, 93 mmol, 1 eq.) in DCM (50 ml) under argon was cooled to -10°C with vigorous stirring. A solution of 3-chloropropionyl chloride (11 g, 93 mmol 1 eq) and indane (10 g, 85 mmol, 0.9 eq) in DCM (15 ml) was added dropwise to the suspension over 0.5 h, maintaining the temperature between -15 and -5°C. The reaction mixture was left to warm to room temperature and stirred overnight. The reaction mixture was added dropwise to cold (0°C) 2 M HCl over 30 min, maintaining the temperature between 0 and 10°C. The layers were separated and the aqueous phase was extracted with DCM (3x30 ml). The combined organic layers were washed successively with water, saturated sodium bicarbonate and brine. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated under reduced pressure to approximately 30 ml. Hexane (50 ml) was added and evaporation continued, the procedure 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)propan-1-one as a tan solid. Y=81%.

¹ H-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-indacene-1-one and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacene1 -He.

To concentrated sulfuric acid (71 ml, 1.34 mol, 3.4 eq.) was added 3-chloro-1(2,3-dihydro-1H-inden-5-yl)propan-1-one (82 g, 0.39 mol, 1 eq.). 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 eq) and concentrated sulfuric acid (26 ml, 0.49 mol, 1.25 eq) was added dropwise. The RM was stirred for 1 h while maintaining the temperature between 0 and 5°C. RM was slowly added to the water/DCM mixture while cooling in an ice bath. The layers were separated and the aqueous layer was extracted with DCM. United Organic

- 46 044707 layers were washed successively with saline and saturated sodium bicarbonate. The organic layers were dried over Na ₂ SO ₄ and filtered. The crude mixture was purified by the FCC (hexane/ethyl acetate) method. The target products were further purified by recrystallization from MeOH.

8-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one: Y=36%. MS ES ⁺ : 218.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.67 (s, 1H), 3.15-3.08 (m, 2H), 3.04 (t, J=8 Hz, 2H), 2.90 (t, J=8 Hz, 2H), 2.77-2.71 (m, 2H), 2.17-2.10 (m, 2H).

4-Nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one: Y=5%. MS ES ⁺ : 218.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.82 (s, 1H), 3.41-3.36 (m, 2H), 3.34-3.29 (m, 3H), 3 .02 (t, J=8 Hz, 2H), 2.77-2.69 (m, 2H), 2.17-2.10 (m, 2H).

Step 3: 1,2,3,5,6,7-hexahydro-s-indacene-4-amine.

A mixture of 8-nitro-1,2,3,5,6,7-hexahydro-8-indacen-1-one and 4-nitro-1,2,3,5,6,7-hexahydro-s-indacen-1-one (7.00 g, 32 mmol, 1 eq.) was suspended in MeOH (70 ml). The solution was treated with 20% palladium hydroxide on carbon (50% wetted with water, 1.72 g, 12 mmol, 0.4 eq.) and methanesulfonic acid (3.41 g, 35 mmol, 1.1 eq.). The mixture was hydrogenated at 35 psi. inch for 5 hours. The catalyst was removed by filtration through a pad of Celite and the filter pad was washed with MeOH. The filtrate was diluted with water (350 ml) and adjusted to pH 11 by adding 2 M NaOH. The resulting slurry was filtered and the crude solid was recrystallized from MeOH/water (9/1) to give 1,2,3,5,6,7-hexahydro-8-indacene-4-amine as colorless needles. Y=73%. MS ES ⁺ : 174.1.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 6.35 (s, 1H), 4.52 (s, 2H), 2.72 (t, J=7 Hz, 4H), 2.59 (t , J=7 Hz, 4H), 2.00-1.93 (m, 4H).

Step 4: 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (intermediate A).

To a stirred solution of 1,2,3,5,6,7-hexahydro-s-indacene-4-amine (1.1 g, 6.35 mmol, 1 eq.) and TEA (0.973 ml, 6.98 mmol, 1.1 equiv.) in THF (20 ml) was added in one portion, triphosgene (0.64 g, 2.16 mmol, 3 equiv.). The mixture was heated to sublimation temperature for 4 hours and cooled to room temperature. THF was evaporated, the residue was taken up in pentane and filtered through a layer of silica gel. Evaporation of the solvent under vacuum provided 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene 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-indacen-4-yl)carbamoyl]oxy}acetic acid (intermediate B).

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

The title compound was prepared according to General Procedure A using t-butyl glycolate and intermediate A as starting materials. The crude product was purified by FCC (0-100% DCM in hexane). Y=65%. MS ES ⁺ ([M+Na] ⁺ ): 354.4.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (s, 1H), 6.95 (s, 1H), 4.48 (s, 2H), 2.81 (t, J=7 Hz , 4H), 2.72 (t, J=7 Hz, 4H), 2.03-1.91 (m, 4H), 1.43 (s, 9H).

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

tert-Butyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}acetate (1.75 g, 5.28 mmol) was dissolved in 20 % TFA solution in DCM (100 ml). The reaction mixture was stirred at room temperature for 2 hours and evaporated to dryness. The residue was evaporated twice with cyclohexane and triturated with hexane. The resulting white powder was filtered, washed with hexane and dried under vacuum. Y=96%. MS ES ⁺ : 276.1.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 12.88 (s, 1H), 9.09 (s, 1H), 6.95 (s, 1H), 4.52 (s, 2H), 2.81 (t, J=7 Hz, 4H), 2.71 (t, J=7 Hz, 4H), 2.04-1.89 (m, 4H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and intermediate A as starting materials. The crude product was purified by FCC (0-100% DCM in hexane). Y=40%. MS ES ⁺ ([M+Na] ⁺ ): 326.2.

1H-NMR (300 MHz, 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=7 Hz, 4H), 2.70 (t, J=7 Hz, 4H), 2.05-1.88 (m, 4H), 1.21 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 1,3-difluoro-2-isocyanatobenzene as the raw materials. The crude product was purified by FCC (0-100% DCM in hexane). Y=28%. MS ES ⁺ ([M+Na] ⁺ ): 282.0.

¹ H-NMR (400 MHz, 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=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 1,3-dichloro-2-isocyanatobenzene as the raw materials. The crude product was purified by FCC (0-25% EtOAc in hexane). Y=65%. MS ES ⁺ ([M+Na] ⁺ ): 314.5.

¹ H-NMR (400 MHz, chloroform-d) δ 7.40 (d, J=8 Hz, 2H), 7.21 (t, J=7 Hz, 1H), 6.54 (s, 1H), 4.72 (s, 2H), 4.30-4.25 (m, 2H), 1.32 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 1-isocyanate naphthalene as the starting materials. The crude product was purified by FCC (0-25% EtOAc in hexane). Y=96%. MS ES ⁺ ([M+Na] ⁺ ): 296.1.

¹ H-NMR (400 MHz, chloroform-d) δ 7.95 (d, J=8 Hz, 1H), 7.92-7.83 (m, 2H), 7.73 (d, J=8 Hz , 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=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 7-isocyanato-2,2-dimethyl-2,3-dihydro-1-benzofuran as the raw materials. The crude product was purified by FCC (0-20% EtOAc in hexane). Y=74%. MS ES ⁺ ([M+Na] ⁺ ): 316.2.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.21 (d, J=8 Hz, 1H), 6.99-6.94 (m, 1H), 6 .75 (t, J=8 Hz, 1H), 4.63 (s, 2H), 4.18-4.12 (m, 2H), 3.02 (s, 2H), 1.43 (s, 6H), 1.21 (t, J=7 Hz, 3H).

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

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

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.26 (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=4 Hz, 3H), 2.81 (t, J=7 Hz, 4H), 2, 71 (t, J=7 Hz, 4H), 2.03-1.92 (m, 4H), 1.21 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl

2-hydroxyacetate and 2-fluoro-5-(trifluoromethyl)phenyl isocyanate as starting materials. The crude product was purified by preparative TLC (20% EtOAc in hexane). Y=14%. MS ES ⁺ ([M+Na] ⁺ ): 332.5.

¹ H-NMR (400 MHz, DMSO-d6) 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=7 Hz, 3H).

- 48 044707

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

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

¹ H-NMR (400 MHz, 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=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 2,6-diethylphenyl isocyanate as the raw materials. The crude product was purified by FCC (0-100% DCM in hexane). Y=57%. MS ES ⁺ ([M+Na] ⁺ ): 302.5.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.20-7.16 (m, 1H), 7.09 (d, J=7 Hz, 2H), 4 .63 (s, 2H), 4.18-4.12 (m, 2H), 2.62-2.53 (m, 4H), 1.22 (t, J=7 Hz, 3H), 1, 12 (t, J=8 Hz, 6H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 2-chloro-6-methylphenyl isocyanate as the raw materials. The crude product was purified by FCC (0-100% DCM in hexane). Y=33%. MS ES ⁺ ([M+Na] ⁺ ): 294.2.

¹ H-NMR (400 MHz, 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=7 Hz, 4H).

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

The title compound was prepared according to General Procedure A using ethyl 2-hydroxyacetate and 2-isocyanatobenzonitrile as starting materials. The crude product was purified by FCC (0-30% EtOAc in hexane). Y=21%. MS ES ⁺ ([M+Na] ⁺ ): 271.0.

¹ H-NMR (400 MHz, 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 yl)propanoate.

Ethyl-2-{[(1,2,3,5,6,7-hexαhydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyridine-313.

Step 1: ethyl 3-(pyridin-3-yl)oxirane-2-carboxylate.

The title compound was prepared according to General Procedure C using 3-pyridinecarboxaldehyde as the starting material. Y=41%. MS ES ⁺ : 194.1.

1H-NMR (300 MHz, 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=2 Hz, 1H), 3.55 (d, J=2 Hz, 1H), 1.36 (t, J= 7 Hz, 3H).

Step 2: ethyl 2-hydroxy-3-(pyridin-3-yl)propanoate.

The title compound was prepared according to General Procedure D using ethyl 3-(pyridin-3-yl)oxirane-2-carboxylate as the starting material. Y=70%. MS ES ⁺ : 196.2.

1H-NMR (300 MHz, chloroform-d) δ 8.50 (d, J=6 Hz, 2H), 7.62 (d, J=8 Hz, 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=7 Hz, 3H).

Step 3: ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyridin-3yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl-49 044707

2-Hydroxy-3-(pyridin-3-yl)propanoate and intermediate A as starting materials. The crude product was purified by reverse phase preparative HPLC. Y=5%. MS ES ⁺ : 395.4.

¹ H-NMR (300 MHz, DMSO-d6) δ 9.15 (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=7 Hz, 4H), 2.71-2.56 (m, 4H), 2.09-1.78 (m, 4H), 1.14 ( t, J=7 Hz, 3H).

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

2-tert-Butylaniline (200 mg, 1.34 mmol, 1 eq.) was dissolved in anhydrous THF (10 mL), and TEA (0.224 mL, 1.61 mmol, 1.2 eq.) was added. The solution was treated with triphosgene (0.159 mg, 0.54 mmol, 0.4 eq.), and the resulting mixture was stirred at 60°C for 4 hours. The reaction mixture was cooled to 0°C, and ethyl glycolate (0.167 ml, 1.61 mmol, 1.2 eq.) and TEA (0.163 mg, 1.61 mmol, 1.2 eq.). The reaction mixture was stirred at room temperature for 15 hours, filtered through Celite, and the filter pad was washed with EtOAc. The filtrate was concentrated under reduced pressure and the residue was purified by FCC (0-20% EtOAc in hexane). Y=47%. MS ES ⁺ ([M+Na] ⁺ ): 302.6.

¹ H-NMR (300 MHz, DMSO-d6) δ 8.94 (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= 7 Hz, 3H).

Example 15 Ethyl 2-((mesitylcarbamoyl)oxy)acetate.

The title compound was prepared according to General Procedure A using ethyl glycolate and 2,4,6-trimethylphenyl isocyanate as starting materials.

The crude product was purified by preparative TLC (20% EtOAc in hexane) and FCC (0-100% DCM in hexane). Y=57%. MS ES ⁺ ([M+Na] ⁺ ): 288.1.

1H-NMR (400 MHz, 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=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl glycolate and 2-isopropylphenyl isocyanate as starting materials. The crude product was purified by FCC (0-20% EtOAc in hexane). Y=49%. MS ES ⁺ ([M+Na] ⁺ ): 288.2.

1H-NMR (400 MHz, 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=7 Hz, 3H), 1.28 (d, J=7 Hz, 6H).

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

The title compound was prepared according to General Procedure A using ethyl glycolate and 2-ethyl-6-methylphenyl isocyanate as starting materials. The crude product was purified by FCC (0-20% EtOAc in hexanes) followed by preparative TLC (100% DCM). Y=35%. MS ES ⁺ ([M+Na] ⁺ ): 288.2.

^1H -NMR (400 MHz, DMSO- _d6 ) main conformer 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=7 Hz, 3H), 1.11 (t, J=7 Hz, 3H).

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

Step 1: ethyl 3-phenyloxirane-2-carboxylate.

The title compound was prepared according to General Procedure C using ethyl chloroacetate and benzaldehyde as starting materials. The crude product was purified by FCC (0-10% EtOAc in hexane). Y=45%. MS ES ⁺ ([M+Na] ⁺ ): 234.1.

- 50 044707

Ή-NMR (400 MHz, DMSO-d ₆ ) δ 7.38 (s, 5H), 4.24-4.18 (m, 2H), 4.16 (d, J=2 Hz, 1H), 3 .81 (d, J=2 Hz,

1H), 1.25 (t, J=7 Hz, 3H).

Step 2: Ethyl 2-hydroxy-3-phenylpropanoate.

The title compound was prepared according to General Procedure D using ethyl 3-phenyloxirane-2-carboxylate as the starting material. Y=96%. MS ES ⁺ : 195.2.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.30-7.24 (m, 2H), 7.24-7.17 (m, 3H), 5.53 (d, J=6 Hz , 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=7 Hz, 3H).

Step 3: ethyl 2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-phenylpropanoate.

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-phenylpropanoate and intermediate A as starting materials. The crude material was purified by two sequential FCC purifications (0-100% DCM in hexane and 0-20% EtOAc in hexane). Y=21%. MS ES ⁺ ([M+Na] ⁺ ): 416.8.

^1H -NMR (400 MHz, 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=7 Hz, 3H).

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

Step 1: ethyl 3-(pyridin-2-yl)oxirane-2-carboxylate.

The title compound was prepared according to General Procedure C using ethyl chloroacetate and 2-pyridinecarbaldehyde as starting materials. The crude product was purified by FCC (0-50% EtOAc in hexane gradient). Y=67%, mixture of diastereoisomers (75/25). MS ES ⁺ : 194.1.

Diastereoisomer 1 (main): ^1H -NMR (400 MHz, 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=7 Hz, 3H).

Diastereoisomer 2 (minor): ^1H -NMR (400 MHz, DMSO-d6) δ 8.54-8.51 (m, 1H), 7.82-7.78 (m, 1H), 7.39-7 .33 (m, 2H), 4.40 (d, J=5 Hz, 1H), 4.10 (d, J=5 Hz, 1H), 3.95-3.92 (m, 2H), 0 .95 (t, J=7 Hz, 3H).

Step 2: ethyl 2-hydroxy-3-(pyridin-2-yl)propanoate.

The title compound was prepared according to General Procedure D using ethyl 3-(pyridin-2-yl)oxirane-2-carboxylate (a mixture of both diastereoisomers) as the starting material. Y=85%. MS ES ⁺ : 196.1.

¹ H-NMR (400 MHz, DMSO-d6) δ 8.51-8.46 (m, 1H), 7.71-7.67 (m, 1H), 7.26 (d, J=8 Hz, 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=7 Hz, 3H).

Step 3: ethyl 2-(((1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)oxy)-3-(niridin-2-yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-(pyridin-2-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-20% EtOAc in hexane). Y=16%. MS ES ⁺ : 395.4.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.08 (s, 1H), 8.52 (d, J=4 Hz, 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=7 Hz, 4H), 2.67-2.55 (m, 4H) , 2.01-1.83 (m, 4H), 1.15 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl (2K)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by FCC (0-20% EtOAc in hexane). Y=24%. MS ES ⁺ ([M+Na] ⁺ ): 340.3.

¹ H-NMR (400 MHz, 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=7 Hz, 4H), 2.70 (t, J=7 Hz, 4H), 2.02-1.91 (m, 4H), 1 .43 (d, J=5 Hz, 3H), 1.21 (t, J=7 Hz, 3H).

Example 21. Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl]oxy}acetate.

The title compound was prepared according to General Procedure A using propan-2-yl-2-hydroxyacetate and intermediate A as starting materials. Crude

- 51 044707 the product was purified by the FCC method (0-100% DCM in hexane). Y=56%. MS ES ⁺ ([M+Na] ⁺ ): 340.3.

1H-NMR (400 MHz, 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=7 Hz, 4H), 2.76-2.66 (m, 4H), 2.11-1.86 (m, 4H), 1.21 (d, J= 6 Hz, 6H).

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

2-{[(1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl]oxy}acetic acid (intermediate B, 200 mg, 0.73 mmol, 1 eq.) suspended in acetone (2 mL), and TEA (152 μL, 1.09 mmol, 1.5 eq.) was added. 1-Iodopropane (78 μL, 0.8 mmol, 1.1 eq.) was added to the resulting solution, and the RM was stirred at RT under Ar atmosphere for 15 h. The RM was diluted with DCM, and the solution was washed with 1 M HCl. The aqueous layer was extracted with DCM twice. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by trituration in hexane to give the title compound. Y=15%. MS ES ⁺ ([M+Na] ⁺ ): 340.4.

1H-NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 6.95 (s, 1H), 4.63 (s, 2H), 4.07 (t, J=7 Hz, 2H), 2.81 (t, J=6 Hz, 4H), 2.71 (t, J=7 Hz, 4H), 2.06-1.89 (m, 4H), 1.66-1, 55 (m, 2H), 0.90 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure E using intermediate B and cyclopropylmethanol as starting materials. The crude product was purified by trituration in Et ₂ O/hexane. Y=69%. MS ES ⁺ ([M+Na] ⁺ ): 352.4.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 6.95 (s, 1H), 4.64 (s, 2H), 3.95 (d, J=7 Hz , 2H), 2.81 (t, J=7 Hz, 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. Cyclobutyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}acetate.

The title compound was prepared according to General Procedure E using intermediate B and cyclobutanol as starting materials. The crude product was purified by trituration with Et ₂ O/hexane. Y=61%. MS ES ⁺ ([M+Na] ⁺ ): 352.3.

¹ H-NMR (400 MHz, 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=7 Hz, 4H), 2.71 (t, J=7 Hz, 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-Methylpropyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}acetate.

The title compound was prepared according to General Procedure E using intermediate B and 2-methylpropan-1-ol as starting materials. The crude product was purified by trituration with Et ₂ O/hexane. Y=56%. MS ES ⁺ ([M+Na] ⁺ ): 354.4.

1H-NMR (400 MHz, DMSO-d6) δ 9.18 (s, 1H), 6.95 (s, 1H), 4.65 (s, 2H), 3.91 (d, J=7 Hz, 2H), 2.81 (t, J=7 Hz, 4H), 2.77-2.64 (m, 4H), 2.01-1.93 (m, 4H), 1.92-1.83 (m, 1H), 0.90 (d, J=7 Hz, 6H).

Example 26. yl]oxy}propanoate.

Ethyl-(2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamo-

Step 1: (2R)-3-(4-cyanophenyl)-2-hydroxypropanoic acid.

(2R)-2-amino-3-(4-cyanophenyl)propanoic acid (500 mg, 2.63 mmol, 1 eq.) was dissolved in deionized water/acetic acid (4/1, 30 ml), and at 0 °C, a solution of sodium nitrite (544 mg, 7.89 mmol, 3 equiv.) in water (5 ml) was slowly added over 10 min. The RM was heated to rt and stirred for 15 hours. The reaction mixture was quenched by adding 2 M methylamine in THF (2 ml) and the resulting mixture was evaporated under reduced pressure to approximately one third of its volume. The residue was made alkaline to pH 9 by adding aq. us. NaHCO3 and washed with EtOAc. The aqueous layer was then acidified to pH 3 by adding 2 M HCl. The mixture was extracted four times with DCM, the combined organic layers were dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by trituration with Et ₂ O/hexane. Y=43%. MS ES: 190.2.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.60 (s, 1H), 7.75 (d, J=8 Hz, 2H), 7.45 (d, J=8 Hz, 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-indacen-4-yl)carbamoyl]oxy}propanoic acid.

The title compound was prepared according to General Procedure A using (2R)-3-(4-cyanophenyl)-2-hydroxypropanoic acid and intermediate A as starting materials. The crude product was purified by trituration with Et ₂ OY=55%. MS ES ⁺ : 391.0.

Step 3: ethyl (2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacene-4-ul)carbamoyl]oxy} propanoate.

(2R)-3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}propanoic acid (200 mg, 0 .51 mmol, 1 equiv.) was suspended in acetone (2 ml) and treated with TEA (107 μl, 0.77 mmol, 1.5 equiv.). Ethyl iodide (49 μL, 0.61 mmol, 1.2 eq.) was added to the resulting solution and stirred RM at RT under Ar atmosphere for 15 h. The reaction mixture was diluted with DCM and washed with 1 M HCl solution. 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 (0-40% EtOAc in hexane). Y=22%. MS ES ⁺ ([M+Na] ⁺ ): 442.1.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.13 (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, 2H), 3.30-3.10 (m, 2H), 2.80 ( t, J=7 Hz, 4H), 2.66-2.57 (m, 4H), 2.00-1.85 (m, 4H), 1.14 (t, J=7 Hz, 3H).

Example 27 Ethyl 2-({[2-methyl-6-(propan-2-yl)phenyl]carbamoyl}oxy)acetate.

The title compound was prepared according to General Procedure A using ethyl glycolate and 2-isopropyl-6-methylphenyl isocyanate as starting materials. The crude product was purified by FCC (0-20% EtOAc gradient in hexane). Y=66%. MS ES ⁺ ([M+Na] ⁺ ): 302.3.

1H-NMR (300 MHz, DMSO-d6) 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=7 Hz, 3H), 1.11 (d, J=7 Hz, 6H).

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

The title compound was prepared according to General Procedure A using glycolic acid and intermediate A as starting materials. The crude product was purified by FCC (0-10% MeOH in DCM). Y=17%. MS ES ⁺ ([M+Na] ⁺ ): 298.3.

1H-NMR (300 MHz, DMSO-d6) δ 12.88 (s, 1H), 9.09 (s, 1H), 6.95 (s, 1H), 4.52 (s, 2H), 2, 81 (t, J=7 Hz, 4H), 2.71 (t, J=7 Hz, 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 eq.) and DMAP (131 mg, 0.11 mmol, 0.5 eq.) in anhydrous ACN (5 ml) was stirred for 5 min. at RT. A solution of 2,6-diethyl-4-methylaniline (350 mg, 2.14 mmol, 1 eq.) in anhydrous ACN (2 ml) was then added dropwise. After 30 min at room temperature, the mixture was concentrated under reduced pressure, dissolved in anhydrous hexane and filtered through a pad of silica gel. The filtrate was evaporated, and the residue was used in 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}acetate.

The title compound was prepared according to General Procedure A using ethyl glycolate and 2,6-diethyl-4-methylphenyl isocyanate as the raw materials. The crude product was purified by reverse phase preparative HPLC (0.1% formic acid buffer).

- 53 044707

Y=50%. MS ES ⁺ ([M+Na] ⁺ ): 316.3.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 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=7 Hz, 3H), 1.10 (t, J=7 Hz, 6H).

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

The title compound was prepared according to General Procedure A with methyl glycolate and intermediate A as starting materials, using THF as the reaction solvent. Purified by FCC (0-25% EtOAc in hexane). Y=66%. MS ES ⁺ ([M+Na] ⁺ ): 312.3.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.17 (s, 1H), 6.95 (s, 1H), 4.64 (s, 2H), 3.69 (s, 3H), 2 .81 (t, J=7 Hz, 4H), 2.71 (t, J=7 Hz, 4H), 2.02-1.93 (m, 4H).

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

The title compound was prepared according to General Procedure A with ethyl (R)-2hydroxy-4-phenylbutyrate and intermediate A as starting materials, using THF as the reaction solvent. The crude product was purified by preparative TLC (100% DCM). Y=9%. MS ES ⁺ ([M+Na] ⁺ ): 430.6.

1H-NMR (400 MHz, DMSO-d6) δ 9.22 (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=7 Hz, 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=7 Hz, 3H).

Example yl)propanoate.

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

Step 1: Ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

Pyrazole (293 mg, 4.30 mmol, 2.5 eq) and ethyl 2,3-epoxypropanoate (200 mg, 1.72 mmol, 1 eq) were loaded into a microwave vial. The substrates were dissolved in absolute EtOH (3 ml) under argon and the vial was sealed. The reaction mixture was heated for 3 days at 90°C (oil bath), and the reaction was monitored by TLC. The solvent was removed in vacuo and the residue was purified by FCC (0-15% EtOAc in hexane). Y=96%. MS ES ⁺ : 185.4.

1H-NMR (400 MHz, DMSO-d6) δ 7.68-7.65 (m, 1H), 7.45-7.41 (m, 1H), 6.21 (t, J=2 Hz, 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=7 Hz, 3H).

Step 2: Ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate 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.

1H-NMR (400 MHz, DMSO-d6) δ 9.18 (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=7 Hz, 4H ), 2.66 (t, J=8 Hz, 4H), 2.01-1.89 (m, 4H), 1.18 (t, J=7 Hz, 3H).

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

Step 1: cyclopentyl-2-(benzyloxy)acetate.

Cyclopentanol (735 mg, 8.53 mmol, 1.05 eq.) was dissolved in anhydrous DCM (8 ml) under Ar and the solution was cooled to 0°C.

Anhydrous pyridine (0.723 mL, 8.94 mmol, 1.1 eq.) was added followed by benzyloxyacetyl chloride (1.5 mg, 8.12 mmol, 1 eq.) added dropwise. The mixture was left to stir in an Ar atmosphere at room temperature.

t. for 16 hours. The reaction mixture was quenched by adding water at 0°C, and the layers were separated. The organic layer was washed with aq. us. NaHCO3, dried over anhydrous Na ₂ SO ₄ and concentrated. The residue was purified by FCC (0-10% EtOAc in hexane). Y=97%.

¹ H-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.

Cyclopentyl-2-(benzyloxy)acetate (1.93 g, 8.25 mmol, 1 eq.) was dissolved in anhydrous MeOH (40 ml). The air was removed using a vacuum pump, and the flask was purged with argon. Pd/C (10% w/w, 190 mg) was added and the Ar atmosphere was replaced with an H2 atmosphere. The reaction mixture was stirred at room temperature and atmospheric pressure for 16 hours. The reaction mixture was filtered through a pad of Celite, the filter layer was washed with MeOH, and the filtrate was evaporated under vacuum. The crude product was used in the next step without further purification. Y=57%.

¹ H-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: cyclopentyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}acetate.

The title compound was prepared according to General Procedure A with cyclopentyl-2hydroxyacetate and intermediate A as starting materials, using THF as the reaction solvent. The crude product was purified by FCC (0-80% DCM in hexane). Y=24%. MS ES ⁺ ([M+Na] ⁺ ): 366.5.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 6.95 (s, 1H), 5.18-5.12 (m, 1H), 4.57 (s , 2H), 2.81 (t, J=7 Hz, 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-8-indacen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1yl)propanoate.

Step 1: Ethyl 2-hydroxy-3-(1H-imidazol-1-yl)propanoate.

1H-imidazole (176 mg, 2.58 mmol, 1 eq.) and ethyl 2,3-epoxypropanoate (300 mg, 2.58 mmol, 1 eq.) were loaded into a microwave vial and the substrates were dissolved in absolute EtOH ( 3 ml) in an Ar atmosphere. 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 (0-10% MeOH in DCM) to give the title compound. Y=33%. MS ES ⁺ : 185.2.

1H-NMR (300 MHz, DMSO- _d6 ) δ 7.58-7.53 (m, 1H), 7.15-7.10 (m, 1H), 6.88-6.83 (m, 1H ), 5.94 (d, J=6 Hz, 1H), 4.28-4.18 (m, 1H), 4.18-4.06 (m, 4H), 1.19 (t, J= 7 Hz, 3H).

Step 2: ethyl 2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1yl)propanoate.

The title compound was prepared according to General Procedure A with ethyl 2hydroxy-3-(1H-imidazol-1-yl)propanoate and intermediate A as starting materials, using THF as the reaction solvent. The crude product was purified by reverse phase preparative HPLC (0.1% formic acid buffer). Y=26%. MS ES ⁺ : 384.4.

1H-NMR (300 MHz, DMSO-d6) δ 9.24 (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= 7 Hz, 4H), 2.72-2.60 (m, 4H), 2.03-1.90 (m, 4H), 1.17 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl glycolate and 2,6-diisopropylphenyl isocyanate as starting materials. The crude product was purified by FCC (4:1 hexane/EtOAc). Y=42%. MS ES ⁺ : 308.3.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.32-7.22 (m, 1H), 7.15 (d, J=8 Hz, 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).

- 55 044707

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

The title compound was prepared according to General Procedure A using ethyl glycolate and 2-chloro-5-(trifluoromethyl)phenyl isocyanate as starting materials. The crude product was purified twice by FCC (hexane/DCM). Y=6%. MS ES ⁺ : 348.6.

A-NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 7.96 (d, J=2 Hz, 1H), 7.76 (d, J=8 Hz, 1H), 7.57 (dd, J=2, 8 Hz, 1H), 4.73 (s, 2H), 4.17 (kv, J=7 Hz, 2H), 1.22 (t, J=7 Hz, 3H).

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

The title compound was prepared according to General Procedure A using ethyl glycolate and 2-tert-butyl-6-methylphenyl isocyanate as the raw materials. The crude product was purified by FCC (4:1 hexane/EtOAc). Y=22%. MS ES ⁺ : 316.2 [M+Na] ⁺ .

A-NMR (400 MHz, 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 (kv, J=7 Hz, 2H), 2.32 (s, 3H), 1.43 (s, 9H), 1.32 (t, J=7 Hz, 3H ).

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

The title compound was prepared according to General Procedure A using ethyl glycolate and 2,5-dimethylphenyl isocyanate as starting materials. The crude product was purified twice by FCC (hexane/EtOAc and then hexane/DCM). Y=22%. MS ES ⁺ : 274.2 [M+Na] ⁺ .

A-NMR (400 MHz, chloroform-d) δ 7.62 (s, 1H), 7.07 (d, J=8 Hz, 1H), 6.89 (d, J=8 Hz, 1H), 6 .56 (s, 1H), 4.70 (s, 2H), 4.29 (kv, J=7 Hz, 2H), 2.34 (s, 3H), 2.26 (s, 3H), 1 .33 (t, J=7 Hz, 3H).

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

Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl]oxy}-3-methoxypropanoate (Example 5F) (51 mg, 0.15 mmol) dissolved in THF/water (1:1, 1.5 ml) and cooled to 0°C. Lithium hydroxide monohydrate (7 mg, 0.16 mmol) was added and the reaction mixture was stirred for 30 minutes. THF was removed under vacuum. RM was acidified to pH 3 by adding 1 M HCl and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated. A precipitate appeared, which was filtered and purified by preparative TLC, eluting 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.

A-NMR (400 MHz, DMSO-d ₆ ) δ 11.74 (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=7 Hz, 4H ), 2.72 (t, J=7 Hz, 4H), 2.00-1.88 (m, 4H).

Example 40. Cyclopropyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)karbamoyl]okCi}acetate.

Step 1: cyclopropyl-2-(benzyloxy)acetate.

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 dropwise, followed by 2-benzyloxyacetyl chloride (256 µl, 1.62 mmol). RM 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 yellow

- 56 044707 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, the RM was purged (argon/vacuum cycles) and then stirred under hydrogen for 18 hours. The RM was filtered through Celite, washed with ACN and evaporated to dryness to give the title compound. Y=67%.

¹ H-NMR (300 MHz, DMSO-d ₆ ) 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: cyclopropyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy} acetate.

The title compound was prepared according to General Procedure A using cyclopropyl-2-(benzyloxy)acetate and intermediate A as starting materials. The crude product was purified by FCC (0-15% EtOAc in hexanes) followed by preparative TLC (silica, 100% DCM). Y=2%. MS ES ⁺ : 315.4.

^1H -NMR (400 MHz, DMSO- _d6 ) δ 9.18 (s, 1H), 6.96 (s, 1H), 4.60 (s, 2H), 4.20-4.12 (m , 1H), 2.81 (t, J=7 Hz, 4H), 2.71 (t, J=8 Hz, 4H), 1.98 (kv, J=7 Hz, 4H), 0.76- 0.61 (m, 4H).

Example 41 .

Step 1: tert-butyl-2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

tert-Butyloxirane-2-carboxylate (10 g, 69.4 mmol) was dissolved in anhydrous absolute EtOH (210 ml). Pyrazole (11.8 g, 174.4 mmol) was added and the reaction mixture was heated at 80°C for 16 hours. The reaction mixture was concentrated in vacuo and co-evaporated with toluene twice. The crude material was purified by FCC (0-40% EtOAc in DCM) followed by reverse phase FCC (C18, 5-90% ACN in H2O) to obtain the title compound as a white solid. Y=19%.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 7.66 (dd, J=2, 1 Hz, 1H), 7.43 (dd, J=2, 1 Hz, 1H), 6.21 ( t, J=2 Hz, 1H), 5.69-5.65 (m, 1H), 4.37-4.18 (m, 3H), 1.39 (s, 9H).

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

The title compound was prepared according to General Procedure A using tert-butyloxirane-2-carboxylate and intermediate A as starting materials. The crude product was purified by FCC (0-40% EtOAc in hexane). Y=22%. MS ES ⁺ : 412.

Step 3: 2-{[(1,2,3,5,6,7-hexαhydro-s-inαcen-4-yl)carbamoyl]oxy}-3-(1H-nirazol-1-yl)propanoic acid.

tert-Butyl-2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate (30 mg, 0.073 mmol) was dissolved in anhydrous 1,4-dioxane (0.3 ml) and cooled to 0°C. Add 4 M HCl (0.5 mL, 2 mmol) and stir RM at 0°C for 16 h. Reaction was not complete so solvent was removed under vacuum and 20% TFA in DCM (0.7 mL) was added , and stirred the reaction mixture at 0°C for 16 hours. The RM was concentrated, co-evaporated with hexane, and then co-evaporated with Et ₂ O three times. The resulting solid was filtered, washed with Et ₂ O and dried to obtain the title product as a gray solid substances. Y=46%. MS ES ⁺ : 356.

1H-NMR (300 MHz, 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=6 Hz, 1H), 4.58 (s, 2H), 2.80 (t, J=7 Hz, 4H), 2.63 (t, J=7 Hz, 4H), 2.03-1.86 (m, 4H).

- 57 044707

Example 41-1. moyl]oxy}propanoate.

Ethyl-(2R)-3-(3-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carba-

Step 1: (2R)-3-(3-cyanophenyl)-2-hydroxypropanoic acid.

A solution of D-3-cyanophenylalanine (0.30 g, 1.58 mmol) was dissolved in water (1.6 ml) and AcOH (0.4 ml) and cooled to 0°C. 1 M sodium nitrite (aq) (2.4 mL, 3.16 mmol) was slowly added to the solution. The RM was allowed to warm to rt and stirred for 16 hours. Methylamine (40% in H2O, 0.285 mL, 4.73 mmol) was added to quench the reaction mixture, then it was acidified to pH~3 by adding 1 M HCl. The mixture was extracted with EtOAc and the organic phase was dried (Na2SO4) and concentrated to give an orange liquid. Add 60% ACN (+0.1% TFA) in water and lyophilize the mixture to obtain the title product. Y=29%.

¹ H-NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 7.77-7.64 (m, 2H), 7.60 (d, J=8 Hz, 1H), 7 .50 (t, J=8 Hz, 1H), 4.26-4.14 (m, 1H), 3.04 (dd, J=14, 4 Hz, 1H), 2.86 (dd, J= 14.8 Hz, 1H).

No OH proton peak was observed.

Step 2: Ethyl (2R)-3-(3-cyanophenyl)-2-hydroxypropanoate.

Thionyl chloride (48 μL, 1.38 mmol). The RM was stirred at room temperature for 1 h and then evaporated under vacuum. The crude material was purified by FCC (silica, hexane/EtOAc) to give the title compound as a pale yellow oil. Y=59%.

1H-NMR (300 MHz, DMSO- _d6 ) δ 7.72-7.66 (m, 2H), 7.63-7.55 (m, 1H), 7.54-7.45 (m, 1H ), 5.63 (d, J=6 Hz, 1H), 4.34-4.22 (m, 1H), 4.08 (kv, J=7 Hz, 2H), 3.02 (dd, J =14.5 Hz, 1H), 2.89 (dd, J=14.8 Hz, 1H), 1.15 (t, J=7 Hz, 3H).

Step 3: ethyl (2R)-3-(3-cyanophenyl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-3-(3-cyanophenyl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by FCC (EtOAc in hexane) followed by preparative HPLC. Y=30%. MS ES ⁺ : 419.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.14 (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 (kv, J=7 Hz, 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=7 Hz, 3H).

Example 42 ]propanoate

Step 1: ethyl 3-[3-(1H-pyrazol-1-yl)phenyl]oxirane-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 and cooled to -78°C. 1.0 M sodium hexamethyldisilazane in THF (2.90 mL, 2.90 mmol) was added dropwise to the solution. The RM was stirred at -78°C for 30 min, then warmed to 0°C and quenched by adding water. RM was concentrated, partitioned between water and Et ₂ O and separated. The organic phase was washed with brine, dried over Na ₂ SO ₄ , 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]propanoate.

In a hydrogenation flask, a solution of ethyl 3-[3-(1H-pyrazol-1-yl)phenyl]oxirane-2-carboxylate

- 58 044707 (0.35 g, 1.36 mmol) in EtOAc (15 ml) was treated with 10% Pd on carbon (14 mg). The RM was purged and then stirred under a hydrogen atmosphere for 16 h at room temperature and atmospheric pressure.

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-indacen-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazol-1yl)phenyl ]propanoate

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-[3-(1H-pyrazol-1-yl)phenyl]propanoate and intermediate A as starting materials. The crude product was purified by FCC (EtOAc in hexane). Y=48%. MS ES ⁺ : 460.6.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.13 (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 (kv, J=7 Hz, 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=7 Hz, 3H).

Example 43 Ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazole -yl)phenyl]propanoate.

1g Vg Vg Vg

Step 1: (2R)-3-(3-bromophenyl)-2-hydroxypropanoic acid.

(2R)-2-amino-3-(3-bromophenyl)propanoic acid (1.0 g, 4.10 mmol) was dissolved in water/AcOH (4:1, 40 ml) and cooled to 0°C. 1 M sodium nitrite (8.2 mL, 8.2 mmol) was slowly added to the solution. The reaction mixture was stirred at RT for 16 hours, treated with 40% aqueous methylamine (0.48 ml, 12.3 mmol) and stirred for an additional 10 minutes. The reaction mixture was acidified to pH 3 by adding 1 M HCl and extracted with EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated to give the title compound as a yellow oil. Y=54%.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.54-7.35 (m, 2H), 7.34-7.16 (m, 2H), 5.76 (s, 1H), 4 .16 (dd, J=8, 4 Hz, 1H), 2.97 (dd, J=14, 4 Hz, 1H), 2.79 (dd, J=14, 8 Hz, 1H).

No CO2H proton peak was 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 RM was left to warm to room temperature and stirred for 1 hour, then evaporated to dryness. The crude material was purified by FCC (EtOAc in hexane) to give the title compound as a pale yellow oil. Y=75%.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 7.51-7.35 (m, 2H), 7.24 (d, J=2 Hz, 2H), 5.59 (d, J=6 Hz , 1H), 4.33-4.18 (m, 1H), 4.14-3.97 (m, 2H), 2.95 (dd, J=14.5 Hz, 1H), 2.83 ( dd, J=14, 8 Hz, 1H), 1.15 (t, J=7 Hz, 3H)

Step 3: ethyl (2R)-3-(3-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate.

A solution of ethyl (2R)-3-(3-bromophenyl)-2-hydroxypropanoate (0.75 g, 3.06 mmol) and imidazole (0.42 g, 6.12 mmol) in DMF (16 ml) was treated with tert -butyldimethylsilyl chloride (0.55 g, 3.67 mmol). The RM was stirred at RT for 16 hours, then diluted with water and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na ₂ SO ₄ and concentrated. The crude material was purified by FCC (EtOAc in hexane) to obtain the title compound as a colorless oil. Y=98%.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 7.48-7.38 (m, 2H), 7.28-7.20 (m, 2H), 4.40 (dd, J=9, 4 Hz, 1H), 4.18-4.05 (m, 2H), 3.02 (dd, J=13, 4 Hz, 1H), 2.81 (dd, J=13, 9 Hz, 1H), 1.19 (t, J=7 Hz, 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]propanoate.

Sealed vial loaded with ethyl (2R)-3-(3-bromophenyl)-2-[(tert-butyldimethylsilyl)oxy]propanoate (0.30 g, 0.77 mmol), pyrazole (79 mg, 1.16 mmol ), copper(I) iodide (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) in 1,4-dioxane (15 ml), degassed and backfilled with argon. The reaction mixture was stirred at 100°C for 16 hours. The RM was filtered through Celite, washed with EtOAc and concentrated. The residue was partitioned between water and EtOAc, then the organic phase was dried (Na2SO4), filtered and concentrated. The crude material 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]propanoate.

To a solution of ethyl (2R)-2-[(tert-butyldimethylsilyl)oxy]-3-[3-(1H-pyrazol-1-yl)phenyl]propanoate (0.10 g, 0.27 mmol) in anhydrous THF (1 ml) triethylamine trihydrofluoride (0.52 ml, 3.2 mmol) was added. The RM was stirred at RT for 16 hours, diluted with EtOAc and washed with dilute sodium bicarbonate solution. The aqueous phase was extracted with EtAOc and the combined organic layers were washed successively with water and brine, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo 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-indacen-4-yl)carbamoyl]oxy}-3-[3-(1H-pyrazole1 -yl)phenyl]propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-2-hydroxy-3-[3-(1H-pyrazol-1-yl)phenyl]propanoate and intermediate A as starting materials. The crude product was purified by FCC (EtOAc in hexane). Y=12%. MS ES ⁺ : 460.6.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.12 (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 (kv, J=7 Hz, 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=7 Hz, 3H).

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

Step 1: tert-butyloxirane-2-carboxylate.

tert-Butyl acrylate (30 g, 234 mmol) was dissolved in DCM (300 ml). A solution of metachloroperoxybenzoic acid (50.5 g, 293 mmol) in DCM (420 mL) was added and the RM was refluxed for 2 days. Additionally, meta-chloroperoxybenzoic acid (67 g, 388 mmol) was added and the reaction mixture was refluxed for an additional 4 days. RM was filtered. The filtrate was cooled in an ice-water bath and we were carefully added. Na ₂ S ₂ O ₃ . The layers were separated. The organic phase was filtered and washed. sodium bicarbonate solution and filtered again. The organic phase was washed with brine and filtered. The filtrate was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The resulting residue was suspended in hexanes, filtered, and the filtrate was concentrated in vacuo to give the title compound as a yellow oil. Y=47%.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 3.34 (dd, J=4, 3 Hz, 1H), 2.95-2.87 (m, 2H), 1.52 (s, 9H ).

Step 2: tert-butyl-2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

tert-Butyloxirane-2-carboxylate (10.0 g, 69.4 mmol) 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 co-evaporated with toluene. Purification by FCC (0-40% EtOAc in DCM) followed by reverse phase FCC (C18, 5-90% ACN in H ₂ O) afforded the title compound as a white solid. Y=19%.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 7.66 (dd, J=2, 1 Hz), 7.43 (dd, J=2, 1 Hz), 6.21 (t, J=2 Hz, 1H), 5.69-5.65 (m, 1H), 4.37-4.18 (m, 3H), 1.39 (s, 9H).

Step 3: tert-butyl-2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using tert-butyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and 2,6-difluorophenyl isocyanate as the raw materials. The crude product was purified by FCC (0-10% MeOH in DCM). Y=69%. MS ES ⁺ : 368.

Step 4: ethyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-1 H-pyrazol-1-yl)propanoate.

A solution of tert-butyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate (0.10 g, 0.27 mmol) in EtOH (2.0 ml) was treated with 4 M HCl in dioxane (0.10 ml, 0.4 mmol) and heated to sublimation for 3 hours. RM was evaporated to dryness and purified by FCC (0-10% MeOH in DCM) to give the title compound as a white solid. Y=22%. MS ES ⁺ : 340.3.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.55 (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 (sq, J =7 Hz, 2H), 1.17 (t, J=7 Hz, 3H).

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

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N Yu

Step 1: tert-butyl 2-[(phenylcarbamoyl)oxy]-3-(III-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using tert-butyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and phenyl isocyanate as the raw materials. The crude product was purified by FCC (0-40% EtOAc in hexane). Y=65%.

¹ H-NMR (300 MHz, DMSO-d6) δ 9.89 (s, 1H), 7.79 (dd, J=2, 1 Hz, 1H), 7.47 (dd, J=2, 1 Hz , 1H), 7.46-7.37 (m, 2H), 7.34-7.24 (m, 2H), 7.04-7.00 (m, 1H), 6.28 (t, J =2 Hz, 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)propanoic acid.

A solution of tert-butyl 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propanoate (218 mg, 0.66 mmol) in DCM/TFA (4:1, 5 ml) was stirred at t for 12 hours. The RM was evaporated and co-evaporated with hexane and then purified by reverse phase HPLC to give the title compound as an off-white solid. Y=14%. MS ES ⁺ : 276.1.

Step 3: Ethyl 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure E using 2-[(phenylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propanoic acid and EtOH as starting materials. The crude material was purified by FCC (0-40% EtOAc in hexane) followed by preparative TLC (40% EtOAc in hexane). Y=18%. MS ES ⁺ : 304.3.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.94 (s, 1H), 7.78 (d, J=2 Hz, 1H), 7.47 (dd, J=2, 1 Hz, 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=5 Hz, 1H), 4.65-4.62 (m, 2H), 4.18-4.11 (m, 2H), 1.18 (t , J=7 Hz, 3H).

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

Stage

Stage 2

Step 1: tert-butyl 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using tert-butyl-2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and 1-ethyl-2-isocyanato-3-methylbenzene as the raw materials. The crude product was purified by FCC (0-40% EtOAc in hexane). Y=50%.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.96 (s, 1H), 7.80 (d, J=2 Hz, 1H), 7.48 (d, J=1 Hz, 1H) , 7.14-7.02 (m, 3H), 6.29 (t, J=2 Hz, 1H), 5.16 (t, J=6 Hz, 1H), 4.59 (d, J= 6 Hz, 2H), 2.12 (s, 3H), 1.40-1.36 (m, 11H), 1.07 (t, J=8 Hz, 3H).

Step 2: 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoic acid.

A solution of tert-butyl 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate (0.22 g, 0.59 mmol) in DCM/TFA (4:1, 5 ml) was stirred at RT for 2 hours. RM was evaporated and co-evaporated with hexane and then purified by reverse phase HPLC to give the title compound as an off-white solid. Y=11%. MS ES ⁺ : 318.4.

Step 3: ethyl 2-{[(2-ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure E using 2-{[(2ethyl-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoic acid and EtOH as starting materials. The crude material was purified by FCC (0-40% EtOAc in hexane). Y=25%. MS ES ⁺ : 346.4.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.00 (s, 1H), 7.79 (d, J=2 Hz, 1H), 7.48 (d, J=1 Hz, 1H), 7.14-7.04 (m, 3H), 6.29 (t, J=2 Hz, 1H), 5.31 (t, J=6 Hz, 1H), 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=7 Hz, 3H), 1.07 (t, J=8 Hz, 3H).

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

Step 1: tert-butyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using tert-butyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and 2,6-dimethylphenyl isocyanate as the raw materials. The crude product was purified by FCC (0-40% EtOAc in hexane). Y=56%.

¹ H-NMR (300 MHz, DMSO-06) δ 8.98 (s, 1H), 7.80 (d, J=2 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.09-7.02 (m, 3H), 6.29 (t, J=2 Hz, 1H), 5.17 (t, J=6 Hz, 1H), 4.60 (d, J=6 Hz, 2H), 2.13 (s, 6H), 1.38 (s, 9H).

Step 2: 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoic acid.

A solution of tert-butyl-2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate (0.36 g, 1.00 mmol) in DCM/TFA ( 4:1, 5 ml) was stirred at RT for 5 hours. RM was evaporated and co-evaporated with hexane three times, and then purified by preparative TLC (10% MeOH, 2% AcOH, 88% DCM) to obtain the title compounds as an off-white solid. Y=7%. MS ES ⁺ : 304.2.

Step 3: ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure E using 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoic acid and EtOH as starting materials. The crude material was purified by FCC (0-40% EtOAc in hexane). Y=34%. MS ES ⁺ : 332.6.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.01 (s, 1H), 7.79 (d, J=2 Hz, 1H), 7.48 (d, J=2 Hz, 1H), 7.10-7.03 (m, 3H), 6.29 (t, J=2 Hz, 1H), 5.30 (t, J=6 Hz, 1H), 4.65-4.62 (m , 2H), 4.16-4.09 (m, 2H), 2.12 (s, 6H), 1.18 (t, J=7 Hz, 3H).

Example 48 The following compounds were synthesized according to the scheme below using a synthetic route similar to that described for Example 47.

Ethyl 2-{[(2,6-diethylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

MS ES ⁺ : 360.4.

1H-NMR (400 MHz, DMSO-d6) δ 8.98 (s, 1H), 7.79 (d, J=2 Hz, 1H), 7.49 (d, J=1 Hz, 1H), 7 .13-7.04 (m, 3H), 6.30 (t, J=2 Hz, 1H), 5.31 (t, J=6 Hz, 1H), 4.63 (d, J=6 Hz , 2H), 4.17-4.09 (m, 2H), 2.49-2.43 (m, 4H), 2.12 (s, 6H), 1.18 (t, J=7 Hz, 3H), 1.13-1.03 (m, 6H).

Ethyl 2-{[(2-fluoro-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

MS ES ⁺ : 336.5.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.24 (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 (kv, J=7 Hz, 2H), 2.17 (s, 3H), 1.17 (t, J=7 Hz, 3H).

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Ethyl 2-{[(2-chloro-6-fluorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

MS ES ⁺ : 356.5.

1H-NMR (400 MHz, DMSO- _d6 ) δ 9.59 (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 (kv, J=7 Hz, 2H), 1.17 (t, J=7 Hz, 3H).

Ethyl 2-{[(2-chloro-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

MS ES ⁺ : 352.5.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.34 (s, 1H), 7.79 (d, J=2 Hz, 1H), 7.48 (d, J=1 Hz, 1H), 7.36-7.31 (m, 1H), 7.27-7.19 (m, 2H), 6.32-6.26 (m, 1H), 5.31 (t, J=6 Hz, 1H), 4.64 (d, J=5 Hz, 2H), 4.13 (kv, J=7 Hz, 2H), 2.18 (s, 3H), 1.18 (t, J=7 Hz , 3H).

Ethyl 2-{[(2,6-dichlorophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

MS ES ⁺ : 372.8.

¹ H-NMR (300 MHz, chloroform-d) δ 7.54 (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 (kv, J=7 Hz, 2H), 1.30 (t, J=7 Hz, 3H).

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

Step 1: Ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

Pyrazole (1.17 g, 17.2 mmol) was added to a stirred solution of ethyl 2,3-epoxypropanoate (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 allowed to cool to room temperature and concentrated in vacuo. The resulting crude residue was poured into water (100 ml) and extracted with ethyl acetate (3x70 ml). The combined organic phases were washed with water (5x70 ml) to remove excess pyrazole. The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound. Y=35%. MS ES ⁺ : 185.2.

Step 2: ethyl 2-[(cyclohexylcarbamoyl)oxy]-3-(1H-pyrazol-1-yl)propanoate.

To a solution of cyclohexyl isocyanate (0.067 g, 0.54 mmol) in DMF (1.5 ml) at room temperature was added ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate (0.1 g, 0. 54 mmol) and copper(I) chloride (0.058 g, 5.90 mmol). 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 (2x30 ml). The combined organic phases were washed with cold water (5x30 ml) and then with brine (30 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (20% ethyl acetate in hexane) to obtain the title compound as a colorless liquid. Y=55%. MS ES ⁺ : 310.2.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 7.73-7.72 (m, 1H), 7.44-7.41 (m, 2H), 6.25 (t, J=4 Hz , 1H), 5.16 (t, J=5 Hz, 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)propanoate.

Synthesized using a synthetic route similar to that described for Example 49. MS ES ⁺ : 296.2.

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Ή-NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J=2 Hz, 1H), 7.50-7.44 (m, 2H), 6.25 (t, J=2 Hz , 1H), 5.16 (t,

J=5 Hz, 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 ]oxy}propanoate.

Step 1: Ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate.

To a solution of ethyl 2,3-epoxypropanoate (0.75 g, 6.45 mmol) in anhydrous EtOH (5 mL) was added 4-cyanopyrazole (0.30 g, 3.22 mmol). RM was heated at 90°C in a sealed tube for 16 hours. RM was evaporated to give the title compound as a yellow liquid, which was used without further purification. MSES ⁺ : 210.1

Step 2: ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl] oxy} propanoate.

The title compound was prepared according to General Procedure B using ethyl 3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by FCC (0-30% EtOAc in hexane). Y=10%. MS ES ⁺ : 409.2.

Ή-NMR (300 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.68-8.61 (m, 1H), 8.10 (s, 1H), 6.96 (s, 1H), 5.35 (br s, 1H), 4.71 (b s, 2H), 4.14 (kv, J=7 Hz, 2H), 2.89-2.79 (m, 4H ), 2.73-2.58 (m, 4H), 2.03-1.89 (m, 4H), 1.19 (t, J=7 Hz, 3H).

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

Synthesized using a synthetic route similar to that described for Example 49. MS ES ⁺ : 324.3.

Ή-NMR (400 MHz, DMSO-d ₆ ) δ 7.72 (d, J=2 Hz, 1H), 7.46-7.44 (m, 2H), 6.25 (t, J=2 Hz , 1H), 5.15 (t, J=5 Hz, 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)propanoate.

Step 1: Ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

To a solution of ethyl 2,3-epoxypropanoate (11 g, 94.7 mmol) in anhydrous EtOH (190 mL) was added pyrazole (16.1 g, 236 mmol). RM was heated at 90°C in a sealed reactor for 3 days. RM was evaporated. The crude material was purified by FCC (0-100% DCM in hexanes, then 0-30% EtOAc in DCM) and then evaporated (55°C, <4 mbar) to give the title compound as a yellow oil. Y=31%.

Ή-NMR (300 MHz, DMSO-d ₆ ) δ 7.66 (dd, J=2, 1 Hz, 1H), 7.43 (dd, J=2, 1 Hz, 1H), 6.21 (t , J=2 Hz, 1H), 5.82 (d, J=6 Hz, 1H), 4.45-4.20 (m, 3H), 4.10 (kv, J=7 Hz, 2H), 1.18 (t, J=7 Hz, 3H).

Step 2: 2-isocyanato-3-methylbenzonitrile.

To a solution of 2-amino-3-methylbenzonitrile (0.85 g, 6.4 mmol) in THF (17 ml) was added triethylamine (0.99 ml, 7.1 mmol) followed by phosgene (20% in toluene, 3 .41 ml, 6.4 mmol). The RM was refluxed for 4 hours and then allowed to cool 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 (compound assayed in diethylamine to give diethylurea).

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Step 3: Ethyl 2-{[(2-cyano-6-methylphenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and 2-isocyanato-3-methylbenzonitrile as starting materials. The crude product was purified by FCC (0-60% EtOAc in hexane) and then preparatively

HPLC. Y=14%. MS ES ⁺ : 343.

¹ H-NMR (300 MHz, chloroform-d) δ 7.58-7.46 (m, 4H), 7.33 (d, J=8 Hz, 1H), 6.93 (s, 1H), 6 .28 (s, 1H), 5.53-5.45 (m, 1H), 4.69 (s, 2H), 4.28 (kv, J=7 Hz, 2H), 2.32 (s, 3H), 1.31 (t, J=7 Hz, 3H).

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

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

Example 5 5. Ethyl 2-{[(2-chloro-6-cyanophenyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

Synthesized using a synthetic route similar to that described for the MS ES ⁺ example: 363.0.

53.

¹ H-NMR (300 MHz, chloroform-d) δ 7.69 (dd, J=8, 1 Hz, 1H), 7.64 (dd, J=8, 1 Hz, 1H), 7.55 (d , J=2 Hz, 1H), 7.49-7.45 (m, 1H), 7.34 (t, J=8 Hz, 1H), 7.08 (s, 1H), 6.31-6 .24 (m, 1H), 5.52 (dd, J=6.5 Hz, 1H), 4.76-4.71 (m, 2H), 4.36-4.19 (m, 2H), 1.73 (s, 1H), 1.30 (t, J=7 Hz, 3H).

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

Step 1: ethyl 2-oxo-3-(pyrazin-2-yl)propanoate.

Methylpyrazine (0.40 g, 4 .25 mmol). The RM was stirred for 15 min and then ethyl 2,2,2-triethoxyacetate (1.03 mL, 4.68 mmol) was added. The solution was left to warm to room temperature and stirred for 16 hours. RM was poured into 1 M HCl and stirred for 1 hour. The mixture was neutralized by adding NaHCO ₃ solution and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by FCC (0-90% EtOAc in DCM) to obtain the title compound as an orange solid. Y=87%.

¹ H-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 (kv, J=7 Hz, 2H), 1.42 (t, J=7 Hz, 3H).

Step 2: ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate.

A solution of ethyl 2-oxo-3-(pyrazin-2-yl)propanoate (0.20 g, 1.03 mmol) in EtOH (40 ml) was cooled to 78°C and treated with NaBH ₄ (0.16 g, 4 .1 mmol). The RM was stirred for 1 hour at -78°C then allowed to warm to rt and stirred for an additional 1 hour. The RM was poured onto ice, acidified to pH 2 by adding 1 M HCl and extracted with DCM. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (EtOAc in hexane) to give the title compound as a yellow oil. Y=30%. MS ES ⁺ : 197.

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Step 3: ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrazin-2-yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-60% EtOAc in hexanes) followed by preparative HPLC. Y=7%. MS ES ⁺ : 396.1.

¹ H-NMR (300 MHz, acetonitrile-d ₃ ) δ 8.60-8.48 (m, 3H), 7.00 (s, 1H), 5.36 (dd, J=8.5 Hz, 1H ), 4.20 (kv, J=7 Hz, 2H), 3.40-3.30 (b. s, 2H), 2.87 (t, J=7 Hz, 4H), 2.74-2 .63 (m, 4H), 2.09-2.01 (m, 4H), 1.24 (t, J=7 Hz, 3H).

Example 57 .

Stage 5

Step 1: (2S)-2-bromo-3-hydroxypropanoic 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 RM was cooled to -13°C under Ar. Sodium nitrite (43 g, 0.63 mol) was slowly added in portions (~5 g every 15 min). After each addition, the RM turned brown, then the color slowly faded, but the solution was not completely discolored. After addition was complete (approximately 2.5 hours), the solution was warmed to 0°C, the Ar purge was stopped, and stirred RM for 6 hours. Excess nitrogen oxides were removed by bubbling the Ar mixture for 1 hour. The solution was extracted with diethyl ether (6x300 ml ). The combined organic layers were concentrated to 0.5 L under vacuum, dried over anhydrous MgSO ₄ , filtered and evaporated to dryness to give the title compound as a pale yellow oil, which was used without further purification. Y=88%.

¹ H-NMR (400 MHz, DMSO-d ₆ ) 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)-oxirane-2-carboxylate.

(2S)-2-bromo-3-hydroxypropanoic acid (74.5 g, 0.45 mol) was dissolved in absolute ethanol (300 ml) and cooled to -20°C under nitrogen atmosphere. A filtered solution of KOH (50 g, 0.89 mol) in absolute ethanol (300 ml) was slowly added. After 2 hours, the mixture was allowed to warm to 0°C and stirred at this temperature for 14 hours. The solution was filtered and the filtrate was further concentrated to approximately half volume. The mixture was filtered again. The combined filtered solids were dried under vacuum to give the title compound as a white solid. Y=95%.

¹ H-NMR (400 MHz, D2O) δ 3.34-3.33 (dd, J=5, 3 Hz, 1H), 2.93-2.90 (dd, J=6, 5 Hz, 1H) , 2.76-2.74 (dd, J=6, 3 Hz, 1H).

Step 3: benzyl-(2R)-oxirane-2-carboxylate.

A suspension of potassium (2R)-oxirane-2-carboxylate (4.0 g, 32 mmol), benzyltriethylammonium 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 triturated with diethyl ether three times. The combined ethereal extracts were filtered, dried (MgSO ₄ and evaporated in vacuo. The crude material was purified by FCC (10-50% EtOAc/petroleum ether) to give the title compound as a colorless oil. Y=46%.

¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.43-7.32 (m, 5H), 5.28-5.18 (m, 2H), 3.49-3.48 (dd, J= 4.2 Hz, 1H), 3.02-2.92 (m, 2H).

Step 4: benzyl-(2R)-2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

Benzyl (2R)-oxirane-2-carboxylate (3.00 g, 16.8 mmol) was dissolved in absolute 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 in vacuo. The crude material was purified by FCC (0-70% EtOAc in 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 H-NMR (400 MHz, DMSO-d6) δ 7.65 (d, J=2 Hz, 1H), 7.46-7.42 (m, 1H), 7.39-7.32 (m, 5H), 6.21 (d, J=2 Hz, 1H), 5.92 (d, J=6 Hz, 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).

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Step 5: benzyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1yl) propanoate

The title compound was prepared according to General Procedure A using benzyl-(2R)-2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-50% EtOAc in hexane). Y=78%.

¹ H-NMR (300 MHz, DMSO-de) δ 9.17 (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=7 Hz, 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-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl) propanoic acid.

A mixture of benzyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1yl)propanoate ( 1.4 g, 3.14 mmol), 10% Pd/C (163 mg, 0.14 mmol) and THF (3 ml) were purged and then stirred under hydrogen for 16 hours. The solution was filtered through a pad of Quadrasil. Filtered solids were extracted with successive washes with acetonitrile, ethanol, and hexane. The combined filtrates were evaporated to give the title compound as a white solid. Y=99%. MS ES ⁺ : 356.2.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.10 (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=7 Hz, 4H), 2.65 (d, 4H), 1 .97-1.90 (m, 4H).

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

Step 1: ethyl 2-oxo-3-(pyridazin-3-yl)propanoate.

To a solution of 2 M LDA in THF/hexane/ethylbenzene (2.2 ml, 4.4 mmol) in anhydrous THF (2.5 ml), cooled to -78°C, was added 2-methylpyridazine (0. 20 g, 2.1 mmol). The RM was stirred for 15 min and then ethyl 2,2,2-triethoxyacetate (0.51 mL, 2.3 mmol) was added. The solution was left to warm to room temperature and stirred for 16 hours. RM was poured into 1 M HCl and stirred for 1 hour. The mixture was neutralized by adding NaHCO ₃ solution and extracted three times with DCM. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by FCC (0-90% EtOAc in DCM) to obtain the title compound as a green solid. Y=51%.

¹ H-NMR (300 MHz, chloroform-d) δ 15.03 (s, 1H), 8.60 (dd, J=4, 2 Hz, 1H), 7.42-7.31 (m, 2H) , 6.33 (s, 1H), 4.38 (kv, J=7 Hz, 2H), 1.42 (t, J=7 Hz, 3H).

Step 2: ethyl 2-hydroxy-3-(pyridazin-3-yl)propanoate.

A solution of ethyl 2-oxo-3-(pyridazin-3-yl)propanoate (0.22 g, 1.12 mmol) in EtOH (40 ml) was cooled to 78°C and treated with NaBH ₄ (0.17 g, 4 .48 mmol). The RM was stirred for 1 hour at -78°C, then allowed to warm to room temperature and stirred for an additional 1.5 hours. The RM was poured onto ice, acidified to pH 2 by adding 1 M HCl, and extracted with DCM. The organic phase was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (MeOH in DCM) to obtain the title compound as a yellow oil. Y=11%. MS ES ⁺ : 197.

Step 3: ethyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacene-4-ul)carbamoyl]oxy}-3-(pyridazin-3-yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-(pyridazin-3-yl)propanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC. Y=10%. MS ES ⁺ : 396.1.

¹ H-NMR (300 MHz, chloroform-d) δ 9.13 (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 (kV, J=7 Hz, 2H), 3.79-3.46 (m, 2H), 2.89 (t, J=7 Hz, 4H), 2.80-2.66 (m, 4H), 2.11-2.00 (m, 4H), 1.29 (t, J=7 Hz, 3H) .

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

2,3-6-trifluorophenylaniline (0.072 ml, 0.68 mmol) and ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate (0.15 g, 0.82 mmol) (for synthesis see Example 49) was 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, then co-evaporated with DCM three times. The crude material was purified by FCC (0-5% MeOH in DCM) and then preparative HPLC to give the title compound as a white solid. Y=24%. MS ES ⁺ : 358.4.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.78 (s, 1H), 7.85-7.62 (m, 1H), 7.53-7.38 (m, 2H), 7 .28-7.16 (m, 1H), 6.26 (s, 1H), 5.31 (t, J=6 Hz, 1H), 4.62 (d, J=4 Hz, 2H), 4 .17-4.09 (m, 2H), 1.18 (t, J=7 Hz, 3H).

Example 60. Benzyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)karbamoyl]oxy}-3-(1H-nirazol1 -yl) propanoate

The title compound was synthesized following the procedures described for Example 57.

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

(2R)-2-{[(1,2,3,5,6,7-hexahydro-3-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoic acid (0.20 g, 0.56 mmol) (for 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 the RM was stirred at room temperature for 16 hours. The RM was concentrated in vacuo and the resulting residue was diluted with us. NaHCO ₃ solution and extracted with DCM. The organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo. The resulting solid was suspended in hexane, filtered, washed thoroughly with hexane and dried under vacuum to give the title compound as a white solid. Y=66%. MS ES ⁺ : 384.3.

¹ H-NMR (300 MHz, chloroform-d) δ 7.55 (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 (kv, J=7 Hz, 2H), 2.90 (t, J=8 Hz , 4H), 2.79 (t, J=7 Hz, 4H), 2.18-1.98 (m, 4H), 1.31 (t, J=7 Hz, 3H).

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

Synthesized using a synthetic route similar to that described for Example 53. Y=63%. MS ES ⁺ : 350.

^1H -NMR (400 MHz, DMSO- _d6 ) δ 9.19 (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=7 Hz, 3H), 1.09 (t, J= 7 Hz, 3H).

Example 63 Ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-imidazol1 -yl) propanoate

Step 1: ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propanoate.

A mixture of benzyl (2R)-oxirane-2-carboxylate (3.00 g, 16.8 mmol) (for synthesis, see Example 5AJ), imidazole (2.87 g, 42.1 mmol) and ethanol (32 ml) heated at 90°C for 16 hours. RM was concentrated in vacuo and purified by FCC (0-10% MeOH in 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-indacen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1yl) propanoate

The title compound was prepared according to General Procedure A using ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-100% (95:5 EtOAc/EtOH) in hexane). Y=32%. MS ES ⁺ : 384.3.

¹ H-NMR (300 MHz, chloroform-d) δ 7.55 (s, 1H), 7.22-6.85 (m, 3H), 6.57 (s, 1H), 5.35 (s, 1H), 4.47 (s, 2H), 4.25 (kv, J=7 Hz, 2H), 2.91 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz , 4H), 2.16-2.02 (m, 4H), 1.29 (t, J=7 Hz, 3H).

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

Step 1: benzyl (2R)-2-hydroxy-3-methoxypropanoate.

A mixture of benzyl-(2R)-oxirane-2-carboxylate (1.36 g, 7.6 mmol) (for 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 in hexanes) to give the title compound in the form of a colorless oil. Y=60%.

¹ H-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, 2 Hz, 2H), 3.38 (s, 3H), 3.06 (d, J=3, 2 Hz, 1H).

Step 2: benzyl-(2R)-2-{[(1,2,3,5,6,7-hexαhydro-s-indacen-4-yl)carbamoyl]oxy}-3-methoxypropαnoate.

The title compound was prepared according to General Procedure B using benzyl (2R)-2-hydroxy-3-methoxypropanoate and intermediate A as starting materials. The crude product was purified by FCC (0-20% EtOAc in hexane). Y=64%. MS ES ⁺ : 410.1.

Step 3: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-methoxypropαnoic acid.

A mixture of benzyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-methoxypropanoate (0.89 g, 2. 17 mmol), 10% Pd/C (0.1 g) and THF (50 ml) were purged and then stirred under hydrogen for 16 hours. The solution was filtered through Celite and concentrated. The crude residue 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 Na ₂ SO ₄ , 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-indacen-4-yl)carbamoyl]oxy}-3-methoxypropanoate.

The title compound was prepared according to General Procedure E using (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3 -methoxypropanoic acid and ethanol as starting materials. The crude product was purified by FCC (0-20% EtOAc in hexane). Y=71%. MS ES ⁺ : 348.2.

1H-NMR (300 MHz, 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=7 Hz, 3H).

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

The title compound was synthesized following the procedures described for Example 64.

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

Synthesized using a synthetic route similar to that described for Example 59. Y=45%. MS ES ⁺ : 406.0.

¹ H-NMR (300 MHz, 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=2 Hz, 1H), 5.35 (t, J=5 Hz, 1H), 4.63 (d, J=5 Hz , 2H), 4.14 (kv, J=7 Hz, 2H), 1.19 (t, J=7 Hz, 3H).

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Example 67 yl)propanoate.

Step 1: Ethyl 2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate.

A solution of 1,2,4-triazole (0.10 g, 1.45 mmol) in anhydrous DMF (1 ml) was treated with NaH (60% in mineral oil, 58 mg, 1.45 mmol). A solution of ethyloxyrane-2-carboxylate in DMF (1 ml) was added to the solution. RM was stirred at 60°C for 4 hours. The resulting mixture was diluted with EtOAc to obtain a solution, washed with us. NH ₄ Cl solution, dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The crude material was purified by FCC (0-5% MeOH in DCM) to give the title compound as an orange oil. Y=30%. MS ES ⁺ : 185.8.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 8.44 (s, 1H), 7.96 (s, 1H), 5.97-5.92 (m, 1H), 4.49-4 .35 (m, 3H), 4.12 (kv, J=7 Hz, 2H), 1.20 (t, J=7 Hz, 3H).

Step 2: ethyl-2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4-triazol- 1 yl)propanoate.

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC. Y=41%. MS ES ⁺ : 385.2.

¹ H-NMR (300 MHz, DMSO-d ₆ ) δ 9.19 (s, 1H), 8.57 (s, 1H), 8.00 (s, 1H), 6.95 (s, 1H), 5.32 (s, 1H), 4.73 (s, 2H), 4.14 (kv, J=7 Hz, 2H), 2.80 (t, J=7 Hz, 4H), 2.71- 2.59 (m, 4H), 1.90-1.80 (m, 4H), 1.19 (t, J=7 Hz, 3H).

Example 68 propanoate

Step 1: Ethyl 2-hydroxy-3-(3-methyl-1H-pyrazol-1-yl)propanoate.

3-methyl-1H-nirazole (0.50 g, 6.09 mmol), ethyloxyrane-2carboxylate (1.41 g, 12.2 mmol) and anhydrous ethanol (6 ml) were loaded into a sealed tube. RM was heated at 90°C for 16 h and then concentrated in vacuo. The crude material was purified by FCC (0-100% DCM in hexane) to obtain the desired product in a 2:1 ratio with ethyl-2-hydroxy-3-(5-methyl-1Hpyrazol-1-yl)propanoate. The mixture was used in the next step without further purification. Y=98%. MSES ⁺ : 199.4

Step 2: ethyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(3-methyl-1H-pyrazol1-yl) propanoate

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(3-methyl-1H-nyrazol-1-yl)pronoate and intermediate A as starting materials. The crude product was purified by preparative HPLC followed by crystallization (hexane and diethyl ether). Y=13%. MS ES ⁺ : 398.1.

¹ H-NMR (300 MHz, chloroform-d) δ 7.03 (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=8 Hz, 4H), 2.79 (t, J=7 Hz, 4H), 2.28 (s, 3H), 2.15-2.00 (m, 4H), 1.36-1.26 (m, 3H).

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

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and 1,3,5-trifluoro-2-isocyanatobenzene as the raw materials. The crude product was purified by FCC (0-5% MeOH in DCM) followed by preparative HPLC. Y=2%. MS ES ⁺ : 358.1.

^1H -NMR (300 MHz, DMSO-d6) 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 (kv, J=7 Hz, 2H), 1, 17 (t, J=7 Hz, 3H).

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

Stage

Step 1: tert-butyloxirane-2-carboxylate.

tert-Butyl acrylate (34.3 ml, 234 mmol) was dissolved in DCM (300 ml). A solution of mCPBA (50.5 g, 293 mmol) in DCM (420 mL) was added and the RM was refluxed for 2 days. Additional mCPBA (67 g, 375 mmol) was added and the RM was refluxed for an additional 4 days. The RM was filtered and the filtrate was cooled to 0°C. They added us drop by drop. Na ₂ S ₂ O ₃ , and then the layers were separated. The organic phase was filtered and washed. sodium bicarbonate solution, filtered, washed with brine, filtered, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was triturated with cold hexanes, filtered and the filtrate was evaporated to dryness to give the title compound as a yellow oil. Y=47%.

Ή-NMR (300 MHz, chloroform-d) δ 3.34 (dd, J=4, 3 Hz, 1H), 2.95-2.87 (m, 2H), 1.52 (s, 9H).

Step 2: tert-butyl-2-hydroxy-3-(1H-pyrazol-1-yl)propanoate.

To a solution of tert-butyloxirane-2-carboxylate (4.80 g, 33 mmol) in absolute EtOH (100 mL) was added pyrazole (5.67 g, 83 mmol). RM was heated at 80°C for 18 h, concentrated and co-evaporated with toluene. The crude material was purified by FCC (0-30% EtOAc in hexane) followed by reverse phase FCC (5-40% MeCN in H2O) to obtain the title compound as a white solid. Y=64%.

Ή-NMR (300 MHz, DMSO-d6) δ 7.66 (dd, J=2, 1 Hz, 1H), 7.43 (dd, J=2, 1 Hz, 1H), 6.21 (t, J=2 Hz, 1H), 5.72-5.61 (m, 1H), 4.37-4.16 (m, 3H), 1.39 (s, 9H).

Step 3: tert-butyl-2-({[2-methyl-6-(propan-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using tert-butyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate and 2-isocyanato-1-methyl-3-(propan-2-yl)benzene as starting materials. The crude product was purified by FCC (0-50% EtOAc in hexane). Y=78%. MS ES+: 388.3.

Step 4: 2-({[2-methyl-6-(propan-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propanoic acid.

tert-Butyl-2-({[2-methyl-6-(propan-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propanoate (0.36 g, 0.92 mmol) was dissolved in a mixture of TFA/DCM (1:4, 10 ml) and stirred at RT for 18 hours. RM was concentrated and co-evaporated with hexane. The crude product was suspended in water, made basic by the addition of NaHCO ₃ and washed with EtOAc. The aqueous phase was acidified to pH 5 by adding 1 M HCl and extracted with EtOAc. The organic phase was dried over sodium sulfate and evaporated. The crude material was purified by FCC (0-20% EtOAc in (hexane+1% AcOH)) and then preparative HPLC to obtain the title compound as a white solid. Y=23%. MS ES ⁺ : 332.3.

Step 5: ethyl 2-({[2-methyl-6-(propan-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure E using 2-({[2-methyl-6-(propan-2-yl)phenyl]carbamoyl}oxy)-3-(1H-pyrazol-1-yl)propane acid and ethanol as starting materials. The crude product was purified by preparative HPLC. Y=18%. MS ES ⁺ : 360.0.

Ή-NMR (400 MHz, 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)propanoate.

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

Ή-NMR (300 MHz, 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=5 Hz, 1H), 4.69 (d, J=5 Hz, 2H), 4.22 (kv, J=7 Hz, 2H), 1.27 (t, J=7 Hz, 3H).

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Example 72 yl)carbamoyl]oxy}propanoate.

Step 1: ethyl (2R)-oxirane-2-carboxylate.

To a mixture of potassium (2R)-oxirane-2-carboxylate (50.0 g, 396 mmol) (for synthesis, see Example 5AJ) in dichloromethane (250 ml) was added bromoethane (172 g) in one portion at 25°C under N ₂ atmosphere , 1.59 mol) and benzyl(triethyl)ammonium chloride (90.2 g, 396 mmol). The mixture was stirred at 45°C for 16 hours. The mixture was cooled to room temperature. The residue was poured into H ₂ O (300 ml) and stirred for 5 minutes. The aqueous phase was extracted with dichloromethane (150 ml). The combined organic phase was washed with brine (100 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (0-50% EtOAc in petroleum ether) to give the title compound as a yellow oil. Y=9%.

¹ H-NMR (400 MHz, 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=7 Hz, 3H).

Step 2: ethyl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate.

In a sealed tube, 1H-pyrazole-4-carbonitrile (2.00 g, 21.5 mmol) and ethyl (2R)-oxirane-2carboxylate (1.00 g, 8.61 mmol) were dissolved in EtOH (7 ml). RM was heated using microwave radiation at 100°C for 180 min. RM was concentrated under reduced pressure and purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 10-40%, 20 min) to obtain the title compound as a yellow oil. Y=42%.

¹ H-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-nirazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacene-4- yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure A using ethyl (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 50-80%, 20 min) to obtain the title compound as a white solid. Y=18%. MS ES ⁺ : 409.2.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.17 (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=7 Hz, 3H).

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

Step 1: benzyl-(2R)-3-(4-cyano-1H-nirazol-1-yl)-2-hydroxypropanoate.

In a sealed test tube, a mixture of benzyl(2R)-oxirane-2-carboxylate (0.50 g, 2.81 mmol) and 4-cyanopyrazole (0.52 g, 5.62 mmol) in EtOH (1 ml) was heated at microwave irradiation at 120°C for 1 hour. RM was concentrated and purified by FCC (EtOAc in hexane) to give the title compound. Y=20%. MS ES ⁺ : 272.2.

Step 2: benzyl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacene-4 -yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure B using benzyl (2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by FCC to obtain the title compound as a white solid. Y=50%. MS ES ⁺ : 471.

1H-NMR (300 MHz, chloroform-d) δ 7.78 (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).

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

Step 1: ethyl 2-oxo-3-(pyrimidin-2-yl)propanoate.

To a solution of 2 M LDA in THF/hexane/ethylbenzene (6.4 ml, 12.8 mmol) in anhydrous THF (15 ml) cooled to -78°C, 2-methylpyrimidine (0.60 g) was added under an inert atmosphere , 6.4 mmol). The RM was stirred for 1 hour and then ethyl 2,2,2-triethoxyacetate (1.31 mL, 7.0 mmol) was added. The solution was left to warm to room temperature and stirred for 3 days. RM was poured into 1 M HCl and stirred for 1 hour. The mixture was neutralized by adding NaHCO ₃ and extracted three times with EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO ₄ , filtered and evaporated. The crude material was purified by FCC (0-50% EtOAc in hexanes) to give the title compound as a yellow solid. Y=35%.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 13.63 (s, 1H), 8.89 (d, J=5 Hz, 2H), 7.43 (t, J=5 Hz, 1H), 6.52 (s, 1H), 4.29 (kv, J=7 Hz, 2H), 1.30 (t, J=7 Hz, 3H).

Step 2: ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate.

A solution of ethyl 2-oxo-3-(pyrimidin-2-yl)propanoate (0.42 g, 2.16 mmol) in EtOH (20 ml) was cooled to -78°C and treated with NaBH ₄ (0.33 g, 8.65 mmol). The RM was stirred for 1 hour at -78°C, then allowed to warm to rt and stirred for an additional 1.5 hours. The RM was poured onto ice, acidified to pH 2 by adding 1 M HCl and extracted sequentially with EtOAc, nBuOH and iPrOH/DCM (4/1). The combined organic phases were dried over Na ₂ SO ₄ , filtered and concentrated in vacuo 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)propanoate.

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate and 2,6-dimethylphenyl isocyanate as starting materials. The crude product was purified by FCC (0-20% MeOH in DCM) to give the title compound as a colorless oil. Y=2%. MS ES ⁺ : 344.0.

1H-NMR (300 MHz, methanol-d4) δ 8.78 (d, J=5 Hz, 2H), 8.74-8.61 (m, 1H), 7.41 (t, J=5 Hz, 1H), 7.13-7.01 (m, 3H), 5.73-5.63 (m, 1H), 4.24 (kV, J=7 Hz, 2H), 3.63-3.44 (m, 2H), 2.20 (s, 6H), 1.28 (t, J=7 Hz, 3H).

Example 75 .

Step 1: ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propanoate.

Benzyl (2R)-oxirane-2-carboxylate (3.00 g, 16.8 mmol) (for 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 in DCM) to give the title compound in the form of a yellow oil. Y=31%.

¹ H-NMR (300 MHz, DMSO-d6) δ 7.56 (d, J=1 Hz, 1H), 7.12 (t, J=1 Hz, 1H), 6.85 (t, J=1 Hz, 1H), 5.96 (d, J=5 Hz, 1H), 4.40-4.30 (m, 1H), 4.29-4.05 (m, 4H), 1.19 (t , J=7 Hz, 3H).

Step 2: (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propanoic acid hydrochloride.

Ethyl (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propanoate (0.97 g, 5.3 mmol) was dissolved in THF/water (1/1, 20 ml) and cooled to 0°C. Add lithium hydroxide monohydrate (0.23 g, 5.5 mmol) and stir RM at 0°C for 30 min, then at RT for 1 h. Remove THF under vacuum, and acidify RM to pH~ 3 by adding 2 M HCl. 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-indacen-4-yl)carbamoyl]oxy}-3-(1H-imidazol-1-yl) about panoic acid.

A solution of (2R)-2-hydroxy-3-(1H-imidazol-1-yl)propanoic acid hydrochloride (96 mg, 0.50 mmol), triethylamine (0.154 ml, 0.11 mmol) and DMSO (3 ml) was treated intermediate A (0.10 g, 0.50 mmol) and stirred for 16 hours. The crude material was purified by preparative HPLC to give the title compound as a white solid. Y=17%. MS ES ⁺ : 356.

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1H-NMR (300 MHz, DMSO-d ₆ ) δ 13.38 (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 =7 Hz, 4H), 2.69 (t, J=8 Hz, 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-indacen-4-yl)carbamoyl] oxy}propanoate.

Step 1: Ethyl 3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxypropanoate.

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

Step 2: ethyl-3-(4-fluoro-1H-pyrazol-1-ul)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl] oxy}propanoate.

The title compound was prepared according to General Procedure B using ethyl 3-(4-fluoro-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. 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 (300 MHz, DMSO-d ₆ ) δ 9.19 (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), 4.13 (kv, J=7 Hz, 2H), 2.81 (t, J=7 Hz, 4H), 2.73-2.59 (m, 4H), 2.01-1.91 (m, 4H), 1.19 (t, J=7 Hz, 3H).

Example 77 propanoate

Step 1: Ethyl 2-hydroxy-3-(5-methyl-1H-imidazol-1-yl)propanoate.

Ethyloxyrane-2-carboxylate (0.10 g, 0.86 mmol) was dissolved in EtOH (1 ml). 5-Methyl-1Nimidazole (71 mg, 0.86 mmol) was added and the RM was heated in a microwave reactor at 120°C for 1 hour. The RM was evaporated to dryness and partitioned between EtOAc and water. The organic phase was dried over anhydrous sodium sulfate and evaporated. The crude material was purified by FCC (0-7% MeOH in DCM) to obtain the title compound as a colorless oil. Y=52%. MS ES ⁺ : 199.

Step 2: ethyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H-imidazol1-yl) propanoate

The title compound was prepared according to General Procedure A using ethyl 2-hydroxy-3-(5-methyl-1H-imidazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-7% MeOH in DCM) to obtain the title compound as a white solid. Y=23%. MS ES ⁺ : 398.1.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.22 (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), 4.18-4.09 (m, 2H), 2.81 (t, J=6 Hz, 4H) , 2.75-2.59 (m, 4H), 2.33 (s, 3H), 2.01-1.91 (m, 4H), 1.19 (t, J=7 Hz, 3H).

Example 78 carbamoyl]oxy}propanoic acid.

To a mixture of propan-2-yl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacene -4yl)carbamoyl]oxy}propanoate (400 mg, 0.95 mmol) (for synthesis, see example 5CI) in dioxane (5 ml) at 20°C, 6 M HCl (5 ml) was added in one portion. The mixture was stirred at 20°C for 48 hours. RM was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC: (column: Phenomenex Luna C18 250x50 mm, 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B%: 45-80%, 20 min) to obtain the title compound as a white solid.

- 74 044707

Y=28%. MS ES ⁺ : 381.0.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 13.40 (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-indacen-4-yl)carbamoyl]oxy}-3-(1H-1,2, 4-triazol1-yl)propanoate.

Step 1: ethyl-(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate.

In a sealed tube, ethyl (2R)-oxirane-2-carboxylate (1.00 g, 8.61 mmol) (for synthesis, see Example 5AY) and 1,2,4-triazole (1.49 g, 21.5 mmol) was dissolved in EtOH (10 ml). RM was heated in a microwave reactor at 100°C for 3 h. RM was concentrated under vacuum and purified by preparative HPLC (column: Agela Innoval ODS-2 250x80 mm; mobile phase: [water (0.1% TFA) - ACN] ; B%: 0-20%, 20 min) to obtain the title compound as a yellow oil. Y=27%. MS ES ⁺ : 186.1.

¹ H-NMR (400 MHz, methanol^) 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=7 Hz, 3H).

Step 2: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-1,2, 4-triazol1-yl)propanoate.

The title compound was prepared according to General Procedure A using ethyl (2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna

C18 250x50 mm, 10 µm; 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 (400 MHz, methanol-d4) 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=7 Hz, 3H).

Example 80 )propanoate

Step 1: Ethyl 2-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propanoate.

In a sealed tube, ethyloxyrane-2-carboxylate (212 mg, 1.83 mmol) and 2-methylimidazole (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 in vacuo and purified by FCC (0-10% MeOH in 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-indacen-4-yl)carbamoyl]oxy}-3-(2-methyl-1H-imidazol1-yl) propanoate

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(2-methyl-1H-imidazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-10% MeOH in DCM) and then further purified by preparative HPLC to obtain the title compound as a white solid. MS ES ⁺ : 398.6.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 9.21 (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=7 Hz, 4H ), 2.75-2.55 (m, 4H), 2.33 (s, 3H), 2.01-1.91 (m, 4H), 1.19 (t, J=7 Hz, 3H) .

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

Step 1: 1-chloro-3-ethyl-2-isocyanatobenzene.

To a solution of 2-chloro-6-ethylaniline (0.25 g, 1.61 mmol) in THF (10 ml) was added triethylamine (0.246 ml, 1.77 mmol) followed by phosgene (20% in toluene, 0.85 ml, 1.61 mmol). RM was heated at 60°C for 4 hours and then allowed to cool to room temperature. THF was evaporated under vacuum and the residue was precipitated by adding 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 (compound assayed in diethylamine to give diethylurea).

Step 2: ethyl 2-{[(2-chloro-6-ethylphenyl)carbamoyl]-oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure B using ethyl 2hydroxy-3-(1H-pyrazol-1-yl)propanoate (for synthesis see Example 49) and 1-chloro-3-ethyl-2-isocyanatobenzene in as starting materials. The crude product was purified by FCC (0-10% MeOH in DCM) and then further purified by preparative TLC to obtain the title compound as an off-white solid. MS ES ⁺ : 366.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.33 (s, 1H), 7.79 (d, J=2 Hz, 1H), 7.48 (d, J=2 Hz, 1H) , 7.36-7.33 (m, 1H), 7.29-7.21 (m, 2H), 6.29 (t, J=2 Hz, 1H), 5.31 (t, J=6 Hz, 1H), 4.66-4.62 (m, 2H), 4.17-4.05 (m, 2H), 2.58-2.52 (m, 2H), 1.18 (t, J=7 Hz, 3H), 1.09 (t, J=8 Hz, 3H).

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

Stage 1: 1-isocyanato-2-methylnaphthalene.

Triphosgene (0 .47 g, 1.59 mmol). The mixture was heated to sublimation temperature for 4 hours. The reaction mixture was left to cool 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 obtain the title compound as a yellow liquid. This substance was used immediately without any further purification. Y=89%.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.08 (d, J=8 Hz, 1H) 7.83 (d, J=8 Hz, 1H), 7.65 (d, J=8 Hz , 1H), 7.58-7.56 (m, 1H), 7.52-7.50 (m, 1H), 7.34 (d, J=8 Hz, 1H), 2.55 (s, 3H).

Step 2: ethyl 2-{[(2-methylnaphthalene-1-yl)carbamoyl]-oxy}-3-(1H-pyrazol-1-yl)propanoate.

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate (for synthesis, see Example 49) and 1-isocyanato-2-methylnaphthalene as starting materials. The crude product was purified by FCC (0-30% EtOAc in hexanes) to give the title compound as a colorless oil. MS ES ⁺ : 368.2.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.53 (s, 1H), 7.91-7.78 (m, 4H), 7.52-7.40 (m, 4H), 6, 34 (s, 1H), 5.35 (t, J=6 Hz, 1H), 4.69 (d, J=6 Hz, 2H), 4.16-4.14 (m, 2H), 2, 46-2.31 (m, 3H), 1.22-1.18 (m, 3H).

Example 8 3. Ethyl-2 - {[(2-methylcyclohexyl)carbamoyl]oxy}-3-(1H-pyrazol-1-yl)propanoate.

Step 1: 1-isocyanato-2-methylcyclohexane.

To a solution of 2-methylcyclohexane-1-amine (0.2 g, 1.77 mmol) in toluene (3 ml) under N ₂ at 0°C was added 20% phosgene in toluene (1 ml, 2.12 mmol). 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)propanoate.

The title compound was prepared according to General Procedure B using ethyl 2hydroxy-3-(1H-pyrazol-1-yl)propanoate (for synthesis, see Example 49) and 1-isocyanato-2-methylcyclohexane as starting materials. The crude product was purified by FCC (0-25% EtOAc in hexanes) to give the title compound as a colorless oil. Y=10%. MS ES ⁺ : 324.1.

1H-NMR (400 MHz, DMSO- _d6 ) δ 7.72-7.71 (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).

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

Step 1: Ethyl (2R)-3-(4-chloro-1H-pyrazol-1-yl)-2-hydroxypropanoate.

₄ -chloro-1H-pyrazole (1.10 g, 10.77 mmol). The mixture was stirred at 80°C for 1 hour, then filtered and concentrated under reduced pressure to obtain a residue. The residue was purified by FCC (30% EtOAc in petroleum ether) to give the title compound as a colorless oil. Y=21%.

^1H -NMR (400 MHz, 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=4 Hz, 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-indacene-4- yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-3-(4-chloro-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by preparative TLC (1/2 EtOAc/hexane) to give the title compound as a white solid. Y=18%. MS ES ⁺ : 418.1.

¹ H-NMR (400 MHz, 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 (kv, J=7 Hz, 2H), 2.99-2.65 (m, 8H), 2.10-2.03 (m , 4H), 1.29 (t, J=7 Hz, 3H).

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

Example 5BL Example 5BM

Step 1: mixture of ethyl (2R)-3-(4-cyano-1H-imidazol-1-yl)-2-hydroxypropanoate and ethyl (2R)-3-(5cyano-1H-imidazol-1-yl) -2-hydroxypropanoate.

To a solution of 4H-imidazole-5-carbonitrile (2.00 g, 21.53 mmol) in EtOH (10 mL) under N2 was added ethyl (2R)-oxirane-2-carboxylate (1 g, 8.61 mmol) in portions ) (for synthesis, see example 5AY). The mixture was stirred at 95°C for 0.5 hour and then concentrated under reduced pressure to obtain a residue. The residue was purified by FCC (1/2 EtOAc/petroleum ether) to give a mixture of (R)-ethyl-3-(4-cyano-1H-imidazol-1-yl)-2-hydroxypropanoate (28% yield) and (R) -ethyl-3-(5-cyano1H-imidazol-1-yl)-2-hydroxypropanoate (yield 28%) as a yellow oil.

Step 2: ethyl-(2R)-3-(4-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4yl) carbamoyl]oxy}-propanoate and ethyl-(2R)-3-(5-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydrosindacene -4-yl)carbamoyl]oxy}-propanoate.

Mixture of ethyl (2S)-3-(4-cyanoimidazol-1-yl)-2-hydroxypropanoate and ethyl (2R)-3-(5-cyanoimidazol-1yl)-2-hydroxypropanoate (200 mg, 0.96 mmol ) was dissolved in anhydrous THF (2 ml) and cooled to 0°C. CuCl (47 mg, 478 µmol) was added, the mixture was stirred for 30 min, and then 4-isocyanato-1,2,3,5,6,7-hexahydro-s-indacene (200 mg, 1.00 mmol) was added slowly ). The reaction mixture was allowed to warm to room temperature and stirring was continued for 10 hours. The reaction mixture was diluted with H2O (5 ml) and extracted with EtOAc (3x5 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by preparative TLC (1/2 EtOAc/petroleum ether) to obtain the desired products as a white solid. This mixture was further separated by SFC (column: OD (250x30 mm, 5 µm); mobile phase: EtOH; B%: 35%, 12 min). We obtained ethyl-(2R)-3-(5-cyanoimidazole- 77 044707

1-yl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyloxy)propanoate (5 mg, 2% yield) and ethyl-(2R)-3-(4cyanoimidazole -1-yl)-2-(1,2,3,5,6,7-hexahydro-s-indacen-4-ylcarbamoyloxy)propanoate (5 mg, 2% yield) as white solids. Results of the analysis of ethyl-(2R)-3-(4-cyano-1H-imidazol-1-yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl) carbamoyl]oxy}propanoate: MS ES+: 409.1.

¹ H-NMR (400 MHz, acetonitrile^) 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=7 Hz, 3H).

Results of the analysis of ethyl-(2R)-3-(5-cyano-1H-imidazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen4-yl)carbamoyl ]oxy}propanoate: MS ES ⁺ : 409.1.

¹ H-NMR (400 MHz, acetonitrile^) δ 7.85 (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=7 Hz, 3H).

Example 86

Synthesized using a synthetic route similar to that described for Example 59 using 2,6-dimethyl-4-(trifluoromethyl)aniline and ethyl 2-hydroxy-3-(1H-pyrazol-1-yl)propanoate (for synthesis, see Example 49). Y=26%. MS ES ⁺ : 400.0.

^1H -NMR (300 MHz, DMSO- _d6 ) 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 (kV, J=7 Hz, 2H), 2.27-2, 03 (m, 6H), 1.18 (t, J=7 Hz, 3H).

Example 87 propanoate

ABOUT ^-

Step 1: Ethyl 2-hydroxy-3-(4-methoxy-1H-pyrazol-1-yl)propanoate.

In a sealed tube, a mixture of 4-methoxy-1H-pyrazole (0.150 g, 1.53 mmol) and ethyloxyrane 2-carboxylate (0.178 g, 1.53 mmol) in EtOH (1 ml) was heated in a microwave reactor at 120 °C for 1 h. An additional equivalent of ethyloxyrane-2-carboxylate (0.178 g, 1.53 mmol) was added and the RM was heated in a microwave reactor at 120°C for 1 h. The RM was evaporated to dryness and purified by FCC (0-10% MeOH in DCM ) to obtain the title compound as a yellow oil. Y=96%.

1H-NMR (300 MHz, DMSO-d ₆ ) δ 7.41 (d, J=1 Hz, 1H), 7.19 (d, J=1 Hz, 1H), 5.82 (d, J=6 Hz, 1H), 4.40-4.33 (m, 1H), 4.18-4.05 (m, 4H), 3.64 (s, 3H), 1.18 (t, J=7 Hz , 3H).

Step 2: ethyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(4-methoxy-1H-pyrazol1-yl) propanoate

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(4-methoxy-1H-pyrazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (EtOAc/hexane) and then further purified by preparative HPLC to give the title compound. Y=1%. MS ES ⁺ : 414.5.

1H-NMR (300 MHz, chloroform-d) δ 7.14 (s, 1H), 7.03 (s, 1H), 6.42 (s, 1H), 5.43 (s, 1H), 4, 53 (s, 2H), 4.27 (kv, J=7 Hz, 2H), 3.74 (s, 3H), 2.90 (t, J=7 Hz, 4H), 2.81 (t, J=7 Hz, 4H), 2.14-2.04 (m, 4H), 1.31 (t, J=7 Hz, 3H).

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

Step 1: Ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate.

Iron diacetoxy (3, 88 g, 22 mmol). The mixture was heated to 101°C and stirred for 48 hours. RM was filtered and concentrated in vacuo. The resulting residue was purified by FCC (0-50% EtOAc in petroleum ether) to give the title compound as a yellow solid. Y=74%.

- 78 044707

1H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 2H), 7.22 (t, J=5 Hz, 1H), 5.77-5.44 (m, 1H),

4.80-4.69 (m, 1H), 4.26 (kv, J=7 Hz, 2H), 3.47-3.56 (m, 1H), 3.36-3.46 (m, 1H), 1.24 (t, J=7 Hz, 3H).

Step 2: ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2yl)propanoate.

The title compound was prepared according to General Procedure B using ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate and intermediate A as starting materials. The crude product was purified by FCC (0-60% EtOAc in hexanes) to give the racemic product as a white solid. This product was separated by chiral SFC (column: DAICEL CHIRALPAK IC (250 mm x 30 mm, 5 µm); mobile phase: EtOH; B%: 22%, 3.9 min). Peak 1 contained the title compound. Y=9%. MS ES ⁺ : 396.1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 2H), 7.21-7.17 (m, 1H), 6.98 (s, 1H), 6 .27 (broad s, 1H), 5.80-5.75 (m, 1H), 4.26 (kv, J=7 Hz, 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=7 Hz, 3H).

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

Step 1: ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate.

Ethyl 2-oxoacetate (56.4 g, 276 mmol) and iron diacetoxy (0.99 g, 6.4 mmol). The reaction mixture was heated at 140°C for 48 hours. The mixture was concentrated under reduced pressure. The residue was purified by FCC (0-10% EtOAc in petroleum ether) to give the title compound. Y=30%.

1H-NMR (400 MHz, chloroform-d) δ 8.54-8.48 (m, 3H), 4.70-4.64 (m, 1H), 4.26 (q, J=8 Hz, 2H ), 3.38-3.33 (m, 1H), 3.25-3.19 (m, 1H), 1.26 (t, J=7 Hz, 3H).

Step 2: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrazin-2yl)propanoate.

The title compound (as a racemic mixture) was prepared according to General Procedure B using ethyl 2-hydroxy-3-(pyrazin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-50% EtOAc in hexanes) to give the racemic product as a white solid. This substance was separated by chiral SFC (column: Daicel Chiralpak AD-H (250x30 mm, 5 µm); mobile phase: EtOH; B%: 24%, 5.5 min). Peak 2 contained the title compound. Y=34%. MS ES ⁺ : 396.1.

1H-NMR (400 MHz, DMSO-d6) δ 9.22-9.15 (b s, 1H), 8.68-8.55 (m, 3H), 6.93 (s, 1H), 5 .40-5.32 (m, 1H), 4.13 (kv, J=7 Hz, 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=7 Hz, 3H).

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

Step 1: ethyl (2E)-3-ethoxy-2-hydroxypropanoate.

To a solution of ethyl (2E)-oxirane-2-carboxylate (100 mg, 0.86 mmol) (for synthesis, see Example 5AY) in EtOAc (1 ml) was added ethanol (0.35 ml, 6.0 mmol), then 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 in petroleum ether) to obtain 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-(2E)-3-ethoxy-2-{[(1,2,3,5,6,7-hexahydro-8-indacen-4-yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure B using ethyl(2R)-3-ethoxy-2-hydroxynpropanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (25% EtOAc in hexanes) to obtain the title compound as a white solid. Y=10%. MS ES ⁺ : 362.1.

1H-NMR (400 MHz, 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=7 Hz, 3H), 1.27-1.19 (m, 3H).

- 79 044707

Example 91 carbamoyl] oxy} propanoate.

Step 1: Ethyl (2R)-3-(3-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate.

Ethyl (2R)-oxirane-2-carboxylate (1.0 g, 8.61 mmol) was added portionwise to a solution of 1H-pyrazole-3-carbonitrile (2.00 g, 21.5 mmol) in EtOH (3 mL). (for synthesis see example 5AY). The mixture was then stirred at 90°C for 0.5 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was purified by FCC (1/2 EtOAc/petroleum ether) to give the title compound as a colorless oil. Y=14%.

¹ H-NMR (400 MHz, chloroform-d) δ 7.59 (d, J=3 Hz, 1H), 6.65 (d, J=3 Hz, 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-indacen-4yl )carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-3-(3-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (33% EtOAc in hexanes) to obtain the title compound as a white solid. Y=10%. MS ES ⁺ : 409.2.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.19 (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=7 Hz, 3H).

Example 92 -pyrazol-1-yl]propanoate.

Step 1: ethyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)-1H-pyrazol-1-yl]propanoate.

To a solution of ethyl (2R)-oxirane-2-carboxylate (0.20 g, 1.72 mmol) (for synthesis, see Example 5AY) in EtOH (2 ml) was added 4-trifluoromethylpyrazole (586 mg, 4.31 mmol ). The solution was stirred at 90°C for 16 hours. The reaction mixture was concentrated, diluted with H ₂ O (20 ml) and extracted with EtOAc (3x15 ml). The combined organic layers were washed with brine (10 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to leave a residue. The residue was purified by FCC (0-9% MeOH in DCM) to give the title compound as a yellow oil. Y=58%.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 13.65-13.55 (b s, 1H), 8.39 (s, 1H), 7.90 (s, 1H), 5.94 ( d, J=6 Hz, 1H), 4.46-4.40 (m, 2H), 4.13-4.08 (m, 2H), 1.17 (t, J=7 Hz, 3H).

Step 2: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-[4-(trifluoromethyl)1H -pyrazol-1-yl]propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-2-hydroxy-3-[4-(trifluoromethyl)-1H-pyrazol-1-yl]nponanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (33% EtOAc in hexanes) to obtain the title compound as a white solid. Y=12%. MS ES ⁺ : 452.2.

1H-NMR (400 MHz, 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 Hydrochloride (2R)-3-{4-[(dimethylamino)methyl]-1H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7hexahydro-8-indacene 4-yl)carbamoyl]oxy}propanoic acid.

- 80 044707

Step 1: benzyl-(2R)-3-{4-[(dimethylamino)methyl]-1H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7-hexahydrosindacene -4-yl)carbamoyl]oxy} propanoate.

To a solution of benzyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-pyrazol1-yl)propanoate (0.20 g, 0.45 mmol) (for synthesis, see Example 5AM) N,N-dimethylmethylideneammonium iodide (0.33 g, 1.80 mmol) was added to acetonitrile (2 ml) and DMF (1 ml). The RM was purged with argon and sealed in a test tube. RM was heated at 90°C for 16 h and then concentrated in vacuo. The residue was purified by FCC (40% EtOAc in hexanes, then 0-10% MeOH in DCM) to give the title compound as a green solid. Y=20%. MS ES ⁺ : 504.

Step 2: hydrochloride (2R)-3-{4-[(dimethylamino)methyl]-1H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7-hexahydros-indacene- 4-yl)carbamoyl]oxy}propanoic acid.

Benzyl-(2R)-3-{4-[(dimethylamino)methyl]-1 H-pyrazol-1-yl}-2-{[(1,2,3,5,6,7-hexahydro-8-indacene -4yl)carbamoyl]oxy}propanoate (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%) were added , 0.05 g).The RM was stirred under hydrogen for 16 hours. The RM was filtered through Celite, washed with MeOH and the filtrate was concentrated in vacuo. The resulting residue was dissolved in a minimal volume of MeOH, precipitated with diethyl ether, and the resulting solid was filtered to give title compound as a yellow solid MS ES ⁺ : 413.

^1H -NMR (300 MHz, 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)propanoate.

Step 1: 2,4-dimethylthiophene-3-carboxylic acid.

To a solution of 4-methylthiophene-3-carboxylic acid (0.5 g, 3.5 mmol) in THF (20 ml) at -78°C under N2, n-butyllithium (1.6 M in hexanes, 5 ml, 8.0 mmol). The resulting reaction mixture was stirred at -78°C for 30 minutes. A solution of iodomethane (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 and 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 conditions. The crude material was purified by trituration with diethyl ether (2x20 ml) and then concentrated in vacuo to give the title compound as an off-white solid. Y=74%.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 12.64 (s, 1H), 6.93 (d, J=1 Hz, 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)propanoate.

To a solution of 2,4-dimethylthiophene-3-carboxylic acid (0.2 g, 1.28 mmol) in toluene (10 ml) at 0°C under N2 was added diphenylphosphoryl azide (0.38 g, 1.41 mmol), and then N,N-diisopropylethylamine (0.20 g, 1.53 mmol). The RM 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)propanoate (0.20 g, 1.28 mmol) was added ) (for synthesis, see example 49) in toluene (5 ml). At 0°C, 1-(isocyanatomethyl)-2-methylbenzene (0.94 g, 5.12 mmol) was added, RM was heated at 120°C for 5 h and then allowed to cool to room temperature. RM was concentrated at vacuum, triturated with diethyl ether (2x20 ml), and filtered the resulting solid. This material was further purified by preparative HPLC to obtain the title compound as a yellow solid. Y=9%. MS ES ⁺ : 338.1.

1H-NMR (400 MHz, DMSO-de) δ 8.98 (s, 1H), 7.78 (d, J=2 Hz, 1H), 7.47 (s, 1H), 6.86 (s, 1H), 6.28 (s, 1H), 5.32-5.24 (m, 1H), 4.62 (d, J=6 Hz, 2H), 4.11 (t, J=7 Hz, 2H), 2.12 (s, 3H), 1.96 (s, 3H), 1.15 (t, J=7 Hz, 3H).

Example ⁹⁵ pyrazol-1-yl)propanoate.

Step 1: 4,10-dioxatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,7-triene-2-carbaldehyde.

To a stirred solution of 4,10-dioxatricyclo[7.3.0.0 ^3,7 ]dodeca-1,3(7),8-triene (0.55 g, 3.39 mmol) in anhydrous DCM (11.5 ml) was added tin(IV) (1.11 g, 4.27 mmol), and stirred RM for 5 min. Under N2 atmosphere at 0°C, dichloromethyl methyl ether (0.39 g, 3.39 mmol) in DCM (0.6 ml) was added. RM was stirred for 15 min at 0°C and then poured into water (25 ml). Water layer

- 81 044707 was extracted with DCM (2x30 ml), and the combined organic layers were washed with 3 M HCl (15 ml). The organic phase was dried over anhydrous Na ₂ SO ₄ , filtered and evaporated under reduced pressure. The crude product was purified by FCC (0.5% ethyl acetate in hexanes) to give the title compound as a yellow solid. Y=49%.

¹ H-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[7.3.0.0 ^3,7 ]dodeca-1(9),2,7-triene-2-carboxylic acid.

To a stirred solution of 4,10-dioxatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,7-triene-2-carbaldehyde (0.32 g, 1.68 mmol) in acetone (3 ml) at At 0°C, sulfamic acid (0.245 g, 2.52 mmol) was added. A solution of sodium chlorite (0.196 g, 2.17 mmol) in water (0.5 ml) was added dropwise and stirred RM at 0°C for 30 min. RM was poured into cold water (20 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting crude product was triturated with pentane (3x30 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[7.3.0.0 ^3,7 ]dodeca-1(9),2,7-trien-2-yl}carbamoyl)oxy]-3(1H- pyrazol-1-yl)propanoate.

Triethylamine was added to a stirred solution of 4,10-dioxatricyclo[7.3.0.0 ^3,7 ]dodeca-1(9),2,7-triene-2-carboxylic acid (0.280 g, 1.35 mmol) in toluene (5 ml) (0.50 ml, 4.07 mmol) and ethyl 2hydroxy-3-(1H-pyrazol-1-yl)propanoate (0.250 g, 1.35 mmol) (for synthesis, see Example 49). After stirring for 5 min, diphenylphosphoryl azide (1.11 g, 4.07 mmol) was added and the RM was heated in a microwave reactor at 100°C for. The reaction mixture was cooled to room temperature, poured into cold water (25 ml) and extracted with ethyl acetate (3x30 ml). The combined organic layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The crude material was purified by FCC (50% ethyl acetate in hexane) and further purified by preparative HPLC to obtain the title compound as an off-white solid. Y=2%. MS ES ⁺ : 388.2.

1H-NMR (400 MHz, DMSO-d6) 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 is obscured by the solvent peak.

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

Step 1: ethyl (2R)-2-hydroxy-3-(2-methoxyethoxy)propanoate.

To a solution of ethyl (2R)-oxirane-2-carboxylate (100 mg, 0.86 mmol) (for synthesis, see Example 5AY) in EtOAc (1 ml) was added 2-methoxyethanol (475 μl, 6.0 mmol) and Magnesium trifluoromethanesulfonate (444 mg, 1.38 mmol). The mixture was stirred at 60°C for 12 hours. The residue was purified by FCC (9-25% EtOAc in petroleum ether) to obtain the title compound as a colorless oil. Y=42%.

1H-NMR (400 MHz, chloroform-d) δ 4.32 (t, J=4 Hz, 1H), 4.27 (t, J=7 Hz, 2H), 3.82 (d, J=4 Hz , 2H), 3.73-3.66 (m, 2H), 3.58-3.51 (m, 2H), 3.38 (s, 3H), 1.31 (t, J=7 Hz, 3H).

Step 2: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(2methoxyethoxy)propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-2-hydroxy-3-(2-methoxyethoxy)propanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (33% EtOAc in hexanes) to obtain the title compound as a white solid. Y=17%. MS ES ⁺ : 392.1.

1H-NMR (400 MHz, chloroform-d) δ 7.01 (s, 1H), 6.50-6.42 (broad 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=7 Hz, 3H).

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

Step 1: ethyl (2R)-2-hydroxy-3-(oxan-4-yloxy)propanoate.

To a solution of ethyl (2R)-oxirane-2-carboxylate (150 mg, 1.29 mmol) (for synthesis, see Example 5AY) in EtOAc (1 ml) was added tetrahydropyran-4-ol (155 μl, 1.55 mmol ) and magnesium trifluoromethanesulfonate (666 mg, 2.07 mmol). The mixture was stirred at 60°C for 36 hours. The residue was purified by FCC (5-10% EtOAc in petroleum ether) to obtain the title compound as a colorless oil. Y=14%.

¹ H-NMR (400 MHz, 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=7 Hz, 1H), 1.93-1.81 ( m, 2H), 1.62-1.52 (m, 2H), 1.30 (t, J=7 Hz, 3H).

Step 2: ethyl (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(oxan-4yloxy)propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-2-hydroxy-3-(oxan-4-yloxy)propanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (50% EtOAc in hexanes) to obtain the title compound as a white solid. Y=10%. MS ES ⁺ : 418.3.

¹ H-NMR (400 MHz, 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=7 Hz, 3H) .

Example 98 Ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H1, 2,4-triazol-1-yl)propanoate and ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}- 3(3-methyl-1H-1,2,4-triazol-1-yl)propanoate.

Example 5BZ

Step 1: ethyl (2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)pronoate and ethyl (2R)-2hydroxy-3-(5-methyl - 1H-1,2,4-triazol-1 -yl)propanoate.

To a solution of ethyl (2R)-oxirane-2-carboxylate (1.50 g, 12.9 mmol) (for synthesis, see Example 5AY) in EtOH (15 ml) was added 5-methyl-1H-1,2,4 -triazole (2.68 g, 32.3 mmol) and DIPEA (5.40 ml, 31.00 mmol). The mixture was stirred at room temperature for 3 hours and then concentrated. The crude substance was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 μm; mobile phase: [A - TFA/H ₂ O=0.075% v/v; B - ACN] B%: 1-20%, 20 min) to obtain ethyl (2R)-2-hydroxy-3-(3methyl-1H-1,2,4-triazol-1-yl)propanoate (12% yield) as a yellow oil and ethyl (2R) -2-hydroxy-3-(5methyl-1H-1,2,4-triazol-1-yl)propanoate (10% yield) as a yellow oil.

Results of analysis of ethyl (2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)propanoate: ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8 .57 (s, 1H), 5.70-5.30 (broad s, 1H), 4.43-4.31 (m, 3H), 4.13 (kv, J=7 Hz, 2H), 2.27 (s, 3H), 1.19 (t, J=7 Hz, 3H).

Results of the analysis of ethyl (2R)-2-hydroxy-3-(5-methyl-1H-1,2,4-triazol-1-yl)propanoate: 1H-NMR (400 MHz, DMSO-d ₆ ) δ 8, 11 (s, 1H), 6.45-6.10 (broad s, 1H), 4.45-4.31 (m, 3H), 4.11 (kv, J=7 Hz, 2H), 2 .46 (s, 3H), 1.19 (t, J=7 Hz, 3H).

Step 2a: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(3-methyl-1H1, 2,4-triazol-1-yl)propanoate.

The title compound was prepared according to General Procedure B using ethyl(2R)-2-hydroxy-3-(3-methyl-1H-1,2,4-triazol-1-yl)npropanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-17% EtOAc in hexane) and then by preparative HPLC (column: Agela Durashell C18 150x25 mm, 5 µm; mobile phase: [A - 10 mM NH ₄ HCO ₃ in

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H2O; B - ACN] B%: 39-69%, 10 min) to obtain the title compound as a white solid. Y=1%. MS ES ⁺ : 399.2.

¹ H-NMR (400 MHz, chloroform-d) δ 8.26 (s, 1H), 7.03 (s, 1H), 6.47 (s, 1H), 5.46 (s, 1H), 4 .65 (s, 2H), 4.28 (kv, 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=7 Hz, 3H).

Step 2b: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(5-methyl-1H1, 2,4-triazol-1-yl)propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-2-hydroxy-3-(5-methyl-1H-1,2,4-triazol-1-yl)propanoate and intermediate A in as starting materials. The crude mixture was purified by preparative TLC (9% MeOH in DCM) to obtain the title compound as a pale yellow solid. Y=1%. MS ES ⁺ : 399.2.

¹ H-NMR (400 MHz, chloroform-d) δ 7.73 (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=7 Hz, 3H).

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

Step 1: ethyl (2R)-2-hydroxy-3-(πpropan-2-yloxy)propanoate.

To a solution of ethyl (2R)-oxirane-2-carboxylate (100 mg, 0.86 mmol) (for synthesis, see Example 5AY) in EtOAc (1 ml) was added propan-2-ol (462 μl, 6.03 mmol ) and magnesium trifluoromethanesulfonate (444 mg, 1.38 mmol). The mixture was stirred at 60°C for 24 hours. The residue was purified by FCC (5-17% EtOAc in petroleum ether) to obtain the title compound as a colorless oil. Y=69%.

¹ H-NMR (400 MHz, 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=7 Hz, 3H), 1.18-1.06 (m, 6H).

Step 2: ethyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(propan-2yloxy)propanoate.

The title compound was prepared according to General Procedure B using ethyl (2R)-2-hydroxy-3-(πpropan-2-yloxy)πpropanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (25% EtOAc in petroleum ether) to obtain the title compound as a white solid. Y=10%. MS ES ⁺ : 376.3.

1H-NMR (400 MHz, chloroform-d) δ 7.00 (s, 1H), 6.50-6.42 (b s, 1H), 5.26 (s, 1H), 4.34-4 .16 (m, 2H), 3.87 (s, 2H), 3.65 (s, 1H), 2.91-2.81 (m, 8H), 2.12-2.01 (m, 4H ), 1.31 (t, J=7 Hz, 3H), 1.21-1.12 (br s, 6H).

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

ooo

Step 1: 2-hydroxy-3-(pyrimidin-2-yl)propanoic acid.

To a mixture of ethyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate (26.0 g, 133 mmol) (for synthesis, see example 5BP) in THF (180 ml) and H2O (180 ml) at 10-20 °C LiOH H ₂ O (7.31 g, 174 mmol) was added in one portion. The RM was stirred at 10 to 20°C for 16 hours. The mixture was concentrated under vacuum to remove THF to obtain an aqueous solution. This solution was washed with EtOAc (3x40 ml). The aqueous layer was acidified to pH~3 by adding 1 M HCl and then concentrated in vacuo to give the title compound as a yellow solid. Y=quantitative.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 8.70 (d, J=6 Hz, 2H), 7.32 (t, J=5 Hz, 1H), 4.44-4.35 (m , 1H), 3.31 (dd, J=14, 4 Hz, 1H), 2.90 (dd, J=14, 10 Hz, 1H).

No interchangeable protons were observed.

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Step 2: benzyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate.

H2SO4 (317 µl, 5 .9 mmol). The RM was heated to 45°C and stirred for 16 hours. The mixture was concentrated and purified by FCC (0-60% ethyl acetate in petroleum ether) to give the title compound as a white solid. Y=19%.

¹ H-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: benzyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2yl)propanoate.

The title compound was prepared according to General Procedure B using benzyl 2-hydroxy-3-(pyrimidin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-60% EtOAc in petroleum ether) to obtain the title compound as a white solid. Y=27%. MS ES ⁺ : 458.1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.64 (d, J=4 Hz, 2H), 7.34 (s, 4H), 7.15 (t, J=5 Hz, 1H), 6.98 (s, 1H), 6.25 (s, 1H), 5.85 (t, J=6 Hz, 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-indacen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2yl)propanoic acid.

To a solution of benzyl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrimidin-2yl)propanoate (790 mg, 1. 73 mmol) in MeOH (20 ml) under N2 atmosphere, 10% Pd/C (1.73 mmol) was added. The mixture was stirred under H2 (15 psi) at 15°C for 2 hours. The mixture was filtered through Celite and concentrated in vacuo to leave a residue. The residue was purified by reverse phase chromatography (column: Waters Xbridge 150x25.5 µm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 14-44%, 12 min) to give the racemic product. This product was separated by chiral SFC (column: Daicel Chiralpak IC (250x30 mm, 5 µm); mobile phase: [0.1% NH3 H2O in EtOH]; B%: 45%, 6 min) to give the title compound in as a white solid. The target (R)-enantiomer corresponded to peak 1. Y=15%. MS ES ⁺ : 368.1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.85 (s, 1H), 8.75 (d, J=5 Hz, 2H), 7.38 (t, J=5 Hz, 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 CO2H proton peak was observed.

Example 101. Propan-2-yl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3(pyrimidine-2 -yl)propanoate.

Step 1: propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate.

To a mixture of 2-hydroxy-3-(pyrimidin-2-yl)propanoic acid (10.0 g, 59.5 mmol) (for synthesis, see Example 5CC) in isopropanol (70 ml) was added H2SO4 (317 μl, 5. 95 mmol) in one serving at a temperature of 10 to 20°C. RM was heated at 45°C for 16 hours. RM was made alkaline to pH~8 by adding aq. NaHCO ₃ and then concentrated in vacuo. The resulting aqueous solution/suspension was extracted with EtOAc (3x50 ml). The combined organic phases were concentrated under vacuum to leave a residue. The residue was purified by FCC (0-50% EtOAc in petroleum ether) to give the title compound as a white solid. Y=23%.

¹ H-NMR (400 MHz, chloroform-d) 8.68 (d, J=5 Hz, 2H), 7.20 (t, J=5 Hz, 1H), 5.14-5.03 (m, 1H), 4.71 (br s, 1H), 4.27 (b s, 1H), 3.55-3.48 (m, 1H), 3.46-3.38 (m, 1H) , 1.25 (d, J=6 Hz, 3H), 1.19 (d, J=6 Hz, 3H).

Step 2: propan-2-yl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(nirimidin2- yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-60% EtOAc in petroleum ether) to obtain a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AY-H (250x30 mm, 5 µm); mobile phase: EtOH; B%: 45%, 8 min) to obtain the title compound as a white solid. The target (R)-enantiomer corresponded to peak 1. Y=8%. MS ES ⁺ : 410.2.

1H-NMR (400 MHz, 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 (b. s, 2H), 2.91-2.81 (m, 4H), 2 .80-2.70 (m, 4H), 2.10-1.98 (m, 4H), 1.27 (d, J=6 Hz, 3H), 1.24 (d, J=6 Hz, 3H).

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

Step 1: cyclopentyl-2-hydroxy-3-(pyrimidin-2-yl)propanoate.

To a mixture of 2-hydroxy-3-(pyrimidin-2-yl)propanoic acid (10.0 g, 59.5 mmol) (for synthesis see Example 5CC) in cyclopentanol (70 ml) at 10 to 20°C H ₂ SO ₄ (317 μl, 5.95 mmol) was added in one portion. RM was heated at 45°C for 16 hours. RM was made alkaline to pH~8 by adding aq. NaHCO ₃ and then concentrated in vacuo. The resulting aqueous solution/suspension was extracted with EtOAc (3x50 ml). The combined organic phases were concentrated under vacuum to leave a residue. The residue was purified by FCC (0-60% EtOAc in petroleum ether) to give the title compound as a white solid. Y=15%.

¹ H-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, h), 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: cyclopentyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrimidin2-yl)propanoate.

The title compound was prepared according to General Procedure B using cyclopentyl-2-hydroxy-3-(pyrimidin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-60% EtOAc in petroleum ether) to obtain a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AY-H (250x30 mm, 5 µm); mobile phase: IPA; B%: 45%, 20 min) to obtain the title compound as a white solid. The target (R)-enantiomer corresponded to peak 1. Y=5%. MS ES ⁺ : 436.2.

1P-NMR (400 MHz, DMSO-d ₆ ) δ 9.07 (b s, 1H), 8.77 (d, J=4 Hz, 2H), 7.41 (t, J=5 Hz, 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 (b. 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-indacen-4-yl)carbamoyl]oxy}-3-(pyrazin-2yl)propanoic acid.

Stage

Stage 3

Stage 4

Step 1: 2-hydroxy-3-(pyrazin-2-yl)propanoic acid.

2 M NaOH (18, 3 ml, 36.6 mmol), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo to obtain an aqueous solution. This solution was washed with ethyl acetate (2x20 ml), the aqueous phase was adjusted to pH~2 and concentrated in vacuo to give the title compound as a brown solid, which was used without purification. Y=quantitative.

¹ H-NMR (400 MHz, D2O) δ 8.54-8.53 (m, 2H), 8.47 (d, J=2 Hz, 1H), 4.50-4.44 (m, 1H) , 3.33-3.26 (m, 1H), 3.17-3.09 (m, 1H).

No interchangeable protons were observed.

Step 2: benzyl 2-hydroxy-3-(pyrazin-2-yl)propanoate.

H2SO4 (317 µl, 5 .9 mmol). The RM was heated to 45°C and stirred for 16 hours. The mixture was concentrated and purified by FCC (0-60% ethyl acetate in petroleum ether) to give the title compound as a white solid.

Step 3: benzyl 2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(pyrazin-2yl)propanoate.

The title compound was prepared according to General Procedure B using benzyl 2-hydroxy-3-(pyrazin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-50% EtOAc in petroleum ether) to give

- 86 044707 of the title compound in the form of a white solid. Y=22%. MS ES ⁺ : 458.1.

1H-NMR (400 MHz, 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 (b s, 2H), 2.90-2.84 (m, 4H), 2.75-2.65 (m , 3H), 2.09-2.00 (m, 4H).

No NH peak was observed.

Step 4: (2R)-2-{[(1,2,3,5,6,7-hexahydro-s-undacen-4-ul)carbamoyl]oxy}-3-(pyrazin-2yl)propanoic acid.

To a solution of benzyl 2-{[(1,2,3,5,6,7-hexahydro-s-undacen-4-yl)carbamoyl]oxy}-3-(pyrazin-2yl)propanoate (400 mg, 0. 87 mmol) in MeOH (8 ml) under N ₂ atmosphere was added 10% Pd/C (0.87 mmol). The mixture was stirred under H ₂ atmosphere at room temperature for 25 minutes. The mixture was filtered through Celite and concentrated in vacuo to give the racemic product. This product was separated by chiral SFC (column: Daicel Chiralpak IC (250x30 mm, 5 µm); mobile phase: [0.1% NH ₃ H2O in EtOH]; B%: 35%, 8 min) to give the title compound as a white solid. The target (R)-enantiomer corresponded to peak 2. Y=45%. MS ES ⁺ : 368.1.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 8.88 (b 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. Propan-2-yl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3(pyrazin-2 -yl)propanoate.

Step 1: propan-2-yl-2-hydroxy-3-(pyrazin-2-yl)propanoate.

To a solution of 2-hydroxy-3-(pyrazin-2-yl)propanoic acid (4.00 g, 23.8 mmol, 1.0 eq.) (for synthesis, see Example 5CF) in isopropanol (28 ml) was added 4 -(dimethylamino)pyridine (290 mg, 2.38 mmol) and then dropwise oxalyl chloride (2.29 ml, 26.2 mmol). RM was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified by FCC (0-15% EtOAc in 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: propan-2-ul-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-ul)carbamoyl]oxu}-3-(pyrazin- 2yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrazin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by FCC (0-50% EtOAc in petroleum ether) to obtain a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AD-H (250x30 mm, 5 µm); mobile phase: EtOH; B%: 30%, 6 min) to obtain the title compound as a white solid. The target (R)-enantiomer corresponded to peak 1. Y=31%. MS ES ⁺ : 410.2.

1H-NMR (400 MHz, DMSO-d ₆ ) δ 9.12 (b 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=6 Hz, 3H), 1.12 (d, J=6 Hz, 3H ).

Example 105. Cyclopentyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-undacen-4-yl)carbamoyl]oxu}-3(pyrazin-2-yl)propanoate .

Step 1: cyclopentyl-2-hydroxy-3-(pyrazin-2-yl)propanoate.

DMAP (290 mg, 2.38 mmol) and then oxalyl chloride (2.29 ml, 26.1 mmol). RM was stirred at room temperature for 12 hours and then concentrated under reduced pressure. The residue was purified by FCC (0-15% EtOAc in 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: cyclopentyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxu}-3-(pyrazin2-yl)propanoate.

The title compound was prepared according to General Procedure B using cyclopentyl-2-hydroxy-3-(pyrazin-2-yl)propanoate and intermediate A as starting materials

- 87 044707 substances. The crude mixture was purified by FCC (0-50% EtOAc in petroleum ether) to obtain a racemic mixture of products as a white solid. Enantiomers were separated by chiral SFC (column: Daicel Chiralpak AD-H (250x30 mm, 5 µm); mobile phase: [0.1% NH3

H ₂ O/MeOH]; B%: 26%, 20 min) to obtain the title compound as a white solid. The target (R)-enantiomer corresponded to peak 2. Y=35%. MS ES ⁺ : 436.2.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.14-9.06 (bs, 1H), 8.73-8.66 (bs, 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 106. Propan-2-yl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen4-yl)carbamoyl]oxy}propanoate.

Step 1: propan-2-yl-(2R)-oxirane-2-carboxylate.

_{Benzyltriethylammonium} chloride ( benzyltriethylammonium chloride ( 54.2 g, 238 mmol) and 2-bromopropane (117 g, 951 mmol). The mixture was stirred at 45°C for 16 hours. RM was left to cool, poured into H2O (500 ml) and stirred for 5 minutes. The aqueous phase was extracted with dichloromethane (100 ml). The organic phase was washed with brine (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FCC (0-50% EtOAc in petroleum ether) to give the title compound as a yellow oil.

^1H -NMR (400 MHz, 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: propan-2-yl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate.

In a microwaving tube, propan-2-yl-(2R)-oxirane-2-carboxylate (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 100x350 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 (400 MHz, 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: propan-2-yl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s- indacen-4yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure A using propan-2-yl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials . The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 50-80%, 20 min) to obtain the title compound as a white solid. Y=26%. MS ES ⁺ : 423.3.

¹ H-NMR (400 MHz, DMSO-d6) δ 9.16 (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 107. Cyclopentyl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen4-yl) carbamoyl]oxy}propanoate.

Step 1: cyclopentyl-(2R)-oxirane-2-carboxylate.

To a mixture of potassium (2R)-oxirane-2-carboxylate (50.0 g, 396 mmol) (for synthesis, see example 5AJ) and cyclopropyl bromide (236 g, 1.59 mol) in dichloromethane (250 ml) at room temperature Under N2 atmosphere, benzyltriethylammonium chloride (90.3 g, 396 mmol) was added in one portion. The mixture was stirred at 45°C for 16 hours. The mixture was left to cool, poured into water (1500 ml) and stirred for 5 minutes. The aqueous phase was extracted with dichloromethane (200 ml). The organic phase was washed with saline solution

- 88 044707 (200 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuum. The residue was purified by FCC (0-50% EtOAc in petroleum ether) to give the title compound as a yellow oil. Y=22%.

'H-NMR (400 MHz, 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: cyclopentyl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate.

In a microwaving tube, cyclopentyl (2R)-oxirane-2-carboxylate (1.50 g, 9.60 mmol) and 4-cyanopyrazole (2.24 g, 24.0 mmol) were dissolved in cyclopentanol (10 mL). RM was heated in a microwave reactor at 100°C for 2 hours. The mixture was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (column: Agela Innoval ODS-2 250x80 mm; mobile phase: [water (0.1% TFA ) - ACN]; B%: 12-42%, 30 min) to obtain the title compound as a yellow oil. MS ES ⁺ : 250.2.

'H-NMR (400 MHz, 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: cyclopentyl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4yl )carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure A using cyclopentyl-(2R)-3-(4-cyano-1H-pyrazol-1-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 50-80%, 20 min) to obtain the title compound as a white solid. Y=5%. MS ES ⁺ : 449.4.

'H-NMR (400 MHz, DMSO-d ₆ ) δ 9.17 (s, 1H), 8.62 (s, 1H), 8.10 (s, 1H), 6.95 (s, 1H), 5.29 (s, 1H), 5.13-5.08 (m, 2H), 4.73-4.67 (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 108 triazol-1yl)propanoic acid and propan-2-yl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3 (1H-1,2,4-triazol-1-yl)propanoate.

Stage 1

Example 5CL

Stage 3

Example 5SK

Step 1: propan-2-yl-(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate.

Microwave propan-2-yl-(2R)-oxirane-2-carboxylate (2.00 g, 15.4 mmol) (for synthesis see Example 5CI) and 1H-1,2,4-triazole ( 2.65 g, 38.4 mmol) was dissolved in isopropanol (10 ml). RM was heated in a microwave reactor at 100°C for 3 hours. The mixture was concentrated under vacuum conditions, and the resulting residue was purified by preparative HPLC: (column: Agela Innoval ODS-2 250x80 mm; mobile phase: [water (0.1% TFA ) - ACN]; B%: 0-21%, 30 min) to obtain the title compound as a yellow oil. MS ES ⁺ : 200.1.

'H-NMR (400 MHz, 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: propan-2-yl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H- 1,2,4triazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using propan-2-yl-(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate and intermediate A in as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 µm; 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.

'H-NMR (400 MHz, DMSO-d6) δ 9.19 (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-indacen-4-yl)carbamoyl]oxy}-3-(1H-1,2,4- triazol-1yl)propanoic acid.

To a mixture of propan-2-yl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-1 ,2,4triazol-1-yl)propanoate (400 mg, 1.00 mmol) in 1,4-dioxane (5 ml) at room temperature, 4 M NI (5 ml) was added in one portion. The mixture was stirred at RT for 48 hours. RM was concentrated under reduced pressure and purified by preparative HPLC: (column: Phenomenex Luna C18 200x40 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN ]; B%: 20-55%, 10 min) to obtain the title compound as a white solid. Y=28%. MS ES ⁺ : 357.0.

'H-NMR (400 MHz, DMSO-d6) δ 13.46-13.28 (b 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).

- 89 044707

Example 109. Cyclopentyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H1,2,4- triazol-1-yl)propanoate.

Step 1: cyclopentyl-(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate.

Microwave cyclopentyl(2R)-oxirane-2-carboxylate (1.00 g, 6.40 mmol) (for synthesis see Example 5CJ) and 1H-1,2,4-triazole (1.11 g , 16.0 mmol) was 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 a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B%: 10-40%, 20 min) to give the title compound in the form of a colorless oil. Y=46%.

^1H -NMR (400 MHz, 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: cyclopentyl-(2R)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(1H-1,2, 4triazol-1-yl)propanoate.

The title compound was prepared according to General Procedure A using cyclopentyl-(2R)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 50-80%, 20 min) to obtain the title compound as a white solid. Y=5%. MS ES ⁺ : 425.1.

^1H -NMR (400 MHz, methanol- _d4 ) δ 8.62 (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 110. Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(6methylpyrazin-2-yl) propanoate

Step 1: propan-2-yl-2-hydroxy-3-(6-methylpyrazin-2-yl)propanoate.

To a solution of isopropyl-2-oxoacetate (1.13 g, 9.71 mmol) in dioxane (8 ml) under N2 was added 2,6-dimethylpyrazine (1.0 g, 9.25 mmol) and iron diacetoxy (80 mg, 462 µmol). The RM was heated at 120°C for 42 hours. The reaction mixture was concentrated in vacuo and the resulting residue was purified by FCC (0-10% MeOH in DCM) to give the title compound as a brown oil. Y=9%.

¹ H-NMR (400 MHz, 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=6 Hz, 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: propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(6-methylpyrazin2-yl) propanoate

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(6-methylpyrazin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (50% EtOAc in petroleum ether) to obtain the title compound as a white solid. Y=14%. MS ES ⁺ : 424.4.

¹ H-NMR (400 MHz, chloroform-d) δ 8.38-8.30 (b.s, 2H), 7.00 (s, 1H), 6.29-6.19 (b.s, 1H ), 5.53-5.45 (m, 1H), 5.15-5.06 (m, 1H), 3.39-3.29 (m, 2H), 2.87 (t, J=7 Hz, 4H), 2.80-2.70 (t, J=7 Hz, 4H), 2.55 (s, 3H), 2.10-1.99 (m, 4H), 1.29-1 .25 (m, 6H).

Example 111. Propan-2-yl-2-{[(3-methylcyclohexyl)carbamoyl]-oxy}-3-(pyrimidin-2-yl)propanoate.

- 90 044707

Step 1: 1-isocyanato-3-methylcyclohexane.

To a solution of triphosgene (655 mg, 2.21 mmol) in DCM (3 ml) were added 3-methylcyclohexanamine (250 mg, 2.21 mmol) and triethylamine (655 μl, 4.64 mmol). The mixture was stirred at room temperature for 1 hour, then concentrated to give the title compound as a yellow solid. This compound was used directly in the next step.

Step 2: 2-methylpyrimidine.

To a solution of 4,6-dichloro-2-methylpyrimidine (240 g, 1.47 mol) in methanol (1.32 1) and H ₂ O (1.101) was added 10% Pd/C (240 g) and MgO (240 g , 5.95 mol). The RM was stirred at RT under H2 (30 psi) for 1 hour. The mixture was filtered through Celite. The filtrate was extracted with DCM (4x1 L). The combined organic phases were distilled at 1 atm to remove DCM at 39°C and methanol at 65°C to give the title compound as a brown liquid. Y=28%.

¹ H-NMR (400 MHz, methanol^) δ 8.66 (d, J=5 Hz, 2H), 7.29 (t, J=5 Hz, 1H), 2.65 (s, 3H).

Step 3: propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate.

Iron diacetoxy (924 mg, 5 .3 mmol). The mixture was heated at 140°C for 48 hours. The reaction mixture was concentrated under vacuum to obtain a residue. This residue was purified by FCC (10 to 50% EtOAc in petroleum ether) to give the title compound as a yellow solid. Y=22%.

¹ H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 2H), 7.22 (t, J=5 Hz, 1H) 5.20-5.07 (m, 1H), 4.73-4.71 (m, 1H), 3.55-3.40 (m, 2H), 1.26 (d, J=6 Hz, 3H), 1.21 (d, J =6 Hz, 3H).

Step 4: propan-2-yl-2-{[(3-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate and 1-isocyanato-3-methylcyclohexane as the raw materials. The crude mixture was purified by preparative TLC (2/1 EtOAc/petroleum ether, Rf=0.3) to obtain the title compound as a white solid. Y=52%. MS ES ⁺ : 350.2.

¹ H-NMR (400 MHz, chloroform-d) δ 8.69 (d, J=5 Hz, 2H), 7.17 (t, J=5 Hz, 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), 2.06-1.83 ( m, 2H), 1.78-1.63 (m, 2H), 1.55-1.31 (m, 2H), 1.27 (d, J=6 Hz, 3H), 1.22 (d , J=6 Hz, 3H), 0.94-0.89 (m, 1H), 0.88 (d, J=3 Hz, 3H), 0.87-0.69 (m, 2H).

Example 112 propanoate

Step 1: propan-2-yl-3-(5-cyanopyrazin-2-yl)-2-hydroxypropanoate.

To a solution of 5-methylpyrazin-2-carbonitrile (1.0 g, 8.39 mmol) in dioxane (7 ml) under N ₂ was added isopropyl-2-oxoacetate (1.17 g, 10.07 mmol) and iron diacetoxy ( 73 mg, 419 µmol). 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 250x50 mm, 10 μm; mobile phase: [water (0.1% TFA) - ACN]; B%: 5-35%, 20 min) to give the title compound in the form of a light yellow oil. Y=23%.

¹ H-NMR (400 MHz, 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=6 Hz, 6H).

Step 2: propan-2-yl-3-(5-cyanopyrazin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl]oxy} propanoate

The title compound was prepared according to General Procedure B using propan-2-yl-3-(5-cyanopyrazin-2-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude mixture was purified by preparative HPLC (column: Nano-Micro Unisil 8-120 C18 Ultra Plus 250x50 mm; mobile phase: [water (10 mM NH4HCO3) - ACN]; B%: 47-70%, 20 min) to obtain the indicated in the title compound as a yellow solid. Y=8%. MS ES ⁺ : 435.3.

^1H -NMR (400 MHz, methanol-d4) δ 8.99 (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 113. Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(2methylpyrimidin-4-yl) propanoate

- 91 044707

Step 1: propan-2-yl-2-hydroxy-3-(2-methylpyrimidin-4-yl)propanoate.

To a solution of 2,4-dimethylpyrimidine (1.00 g, 9.25 mmol) in dioxane (7 ml) under nitrogen atmosphere was added isopropyl-2-oxoacetate (1.18 g, 10.17 mmol) and iron diacetoxy (80 mg, 0.46 mmol). The mixture was stirred at 120°C for 48 hours under a nitrogen atmosphere. The solvent was removed under reduced pressure. The residue was purified by FCC (33-100% EtOAc in petroleum ether) to give the title compound as a light brown oil. Y=14%.

¹ H-NMR (400 MHz, chloroform-d) δ ppm 8.53 (d, J=5 Hz, 1H), 7.04 (d, J=5 Hz, 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: propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(2methylpyrimidin-4-yl) propanoate

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(2-methylpyrimidin-4-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by preparative HPLC (column: Xtimate C18 10 μm, 250x50 mm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) - ACN]; B%: 40-60%, 25 min) to obtain the title compound as a white solid. Y=2%. MS ES ⁺ : 424.3.

¹ H-NMR (400 MHz, methanol-d ₄ ) δ 8.58 (bs, 1H), 7.32 (bs, 1H), 6.90 (s, 1H), 5.45 (bs .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 114. Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(5methylpyrazin-2-yl) propanoate

Step 1: propan-2-yl-2-hydroxy-3-(5-methylpyrazin-2-yl)propanoate.

To a solution of isopropyl-2-oxoacetate (564 mg, 4.85 mmol) in dioxane (5 ml) under N2 was added 2,5-dimethylpyrazine (0.50 g, 4.62 mmol) and iron diacetoxy (24 mg, 0. 14 mmol). The reaction mixture was stirred at 140°C for 48 hours. The reaction mixture was concentrated in vacuo, then purified by preparative HPLC and then by FCC (9% MeOH in DCM) to give the title compound as a yellow oil. Y=17%.

¹ H-NMR (400 MHz, chloroform-d) δ ppm 8.38 (s, 1H), 8.37 (s, 1H), 5.14-5.04 (m, 1H), 4.61-4 .56 (m, 1H), 3.67 (d, J=6 Hz, 1H), 3.35-3.09 (m, 2H), 2.55 (s, 3H), 1.27-1, 24 (m, 6H).

Step 2: propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(5-methylpyrazin2-yl) propanoate

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(5-methylpyrazin-2-yl)propanoate and intermediate A as starting materials. The crude mixture was purified by preparative TLC (1/1 EtOAc/petroleum ether) to obtain the title compound as a white solid. Y=18%. MS ES ⁺ : 424.2.

¹ H-NMR (400 MHz, chloroform-d) δ ppm 8.43 (b s, 2H), 7.00 (s, 1H), 6.27 (b 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 115. Propan-2-yl-2-{[(1-methylcyclohexyl)carbamoyl]-oxy}-3-(pyrimidin-2-yl)propanoate.

Step 1: 1-isocyanato-1-methylcyclohexane.

To a mixture of triphosgene (393 mg, 1.33 mmol) in DCM (2 ml), cooled to 0°C, 1-methylcyclohexanamine (150 mg, 1.33 mmol) and triethylamine (369 μl, 2.65 mmol). 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, which was used directly in the next step. Y=100%.

Step 2: propan-2-yl-2-{[(1-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using pro

- 92 044707 pan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate (for synthesis, see example 5CO) and 1-isocyanato-1methylcyclohexane as starting materials. The crude mixture was purified by preparative TLC (2/1 EtOAc/petroleum ether) to obtain the title compound as a colorless gum. Y=9%. MS ES ⁺ : 350.1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.69 (d, J=5 Hz, 2H), 7.17 (t, J=5 Hz, 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=6 Hz, 3H).

Example 116 Propan-2-yl-2-{[(2-chloro-6-fluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

Step 1: 1-chloro-3-fluoro-2-isocyanatobenzene.

To a solution of triphosgene (408 mg, 1.37 mmol) in DCM (3 ml) was added 2-chloro-6-fluoroaniline (200 mg, 1.37 mmol). RM was cooled to 0°C and treated with triethylamine (402 μL, 2.89 mmol). The RM was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the title product as a white solid and used in the next step without further purification. MS ES ⁺ : 204.2 (in methanol).

Step 2: propan-2-yl-2-{[(2-chloro-6-fluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate (for synthesis see Example 5CO) and 1-chloro-3-fluoro- 2isocyanatobenzene as starting materials. The crude mixture was purified by preparative TLC (1/1 EtOAc/petroleum ether, Rf=0.4) to obtain the title compound as a colorless gum. Y=28%. MS ES ⁺ : 382.1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 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=6 Hz, 3H), 1.25 (d, J=6 Hz, 3H).

Example 117 Propan-2-yl-2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

Step 1: 1,3-difluoro-2-isocyanatobenzene.

To a solution of triphosgene (460 mg, 1.55 mmol) in DCM (3 ml) was added 2,6-difluoroaniline (200 mg, 1.55 mmol). RM was cooled to 0°C and treated with triethylamine (453 μL, 3.25 mmol). The RM was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the title product as a white solid and used in the next step without further purification. MS ES ⁺ : 188.3 (in methanol).

Step 2: propan-2-yl-2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate (for synthesis see Example 5CO) and 1,3-difluoro-2 isocyanatobenzene as starting materials. The crude mixture was purified by preparative TLC (1/1 EtOAc/petroleum ether, Rf=0.4) to obtain the title compound as a colorless gum. Y=12%. MS ES ⁺ : 366.1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 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=6 Hz, 3H), 1.25 (d, J=6 Hz, 3H).

Example 118 Propan-2-yl-2-{[(2,6-dichlorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

Step 1: 1,3-dichloro-2-isocyanatobenzene.

To a solution of triphosgene (366 mg, 1.23 mmol) in DCM (3 ml) was added 2,6-dichloroaniline (200 mg, 1.23 mmol). RM was cooled to 0°C and treated with triethylamine (361 μL, 2.59 mmol). The RM was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to give the title product as a white solid and used in the next step without further purification. MS ES ⁺ : 220.2 (in methanol).

- 93 044707

Step 2: propan-2-yl-2-{[(2,6-dichlorophenyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate (for synthesis see Example 5CO) and 1,3-dichloro-2isocyanatobenzene in as starting materials. The crude mixture was purified by preparative TLC (1/1 EtOAc/petroleum ether, Rf=0.4) to obtain the title compound as a colorless gum. Y=28%. MS ES ⁺ : 398.1.

¹ H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 2H), 7.34 (d, J=8 Hz, 2H), 7.22-7.11 (m , 2H), 6.48-6.35 (b s, 1H), 5.82-5.76 (m, 1H), 5.18-5.07 (m, 1H), 3.70-3 .43 (m, 2H), 1.28 (d, J=6 Hz, 3H), 1.25 (d, J=6 Hz, 3H).

Example 119. Pronan-2-yl-(2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-{[(1,2,3,5,6, 7-hexahydro-s-indacen4-yl)carbamoyl]oxy}propanoate.

Step 1: npropan-2-yl-(2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-hydroxynpropanoate.

To a solution of isopropyl-(2R)-oxirane-2-carboxylate (0.4 g, 3.07 mmol) (for synthesis, see Example 5CI) in EtOH (10 ml) was added 1H-1,2,4-triazole-3 -carbonitrile (723 mg, 7.68 mmol) and DIPEA (1.28 ml, 7.38 mmol). The mixture was stirred at room temperature for 16 hours and then concentrated in vacuo. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 250x50 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%.

¹ H-NMR (400 MHz, 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: propan-2-yl-(2R)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-{[(1,2,3,5,6, 7-hexahydro-s-indacen-4yl)carbamoyl]oxy}propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-(2K)-3-(3-cyano-1H-1,2,4-triazol-1-yl)-2-hydroxypropanoate and intermediate compound A as starting materials. The crude product was purified by preparative HPLC (column: Waters Xbridge 150x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 47-67%, 12 min) to give the title compound as a white solid. Y=8%. MS ES ⁺ : 424.1.

1H-NMR (400 MHz, chloroform-d) δ 8.25 (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=6 Hz, 6H).

Example 120 Propan-2-yl-2-[({bicyclo[2,2,2]octan-1-yl}carbamoyl)oxy]-3-(pyrimidin-2yl)propanoate.

Step 1: 1-isocyanatobicyclo[2.2.2]octane.

To a solution of triphosgene (119 mg, 399 µmol) in DCM (2 ml), cooled to 0°C, was added bicyclo[2.2.2]octan-4-amine (50 mg, 399 µmol), followed by Et ₃ N (0.167 ml, 1.20 mmol). The mixture was stirred at room temperature for 1 hour, then the solvent was removed under reduced pressure to obtain the title compound as a white solid. The product was used directly in the next step. Y=99%. MS ES ⁺ : 184.1 (in methanol).

Step 2: propan-2-yl-2-[({bicyclo[2.2.2]octna-1-yl}carbamoyl)oxy]-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate (for synthesis see Example 5CO) and 1-isocyanatobicyclo[2.2.2] octane as starting materials. The crude mixture was purified by preparative TLC (1/1 EtOAc/petroleum ether, Rf=0.35) to obtain the title compound as a white solid. Y=19%. MS ES ⁺ : 362.2.

1H-NMR (400 MHz, methanol-d4+D2O) δ 8.72 (d, J=5 Hz, 2H), 7.36 (t, J=5 Hz, 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).

- 94 044707

Example 121 Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3(pyridazin-4-yl)propanoate .

Step 1: propan-2-yl-2-hydroxy-3-(pyridazin-4-yl)propanoate.

To a solution of 4-methylpyridazine (500 mg, 5.31 mmol) in dioxane (5 ml) under N2 was added isopropyl-2-oxoacetate (1.23 g, 10.62 mmol) and iron diacetoxy (46 mg, 0.27 mmol ). The reaction mixture was heated at 100°C for 24 hours. The reaction mixture was filtered and the filtrate was immediately purified by preparative HPLC (column: Phenomenex Luna C18 250x50 mm, 10 μm; mobile phase: [water (0.1% TFA) - ACN] ; B%: 1-20%, 20 min) to obtain the title compound as rose oil. Y=38%.

^1H -NMR (400 MHz, 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: propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl]oxy}-3-(niridazin-4yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyridazin-4-yl)propanoate and intermediate A as starting materials. The crude product was purified by preparative HPLC (column: Nano-micro Kromasil C18 100x30 mm, 5 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 40-55, 10 min) to obtain the following The title compound appears as a brown solid. Y=1%. MS ES ⁺ : 410.2.

¹ H-NMR (400 MHz, 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 122. Propan-2-yl-2-{[(trans-2-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2yl)propanoate.

Step 1: trans-1-isocyanato-2-methylcyclohexane.

To a mixture of triphosgene (131 mg, 0.44 mmol) in DCM (1 ml) at 0°C under N2, trans-2-methylcyclohexanamine (50 mg, 0.44 mmol) and Et ₃ N (89 mg, 0 .88 mmol). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to obtain the title compound as a white solid. Y=100%.

Step 2: propan-2-yl-2-{[(trans-2-methylcyclohexyl)carbamoyl]oxy}-3-(pyrimidin-2-yl)propanoate.

The title compound was prepared according to General Procedure B using propan-2-yl-2-hydroxy-3-(pyrimidin-2-yl)propanoate (for synthesis see Example 5CO) and trans-1-isocyanato2-methylcyclohexane in as starting materials. The crude mixture was purified by preparative HPLC (column: Waters Xbridge 150x50 mm, 10 µm; mobile phase: [water (0.1% TFA) - ACN]; B%: 30-60%, 12 min) to give the title compound as a white solid. Y=5%. MS ES ⁺ : 350.2.

¹ H-NMR (400 MHz, chloroform-d) δ 8.70 (d, J=5 Hz, 2H), 7.20-7.17 (m, 1H), 5.66-5.60 (m, 1H), 5.15-5.01 (m, 1H), 4.58 (d, J=9 Hz, 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 123. Propan-2-yl-3-(5-cyanopyrimidin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl]oxy} propanoate

Step 1: propan-2-yl-3-(5-cyanopyrimidin-2-yl)-2-hydroxypropanoate.

To a mixture of 2-methylpyrimidine-5-carbonitrile (200 mg, 1.68 mmol) and isopropyl-2-oxoacetate (585 mg, 5.04 mmol) in dioxane (3 ml) under N2, diacetoxyiron (29 mg, 0.17 mmol). 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 (3x20 ml). The combined organic phases were washed

- 95 044707 saline solution (10 ml), dried over anhydrous Na ₂ SO ₄ , filtered and concentrated in vacuo. The residue was purified by FCC (0-100% EtOAc in petroleum ether) to give the title compound as a white solid. Y=30%.

¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 9.24 (s, 1H), 5.66 (d, J=6 Hz, 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: pronan-2-yl-3-(5-cyanopyrimidin-2-yl)-2-{[(1,2,3,5,6,7-hexahydro-s-indacen-4yl)carbamoyl]oxy} propanoate

The title compound was prepared according to General Procedure B using propan-2-yl-3-(5-cyanopyrimidin-2-yl)-2-hydroxypropanoate and intermediate A as starting materials. The crude product was purified by preparative TLC (SiO ₂ , 1/1 EtOAc/petroleum ether) to give the title compound as a colorless oil. Y=34%. MS ES ⁺ : 435.2.

¹ H-NMR (400 MHz, chloroform-d) δ 8.95 (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).

The biological activity of the compounds of the present invention was determined using the assay method described herein.

Assay method for determining IC ₅₀ of PBMC.

The compounds of the present invention were tested for their inhibitory activity on IL-Ιβ release following activation of NLRP3 in peripheral blood mononuclear cells (PBMC).

PBMCs were isolated from buffy coats by density gradient centrifugation on Histopaque-1077 (Sigma, cat. no. 10771). The isolated cells were seeded into the wells of a 96-well plate and incubated for 3 hours with lipopolysaccharide (LPS). After replacing the medium, compounds of the present invention were added (one compound per well) and the cells were incubated for 30 minutes. Cells were then stimulated with either ATP (5 mM) or nigericin (10 μM) for 1 h, and culture medium from the wells was collected for additional analysis.

The release of IL-Ιβ into the medium was determined by quantifying IL-Ιβ in the medium using the IL-Ιβ enzyme-linked immunosorbent assay (ELISA) Ready-SET-Go!, eBioscience cat. No. 88-7261-88. Briefly, in the first step, the specific immobilized antibody included in the kit (anti-human IL-Ιβ ref. 14-7018-68). The plates were then blocked with blocking buffer for 1 h at room temperature (RT) and, after washing with buffer (PBS with 0.05% Tween-20), incubated with protein standard and culture medium. After 2 hours of incubation at RT, the plates were washed and incubated with the biotinylated detection antibodies included in the kit (anti-human IL-Ιβ Biotin ref. 33-7110-68) for 1 hour at RT. Plates washed, incubated with HRP-streptavidin for 30 min at RT and washed again. The signal developed after the addition of 3,3,5,5-tetramethylbenzidine peroxidase (TBM) until color developed and the reaction was stopped by the addition of 2 M H ₂ SO ₄ . A microplate spectrophotometer (BioTek) was used to determine signals at 450 nm. The IL-Ιβ ELISA detection range was 2-150 ng/ml.

Determination of IC ₅₀ values was carried out using GraphPad Prism software, and the measured IC ₅₀ values for the compounds of the present invention are presented below in table. 2 (A means IC ₅₀ <10 nM; B means IC ₅₀ in the range from 10 to 100 nM; C means IC ₅₀ in the range from 100 nM to 1 μM; D means IC ₅₀ in the range >1 to 10 μM; E means IC ₅₀ >10 µM). These results demonstrate that the compounds of the present invention are capable of inhibiting the release of IL-Ιβ following activation of the inflammasome.

___________________________________________________________Table 2

Connection No. PBMS 1C ₅ o (μΜ) Connection No. PBMS 1C ₅ o (μΜ) Connection No. PBMC 1C ₅₀ (μΜ) 1 WITH 45 E 89 WITH 2 D 46 WITH 90 D 3 WITH 47 WITH 91 D 4 D 48 WITH 92 WITH 5 E 49 WITH 93 A 6 IN 50 WITH 94 A

- 96 044707

7 D 51 D 95 WITH 8 WITH 52 D 96 WITH 9 WITH 53 D 97 With 10 D 54 D 98 D eleven D 55 A 99 WITH 12 IN 56 E 100 D 13 D 57 E 101 WITH 14 D 58 D 102 WITH 15 D 59 E 103 IN 16 WITH 60 IN 104 D 17 WITH 61 WITH 105 IN 18 WITH 62 WITH 106 WITH 19 D 63 WITH 107 A 20 WITH 64 WITH 108 A 21 WITH 65 WITH 109 WITH 22 WITH 66 WITH BY A 23 WITH 67 WITH 111 A 24 WITH 68 D 112 A 25 WITH 69 WITH 113 A 26 WITH 70 D 114 WITH 27 D 71 IN 115 A 28 D 72 IN 116 A 29 D 73 With 117 A thirty WITH 74 With 118 D 31 IN 75 With 119 A 32 WITH 76 A 120 IN 33 WITH 77 IN 121 IN 34 D 78 With 122 E (60% inhibition) 35 E 79 D 123 WITH 36 D 80 IN 124 WITH 37 WITH 81 D 125 D 38 D 82 IN 126 IN 39 D 83 A 127 D 40 WITH 84 D 128 WITH 41 IN 85 IN 129 D 42 WITH 86 IN 130 IN 43 WITH 87 D 44 WITH 88 IN

Equivalents

Details of one or more embodiments of the invention herein are set forth above in the accompanying description. Although any methods and substances similar or equivalent to those described herein may be used in the practice of applying or testing the present invention, preferred methods and substances are described herein. Other features, objects and advantages of the present invention will become apparent from the present description and claims. As used in the present specification and the accompanying claims, the singular forms include the plural forms unless the context clearly requires otherwise. Unless otherwise specified, all technical and scientific terms used in this document

-

Claims (22)

have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. All patents and publications cited in this specification are incorporated herein by reference. The foregoing description has been presented for illustrative purposes only and is intended to limit the invention not by the precise form disclosed but by the claims appended thereto. CLAIM 1. Compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ₁ is a) C8-C16 polycyclic cycloalkyl, optionally substituted with one or more R6; b) benzofuranyl or dihydrobenzofuranyl, optionally substituted with one or more R6; - 98 044707 R3 is H or C1- _C4 alkyl, optionally substituted by one or more _R7 ; R4 is H, C ₁ -C ₆ -alkyl, -(CH ₂ ) _0-3 -(C ₃ -C ₆ -cycloalkyl) or -(CH ₂ ) _0-3 -C ₆ -aryl; R ₆ represents C ₁ -C ₆ -alkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ -alkoxy, C ₃ -C ₈ -cycloalkyl, halogen, oxo, -OH, -CN, -NH2, - NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl) ₂ , -CH2F, -CHF2 or -CF3; R ₇ is -OR ₈ , C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl, wherein C ₆ -C ₁₀ -aryl or 5-10 membered heteroaryl is optionally substituted by one or more R _7S , wherein each R _7S independently represents C ₁ -C ₆ -αalkyl, C ₁ -C ₆ -alkoxy, 5-10 membered heteroaryl, halogen, -OH, -CN, -(CH2) _0-3 -NH2, -(CH2)o- 3-NH(C1-C6-alkyl), -(CH2)o-3-N(C1-C6-alkyl)2, -CH2F, -CHF2 or -CF3; And R ₈ represents a C ₁ -C6 alkyl or 5-7 membered heterocycloalkyl, wherein the C ₁ -C ₆ alkyl or 5-7 membered heterocycloalkyl is optionally substituted by one or more R _7S , wherein said heterocycloalkyl rings contain from 1 to 6 heteroatoms selected from O, N, S, P and Se, and wherein said heteroaryl rings contain from 1 to 6 heteroatoms selected from N, O and S. 2. A compound according to claim 1, where R1 is C ₈ -C ₁₆ -cycloalkyl, polycyclic cycloalkyl, optionally substituted with one or more C ₁ -C ₆ -αalkyl, C ₂ -C ₆ -alkenyl, C ₁ -C ₆ groups -αalkoxy, C ₃ -C ₈ -cycloalkyl, halogen, oxo, -OH, -CN, -NH2, -NH(C ₁ -C ₆ -alkyl), -N(C ₁ -C ₆ -alkyl) ₂ , - CH2F, -CHF2 or -CF3. 3. The connection according to any one of claims 1, 2, where R1 represents 4. A compound according to any one of claims 1-3, where R3 represents C ₁ -C ₄ -alkyl, optionally substituted with one or more groups selected from -OR ₈ , C ₆ -C ₁₀ -aryl and 5-10-membered heteroaryl. 5. A compound according to any one of claims 1 to 4, where R ₃ represents methyl substituted with one or more 5-10 membered heteroaryls, where the 5-10 membered heteroaryl is optionally substituted with one or more C ₁ -C ₆ alkyls, C ₁ -C ₆ -alkoxy, halogens, -CN, -(CH ₂ ) _0-3 -N(C ₁ -C ₆ -αalkyl) ₂ or -CF3. 6. A compound according to any one of claims 1 to 4, where R3 represents - 99 044707 7. A compound according to any one of claims 1 to 6, where R4 represents H. 8. A compound according to any one of claims 1 to 6, where R ₄ represents C ₁ -C ₆ -alkyl, -(CH2) ₀ . ₃ -(C3-C ₆ cycloalkyl) or -(CH ₂ ) ₀ . ₃ -C ₆ -aryl. 9. A compound according to any one of claims 1-6 and 8, where R4 represents methyl, ethyl, propyl, butyl, 10. A compound according to any one of claims 1 to 9, wherein at least one R ₇ is a 5-10 membered heteroaryl, optionally substituted with one or more groups selected from halogen, -OH, -CN, -(d^j -NH, -(CH2)o.3-NH(C1-C6-alkyl), -(ODX3-^CrCl-alkyl, -CH2F, -CHF2 - 100 044707 or -CF3. 11. A compound according to any one of claims 1 to 10, characterized by formulas (Ia), (Ib), (II), (IIa), (IIb), (III), (IIIa), (IIIb), (IV), (IVa), (IVb), (V), (Va), (Vb), (VI), (VIa), (VIb), (VII), (VIIa), (VIIb), (VIII), (VIIIa) ), (VIIIb), (IX), (IXa), (IXb), (X), (Xa) and (Xb): - 101 044707 - 102 044707 or a pharmaceutically acceptable salt thereof. 12. Connection selected from the following connections No. 1-130: Connection No. Structure Name 1 Ethyl 2-{[(1,2,3,5,6,7-hexahydrosind acen-4-yl)carbamoyl]oxy} acetate I ί ^{v 1} ' ?[ Ethyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}acetate 3 GI L G d .o .. Τ L ' ^s 'U' ⁴ ' CI ϋ Ethyl-2-{[(2,6-dichlorophenyl)carbamoyl] oxy} acetate 4 . ^! / g LT th - ;g Ethyl-2- {[(naphthalene-1 yl)carbamoyl]oxy) acetate 5 D 9 n ⁰ 9 D. .N. With. D g g ¹ ' Ethyl 2-{[(2,2-dimethyl-2,3-dihydro-1 benzofuran-7-yl)carbamoyl]oxy} acetate 6 ? * D”’ ,0. , < Т Н '° Ϊ Ethyl 2-{[(1,2,3,5,6,7-hexahydrosind acen-4-yl)carbamoyl]oxy}-3 methoxypropanoate - 103 044707 7 •pD. )—4-π У у 4 ιζ BEFORE H V-* /\ Ethyl 2-({ [2-fluoro-5(trifluoromethyl)phenyl]carbamoyl} oxy)acetate 8 ί Υ A ~ _l , t in °' y ~ Ethyl-2-{[(2,6-dimethylphenyl)carbamoyl] oxy} acetate 9 D<>···'· o Ch -- Ch „ o . { ίΐ °' 7 ~ Ethyl-2-{[(2,6- diethylphenyl)carbamoyl] oxy(acetate 10 O Before /\ O / o =\ ) ( _ g D— Q Ethyl 2-({ [2-(chloro-6methylphenyl)carbamoyl] oxy} acetate 11 dO o H d o .- D Ν Ό X ^ν 1 μ .1 CN O Ethyl-2-{[(2-cyanophenyl)carbamoyl]oxy}acetate 12 GL '' g Lch / αά ,Ν •j 0 G ^v 1 d 1 η Μ Η °' Ethyl-2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl )carbamoyl]oxy}-3 (pyridin-3-yl)propanoate 13 Q 1 .... ο , A ⁰ ϊ — 0 Ethyl 2-{\(2-tert-butylphenyl)carbamoyl] oxy} acetate 14 CC ϊ,... ο... Г η' ⁰ 7 Ethyl 2-((mesitylcarbamoyl)oxy)acetate 15 Ο Λ ,. η , ν n 7Τ V '- J ⁿ A Ethyl 2-(((2-isopropylphenyl)carbamoyl)oxy)acetate 16 OD „ .·, .. D -G -- Ύ Ethyl-2-(((2-ethyl-6- methylphenyl)carbamoyl)oxy)acetate 17 p O o ϊ ..s; M i ^g .1 Ethyl 2-(((1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl)oxy)-3 phenylpropanoate 18 D-b Before -D. W____!U Ethyl 2-(((1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl)oxy)-3 (pyridin-2-yl)propanoate 19 m.4 ϊ o , \ J and ⁰ G Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl] oxy } propanoate - 104 044707 20 21 Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy } acetate 2-{[(1,2,3, 5,6,7-G hexahydro-s-indacen-4yl)carbamoyl] oxy} acetate p, Gt -J. ..0.. .-X T ^v O 22 \_j h X .Οχ Ϊ 0 Cyclopropylmethyl-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy} acetate 23 V 3 γ technical specifications \ 1 H -*··χ ^0 > . V ΤΊ O Cyclobutyl-2-{[(1,2,3,5,6,7-hexahydro8-indacen-4-yl)carbamoyl]oxy} acetate 24 r~\λ ' I ..^ A . ( V 'Ν Ό' 0 2-methylpropyl-2-{[(1,2,3,5,6,7- hexahydro-8-indacen-4yl)carbamoyl] oxy} acetate 25 C/IXJ n ^ϋ χ.Ν Ά Ethyl 3-(4-cyanophenyl)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy} propanoate 26 (X A, T H°' 0 Ethyl 2-({ [2-methyl-6-(propan-2yl)phenyl] carbamoyl} oxy)acetate 27 r\ L A _l ..one ( G I ° I - ¹ 0 2- {[(1,2,3,5,6,7-G hexahydro-8-indacen-4yl)carbamoyl]oxy}acetic acid 28 ΎΎ ¹ S 1 7. ⁰ Ύ ⁰ '- Ο Ethyl 2-{[(2, b-diethyl-4methylphenyl)carbamoyl]oxy}acetate 29 A'A o «D A ,-. .o. ,: ~r N '0' Y lJ ^H 0 Methyl-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl] oxy } acetate [i Ί 30 Z3 Ϊ L 1 5 \J' H °' J Ί γ ⁰ ^ 0 Ethyl-(2К)-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl) carbamoyl] oxy } -4phenylbutanoate 31 O Cl A / h' ^O ' \ H GL f ^{N N} ' A o. „.p 0 Ethyl-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl] oxy} -3 -(1Hpyrazol-1 -yl)propanoate - 105 044707 32 Of Iо., \ T И' ⁰ Y -. / 0 -- A Cyclopentyl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy } acetate 33 g 11 x:,., <3^1 Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl {carbamoyl] oxy} -3 -(1Nimidazol-1 -yl)propanoate 34 /V/ ΞΕΖ Oh oh Ethyl 2-({ [2,6-bis(propan-2yl)phenyl] carbamoyl} oxy)acetate 35 IZ O 4 O Ethyl 2-({[2-chloro-5-(trifluoromethyl)phenyl]carbamoyl}oxy)acetate 36 OOO ⁰ La λ „,,o,/ Va^o V /A ^H θ Ethyl 2-{[(2-tert-butyl-6methylphenyl)carbamoyl]oxy}acetate 37 h IZ ' )=° O 4 o Ethyl-2-{[(2.5- dimethylphenyl)carbamoyl]oxy}acetate 38 δ - ο °4 ,, ^ΖΙ 2- {[(1,2,3,5,6,7-hexahydro-5-ind acen-4yl)carbamoyl]oxy} -3 methoxypropanoic acid 39 ΙΖ >° o 0 cyclopropyl-2-{ [(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy } acetate 40 I ζ ο □ =/ ζ-, 8 =0 2-{[(1,2,3,5,6,7-hexahydro-5-ind acen-4yl)carbamoyl]oxy}-3 -(1H-pyrazol-1yl)propanoic acid 41 Ν #4- Ethyl-(2H)-3-(3-cyanophenyl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate - 106 044707 42 nA N /U Ethyl 2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy}-3-[3-(1Hpyrazol-1-yl)phenyl]propanoate 43 O N /χέ Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy} -3 - [3 -(1Hpyrazol-1-yl)phenyl ]propanoate 44 rr ^F ° SAW- F 0 Ethyl 2-{[(2,6-difluorophenyl)carbamoyl]oxy}-3-1Hpyrazol-1-yl)propanoate 45 rii o fn ⁿ o Ethyl-2-[(phenylcarbamoyl)oxy]-3 -(1Hpyrazol-1-yl)propanoate 46 fl/. Ethyl-2-{[(2-ethyl-6- methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 47 Ethyl-2-{[(2,6- dimethylphenyl)carbamoyl] oxy} -3 -(1Hpyrazol-1 -yl)propanoate 48 Ethyl 2-{[(2,6diethylphenyl)carbamoyl]oxy}-3 -(1Hpyrazol-1-yl)propanoate 49 TUX- F ^H O Ethyl-2-{[(2-fluoro-6-methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 50 F ^H O Ethyl-2- {[(2-chloro-6fluorophenyl)carbamoyl] oxy} -3 -(1Hpyrazol-1 -yl)propanoate 51 > h^° o °=< o ZI V/ Ethyl-2-{[(2-chloro-6- methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate - 107 044707 52 ^ ^Cl rY o < ⁿ γγ,νCl ⁿ 0 Ethyl-2-{[(2,6dichlorophenyl)carbamoyl] oxy } -3 -(1Hpyrazol-1 -yl)propanoate 5, l, ,χχ ΓΊ ⁰ G ^{N no} Ethyl-2-[(cyclohexylcarbamoyl)oxy]-3(1 H-pyrazol-1-yl)propanoate 54 /-η o ⁿ 0 Ethyl-2-[(cyclopentylcarbamoyl)oxy] 3 -(1 H-pyrazol-1-yl)propanoate 55 N Ethyl 3-(4-cyano-1 H-pyrazol-1-yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl] oxy } propanoate 56 0 ΙΖ >° o O=( Ζ—, O ζ/Λ ( Ethyl 2-[(cycloheptylcarbamoyl)oxy]-3 (1H-pyrazol-1-yl)propanoate 57 ΙΖ '>= ^o o ( Ethyl-2-{[(2-cyano-6-methylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 58 Ν Ethyl 2-{[(2-cyano-6ethylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 59 Ζ^IZ ^Z Q o O=/ Ζ —, O Ζ ( Ethyl-2- {[(2-chloro-6cyanophenyl)carbamoyl]oxy} -3 -(1Hpyrazol-1 -yl)propanoate 60 _χ Ν γγ Ethyl-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy } -3 (pyrazin-2-yl)propanoate - 108 044707 61 O ^z А ζ V=o о °=κ (2R)-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl] oxy} -3 -( 1Hpyrazol-1-yl)propanoic acid 62 \=Ζ \=ο ο ots ^-χ ^2Τ Μ^ΓΊ Ethyl-2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl] oxy} -3 (pyridazin-3-yl)propanoate 63 F ^I 0 Ethyl-3 -(1 H-pyrazol-1 -yl)-2- {[(2,3,6trifluorophenyl)carbamoyl] oxy} propanoate 64 Benzyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]-oxy}-3-(111pyrazol-1-yl)propanoate 65 ί > 4 '—ζ Υ=ο ο °=< ^{ζ τ} Α-<Ί 3thh-(2R)-2- {[(1,2,3,5,6,7-hexahydro-sind acene-4- yl)carbamoyl] oxy} -3 -(1Hpyrazol-1 -yl)propanoate About ιζ -π >° ο Ο=/ ζ—. Ο ζ ς and Ethyl 2-{[(2-ethyl-bfluorophenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 67 Ο °ν ο °=< ^ζτ Ethyl-(2К)-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl] oxy} -3 -(1Nimidazole -1-yl)propanoate 68 ο — ^== ο ο °F __ Ζ X ν_<Ί 3thh-(2R)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy}-3 methoxypropanoate 69 Α\ / AsJk >h vvk .on CJ4 °'Ύ (2R)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy}-3 methoxypropanoic acid 70 ΓΊ ϊ F Cl ^H 0 Ethyl 2-({ [2-chloro-3(trifluoromethyl)phenyl] carbamoyl } oxy)3-(1 H-pyrazol-1 -yl)propanoate - 109 044707 71 IZ >° o o = / Z -. ABOUT ( Ethyl 2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy}-3 -(1H1,2,4-triazol-1-yl)propanoate 72 A > CQ-o O °h ΖZE Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 -(3 methyl-1H-pyrazol-1-yl)propanoate 73 ΤΊ with IZ -P N° o o=( Z—, o Ethyl-3 -(1H-pyrazol-1-yl)-2-{[(2,4,6trifluorophenyl)carbamoyl]oxy}propanoate 74 >= ^{o o} o=/ Z—, □ z D Ethyl-2-({ [2-methyl-6-(propan-2yl)phenyl] carbamoyl} oxy)-3 -(1Hpyrazol-1 -yl)propanoate 75 F ^H O Ethyl-2-{[(3-chloro-2,6-difluorophenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 76 IZ >° o o =/ Z —, O X Ethyl-(2C)-3 -(4-cyano-1H-pyrazol-1-yl)2-{[(1,2,3,5,6,7-hexahydro-8-ind acen-4yl)carbamoyl] oxy} propanoate 77 o^v IZ >° Oh, o=/ g—. About zi b Benzyl-(2C)-3 -(4-cyano-1H-pyrazol-1yl)-2-{[(1,2,3,5,6,7-hexahydro-8indacen-4yl)carbamoyl]oxy}propanoate 78 NA ) o °h to ^zx Ethyl 2-{[(2,6-dimethylphenyl)carbamoyl]oxy}-3(pyrimidin-2-yl)propanoate 79 gl XI a ...Son sgk ° γ (2R)-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy} -3 -(1Nimidazol-1-yl)propanoic acid - 110 044707 80 F n A ΑΛΑ Ethyl 3-(4-fluoro-1H-pyrazol-1-yl)-2{[(1,2D5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy} propanoate 81 Zho ots V_/A Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8indacen-4-yl)carbamoyl]oxy}-3-(5methyl-1H-imidazol-1-yl)propanoate 82 IZ o O=( Z—. (2R)-3 -(4-cyano-1 H-pyrazol-1 -yl)-2- {[(1,2,3,5,6,7-hexahydro-3-indacene-4- yl)carbamoyl]oxy}propanoic acid 83 aq= _o o °h .. ^ζτ Ethyl-(2К)-2-{ [(1,2,3,5,6,7-hexahydrozinde acen-4-yl)carbamoyl] oxy} -3 -( 1H1,2,4-triazol-1-yl)propanoate 84 w % Αγ° o °h ^ζτ \n Ethyl-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl] oxy} -3 -(2methyl-1H -imidazol-1-yl)propanoate 85 \_^ JLZ About >°o o=/Z—, O Ζ L ( Ethyl 2-{[(2-chloro-6ethylphenyl)carbamoyl]oxy}-3-(1Hpyrazol-1-yl)propanoate 86 Ж ^ζ V '—ζ У=о \о оЧ /=\ ΖΙ Chr_/“ Ethyl-2- {[(2-methylnaphthalene-1 yl)carbamoyl]oxy} -3 -(1 H-pyrazol-1 yl) propanoate 87 Ethyl 2-{[(2methylcyclohexyl)carbamoyl]oxy}-3(1H-pyrazol-1-yl)propanoate 88 O”A IZ □ o=/ Z—. ( - Ethyl-(2R)-3 -(4-chloro-1H-pyrazol-1-yl)-2{[(1,2,3,5,6,7-hexahydro-8-indacen-4yl)carbamoyl]oxy } propanoate - 111 044707 89 o °H Ethyl-(2R)-3 -(4-cyano-1H-imide azol-1 yl)-2-{[(1,2,3,5,6,7-hexahydro-8indacen-4yl)carbamoyl]oxy} propanoate 90 N. D ⁷ # Ethyl-(2K)-3 -(5-cyano-1 H-imide azol-1 yl)-2-{[(1,2,3,5,6,7-hexahydrosindacen-4yl)carbamoyl ]oxy} propanoate 91 /h > £ ν *- ζ 2=° O G LL LL Ethyl-2-({ [2,6-dimethyl-4- (trifluoromethyl)phenyl]carbamoyl}oxy)3-(1H-pyrazol-1-yl)propanoate 92 \ O Ethyl 2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3-(4methoxy-1H-pyrazol-1-yl)propanoate 93 o ots ^ζτ V^Q Ethyl-(2К)-2-{ [(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl] oxy} -3 (pyrimidin-2- yl)propanoate 94 loop IZ >°o Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl]oxy}-3 (pyrazin-2-yl)propanoate 95 IZ >° O o=^o\ < Ethyl-(2K)-3-ethoxy-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate 96 N / γ—Ά №=\ /XX ^AoVVJ ⁿ o Ethyl-(2K)-3 -(3-cyano-1 H-pyrazol-1-yl)2- {[(1,2,3,5, 6,7-hexahydro-8-ind acen-4yl)carbamoyl]oxy}propanoate - 112 044707 97 40 o °h ^z=c Ethyl-(2K)-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl] oxy} -3 - [4( trifluoromethyl)-1H-pyrazol-1 yl]propanoate 98 o 400 § 1 ^-z 2=0 o ^O =K ^{z t} (2R)-3 - { 4-[(dimethylamino)methyl]-1Hpyrazol-1-yl}-2-{[(1,2,3 ,5,6,7hexahydro-8-indacen-4-yl)carbamoyl]oxy } propanoic acid hydrochloride 99 ω I -Z. O o=/ ζ—, =0 Ethyl 2-{[(2,4-dimethylthiophene-Zyl)carbamoyl]oxy}-3-(1H-pyrazol-1yl)propanoate 100 \ Q % _o m o °h °4Ζ^ Ethyl-2-[({4,10-dioxatricyclo[7.3.0.0 ³ ' ⁷ ]dodeca-1,3 (7), 8-trien-2-yl } carbamoyl )oxy]-3 (1 H-pyrazol-1 -yl)propanoate 101 ΙΣ >° o. \0^. O V _o ( ⁴ Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy} -3 -(2methoxyethoxy)propanoate 102 ^lX ⁰ ^ Ethyl-(2K)-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl] oxy} -3 -(oxan4-yloxy)propanoate 103 O“A IZ >=° o o=/ Z—/ about Z.X Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4-yl)carbamoyl]oxy}-3-(5methyl-1H-1,2,4-triazole -1-yl)propanoate 104 ) Vo Vo o °h ^ZJ νχΊ Ethyl-(2К)-2- {[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl] oxy} -3 (propan- 2-yloxy)propanoate - 113 044707 105 ζ 2=0 ο °=< _σι Ethyl-(2K)-2-{[(1,2,3,5,6,7-hexahydro-sind acen-4-yl)carbamoyl]oxy}-3 -(3 methyl-1H-1,2,4 -triazol-1-yl)propanoate 106 f Λ е Z=V >Ο ο °=< .. ^ζζ: (2К)-2-{[(1,2,3,5,6,7-hexahydro-8ind acen-4-yl)carbamoyl] oxy } -3 (pyrimidin-2-yl)propanoic acid 107 ΙΖ ο Ο y=Z _ζ Propan-2-yl-(2К)-2- {[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy } -3 -(pyrimide in-2yl)propanoate 108 <λ9 ζ=Ζ \=ο ο .. ΖΙ Cyclopentyl-(2K)-2-{[(1,2,3,5,6,7hexahydro-3-indacen-4yl)carbamoyl]oxy} -3 -(pyrimide in-2yl)propanoate 109 7? · (2R)-2-{[(1,2,3,5,6,7-hexahydrozind acen-4-yl)carbamoyl]oxy}-3 (pyrazin-2-yl)propanoic acid 110 ΙΖ ο ο=^ У=\ Ο ζ, ζ Propan-2-yl-(2K)-2-{[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy } -3 -(pyrazin-2yl)propanoate 111 2=ο ο 0=^ ^- ο ζ, ,ζ ό Cyclopentyl-(2K)-2- {[(1,2,3,5,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy } -3 -(pyrazin-2yl)propanoate 112 ΙΖ >° ο °4^ζ _Ί Ο Propan-2-yl-(2K)-3 -(4-cyano-1Hpyrazol-1-yl)-2-{[(1,2,3,5,6, 7hexahydro-8-indacen-4yl)carbamoyl]oxy } propanoate FROM ΙΖ 2=0 ο ο=( Ζ~. Ο Ζ. b * ^ζ Cyclopentyl-(2K)-3 -(4-cyano-1Hpyrazol-1-yl)-2-{[(1,2,3,5 ,6,7hexahydro-8-indacen-4yl)carbamoyl]oxy}propanoate - 114 044707 _r ^N l/ (2R)-2- {[(1,2,3,5,6,7-hexahydro-s- 114 Dream ind acen-4-yl)carbamoyl] oxy} -3 -(1 Η- Ζ^Τ^Ν^Ο \U ^Η ύ o 1,2,4-triazol-1-yl)propanoic acid Y Propan-2-yl-(2К)-2-{ [(1,2,3,5,6,7- 1 Ί hexahydro-s-indacene-4- L 1 A O^ yl)carbamoyl]oxy } -3 -(1H-1,2,4-triazol-\___ι η T | 0 ¹ 1-yl)propanoate Z Cyclopentyl-(2K)-2-{[(1,2,3,5,6,7- 1 Ί 6 γγ ? Γ -Υι hexahydro-8-indacene-4- /γΧ _Ν ^ο' yl)carbamoyl]oxy } -3 -(1H-1,2,4-triazol- st o z./ 1-yl)propanoate l Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro- 117 OL d L o s-ind acen-4-yl)carbamoyl] oxy} -3 -(6- \__/ Η Υγ 0 ¹ methylpyrazin-2-yl)propanoate [ νΎ ζ\. Α Y _N J Propan-2-yl-2- {[(3 - 118 1 1 ί D methylcyclohexyl)carbamoyl]oxy } -3 - YYAcZ Η ϊΥ 0 ¹ (pyrimidin-2-yl)propanoate Γύ X J Propan-2-yl-3 -(5-cyanopyrazin-2-yl)-2- 119 ΓΪ Η ί Υ/ {[(1,2,3,5,6,7-hexahydrose-indacen-4- _Υ γ yl)carbamoyl]oxy}propanoate V/ ^Η 0 ¹ Η Υ Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro- 120 £ΎX I ο / s-ind acen-4-yl)carbamoyl] oxy} -3 -(2- /γΥ'ν \_J ^Η γγ ο ¹ methylpyrimidin-4-yl)propanoate XJ Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydro- 121 ML £ 1π s-ind acen-4-yl)carbamoyl] oxy} -3 -(5 - /Υ^Ν^Ο' Υγ methylpyrazin-2-yl)propanoate \__1 Η Ο 1 νΥ L/ Propan-2-yl-2- {[(1 - 122 [ X ϊ I methylcyclohexyl)carbamoyl]oxy } -3 - η γγ ο ¹ (pyrimidin-2-yl)propanoate N-y uud o g Propan-2-yl-2-{[(2-chloro-6- 123 GT X ί fluorophenyl)carbamoyl]oxy} -3 - S^N'XT vV (pyrimidin-2-yl)propanoate Cl ⁿ o ' νΥ l J Propan-2-yl-2- {[(2,6- 124 OCX h difluorophenyl)carbamoyl] oxy} -3 - F ^Η τΥ o ¹ (pyrimidin-2-yl)propanoate νΥ Propan-2-yl-2-{[(2,6- 125 o g CX X J dichlorophenyl)carbamoyl] oxy} -3 - Y^N^cr (pyrimidin-2-yl)propanoate CI ⁿ Ο 1 Propan-2-yl-(2К)-3 -(3 -cyano-1 Η-1,2,4- 126 Π ί g ' ^Ν Ύ ^Ν triazol-1-yl)-2-{[(1,2,3,5,6,7-hexahydro-ζΧ9+ _Ν D st 8-indacene-4-\y n Υ ι 0 ¹ yl)carbamoyl]oxy } propanoate - 115 044707 127 128 129 130 Propan-2-yl-2-[({bicyclo[2.2.2] octan-1 yl} carbamoyl)oxy]-3 -(pyrimide in-2yl)propanoate Propan-2-yl-2-{[(1,2,3,5,6,7-hexahydros-ind acen-4-yl)carbamoyl]oxy}-3 (pyridazin-4-yl)propanoate Propan-2-yl-2-{\(trans-2methylcyclohexyl)carbamoyl]oxy}-3 (pyrimide in-2-yl)propanoate Propan-2-yl-3-(5-cyanopyrimidin-2yl)-2-{[(1,2,3,5,6,7-hexahydro-sindacen-4yl)capbamoyl]oxy }propanoate 13. A pharmaceutical composition containing a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier. 14. A method of inhibiting inflammasome activity, comprising contacting a cell with an effective amount of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof. 15. The method of claim 14, wherein the inflammasome is an NLRP3 inflammasome and the activity is in vitro or in vivo activity. 16. A method of treating or preventing an autoinflammatory disorder, an autoimmune disorder, a neurodegenerative disease, or a malignant tumor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of claim 13 . 17. The method of claim 16, wherein the disease or disorder is an autoinflammatory disorder or an autoimmune disorder. 18. The method of claim 17, wherein the disease or disorder is selected from cryopyrin-associated periodic syndrome (CAPS, e.g. familial cold autoinflammatory syndrome (FCAS)), Muckle-Wells syndrome (MWS), chronic infantile neurological cutaneous articular syndrome (CINCA) , neonatal multisystem inflammatory disease (NOMID), familial Mediterranean fever and non-alcoholic fatty liver disease (NAFLD), non-alcoholic 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 neuroinflammation that occurs in protein misfolding diseases (eg, prion diseases). 19. The method of claim 16, wherein the disease or disorder is a neurodegenerative disease. 20. The method of claim 19, wherein the disease or disorder is Parkinson's disease or Alzheimer's disease. 21. The method of claim 16, wherein the disease or disorder is a malignant tumor. 22. The method of claim 21, wherein the cancer is a metastatic cancer, a gastrointestinal cancer, a skin cancer, a non-small cell lung carcinoma, or a colorectal adenocarcinoma. Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky lane, 2 -116-