EA040531B1 - COMPOUNDS AND COMPOSITIONS FOR INDUCING CHONDROGENESIS - Google Patents

Description

This application claims priority over U.S. Provisional Application Serial Number 62/517394, filed June 9, 2017, which is incorporated herein by reference in its entirety.

The field of technology to which the invention belongs

The present invention relates to compositions and methods for treating or preventing joint damage from joint injury and arthritis.

Prerequisites for the creation of the invention

Osteoarthritis (OA) is the most common disease of the musculoskeletal system. It currently affects approximately 40 million Americans; this number is projected to increase to 60 million over the next twenty years as a result of population aging and increased life expectancy, making it the fourth leading cause of disability. OA is characterized by slow degenerative destruction of the joint, affecting both the articular cartilage (which contains the cells and matrix that lubricate and act as a shock absorber for the joint) and the subchondral bone underlying the articular cartilage. OA can be considered a consequence of various etiological factors. For example, it may be due to abnormal biomechanical stress or genetic or acquired abnormalities of articular cartilage or bone. Current treatments for OA include analgesia with oral NSAIDs or selective cyclooxygenase 2 (COX-2) inhibitors, intra-articular (IA) injection with agents such as corticosteroids and hyaluronan, and surgical approaches.

Damage to the joint, such as acute trauma to the joint, such as a torn meniscus or ligament, or intra-articular fracture, can also lead to arthritis, such as post-traumatic arthritis. Because articular cartilage has a limited ability to repair itself, even small, undetected damage can often worsen over time and lead to OA. Current treatments for joint injuries may include surgery and other invasive procedures to regenerate damaged joints, as well as treatments to reduce pain and inflammation.

Mesenchymal stem cells (MSCs) are present in adult articular cartilage and, once isolated, can be programmed in vitro to differentiate into chondrocytes and other mesenchymal cell lineages, and can also be used for cartilage regeneration. This process is regulated in part by growth factors (TGFe, BMP), serum conditions and cell-cell contact.

WO 2011/008773 describes peptide compositions and the use of these compositions for the treatment or prevention of arthritis and joint injury and for inducing differentiation of mesenchymal cells into chondrocytes. In addition, WO 2012/129562 describes small molecule compounds, compositions and the use of these compositions to relieve arthritis and joint injury and to induce differentiation of mesenchymal cells into chondrocytes.

Although surgical techniques and regenerative technologies have made some progress in cartilage repair, retardation of degeneration, and improved recovery of an injured joint, there is a continuing need for improved compositions and methods for effective cartilage regeneration, treatment of joint damage, and alleviation or prevention of OA.

Brief description of the invention

The present invention relates to compositions and methods for treating or preventing joint damage from joint injury and arthritis.

In one aspect, the invention relates to a compound of formula (2A) or (2G) or a pharmaceutically acceptable salt thereof o o

Where

R ^1a is hydroxyl;

R ² is phenyl substituted with 1-2 substituents independently selected from chlorine, fluorine, trifluoromethyl, trifluoromethoxy, cyano and halo-substituted phenyl;

R ³ is pyridyl, unsubstituted or substituted with 1-2 substituents independently selected from fluorine, trifluoromethyl, methyl and methoxy.

In another aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (2A) or (2G) or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers.

The compounds of this invention, alone or in combination with one or more therapeutically active agents, may be used to treat, ameliorate or prevent acute joint injury or injury such as arthritis (osteoarthritis, traumatic arthritis, systemic rheumatoid arthritis) or degenerative disc disease.

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Unless otherwise indicated, the term compounds of the present invention refers to compounds of formula (2A) or (2G) and their pharmaceutically acceptable salts.

Detailed description of the invention

The present invention provides novel compounds that stimulate the production of hyaline cartilage in injured joints.

In one aspect of the present invention, novel compounds and compositions are provided for cartilage repair. Also provided are compositions and methods for treating, preventing, or alleviating arthritis or joint injury by administering a compound or composition of this invention to a joint, cartilage tissue, or proximal cartilage tissue, or systemically.

Definitions

For purposes of interpretation of this specification, the following definitions will apply and, where appropriate, terms used in the singular will also include the plural and vice versa.

As used herein, the term _{C1_6} alkoxy means a radical of the formula -OR _a , where R _a is a _{C1_6} alkyl radical as generally defined above. Examples of _{C1_6} alkoxy groups include, without limitation, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy groups. The alkyl portion of the alkoxy group may be optionally substituted, and the substituents include those described for the alkyl group below.

As used herein, the term _{C1_6} alkyl means a straight or branched chain hydrocarbon radical consisting of only carbon and hydrogen atoms, free from unsaturations, containing from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond. The term _{C1_4} alkyl is to be construed accordingly. Examples of _C1-6 alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl). Representative substituents include, but are not limited to, halogen, hydroxyl, alkoxy, cyano, amino, acyl, aryl, arylalkyl, and cycloalkyl, or a heteroform of one of these groups, each of which may be substituted with substituents suitable for the particular group.

Aromatic, as used herein, refers to a moiety in which the constituent atoms form an unsaturated ring system, where all the atoms in the sp ² ring system are hybridized and the total number of π electrons is 4n+2. The aromatic ring may be such that the ring atoms are only carbon atoms or may include carbon atoms and atoms other than carbon (see Heteroaryl).

Aryl as used herein refers to a monocyclic or polycyclic aromatic ring population containing 6-14 ring atoms, where all ring atoms are carbon atoms. Typically, aryl is a 6-membered (ring atoms) monocyclic, 1012-membered bicyclic or 14-membered fused tricyclic aromatic ring system. 6-14 membered aryls include, but are not limited to, phenyl, biphenyl, naphthyl, azulenyl, and anthracenyl. Aryl may be unsubstituted or substituted with 1-5 (e.g., one, or two, or three) substituents independently selected from the group consisting of hydroxy, thiol, cyano, nitro, _{C1_4} alkyl, _{C1_4} alkenyl, _{C1_4} alkynyl , C1_ ₄ alkoxy groups, thio-C1_ ₄ alkyl, C1_ ₄ alkenyloxy groups, C1_ ₄ alkynyloxy, halo, C1_ ₄ alkylcarbonyl, carboxy groups, C1_ ₄ alkoxycarbonyl, amino groups, C1_ ₄ alkylamino groups, di-C1_ ₄ alkylamino groups, C1_ ₄ alkyl-aminocarbonyl ₄ alkylaminocarbonyl, C1_ ₄ alkylcarbonylamino groups, C1. ₄ alkylcarbonyl( _C1.4 alkyl)amino, sulfonyl, sulfamoyl, alkylsulfamoyl, _{C1_4} alkylaminosulfonyl, aryl, heteroaryl, cycloalkyl and heterocyclyl, wherein each of the above substituents may be further substituted with one or more substituents independently selected from halo, alkyl, hydroxy - or C1_ ₄ alkoxy groups. When aryl is present together with another radical such as arylalkyl, aryloxyalkyl, aryloxycarbonyl, aryloxycarbonylalkyl, then the aryl moiety shall have the same meaning as in the above definition of aryl. The term bicyclic or bicyclyl in this context refers to a cyclic assembly of two rings, where the two rings are fused together, linked by a single bond, or linked by two bridging atoms. The rings may be carbocyclyl, heterocyclyl, or a mixture thereof.

An internally bridged ring in this context means a polycyclic ring system where the ring atoms that are common to the two rings are not directly bonded to each other. One or more rings of the ring system may also contain heteroatoms as ring atoms. Non-exclusive examples of bridged rings include norbornanyl, oxabicyclo[2.2.1]heptanyl, azabicyclo[2.2.1]heptanyl, adamantanyl, and the like.

The cyano group in the context of this description refers to the radical -CN.

The term EC ₅₀ in this context means the molar concentration of the modulator, which provides 50% efficiency.

The term IC ₅₀ in this context means the molar concentration of the inhibitor or modulator, which provides 50%efficiency.

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The term fused ring in this context refers to a collection of many rings, where the rings included in the collection of rings are connected so that the atoms of the ring, which are common to two rings, are directly connected to each other. Condensed ring sets can be saturated, partially saturated, aromatic, carbocyclic, heterocyclic, and the like. Non-limiting examples of conventional fused rings include decalin, naphthalene, anthracene, phenanthrene, indole, benzofuran, purine, quinoline, and the like.

The term halo or halogen in this context refers to fluorine, chlorine, bromine and iodine.

The term halogenated C _1-6 alkyl as used herein means a C^ alkyl radical as defined above which is substituted by one or more halogen radicals as defined above. Examples of halogenated C _1-6 alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4, 4-trifluorobutan-2-yl.

Heteroaryl in this context refers to a 5- or 6-membered aromatic monocyclic ring radical that contains 1, 2, 3 or 4 heteroatoms, each selected from nitrogen, oxygen and sulfur. The heteroaryl radical may be attached at a carbon atom or a heteroatom. Examples of heteroaryl include, but are not limited to, furyl, pyrrolyl, thienyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazinyl, pyridazinyl, pyrimidyl, or pyridyl. Heteroaryl may be unsubstituted or substituted with one or more substituents independently selected from hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C _1-4 alkyl, C _1-4 alkenyl, C _1-4 alkynyl, C _{1- 4} alkoxy groups, thioC _1-4 alkyl, C1. ₄ alkenyloxy groups, C1. ₄ alkynyloxy groups, halogen, C _1-4 alkylcarbonyl, carboxyl, C _1-4 alkoxycarbonyl, amino groups, C ^ alkylamino groups, di-C ₁ . ₄ alkylamino groups, C _1-4 alkylaminocarbonyl, di-C ^ alkylaminocarbonyl, C _1-4 alkylcarbonylamino groups, C ₁ _ ₄ alkylcarbonyl (C ₁ _ ₄ alkyl) amino groups, sulfonyl, sulfamoyl, alkylsulfamoyl, C _1-4 alkylaminosulfonyl, where each of the aforementioned hydrocarbon groups (eg alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted with one or more residues independently selected in each occurrence from halogen, hydroxyl or C^alkoxy. When heteroaryl is present together with another radical such as heteroaryloxy, heteroaryloxyalkyl, heteroaryloxycarbonyl, then the heteroaryl moiety shall have the same meaning as in the above definition of heteroaryl.

The term heteroatom in this context refers to an atom that is not a carbon atom. Specific examples of heteroatoms include, but are not limited to, nitrogen, oxygen, and sulfur.

Heterocyclyl or heterocyclic as used herein refers to a stable 5- or 6-membered non-aromatic monocyclic ring radical that contains 1, 2 or 3 heteroatoms each selected from nitrogen, oxygen and sulfur. The heterocyclyl radical may be attached at a carbon atom or a heteroatom. Examples of heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl. The heterocyclyl may be unsubstituted or substituted with 1-5 substituents (e.g., one or two or three) each independently selected from hydroxyl, thiol, cyano, nitro, oxo, alkylimino, C _1-4 alkyl, C _1-4 alkenyl, C _1-4 alkynyl, C _{1-4 alkoxy} , thioC _1-4 alkyl, C _1-4 alkenyloxy, C _1-4 alkynyloxy, halogen, C _1-4 alkylcarbonyl, carboxyl, C _1-4 alkoxycarbonyl , amino groups, C _1-4 alkylamino groups, di-C ₁ . ₄ alkylamino groups, C _1-4 alkylaminocarbonyl, di-C ₁ _ ₄ alkylaminocarbonyl, C _1-4 alkylcarbonylamino groups, C ₁ .4αlkulkαrbonyl (C ₁ .4alkyl) αmonogroups, sulfonyl, sulfamoyl, alkylsulfamoyl, C _1-4 alkylaminosulfonyl, where each of the aforementioned hydrocarbon groups (eg alkyl, alkenyl, alkynyl, alkoxy residues) may be further substituted with one or more residues independently selected in each occurrence from halogen, hydroxyl or C^alkoxy.

Hydroxy, hydroxy or hydroxy as used herein refers to the -OH radical. Protected derivatives in this context refer to derivatives of inhibitors in which the reactive site or sites are blocked by protective groups. Protected derivatives are used in the preparation of inhibitors or may themselves be active inhibitors. Examples of a protected group include, but are not limited to, acetyl, tetrahydropyran, methoxymethyl ether, β-methoxyethoxymethyl ether, p-methoxybenzyl, methylthiomethyl ether, pivaloyl, silyl ether, carbobenzyloxy, benzyl, t-butoxycarbonyl, p-methoxyphenyl, 9- fluorenylmethyloxycarbonyl, acetals, ketals, acylals, dithianes, methyl esters, benzyl esters, tert-butyl esters and silyl esters. A complete list of suitable protecting groups can be found in T.W. Greene, Protecting Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, Inc. 1999.

The terms unsubstituted or substituted or optionally substituted in this context means a substituent associated with the available valence of the specified group or radical. The term unsubstituted in this context indicates that the specified group or radical does not contain additional substituents that are not hydrogen. The term is substituted or optionally

- 3 040531 placed in this context indicates that at least one of the available hydrogen atoms of the named group or radical has been (or may be) replaced by a non-hydrogen substituent. Unless otherwise indicated, examples of substituents may include, but are not limited to, halogen, nitro, cyano, thio, oxy, hydroxy, carbonyloxy, C _1-6 alkoxy, 6-10 membered aryloxy, 5-10 -membered heteroaryloxy, carbonyl, oxycarbonyl, aminocarbonyl, amino, C _1-6 alkylamino, sulfonamido, imino, sulfonyl, sulfinyl, C _1-6 alkyl, C _1-6 haloalkyl, hydroxy- _{C1_6} alkyl, carbonyl- _{C1_6} alkyl, thiocabonyl-C ₁ _ ₁₀ alkyl, sulfonyl-C1_ ₆ alkyl, sulfinyl-C1_ ₆ alkyl, C1_ ₁₀ azaalkyl, imino-C1_ ₆ alkyl, 3-12-membered cycloalkyl-C1_ ₆ alkyl, 4-15-membered heterocycloalkyl-C _{1 -6} alkyl, 6-10 membered aryl-C _1-6 alkyl, 5-10 membered heteroaryl-C _1-6 alkyl, 10-12 membered bicycloaryl-C _1-6 alkyl, 9-12 membered heterobicycloaryl-C _{1 -6} alkyl, 3-12 membered cycloalkyl, 4-12 membered heterocyclyl, 9-12 membered bicycloalkyl, 3-12 membered heterobicycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl,

Any definition in this document may be used in conjunction with any other definition to describe a group with a complex structure. Traditionally, the last element of any such definition is the one attached to the original fragment. For example, a complex alkoxyalkyl group is an alkoxy group attached to the parent molecule through an alkyl group.

As used herein, the term chondrocytes refers to differentiated cartilage cells. Chondrocytes produce and maintain the cartilage matrix, which is made up of collagen and proteoglycans. Chondrocytes are formed by differentiation of chondrogenic progenitor cells (CPCs). Differentiation is the process by which a specialized cell type is formed from less specialized cell types, such as the formation of a chondrocyte from a chondrogenic progenitor cell (CPC).

As used herein, the term chondrocyte differentiation agent refers to an agent that induces the differentiation of chondrogenic cells into a mature chondrocyte, which then synthesizes cartilage extracellular matrix (ECM).

As used herein, the term subject refers to primates (eg, male or female humans), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In other embodiments, the subject is a human.

As used herein, the term inhibit, inhibition, or inhibitory refers to the reduction or amelioration of a given condition, symptom, or disorder, or disease, or a significant reduction in the original activity of a biological activity or process.

As used herein, the term treating, treating, or treating any disease or disorder refers to alleviating or lessening the severity of the disease or disorder (ie, slowing or stopping the progression of the disease or at least one of its clinical symptoms); or alleviate or decrease at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be apparent to the patient.

As used herein, the term prevent, preventative, or prevention of any disease or disorder refers to the prophylactic treatment of a disease or disorder, or to slow the onset or progression of a disease or disorder.

In the context of this invention, a subject is in need of treatment if, as a result of such treatment, such a subject will benefit from a biological, medical point of view or improve his quality of life.

As used herein, the term "therapeutically effective amount of a compound of the present invention" refers to an amount of a compound of the present invention that will elicit a biological or medical response in a subject, such as reducing or inhibiting enzyme or protein activity, or lessening the severity of symptoms, alleviating a condition, slowing or arresting the progression of a disease, or prevent disease, etc. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount of a compound of the present invention that, when administered to a subject, is effective in (1) at least partially alleviating, suppressing, preventing and/or reducing the severity of joint injury due to joint injury and arthritis. In another non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the present invention which, when administered to a cell or tissue or non-cellular biological material or medium, is effective in promoting chondrogenesis.

The terms treat, treat, treat plus ameliorate, and ameliorate, as used herein, refer to any indication of success in treating or ameliorating an injury, pathology, condition, or symptom (eg, pain), including any objective or subjective parameters such as pain relief; remission; reducing symptoms or making the symptom, injury, pathology, or condition more tolerable to the patient; reduction in the frequency or duration of a symptom or condition; or, in some situations, preventing a symptom or condition from occurring. Treatment or relief of symptoms may be based on any objective or subjective parameter; including, for example, the result of a medical examination.

As used herein, the term insertion refers to insertion into a particular joint.

As used herein, the term pharmaceutical composition refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, together with at least one pharmaceutically acceptable carrier in a form suitable for oral or parenteral administration.

As used herein, the term pharmaceutically acceptable carrier means a substance suitable for the preparation of or use in a pharmaceutical composition and includes, for example, suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonic agents, buffer agents, emulsifiers, absorption delay agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, coloring agents, and combinations thereof, as will be known to those skilled in the art (see, e.g., , Remington The Science and Practice of Pharmacy, ^22nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070).

As used herein, terms in the singular form and similar terms used in the context of the present invention (in particular, in the context of the claims) should be construed as covering both the singular form and the plural form, unless otherwise indicated in this document. or there is no clear contradiction with the context.

Description of Preferred Embodiments

The present invention relates to compositions and methods for treating or preventing joint damage from joint injury and arthritis.

This document describes various numbered embodiments of the present invention. Features described in each embodiment can be combined with other features described to provide additional embodiments of the present invention.

In one aspect, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, as described above.

Embodiment 1.

A compound of formula (2A) or (2G) or a pharmaceutically acceptable salt o o

Where

R ^1a is hydroxyl;

R ² is phenyl substituted with 1-2 substituents independently selected from chlorine, fluorine, trifluoromethyl, trifluoromethoxy, cyano and halogenated phenyl;

R ³ is pyridyl, unsubstituted or substituted with 1-2 substituents independently selected from fluorine, trifluoromethyl, methyl and methoxy.

Embodiment 2.

The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from (1R,2R,3S, 4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methyl 4-y!)-7oxabicyclo[2.2.1]heptane-2-carboxamide, (lS,2S,3R,4S,5R)-N-(3,4-dichloroφenyl)-5-hydroxy-3-(2-methylpyridine) -4-yl)-7oxabicyclo[2.2.1]heptane-2-carboxamide, (1Sh2Sh38Shch58)-M-(3,4-dichlorophenyl)-3-(2-fluoropyridine-4-y1)-5-hydroxy-7oxabicyclo[ 2.2.1 ]heptane-2-carboxamide, (lS,2S,3R,4S,5R)-N-(3,4-dichloroφenyl)-3-(2-φτoppyridine-4-yl)-5-hydroκci-7oxabicyclo[ 2.2.1 ]heptan-2-carboxamide, (lR,2R,3S,4R,5S)-N-(3,4-dichloroφenyl)-5-hydroκci-3-(2-(τpiφtormethyl)pyridine-4y 1)- 7-oxabicyclo[2.2.1] heptane-2-carboxamide, (lS,2S,3R,4S,5R)-N-(3,4-dichloroφenyl)-5-hydroκci-3-(2-(τpiφtormethyl)pyridine- 4y 1 )-7-oxabicyclo[2.2.1]heptane-2-carboxamide.

Embodiment 3. Pharmaceutical composition for the treatment, amelioration or prevention of arthritis or joint damage in a mammal; or for cartilage repair, comprising a compound according to any of the above embodiments 1 or 2, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.

Depending on the choice of starting materials and procedures, the compounds can be in the form of one of the possible stereoisomers or mixtures thereof, e.g. pure optical isomers, or mixtures of stereoisomers such as racemates and mixtures of diastereoisomers, depending on the number of asymmetric atoms. carbon. The present invention is intended to cover all such possible stereoisomers, including racemic mixtures, mixtures of diastereoisomers, and optically pure forms. Optically active (R)- and (S)-stereoisomers can be obtained using chiral synthons or chiral reagents or isolated using conventional techniques. If the compound contains a double bond, the substituent may be in the E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may be in the cis or trans configuration. It is also intended to include all tautomeric forms.

Any asymmetric atom (eg carbon or the like) of the compound(s) of the present invention may be in racemic or enantiomerically enriched form, eg in the (R)-, (S)- or (R,S)-configuration. In certain embodiments, each asymmetric atom is characterized by at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least at least 95% enantiomeric excess or at least 99% enantiomeric excess in the (R)- or ^-configuration. Substituents on atoms with unsaturated double bonds may, if possible, be in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein, a compound of the present invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers, or mixtures thereof, e.g., substantially pure geometric (cis or trans) stereoisomers, diastereoisomers, optical isomers (antipodes), racemates or mixtures thereof.

Any resulting mixtures of stereoisomers may be separated, on the basis of the physicochemical differences of the constituents, into pure or substantially pure geometric or optical isomers, diastereoisomers, racemates, for example by chromatography and/or fractional crystallization.

Any resulting racemates of end products or intermediates may be resolved into optical antipodes by known methods, for example by separating their diastereomeric salts prepared with an optically active acid or base and isolating the optically active acidic or basic compound. In particular, the basic fragment can thus be used to separate the compounds of the present invention into their optical antipodes, for example by fractional crystallization of a salt formed with an optically active acid, for example tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O '-p-toluotartaric acid, mandelic acid, malic acid or camphor-10sulfonic acid. Racemic products can also be separated by chiral chromatography, for example high pressure liquid chromatography (HPLC) using a chiral adsorbent.

Unless otherwise indicated, a compound represented herein as a single stereoisomer includes an enantiomeric mixture (eg, an enantiomer of a depicted compound and mixtures of enantiomers). In addition, when a compound is described as a single regioisomer, it is understood that a sample of the compound may still contain small amounts of the other regioisomer and may also exist as an enantiomeric mixture. Typically, when a compound is described as a single regioisomer or enantiomer, said structure represents at least 90% by weight of the total weight of the depicted compound plus its isomers; preferably, the specified isomer, diastereomer or enantiomer is at least 95 wt.% of the total mass, including other isomers.

Any formula given herein also implies the presence of unlabeled forms as well as isotopically labeled forms of the compounds. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Isotopes that can be included in the compounds of the present invention include, for example, isotopes of hydrogen.

In addition, the incorporation of certain isotopes, particularly deuterium (i.e., ² H or D), may confer certain therapeutic benefits due to higher metabolic resistance, such as increased in vivo half-life, or reduced dosage required, or improved therapeutic index. or portability. It is understood that deuterium in this context is considered as a substituent in the compound of formula (I). The deuterium concentration can be determined from the isotopic enrichment factor. As used herein, the term isotopic enrichment factor means the ratio of the abundance of an isotope to the natural abundance of said isotope. When a substituent in a compound of the present invention is listed as deuterium, that compound has an isotopic enrichment factor for ka

- 6 040531 of each designated deuterium atom, which is at least 3500 (introduction of 52.5% deuterium for each designated deuterium atom), at least 4000 (introduction of 60% deuterium), at least 4500 (introduction of 67.5% deuterium) , at least 5000 (introduction of 75% deuterium), at least 5500 (introduction of 82.5% deuterium), at least 6000 (introduction of 90% deuterium), at least 6333.3 (introduction of 95% deuterium), at at least 6466.7 (introduction of 97% deuterium), at least 6600 (introduction of 99% deuterium), or at least 6633.3 (introduction of 99.5% deuterium). It should be understood that the term isotopic enrichment factor can be used with respect to any isotope in the same manner as described for deuterium.

Other examples of isotopes that can be included in the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as ³ H, ⁿ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ F ³¹ P , ³² P, ³⁵ S, ³⁶ Cl, ¹²³ I, ¹²⁴ I, ¹²⁵ I, respectively. However, it should be understood that the present invention includes compounds in which one or more of any of the above isotopes is included, including, for example, radioactive isotopes such as ³ H and ¹⁴ C, or compounds in which non-radioactive isotopes are present, such as ² H and ¹³ C. Such isotopically labeled compounds are useful in metabolic studies (using ¹⁴ C), studies of reaction kinetic parameters (for example, using ² H or ³ H), detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including analyzes of the distribution of the drug or substrate in tissues, or in radiation therapy of patients. In particular, ¹⁸ F or a labeled compound may be particularly useful for PET or SPECT studies. Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art, or by methods analogous to those described in the accompanying examples and preparation methods, using an appropriate isotopically labeled reagent instead of an unlabeled reagent, previously used.

The compounds of the present invention are obtained either in free form or as a salt thereof. As used herein, the terms salt or salts mean an acid addition or base addition salt of a compound of the present invention. Salts include, in particular, pharmaceutically acceptable salts. The term pharmaceutically acceptable salts means salts which retain the biological efficacy and properties of the compounds of the present invention and which are generally not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acidic and/or basic salts due to the presence of amino and/or carboxyl groups or the like.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonium and metal salts from Groups I-XII of the Periodic Table of the Elements. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include the ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

In another aspect, the present invention provides compounds of the present invention in the form of a salt, which is acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, caprate, chloride/hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelic acid salt, mesylate, methyl sulfate, mucic acid salt, naphthoic acid salt, napsilate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/hydrophosphate/dihydrogen phosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate triphenate, trifluoroacetate, or xinafoate.

Methods for preparing the compounds of this invention

All of the methods described herein may be performed in any suitable order, unless otherwise noted or clearly conflicting with the context.

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Compounds of formula (2A) and (2G) can be prepared as generally shown in Schemes 1-7, wherein R ¹ encompasses R ^1a groups that are attached to ring carbons at positions 5 or 6; Ar encompasses R ³ heteroaryl groups; and R ^1a , R ² and R ³ are as defined above. In the schemes below, the formula, represented as formula (1A)-(1L)* and formula (2A)-(2L)*, includes a mixture of the formulas shown in the figure and their respective enantiomers and regioisomers.

Scheme 1

Formulas (1AH1L)* Formulas (2A)-(21_)*

Intermediate GS1b can be prepared from commercially available GS1a methyl propiolate by bromination and Diels-Alder reaction with furan. Intermediate GS1c can be prepared by functionalization of GSb1 using reactions including but not limited to cyclopropanation and hydroboration/oxidation followed by further functionalization including methylation, fluorination, oxidation and reduction. Intermediates GS1d and GS1e can be obtained from GS1c by debromination and conjugated addition. Subsequent amide bond formation can give compounds of formula (1A)-(1L)* and formula (2A)-(2L)*. Alternatively, amide bond formation and debromination of GS1c can give GS1f, which after conjugated addition can provide compounds of formula (1A)-(1L)* and formula (2A)-(2L)*.

Scheme 2

In Scheme 2, bromination of methyl propiolate 1a using N-bromosuccinimide or a similar brominating reagent in the presence of a silver catalyst such as silver nitrate gives intermediate 1b. Cyclic Diels-Alder addition of 1b in excess of fur on low heating (about 80°C) gives intermediate 1c. Cyclopropanation of 1c using diethylzinc and diiodomethane gives intermediate 1d. Hydroboration of 1c using a borane-tetrahydrofuran complex followed by oxidation with hydrogen peroxide gave intermediate 1e as a mixture of alcohol regioisomers. Methylation of 1e with silver oxide and iodomethane gives 1f as a mixture of methoxyregioisomers. Fluorination of 1e using DAST gave 1g as a mixture of fluorinated regioisomers. Oxidation

1e using DMP gives 1h as a mixture of ketone regioisomers. Reduction of 1h with sodium borohydride gives 1i as a mixture of alcohol regioisomers. Fluorination of 1i using DAST results in 1j as a mixture of fluorinated regioisomers.

Scheme 3

Scheme 3 shows debromination of intermediate 1d-j using zinc and acetic acid to give 2a as a mixture of regioisomers. A conjugated 1,4 addition reaction involving 2a and an arylboronic acid or ester thereof on a rhodium catalyst in the presence of a base such as potassium carbonate and a ligand such as BINAP gives 2b and 2c as mixtures of regioisomers. Formation of an amide bond using 2b, trimethylaluminum and an amine or aniline gives compounds of formula (1A)-(1L)* as a mixture of regioisomers. Formation of an amide bond using 2c, trimethylaluminum and an amine or aniline gives compounds of formula (1A)-(1L)* as a mixture of regioisomers.

Scheme 4

Formulas (1AH1L)* Formulas (2AH2LJ*

According to scheme 4, the formation of an amide bond using 1d-j, trimethylaluminum and aniline leads to the formation of 3a as a mixture of regioisomers. Debromination of intermediate 3a using zinc and acetic acid gives 3b as a mixture of regioisomers. A conjugated 1,4-addition reaction involving 3b and an arylboronic acid or ester thereof on a rhodium catalyst in the presence of a base such as potassium carbonate and a ligand such as BINAP results in compounds of formula (1A)-(1L)* and formulas (2A)-(2L)* as mixtures

regioisomers. Scheme 5 ₂ XtalFluor-E _N ' ^R Et ₃ N-3HF n Step A

4a 4b

Scheme 5 shows the preparation of compounds 4b of formula I from 4a by fluorination using XtalFluor-E and triethylamine trihydrofluoride.

- 9 040531

Scheme 6

Scheme 6 shows the dihydroxylation of 1c using osmium tetroxide and N-methylmorpholine N-oxide to give 5 a. Protection of the diol at 5a using (dimethoxymethyl)benzene leads to 5b. Amide bond formation using 5b, trimethylaluminum and aniline gives 5c. Debromination of intermediate 5c using zinc and acetic acid gives 5d. A conjugated 1,4-addition reaction involving 5d and an arylboronic acid or ester thereof on a rhodium catalyst in the presence of a base such as potassium carbonate and a ligand such as BINAP results in 5e and 5f. Intermediates 5e and 5f are deprotected using boron trichloride to give 5 g and 5h, respectively.

Stage A

XtalFluor-E Et ₃ N-3HF

Scheme 7

Scheme 7 shows the fluorination of 6a using XtalFluor-E and triethylamine trihydrofluoride which gives 6b. Oxidation of 6a using DMF gives 6c. Reductive amination of 6c using an amine and sodium borohydride leads to 6d. Treatment of 6c with methylmagnesium bromide leads to the formation of 6e. Recovery of 6c using sodium borohydride gives 6f.

The present invention further includes any variant of the methods of the present invention; for example, where the intermediate product obtained at any stage is used as a starting material and the remaining stages are carried out; or where the starting materials are produced in situ under reaction conditions; or where the components of the reaction mixture are used in the form of their salts or optically pure substance. The compounds of the present invention and intermediates/products can also be converted into each other according to methods well known to those skilled in the art.

Pharmacology and applicability

The present invention provides a method of treating, ameliorating, or preventing joint damage in a mammal in need of such treatment, including administering to the mammal a therapeutically effective amount of a preparation of the invention, wherein the subject has joint damage or the subject suffers from arthritis or is at risk of such damage or arthritis. The invention also relates to a method of treating, ameliorating or preventing arthritis or joint injury in a human patient, comprising orally administering to the patient a composition containing an effective amount of a compound of the invention to treat, ameliorate or prevent arthritis or joint injury at the patient. In some embodiments, the patient suffers from arthritis or has suffered a joint injury. In some embodiments, the individual does not have arthritis or joint injury, but is at risk of developing them. In some embodiments, the arthritis is osteoarthritis, traumatic arthritis, or autoimmune arthritis.

The compounds of the present invention are also useful for inducing hyaline cartilage formation by chondrogenic progenitor cells. In some embodiments, the present invention relates to a method for preventing hypertrophy of chondrocyte progenitor cells of chondrocytes. In some embodiments, the present invention relates to a method of inducing differentiation of chondrogenic progenitor cells into mature chondrocytes, comprising contacting the chondrogenic progenitor cells with a sufficient amount of a compound of the invention, thereby inducing differentiation into mature chondrocytes producing hyaline cartilage extracellular matrix.

CPCs can differentiate into various cell types including, but not limited to, osteoblasts, hyaline chondrocytes, and hypertrophic chondrocytes. Differentiation is the process by which a specialized cell type is formed from less specialized cell types, such as the formation of a chondrocyte from a chondrogenic progenitor cell. In some embodiments, the method is performed in vitro. In some embodiments, the implementation of the method in application to a mammal is performed in vivo, while the mammal has progenitor cells.

Induction of chondrocyte differentiation from a chondrogenic progenitor cell can be accomplished using any suitable amount of a compound of the present invention. In some embodiments, the content of a compound of the present invention may be from about 0.1 to about 10,000 mg, such as from 1.0 to 1000 mg, such as from 10 to 500 mg, in accordance with the specific use and potency of the active ingredient. In some embodiments, the compounds of the present invention may be administered orally once a day at a dose of 1 to about 300 mg/kg. The duration of treatment can vary from a week or less to permanent treatment for severe osteoarthritis.

It is contemplated that the compounds, compositions, and methods of the present invention may be used to treat, alleviate, or prevent any type of damage to articular cartilage (e.g., damage or injury to a joint), including, for example, damage resulting from injury or rupture of a tendon or ligament. In some embodiments, compounds or compositions of this invention are administered to prevent or alleviate arthritis or joint damage, for example, when there is a genetic or family history of arthritis or joint damage or joint injury, or before or during joint surgery. In some embodiments, the compositions and methods are used to treat joint injury. In certain embodiments, the joint injury is a traumatic joint injury. In other embodiments, the damage to the joint is damage associated with age or lack of activity. In yet other embodiments, the joint injury is an injury associated with an autoimmune disorder. In other embodiments, the joint injury is injury associated with a metabolic disorder (eg, diabetes). In some embodiments of this invention, the compounds, compositions and methods of the present invention can be used to treat osteoarthritis, alleviate or prevent osteoarthritis. In some embodiments, the compounds, compositions and methods are used to reduce or prevent arthritis in a subject who may have arthritis or is at risk of developing arthritis. In some embodiments, the compounds, compositions and methods are used to reduce or prevent joint injury in a subject who may have a joint injury or is at risk of developing a joint injury.

In some embodiments, based on the compounds, compositions and methods of the present invention, there is provided a method for stimulating chondrocyte proliferation and/or cartilage production in cartilage tissues that have been damaged, for example, due to traumatic injury or chondropathy. In certain embodiments, the compounds, compositions and methods of the present invention are useful in the treatment of cartilage damage in joints, e.g., articular surfaces, e.g., spine, shoulder, elbow, wrist, knuckles, hip, knee, ankle, and foot joints. Examples of diseases or disorders that may benefit from treatment include osteoarthritis, rheumatoid arthritis, other autoimmune diseases, or osteochondritis dissecans. In addition, cartilage damage or destruction occurs as a result of certain genetic or metabolic disorders, cartilage pathology is often observed in humans with various forms of dwarfism, and/or cartilage damage or destruction is often the result of reconstructive surgery, so the compounds, compositions and methods will be applicable as therapy for such patients, whether used alone or in combination with other approaches.

- 11 040531

Pharmaceutical compositions, dosage and administration

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In an additional embodiment, the composition contains at least two such pharmaceutically acceptable carriers as described herein. The pharmaceutical composition may be formulated for specific routes of administration such as oral administration, parenteral administration (eg, by injection, infusion, transdermal or topical administration), and rectal administration. Topical administration may also refer to inhalation or intranasal administration. The pharmaceutical compositions of the present invention can be formulated in solid form (including, without limitation, capsules, tablets, pills, granules, powders, or suppositories) or liquid form (including, but not limited to, solutions, suspensions, or emulsions). Tablets may be either coated or enteric coated according to methods known in the art. Typically, pharmaceutical compositions are tablets or gelatin capsules containing the active ingredient together with one or more of:

a) diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and/or glycine;

b) lubricants, for example silica, talc, stearic acid, its magnesium or calcium salt and/or polyethylene glycol; also in the case of tablets

c) binders, for example magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone; if necessary

d) disintegrants, for example types of starch, agar, alginic acid or its sodium salt or effervescent mixtures; And

e) absorbents, colors, flavors and sweeteners.

Typically, the compounds of the present invention are administered in therapeutically effective amounts, as described above, in any of the usual and acceptable regimens known in the art, either alone or in combination with one or more therapeutic agents. In some embodiments, the compounds and compositions of the present invention are administered by direct injection into joint synovial fluid, systemic administration (oral or intravenous), or directly into a cartilage defect, alone or in combination with a suitable carrier for sustained release of the compound. In some embodiments, the compounds or compositions are administered in a biocompatible matrix or scaffold.

The compounds, compositions and methods of the present invention may also be used in conjunction with a surgical procedure on an affected joint. Administration of a compound or compounds of this invention can be done before, during, or in combination with and/or after a surgical procedure. For example, the compounds, compositions and methods of this invention can be used to increase chondrocyte populations in culture for autologous or allogeneic chondrocyte implantation. Chondrocytes can optionally be implanted while undergoing treatment with the compounds and compositions of the present invention. In such procedures, for example, chondrocytes can be harvested arthroscopically from an unaffected, lightly loaded area of the injured joint and cultured in vitro, optionally in the presence of compounds and compositions of the present invention and/or other growth factors, to increase cell numbers prior to transplantation. The propagated cultures are then optionally mixed with the compounds and compositions of the present invention and/or placed in the joint space or directly in the area of the defect. In certain embodiments, propagated cultures (optionally with compounds of the present invention) are placed in the joint space suspended in a matrix or membrane.

In other embodiments, the compounds and compositions of the present invention may be used in combination with one or more periosteal or perichondria grafts that contain cartilage-forming cells and/or help hold the transplanted chondrocytes or chondrocyte progenitor cells in their intended location. In some embodiments, compounds and compositions of the present invention are used to repair cartilage damage (e.g., articular cartilage damage) in combination with other procedures, including, but not limited to, joint cavity lavage, bone marrow stimulation, abrasion arthroplasty, subchondral bone reaming, or proximal microfractures. subchondral bone. Optionally, following administration of the compounds and compositions of the present invention and cartilage growth, additional surgical treatment may be beneficial to properly contour the newly formed cartilage surface(s).

The compounds of the present invention can be administered either simultaneously with one or more other therapeutic agents, or before or after their administration. The compound of the present invention can be administered separately from other agents by the same or different route of administration, or together with them in the same pharmaceutical composition. A therapeutic agent is, for example, a chemical compound, peptide, antibody, antibody fragment, or nucleic acid that is therapeutically active or enhances therapeutic activity when administered to a patient in combination with a compound of the present invention.

The pharmaceutical composition or combination formulation of the present invention may be in a single dosage of about 1-1000 mg of the active ingredient(s) for a subject weighing about 50-70 kg, or about 1-500 mg, or about 1-250 mg, or about 1-150 mg, or about 0.5-100 mg, or about 1-50 mg of the active ingredients. A therapeutically effective dose of a compound, pharmaceutical composition, or combinations thereof will depend upon the type of subject, body weight, age, and individual condition, disorder, or disease being treated, or their severity. A skilled physician, clinician or veterinarian can easily determine the effective amount of each of the active ingredients necessary to prevent, treat or inhibit the progression of the disorder or disease.

The above dosage parameters are evident in in vitro and in vivo tests using predominantly mammals, eg mice, rats, dogs, non-human apes or isolated organs, tissues and preparations thereof. The compounds of the present invention can be administered in vitro as solutions, eg aqueous solutions, and in vivo either enterally or parenterally, preferably intravenously, eg as a suspension or aqueous solution. The in vitro dosage may be in the range of molar concentrations from about 10 ^-3 to about 10 ^-9 . A therapeutically effective amount in vivo, depending on the route of administration, may be in the range of about 0.1-500 mg/kg, or about 1-100 mg/kg.

Examples

Temperature values are given in degrees Celsius. The structure of end products, intermediates and starting materials is confirmed using standard analytical methods, eg microanalysis and spectroscopic characterization, eg MS, IR, NMR. The abbreviations used are standard abbreviations in the art.

All starting materials, building blocks, reagents, acids, bases, dehydrogenators, solvents and catalysts used in the synthesis of the compounds of the present invention are either commercially available or can be obtained by organic synthetic methods known to one of ordinary skill in the art. (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21). Unless otherwise noted, raw materials are generally commercially available from companies such as, but not limited to, TCI Fine Chemical (Japan), Aurora Fine Chemicals LLC (San Diego, CA), FCH Group (Ukraine), Aldrich Chemicals Co. . (Milwaukee, WI), Acros Organics (Fairlon, NJ), Maybridge Chemical Company, Ltd. (Cornwall, England), Matrix Scientific (USA), Enamine Ltd (Ukraine), Combi-Blocks, Inc. (San Diego, California), Oakwood Products, Inc. (USA), Apollo Scientific, Ltd. (Great Britain).

The Examples section of this document merely explains the present invention and does not limit the scope of the present invention as claimed in any form. Also, the compounds of the present invention can be obtained by organic synthesis methods known to the person of ordinary skill in the art, as shown in the following examples. Where necessary, conventional protecting groups are used to protect reactive functional groups in accordance with standard practice, for example see T. W. Greene and PGM. Wuts in Protecting Groups in Organic Synthesis, John Wiley and Sons, 1991.

Abbreviations

The abbreviations used in this document are defined as follows: 1x means once, 2x means twice, 3x means thrice, °C means degrees Celsius, aq. means aqueous solution, FCC means flash column chromatography, eq. means equivalent or equivalents, g means grams or grams, mg means milligram or milligrams, l means liter or liters, ml means milliliter or milliliters, μl means microliter or microliters, n.a. means normal, M means molar, µM means micromolar, nM means nanomolar, mole means mole or moles, mmol means millimoles or millimoles, min means minute or minutes, h means hour or hours, k.t. means room temperature, ON means during the night, atm. means atmosphere, psi. inch means pounds per square inch, conc. means concentrated, aq. means aqueous solution, sat. or sat. means saturated, MM means molecular weight, mw or μwave means microwave, m.p. means melting point, weight. means weight, MS or Mass Spec means mass spectrometry, ESI means electrospray ionization mass spectrometry, BP means high resolution, HRMS means high resolution mass spectrometry, LCMS or LCMS means liquid chromatography with mass spectrometry, HPLC or HPLC means high resolution liquid chromatography pressure, RP HPLC means reverse phase HPLC, TLC means thin layer chromatography, NMR means nuclear magnetic resonance spectroscopy, nOe means nuclear Overhauser effect spectroscopy, 1H means proton, δ means

- 13 040531 delta, s means singlet, d means doublet, t means triplet, q means quartet, m means multiplet, br means broad, Hz means hertz, ee means enantiomeric excess, and α, β, R, r, S, s , E, and Z are stereochemical designations known to the person skilled in the art.

The following abbreviations, as used in this document below, have their respective meanings:

AcOH acetic acid app observable

ATP adenosine 5'-triphosphate

BINAP racemic 2,2'-bis(diphenylphosphino)-1,G-binaphthyl

BOC tertiary butylcarboxyl

B SA bovine serum albumin cPhor cyclopropyl

DAST diethylaminosulfur trifluoride dd doublet of doublets

DCE dichloroethane

DXM dichloromethane

DIEA diethylisopropylamine

DME 1,4-dimethoxyethane

DMF N, N-dimethylformamide

DMP periodinan Dessa-Martin

DMSO dimethyl sulfoxide

EDTA ethyl ide and aminetetraacetic acid

ESI sputter ionization in an electric field

Et ₃ N-3HF triethylamine trihydrofluoride

EtOAc ethyl acetate

HC1 hydrochloric acid

LiHMDS lithium bis(trimethylsilyl)amide

MeOH methanol

MHz megahertz

MTBE methyl tert-butyl ether mass/charge mass-charge ratio

NBS N-bromosuccinimide

NMO X-methylmorpholine-X-oxide

PE petroleum ether

ppm pTsOH p-toluenesulfonic acid gasracemic

Rt retention time

TFA trifluoroacetic acid

THF tetrahydrofuran

Tris-HCI aminotris(hydroxymethyl)methane hydrochloride

XtalFluor-E (diethylamino) difluorosulfonium tetrafluoroborate

Equipment

LCMS methods used to characterize examples

Analytical LC/MS was performed on Agilent systems using ChemStation software.

The system consists of an Agilent G1312 two-component mixture pump, an Agilent G1367 automatic well plate dispenser, an Agilent G1316 thermostated column compartment, an Agilent G1315 diode array detector, an Agilent 6140/6150 mass spectrometer, a SOFTA evaporative light scattering detector,

The method uses the following typical conditions:

Flow rate: 0.9 ml/min,

Column: column Waters Acquity HSS T3 C18, 1.8 µm, 2.1x50 mm, mobile phase A: water + 0.05% TFA,

- 14 040531 mobile phase B: acetonitrile + 0.035% TFA, run time: 2.25 min.

Method A: Unless otherwise noted, in-system analysis was performed with a gradient from 10% B to 90% B over

1.35 minutes. Washing was carried out for 0.6 min at 100% B after using the gradient. In the remaining time from the specified duration, the system returns to the initial conditions.

Method B: The initial gradient in the system is 20% B, not 10% B.

Method C: The initial gradient in the system is 30% B, not 10% B.

Method D: The initial gradient in the system is 40% B, not 10% B.

The typical scanning range of the mass spectrometer was 100-1000 amu.

NMR methods

Proton spectra were recorded on a Bruker AVANCE II 400 MHz with a 5 mm QNP cryoprobe or a Bruker AVANCE III 500 MHz with a 5 mm QNP probe, unless otherwise noted. Chemical shifts are given in ppm. relative to dimethyl sulfoxide (δ 2.50), chloroform (δ 7.26), methanol (δ 3.34), dichloromethane (5.32), acetone (δ 2.05) or acetonitrile (δ 1.94). A small amount of dry sample (2-5 mg) was dissolved in a suitable deuterated solvent (0.6 ml).

ISCO methods used to clean up examples

ISCO flash chromatography was performed on a Teledyne COMBIFLASH® system with a RediSep® column preloaded with silica.

Preparative HPLC methods used to purify examples

Preparative HPLC was performed on Waters Autoprep systems using MassLynx and FractionLynx software.

The system consists of a Waters 2767 automatic fractionator/collector, a Waters 2525 two-component pump, and a Waters 515 make-up pump.

Waters 2487 UV detector operating at two wavelengths of a Waters ZQ mass spectrometer

The method uses the following typical conditions:

Flow rate: 100 ml/min.

Column: Waters Atlantis T3 C18 column, 10 µm, 19x50 mm injection volume: 0-1000 µl mobile phase A: water + 0.05% TFA mobile phase B: acetonitrile + 0.035% TFA run time: 4.25 min

The system was analyzed with a gradient from X% B to Y% B, applicable for a particular example, for 3 minutes after a 0.25-minute soak at baseline. Washing was carried out for 0.5 min at 100% B after using the gradient. In the remaining time from the specified duration, the system returns to the initial conditions. Fraction collection was triggered by mass detection using FractionLynx software.

Chiral preparative HPLC methods used to purify examples

SFC-based chiral screening was performed on a Thar Instruments Prep Investigator system connected to a Waters ZQ mass spectrometer. The Thar Prep Investigator system consists of a Leap HTC PAL automatic dispenser, a Thar Fluid feed module (0 to 10 mL/min), a 10 position Thar SFC column oven,

Waters 2996 PDA, Jasco CD-2095 chiral detector, Thar automatic back pressure regulator.

All Thar components are part of the SuperPure Discovery Series. The system was provided with a flow rate of 2 ml/min (4 ml/min for a column of WhelkO-1) and maintained a temperature of 30°C. The back pressure of the system was set to 125 bar. Each sample was screened through six consecutive 3 µm columns:

µm 4.6x50 mm ChiralPak AD µm 4.6x50 mm ChiralPak OD µm 4.6x50 mm ChiralPak OJ µm 4.6x250 mm Whelk O-1 µm 4.6x50 mm ChiralPak AS µm 4.6x50 mm Lux-Cellulose-2

The system assay was run with a gradient from 5% co-solvent to 50% co-solvent over 5 min followed by a 0.5 min hold at 50% co-solvent, changed back to 5% co-solvent and held for 0.25 min at baseline. Between the use of each

- 15 040531 gradient used the technique of 4-minute equilibration, while applying a stream with 5% co-solvent through the next column for screening. Typical solvents used for screening are MeOH, MeOH+20 mM NH3, MeOH+0.5%DEA, IPA and IPA+20 mM NH3. Once the separation is confirmed using one of the gradient methods, an isocratic method is developed and, if necessary, scaled up for purification using the Thar Prep80 system.

Intermediates

Intermediates 1c-1j were prepared following the general procedures in Scheme 1.

Intermediate connection 1s. Methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate a:*

Stage A:

To a stirred solution of methyl propiolate (200 g, 2.38 mol, 198 ml) in acetone (2.50 L) was added AgNO ₃ (36.4 g, 214 mmol, 36.0 ml). After 5 min NBS (445 g, 2.50 mol) was added portionwise and the reaction mixture was stirred at 25° C. for 12 h. concentrated again. The residue was purified by column chromatography (0-5% EtOAc/PE) to give methyl 3-bromopropiolate (1b) as a yellow oil which was used directly for the next step.

Stage B:

A solution of methyl 3-bromopropiolate (1b, 200 g, 1.23 mol), furan (419 g, 6.15 mol, 445 ml) in toluene (2.50 L) was degassed by passing nitrogen gas through the reaction vessel for 2 min at 0°C, then the reaction mixture was heated to 90°C for 72 h, obtaining a black solution. The reaction mixture was concentrated and the residue was purified by column chromatography (2-5% EtOAc/PE) to give methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate. Four batches were purified separately and combined to give methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1c) as a yellow oil.

1H NMR (400 MHz, CDCl ₃ ) δ=7.25-7.17 (m, 2H), 5.70 (t, J=1.6 Hz, 1H), 5.33 (t, J=1, 7 Hz, 1H), 3.82-3.75 (m, 3H).

Intermediate 1d. Methyl-(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6carboxylate o

Stage C:

A solution of 2,2,2-trichloroacetic acid (91.2 g, 558 mmol, 56.3 ml) in 1,2-dichloroethane (300 ml) was added to a chilled solution of diethylzinc (1 M, 558 ml, 558 mmol) in 1 ,2-dichloroethane (1200 ml) at -45°C. The solution was heated to 0°C and stirred for 20 minutes. Diiodomethane (150 g, 558 mmol, 45.0 mL) was added to the reaction mixture and stirred at 0° C. for an additional 10 min. A solution of methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1c, 60.0 g, 260 mmol) in 1,2-dichloroethane (300 ml) was added to the reaction mixture, which was stirred at 15°C for 16 hours, the Reaction mixture was diluted with 1M HCl (1200 ml) and the aqueous phase was extracted using DCM (2x2000 ml). The combined organic layers were washed with sat. aq. NaHCO ₃ (1000 ml), brine (1000 ml), dried over Na ₂ SO ₄ , filtered and concentrated to give a yellow oil. The crude product was purified by column chromatography (0-10% EtOAc/PE) to give methyl-(1S,2S,4R,5R)-7bromo-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxylate (1d as yellow oil.

1H NMR (400 MHz, DMSO-d ₆ ) δ 4.97-4.92 (m, 1H), 4.89-4.85 (m, 1H), 3.73 (s, 3H), 1.58 -1.52(m, 2H), 1.44-1.38(m, 1H), 1.04-0.95(m, 1H).

Intermediate 1e.

Methyl-( 1 R,4S,5 S)-3-bromo-5-hydroxy-7-oxabicyclo [2.2.1 ]hept-2-en-2-carboxylate and methyl(1S,4S,6R)-3-bromo -6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate

Stage D:

A solution of methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (1c, 130 g, 563 mmol, 1.00 eq.) in THF (800 mL) was treated using BH ₃ -THF (1 M, 563 ml, 563 mmol) and stirred at 0°C for 2 hours. A phosphate buffer solution, pH=7 (1000 ml) was added dropwise, and then a mixture of H2O2 (270 ml, 2.81 mol, 30% v/v) and NaOH (2 M, 338 ml, 676 mmol) and the mixture was stirred at 0°C for 2 hours. The reaction mixture was extracted with ethyl acetate (3x500 ml) and the combined organic layers were washed sat. water, NaHSO ₃ solution (2x500 ml), brine (500 ml), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (250% EtOAc/PE) to give the desired product. The two batches were combined to give 1e as a 1.3:1 mixture of alcohol regioisomers dominated by the 5-hydroxy product as a yellow solid. 1.3:1 mixture of alcohol regioisomers:

Ή NMR (400 MHz, CDCl ₃ ) δ 5.25-5.02 (m, 1H), 4.94-4.74 (m, 1H), 4.23-4.14 (m, 1H), 3 .80-3.78 (m, 3H), 2.14-2.01 (m, 1H), 1.91-1.81 (m, 1H), 1.69-1.60 (m, 1H) .

Intermediate 1f. Methyl-(1R,4S,5S)-3-bromo-5-methoxy-7-oxαbicyclo[2.2.1]hept-2-en2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6- methoxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate, CO ₂ Me MeO ^ ^. ,CO ₂ Me ί I TrT

MeC<'^ Br ^^Br

Stage E:

Suspension of 1e (500 mg, 2.01 mmol) and silver oxide (465 mg, 2.01 mmol) in acetonitrile (5 mL) at rt. treated with iodomethane (0.125 ml, 2.01 mmol) and heated at 80° C. for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The solvent was evaporated and the resulting residue was purified by column chromatography using hexanes and EtOAc to give 1f as a mixture of methoxy-regioisomers.

LC-MS: Rt=1.25 min; MS mass/charge [M+H]+ 263.0.

Intermediate 1g. Methyl-(1R,4S,5R)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-en-2carboxylate and methyl-(1S,4S,6S)-3-bromo-6- fluoro-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate

J SK,

Step F: Solution 1e (1.00 g, 4.02 mmol) in DCM (80 mL) at rt. Work up with DAST (3.71 ml, 28.1 mmol) and stir for 18 hours. The reaction mixture was concentrated and purified with FCC (0-50% EtOAc/DCM) to give 1g as a mixture of fluorinated regioisomers.

LCMS: Rt=1.15 min; MS mass/charge [M+H]+ 251.1.

Intermediate 1h. Methyl 3-bromo-5-oxo-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate and methyl 3-bromo-6-oxo-7-oxabicyclo[2.2.1]hept-2- en-2-carboxylate

Stage G:

A solution of 1e (2.00 g, 8.03 mmol) in DCM (40 mL) at 0°C was treated portionwise with DessMartin's reagent (10.2 g, 24.1 mmol) for 5 min. The reaction mixture was allowed to warm up to rt. and stirred for 6 hours. The reaction was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate. The aqueous layer was washed with DCM x3. The combined organic layer was dried over anhydrous sodium sulfate. The crude compound was purified by silica gel column chromatography to give 1h as a mixture of ketone regioisomers.

LC-MS: Rt=1.10 min; MS mass/charge [M+H]+ 246.9.

Intermediate 1i. Methyl-(1R,4S,5R)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2en-2-carboxylate and methyl-(1S,4S,6S)-3-bromo-6- hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate ,,aG CCG

Stage H:

Solution 1h (50.0 mg, 0.202 mmol) in THF (2 mL) at RT treated with NaBH ₄ (15.3 mg, 0.405 mmol) and stirred at rt. within 16 hours the Reaction mixture was diluted using EtOAc and feast upon. aq. NH ₄ Cl, washed with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated to give 1i as a mixture of alcohol regioisomers.

LC-MS: Rt=0.57 min; MS mass/charge [M+H]+ 249.0.

Intermediate 1j.

Methyl-(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate and methyl-(1S,4S,6R)3-bromo-6 -fluoro-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate

XO _: Me F. XO _; Me

G I 1?T

F^^ Br 7-'β _Γ

Stage I:

A solution of 1i (3.70 g, 14.9 mmol) in DCE (74 mL) was treated with triethylamine trihydrofluoride (7.26 mL, 44.6 mmol) followed by XtalFluor-E (6.83 g, 29.7 mmol ) and heated at 80° C. for 1 h. The reaction mixture was cooled to rt, diluted with DCM, washed with sat. aq. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by FCC to give 1j as a mixture of fluorine regioisomers.

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LC-MS: Rt=1.18 min; MS mass/charge [M+H]+ 251.1.

Examples

Unless otherwise indicated, the examples described below consist of a mixture of enantiomers, and in some examples, a mixture of alcohol, fluorinated or methoxy regioisomers. In the case of a mixture of regioisomers, the structure and name of the main regioisomer are given with an approximate ratio of regioisomers.

^Example 1 ⁴ ]octane-6-carboxamide

The title compound was prepared from methyl-(1S,2S,4R,5R)-7-bromo-8oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6-carboxylate (Intermediate 1d) using steps A- C in diagram 2.

Stage A:

To a stirred solution of 1d (4.70 g, 19.2 mmol) in THF (25 ml) and water (6 ml) was added acetic acid (4.40 ml) at 0°C and Zn (5.00 g, 77.0 mmol). The reaction suspension was stirred until reaching room temperature for 15 minutes. The reaction mixture was filtered and neutralized with saturated sodium bicarbonate to pH 7. The compound was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under vacuum. The crude compound (1S,2S,4R,5R)-methyl 8oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6-carboxylate was used in the next step without further purification.

LCMS: Rt=1.16 min; MS mass/charge [M+H]+ 167.1.

Stage B:

Mixture of (1S,2S,4R,5R)-N-(8-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxamide (500 mg, 3.01 mmol), ( 2-methoxypyridin-4-yl)boronic acid (598 mg, 3.91 mmol), 2,2'bis(diphenylphosphino)-1,1'-binaphthalene (187 mg, 0.301 mmol), chloro-(1.5 -cyclooctadiene)rhodium (I) (74.0 mg, 0.150 mmol) and potassium carbonate (208 mg, 1.50 mmol) in dioxane (10 ml) and water (2.5 ml) were heated in a microwave oven at 100°C within 1 h. The resulting material was passed through celite and the solvent was evaporated. The compound was purified by silica gel column chromatography to give (1S,2S,4R,5R,6S,7S)methyl-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octan-6- carboxylate (cis) and (1 S,2S,4R,5R,6R,7S)methyl-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxylate (trans), cis LC-MS: Rt=1.15 min; MS mass/charge [M+H]+ 276.1. trans LC-MS: Rt=1.26 min; MS mass/charge [M+H]+ 276.1.

Stage C:

To a stirred solution of 5,6-dichloropyridine-3-amine (68.0 mg, 0.418 mmol) in anhydrous toluene (2 ml) at 0°C under nitrogen atmosphere was added trimethylaluminum in toluene (2M, 0.623 ml, 1.25 mmol) . After 10 minutes, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. (1S,2S,4R,5R,6S,7S)methyl-7-(2-methoxypyridin-4-yl)-8-oxatricyclo [3.2.1.0 ^2,4 ]octane-6carboxylate (115 mg, 0.418 mmol) was added to as a solid and the reaction mixture was stirred at room temperature for 1 h and then heated to 80° C. overnight. The reaction mixture was cooled to 0° C. and quenched with methanol. The solvent was removed in a stream of nitrogen. The solid was dissolved in methanol and filtered through a Celite pad. The solvent was evaporated, the crude compound was purified by silica gel column chromatography to give (1S,2S,4R,5R,6S,7S)-N-(5,6dichloropyridin-3-yl)-7-(2-methoxypyridin-4-yl)- 8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide.

LC-MS: Rt=1.38 min; MS mass/charge [M+H]+ 406.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.98 (s, 1H), 8.03 (d, J=2.4 Hz, 1H), 7.84 (d, J=5.3 Hz, 1H), 7.77 (d, J=2.4 Hz, 1H), 6.83 (dd, J=5.3, 1.4 Hz, 1H), 6.68 (s, 1H), 4, 66 (s, 1H), 4.31 (s, 1H), 3.67 (s, 3H), 3.49 (d, J=9.7 Hz, 1H), 3.30 (d, J=9 .7 Hz, 1H), 1.36-1.26 (m, 2H), 0.45-0.39 (m, 1H), 0.22-0.15 (m, 1H).

Example 2 rac-(1S,2S,4R,5R,6S,7S)-N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

Example 2 was synthesized according to the protocol described for Example 1 using methyl(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxylate ( intermediate 1d) and (6-methylpyridin-3-yl)boronic acid in step B and 6-methoxypyridin-3-amine in step C. LCMS: Rt=0.95 min; MS mass/charge [M+H]+ 352.0.

1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.31 (d, J=2.1 Hz, 1H), 7.71-7.68 (m, 1H), 7.550 2 (dd, J=8.0, 2.3Hz, 1H), 7.14 (dd, J=8.9, 2.7Hz, 1H), 7.00 (d, J=8.0Hz , 1H), 6.62-6.57 (m, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.73 (s, 3H), 3.49 (d, J=9.6Hz, 1H), 3.21(d, J=9.6Hz, 1H), 2.27(s, 3H), 1.36-1.29(m, 1H), 1, 29-1.24(m, 1H), 0.44-0.38(m, 1H), 0.20-0.15(m, 1H).

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Examples 3 and 4 (corresponding to peak 1 and peak 2).

(1S,2S,4R,5R,6S,7S)-N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide or (1R,2R,4S,5S,6R,7R)-N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide

Chiral resolution rac-(1S,2S,4R,5R,6S,7S)-N-(6-methoxypyridin-3-yl)-7-(6-methylpyridin-3yl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 21x250 mm Cellulose-2 at 30°C

Mobile phase: 70% CO ₂ /30% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.64 min. LC-MS: Rt=1.00 min; MS mass/charge [M+H]+ 352.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.31 (dd, J=2.4, 0.8 Hz, 1H), 7.70 (dd, J= 2.7, 0.7 Hz, 1H), 7.52 (dd, J=8.0, 2.3 Hz, 1H), 7.14 (dd, J=8.8, 2.7 Hz, 1H ), 7.00 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.8, 0.7 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.73 (s, 3H), 3.49 (d, J=9.6 Hz, 1H), 3.21 (d, J=9.6 Hz, 1H), 2.27 (s, 3H), 1.36-1.30 (m, 1H), 1.30-1.21 (m, 1H), 0.44-0.38 (m, 1H), 0.20-0 .15 (m, 1H).

Peak 2: SFC Retention time=3.30 min. LC-MS: Rt=1.00 min; MS mass/charge [M+H]+ 352.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.42 (s, 1H), 8.31 (dd, J=2.4, 0.8 Hz, 1H), 7.70 (dd, J= 2.7, 0.7 Hz, 1H), 7.52 (dd, J=8.0, 2.3 Hz, 1H), 7.14 (dd, J=8.8, 2.7 Hz, 1H ), 7.00 (d, J=8.0 Hz, 1H), 6.60 (dd, J=8.8, 0.7 Hz, 1H), 4.62 (s, 1H), 4.24 (s, 1H), 3.73 (s, 3H), 3.49 (d, J=9.6 Hz, 1H), 3.21 (d, J=9.6 Hz, 1H), 2.27 (s, 3H), 1.36-1.30 (m, 1H), 1.30-1.21 (m, 1H), 0.44-0.38 (m, 1H), 0.20-0 .15 (m, 1H).

Examples 5-13 below were synthesized according to the protocol described for Example 1 using methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1e) and various boronic acids/esters in stage B and various anilines in stage D, obtaining a mixture of alcohol regioisomers.

Example 5 (1 R,2R,3S,4R,5S)-N-(4,5-dichloropyridin-2-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7 oxabicyclo[2.2 .1]heptane-2-carboxamide

LCMS: Rt=0.62 min; MS mass/charge [M+H]+ 394.1.

Example 6 oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.53 min; MS mass/charge [M+H]+ 374.1.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.62 (s, 1H), 8.12 (dd, J=5.2, 0.8 Hz, 1H), 8.00 (d, J= 2.2 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.12 (s, 1H), 7.03 (dd, J=5.2, 1.6 Hz, 1H), 4.95-4.92(m, 1H), 4.85-4.81(m, 1H), 4.18(s, 1H), 4.04-4.00(m, 1H) , 3.26 (d, J=9.8 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.38 (s, 3H), 2.27 (s, 3H) , 2.04-1.97(m, 1H), 1.50-1.44(m, 1H). ~6:1 mixture of alcohol regioisomers.

Examples 7 and 8 (corresponding to peak 1 and peak 2). (1R,2S,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide or (1S,2R,3R,4S,5R)N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[ 2.2.1]heptane-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2. 1]heptane-2-carboxamide was carried out by the method of supercritical

- 19 040531 liquid chromatography using the following conditions, which allowed to obtain the compounds listed below:

Method details:

Column: 21x250 mm 1C at 30°C

Mobile phase: 65% CO ₂ /35% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.28 min. LC-MS: Rt=0.95 min; MS mass/charge [M+H]+ 394.2.

1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H ), 7.79 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 7.04-7.00 (m, 1H), 4.99-4.93 (m, 1H), 4.87-4.80(m, 1H), 4.19(s, 1H), 4.06-4.00(m, 1H), 3.30-3.25(m, 1H) , 3.07 (d, J=9.8 Hz, 1H), 2.26 (s, 3H), 2.05-1.94 (m, 1H), 1.52-1.43 (m, 1H ).

Peak 2: SFC Retention time=2.85 min. LC-MS: Rt=0.95 min; MS mass/charge [M+H]+ 394.2.

1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H ), 7.79 (d, J=2.4 Hz, 1H), 7.10 (s, 1H), 7.04-7.00 (m, 1H), 4.99-4.93 (m, 1H), 4.87-4.80(m, 1H), 4.19(s, 1H), 4.06-4.00(m, 1H), 3.30-3.25(m, 1H) , 3.07 (d, J=9.8 Hz, 1H), 2.26 (s, 3H), 2.05-1.94 (m, 1H), 1.52-1.43 (m, 1H ).

Example 9 (1 R,2S,3S,4R,5S)-5-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7 oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.04 min; MS mass/charge [M+H]+ 393.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.64 (s, 1H), 8.10-8.07 (m, 1H), 7.46 (s, 1H), 7.38-7.33 (m, 1H), 7.287.22 (m, 2H), 7.12 (s, 1H), 7.03 (dd, J=5.2, 1.7Hz, 1H), 4.99-4, 92 (m, 1H), 4.88-4.82 (m, 1H), 4.17 (s, 1H), 4.05-3.99 (m, 1H), 3.27 (d, J= 9.8 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.23 (s, 3H), 2.05-1.96 (m, 1H), 1.51- 1.43(m, 1H). >20:1 mixture of alcohol regioisomers.

Example 10 (1S,2S,3S,4R)-6-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7oxabicyclo[2.2.1]heptan-2- carboxamide

LC-MS: Rt=1.00 min; MS mass/charge [M+H]+ 393.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.75 (s, 1H), 8.09 (dd, J=5.2, 0.8 Hz, 1H), 7.46 (s, 1H), 7.39-7.34 (m, 1H), 7.30-7.23 (m, 2H), 7.13 (s, 1H), 7.06 (dd, J=5.2, 1.6 Hz, 1H), 4.97-4.91(m, 1H), 4.59(s, 1H), 4.51-4.47(m, 1H), 4.01-3.95(m, 1H), 3.24 (d, J=9.7 Hz, 1H), 3.05 (d, J=9.7 Hz, 1H), 2.22 (s, 3H), 2.05-1, 97 (m, 1H), 1.531.45 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 11 rac-(1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7oxabicyclo[2.2.1 ]heptan-2-carboxamide

LCMS: Rt=0.92 min; MS mass/charge [M+H]+ 381.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.30-8.27 (m, 2H), 8.00 (d, J=2.4 Hz, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.28-7.23 (m, 2H), 4.98-4.95 (m, 1H), 4.87-4.83 ( m, 1H), 4.21 (s, 1H), 4.07-4.02 (m, 1H), 3.36-3.29 (m, 1H), 3.09 (d, J=9, 8 Hz, 1H), 2.06-1.98 (m, 1H), 1.52-1.44 (m, 1H). ~3:1 mixture of alcohol regioisomers.

Example 11a. (corresponding to peak 1)(1R,2S,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3(pyridin-4-yl)-7-oxabicyclo[2.2. 1]heptan-2-carboxamide or (1S,2R,3R,4S,5R)-N-(5,6-dichloropyridin3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[ 2.2.1]heptane-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-N-(5,6-diclopyridin-3-yl)-5-hydroxy-3-(pyridin-4yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (example 10) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

column: 21x250 mm IC at 30°C

Mobile phase: 65% CO ₂ /35% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.74 min. LCMS: Rt=0.92 min; MS mass/charge [M+H] ⁺ 381.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.30-8.26 (m, 2H), 7.99 (d, J=2.3 Hz, 1H), 7.80 (d, J=2.4

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Hz, 1H), 7.26-7.22(m, 2H), 4.97(s, 1H), 4.88-4.82(m, 1H), 4.20(s, 1H), 4 .07-4.00 (m, 1H), 3.36-3.31 (m, 1H),

3.09 (d, J=9.8 Hz, 1H), 2.06-1.98 (m, 1H), 1.53-1.43 (m, 1H).

Example 12 rac-(1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7oxabicyclo [2.2.1] heptane- 2-carboxamide

LCMS: Rt=0.96 min; MS mass/charge [M+H] ⁺ 379.2.

'H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.27-8.24 (m, 2H), 7.47 (s, 1H), 7.37-7, 31 (m, 1H), 7.277.22 (m, 4H), 4.99-4.93 (m, 1H), 4.90-4.83 (m, 1H), 4.18 (s, 1H) , 4.06-4.01 (m, 1H), 3.34-3.31 (m, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.07-1.95 (m, 1H), 1.52-1.41 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 12a. (corresponds to peak 1). (1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2R,3R,4S,5R)-5-hydroxy-3(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide (Example 11) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

column: 21x250 mm IC at 30°C

Mobile phase: 95-50% CO ₂ /5-50% MeOH + 0.5% isopropylamine in 5 minutes

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.59 min. LCMS: Rt=0.96 min; MS mass/charge [M+H] ⁺ 379.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.27-8.24 (m, 2H), 7.47 (s, 1H), 7.37-7.31 (m, 1H), 7.277.22 (m, 4H), 4.99-4.93 (m, 1H), 4.90-4.83 (m, 1H), 4.18 (s, 1H), 4.06-4.01 (m, 1H), 3.34-3.31 (m, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.07-1.95 ( m, 1H), 1.52-1.41 (m, 1H).

Example

13. (1S,2S,3S,4S,6R)-6-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7 oxabicyclo [2.2.1]heptan-2- carboxamide

LC-MS: Rt=0.84 min; MS mass/charge [M+H] ⁺ 379.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.26-8.24 (m, 2H), 7.47 (s, 1H), 7.38-7.33 (m, 1H), 7.297.23 (m, 4H), 4.97-4.93 (m, 1H), 4.60 (s, 1H), 4.52-4.49 (m, 1H), 4.02-3.96 (m, 1H), 3.32-3.29 (m, 1H), 3.07 (d, J=9.6 Hz, 1H), 2.05-1.99 ( m, 1H), 1.55-1.47 (m, 1H). >20:1 mixture of alcohol regioisomers.

Examples 14-16 below were synthesized according to the protocol described for example 1 using methyl-(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1g) and various boronic acids/esters in stage B and various anilines in stage C.

Example 14 (1 R,2S,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

LCMS: Rt=1.16 min; MS mass/charge [M+H] ⁺ 395.2. A mixture of fluorinated regioisomers.

Example 15 (1 R,2S,3 S,4R,5R)-5-fluoro-N-(6-methoxypyridin-3-yl)-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2 .1]heptane-2-carboxamide

LC-MS: Rt=0.42 min; MS mass/charge [M+H]+ 358.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.48 (s, 1H), 8.18 (dd, J=5.1, 0.8 Hz, 1H), 7.77-7.73 (m , 1H), 7.26 (dd, J=8.8, 2.7 Hz, 1H), 7.18 (s, 1H), 7.12-7.09 (m, 1H), 6.62 ( dd, J=8.8, 0.7 Hz, 1H), 5.29-5.08(m, 1H), 4.90-4.84(m, 1H), 4.69-4.63( m, 1H), 3.94-3.89 (m, 1H), 3.74 (s, 3H), 3.40-3.35 (m, 1H), 2.29 (s, 3H), 2 .27-2.13 (m, 1H),

- 21 040531

1.72-1.58 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 16 (1R,2S,3S,4R,5R)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7oxabicyclo[2.2.1]heptane- 2-carboxamide

LCMS: Rt=1.14 min; MS mass/charge [M+H]+ 395.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.80 (s, 1H), 8.11 (dd, J=5.1, 0.8 Hz, 1H), 7.48 (s, 1H), 7.40-7.34 (m, 1H), 7.30-7.24 (m, 2H), 7.18 (d, J=1.6 Hz, 1H), 7.10-7.06 ( m, 1H), 5.29-5.08 (m, 1H), 4.91-4.87 (m, 1H), 4.704.64 (m, 1H), 3.97-3.90 (m, 1H), 3.44-3.38 (m, 1H), 2.28-2.18 (m, 1H), 2.23 (s, 3H), 1.71-1.59 (m, 1H) . >20:1 mixture of fluorinated regioisomers.

Examples 17-23 below were synthesized according to the protocol described for example 1 using methyl-(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-( 1 S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1 ]hept-2-en-2-carboxylate (intermediate 1j) and various boronic acids /esters in step B and various anilines in step C.

Example 17 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.19 min; MS mass/charge [M+H] ⁺ 395.2.

¹ H NMR (500 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.13 (dd, J=5.2, 0.7 Hz, 1H), 7.40-7.35 (m , 2H), 7.11 (s, 1H), 7.02 (dd, J=5.3, 1.6 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 5.24-5.08(m, 1H), 4.97-4.92(m, 1H), 4.63-4.55(m, 1H), 3.34-3.27( m, 1H), 3.05 (d, J=9.9 Hz, 1H), 2.27 (s, 3H), 2.21-2.11 (m, 1H), 1.85-1.70 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 18 2-carboxamide

LCMS: Rt=1.15 min; MS mass/charge [M+H] ⁺ 395.2.

1H NMR (400 MHz, Acetonitrile-d ₃ ) δ 8.15 (dd, J=5.2, 0.8 Hz, 1H), 8.06 (s, 1H), 7.43 (s, 1H), 7.32 (dd, J=7.9, 0.8 Hz, 1H), 7.28-7.24 (m, 2H), 7.15 (s, 1H), 7.05 (dd, J= 5.2, 1.7Hz, 1H), 5.15-4.98(m, 1H), 5.06-5.02(m, 1H), 4.74-4.68(m, 1H) , 3.36-3.30 (m, 1H), 3.07-3.02 (m, 1H), 2.29 (s, 3H), 2.24-2.16 (m, 1H), 1 .93-1.79 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 19 (1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.06 min; MS mass/charge [M+H] ⁺ 396.1.

1H NMR (400 MHz, Acetonitrile-d ₃ ) δ 8.20-8.14 (m, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.75 (d, J=2 .4 Hz, 1H), 7.12 (s, 1H), 7.04 (dd, J=5.2, 1.7 Hz, 1H), 5.14-4.97 (m, 1H), 5 .03-5.01 (m, 1H), 4.73-4.68 (m, 1H), 3.33 (d, J=9.7 Hz, 1H), 3.07 (d, J=9 .7 Hz, 1H), 2.32 (s, 3H), 2.24-2.13 (m, 1H), 1.93-1.79 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 20 (1 R,2S,3 S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7 oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.36 min; MS mass/charge [M+H] ⁺ 411.2.

1H NMR (500 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.85 (dd, J=5.3, 0.7 Hz, 1H), 7.40-7.36 (m, 2H), 7.00 (dd, J=8.8, 2.5 Hz, 1H), 6.83 (dd, J=5.3, 1.5 Hz, 1H), 6.68 (s, 1H ), 5.23-5.08 (m, 1H), 4.97-4.90 (m, 1H), 4.61-4.55 (m, 1H), 3.69 (s, 3H), 3.32 (d, J=9.9 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.21-2.11 (m, 1H), 1.83-1 .70 (m, 1H).

- 22 040531 >20:1 mixture of fluorinated regioisomers.

Example 21 (1R,2S,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-fluoro-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LCMS: Rt=1.14 min; MS mass/charge [M+H]+ 397.1.

¹ H NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 8.05 (s, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.42 ( d, J=8.8 Hz, 1H), 7.08 (dd, J=8.8, 2.5 Hz, 1H), 6.32 (s, 2H), 5.23-5.05 (m , 1H), 4.91-4.87 (m, 1H), 4.58-4.52 (m, 1H), 3.19 (d, J=9.6 Hz, 1H), 2.94 ( d, J=9.7 Hz, 1H), 2.20-2.09 (m, 1H), 1.81-1.63 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 22 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane -2-car boxamide

LCMS: Rt=1.23 min; MS mass/charge [M+H]+ 395.1.

1H NMR (500 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.29 (dd, J=2.3, 0.8 Hz, 1H), 7.50 (dd, J=8, 0, 2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.99 (d, J= 8.0 Hz, 1H), 6.94 (dd, J=8.8, 2.4 Hz, 1H), 5.26-5.10 (m, 1H), 4.96-4.89 (m , 1H), 4.58-4.53 (m, 1H), 3.36 (d, J=9.7 Hz, 1H), 3.01 (d, J=9.8 Hz, 1H), 2 .25 (s, 3H), 2.21-2.11 (m, 1H), 1.83-1.69 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 23 (1 R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.40 min; MS mass/charge [M+H]+ 399.1.

Ή NMR (400 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.97 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H ), 7.40 (d, J=8.8 Hz, 1H), 7.21-7.17 (m, 1H), 7.02 (dd, J=8.8, 2.4 Hz, 1H) , 6.96 (s, 1H), 5.25-5.07 (m, 1H), 4.97-4.94 (m, 1H), 4.69-4.64 (m, 1H), 3 .47 (d, J=9.8 Hz, 1H), 3.11 (d, J=9.8 Hz, 1H), 2.24-2.13 (m, 1H), 1.86-1, 70 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 24 rac-(1S,2S,4R,5R,6S,7S)-N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

The title compound was prepared from methyl-(1S,2S,4R,5R)-7-bromo-8oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6-carboxylate (Intermediate 1d) using steps A- C in diagram 3.

Stage A:

To a stirred solution of 3,4-dichloroaniline (568 mg, 3.51 mmol) in anhydrous toluene (10 mL) at 0° C. under nitrogen was added trimethylaluminum in toluene (2 M, 3.90 mL, 7.79 mmol). After 10 minutes, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was again cooled to 0°C and 1d (955 mg, 3.90 mmol, dissolved in 2 ml toluene) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction was cooled to 0°C and quenched with a solution of saturated aqueous NH ₄ Cl and methanol. The suspension was filtered and the solid washed with EtOAc. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography using DCM and EtOAc to give (1S,2S,4R,5R)-7-6pom-N-(3,4dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]oct-6 -en-6-carboxamide. LC-MS: Rt=1.63 min; MS mass/charge [M+H]+ 373.9.

1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.65 (dd, J=8.9, 2, 3 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 5.15 (s, 1H), 4.87 (s, 1H), 1.70-1.66 (m, 1H), 1.60-1.55 (m, 1H), 1.42-1.39 (m, 1H), 1.02-0.98 (m, 1H).

Stage B:

To a stirred solution of (1S,2S,4R,5R)-7-bromo-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxamide (525 mg , 1.40 mmol) in THF (10 ml) and water (2.5 ml), acetic acid (0.321 ml) was added at 0° C. and Zn (366 mg, 5.60 mmol) was added in portions. The reaction suspension was stirred until reaching room temperature for 15 minutes. The reaction mixture was filtered and neutralized with saturated sodium bicarbonate to pH ~7. The compound was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography (hexanes:EtOAc) to give (1S,2S,4R,5R)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene -6 carboxamide. LC-MS: Rt=1.54 min; MS mass/charge [M+H]+ 296.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.11 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.9, 2 .4 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.37 (d, J=1.7 Hz, 1H), 4.98 (s, 1H), 4, 89 (d, J=1.7 Hz, 1H), 1.42-1.36 (m, 3H), 0.96-0.90 (m, 1H).

Stage C:

Mixture of (1S,2S,4R,5R)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxamide (150 mg, 0.507 mmol), 2 -methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (133 mg, 0.608 mmol), 2,2-bis(diphenylphosphino)-1,1- binaphthalene (32 mg, 0.051 mmol), chloro-(1,5cyclooctadiene)rhodium(1) dimer (12 mg, 0.025 mmol) and potassium carbonate (35 mg, 0.253 mmol) in 1,4-dioxane (2 ml) and water (0.5 ml) was heated in a microwave oven at 100°C for 1 h. The crude reaction mixture was passed through celite and the solvent was evaporated to dryness. The crude compound was purified by silica gel column chromatography using DCM and EtOAc to give (1S,2S,4R,5S,6S,7S)-N-(3,4dichlorophenyl)-7-(2-methylpyridin-4-yl)-8 -oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide (Example 23) and (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2-methylpyridine -4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6carboxamide (trans). LC-MS: Rt=1.29 min; MS mass/charge [M+H]+ 389.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.14 (d, J=5.2 Hz, 1H), 7.40-7.37 (m, 2H), 7.16-7.13 (m, 1H), 7.06 (dd, J=5.3, 1.6 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 4.65 (s, 1H), 4.30 (s, 1H), 3.48 (d, J=9.7 Hz, 1H), 3.28 (d, J=9.7 Hz, 1H), 2.28 (s, 3H), 1.35-1.23 (m, 2H), 0.44-0.39 (m, 1H), 0.22-0.15 (m, 1H) .

Examples 24a and 24b (corresponding to peak 1 and peak 2).

(1S,2S,4R,5R6S,7S)-N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxαtricyclo[3.2.1.0 ^2,4 ]octane6-carboxamide or ( 1R,2R,4S,5S,6R,7R)-N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6- carboxamide

Chiral resolution of rac-(1S,2S,4R,5R,6S,7S)-N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane -6-carboxamide (Example 23) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

column: 21x250 mm IC at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.80 min. Method B LC-MS: Rt=1.06 min; MS mass/charge [M+H]+ 388.9.

1H NMR (400 MHz, DMSO-d6) δ 9.68 (s, 1H), 8.11 (d, J=5.1 Hz, 1H), 7.39 (s, 1H), 7.38 (d , J=6.6Hz, 1H), 7.11(s, 1H), 7.03-6.97(m, 2H), 4.65(s, 1H), 4.29(s, 1H) , 3.46 (d, J=9.7 Hz, 1H), 3.26 (d, J=9.7 Hz, 1H), 2.26 (s, 3H), 1.35-1.25 ( m, 2H), 0.43-0.39 (m, 1H), 0.22-0.16 (m, 1H).

Peak 2: SFC Retention time=3.26 min. Method B LC-MS: Rt=1.06 min; MS mass/charge [M+H]+ 388.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.68 (s, 1H), 8.11 (d, J=5.1 Hz, 1H), 7.39 (s, 1H), 7.38 ( d, J=6.6Hz, 1H), 7.11(s, 1H), 7.03-6.97(m, 2H), 4.65(s, 1H), 4.29(s, 1H ), 3.46 (d, J=9.7 Hz, 1H), 3.26 (d, J=9.7 Hz, 1H), 2.26 (s, 3H), 1.35-1.25 (m, 2H), 0.43-0.39 (m, 1H), 0.22-0.16 (m, 1H).

Examples 25-46 below were synthesized following the protocol described for Example 23 using methyl-(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0 ^2.4 ]oct- 6-ene-6carboxylate (intermediate 1d) and various anilines in step A and various boronic esters/boronic acids in step C.

Example ²⁵ 6-carboxamide

Method B LC-MS: Rt=1.40 min; MS mass/charge [M+H]+ 405.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.72 (s, 1H), 7.83 (dd, J=5.3, 0.6 Hz, 1H), 7.39 (d, J=5 .1 Hz, 1H), 7.38 (d, J=1.2 Hz, 1H), 7.01 (dd, J=8.8, 2.4 Hz, 1H), 6.83 (dd, J =5.4, 1.4 Hz, 1H), 6.69-6.66 (m, 1H), 4.65 (s, 1H),

- 24 040531

4.28 (s, 1H), 3.68 (s, 3H), 3.47 (d, J=9.7 Hz, 1H), 3.26 (d, J=9.7 Hz, 1H), 1.35-1.29(m, 1H), 1.29-1.24(m, 1H),

0.44-0.38 (m, 1H), 0.21-0.14 (m, 1H).

Example 26 (1S,2S,4R,5R6S,7S)-N-(3,4-dichlorophenyl)-7-(2-fluoropyridin-4-yl)-8-oxatricyclo[3.2.1.02.4]octane-6 -carboxamide

LC-MS: Rt=1.63 min; MS mass/charge [M+H]+ 393.0.

Ή NMR (400 MHz, DMSO-d ₆ ) δ 9.83 (s, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.45 (d, J=2.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 7.19 (d, J=5.0 Hz, 1H), 7.02 (dd, J=8.9, 2.5 Hz, 1H), 6.95 (s, 1H), 4.67 (d, J=2.7 Hz, 1H), 4.35 (d, J=2.7 Hz, 1H), 3.61 ( d, J=9.6Hz, 1H), 3.31(d, J=9.6Hz, 1H), 1.36-1.25(m, 2H), 0.44-0.39(m , 1H), 0.23-0.18 (m, 1H).

Example 27 (1S,2S,4R,5R,6S,7S)-7-(2-methyliridin-4-yl)-N-[3-(trifluoromethyl)phenyl]-8-oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide

LC-MS: Rt=1.29 min; MS mass/charge [M+H] ⁺ 389.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.08 (d, J=5.1 Hz, 1H), 7.46 (s, 1H), 7.36 ( t, J=7.9 Hz, 1H), 7.26 (t, J=9.2 Hz, 2H), 7.12 (s, 1H), 7.03 (dd, J=5.1, 1 .2 Hz, 1H), 4.66 (s, 1H), 4.29 (s, 1H), 3.47 (d, J=9.7 Hz, 1H), 3.29 (d, J=9 .7 Hz, 1H), 2.23 (s, 3H), 1.35-1.26 (m, 2H), 0.44-0.41 (m, 1H), 0.21-0.16 ( m, 1H).

Examples 28 and 29 (corresponding to peak 1 and peak 2).

(1S,2S,4R,5R,6S,7S)-N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6carboxamide or ( 1 R,2R,4S,5S,6R,7R)-N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide

Chiral resolution of rac-(1S,2S,4R,5R,6S,7S)-N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane-6 α-carboxamide was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

column: 21x250 mm IB at 30°C

Mobile phase: 75% CO ₂ /25% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.28 min. Method C LC-MS: Rt=1.03 min; MS mass/charge [M+H] ⁺ 375.8.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.93 (s, 1H), 8.82 (s, 1H), 8.61 (s, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.01-6.98 (m, 1H), 4.66 (s, 1H), 4.41 (s, 1H), 3.57 (d, J=9.5 Hz, 1H ), 3.29 (d, J=9.7 Hz, 1H), 1.38-1.27 (m, 2H), 0.45-0.40 (m, 1H), 0.24-0, 18(m, 1H).

Peak 2: SFC Retention time=2.76 min. Method C LC-MS: Rt=1.03 min; MS mass/charge [M+H] ⁺ 375.9.

'H NMR (400 MHz, DMSO-d6) δ 9.93 (s, 1H), 8.82 (s, 1H), 8.61 (s, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.01-6.98 (m, 1H), 4.66 (s, 1H), 4.41 (s, 1H), 3.57 (d, J=9.5 Hz, 1H ), 3.29 (d, J=9.7 Hz, 1H), 1.38-1.27 (m, 2H), 0.45-0.40 (m, 1H), 0.24-0, 18(m, 1H).

Examples 30 and 31 (corresponding to peak 1 and peak 2).

(1S,2S,4R,5R,6S,7S)-N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane -6-carboxamide or (1R,2R,4S,5S,6R,7R)-N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

Chiral resolution of rac-(1S,2S,4R,5R6S,7S)-N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane -6-carboxamide was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed

- 25 040531 below:

Method details:

column: 21x250 mm IA at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.63 min. LCMS Method D: Rt=1.23 min; MS mass/charge [M+H]+ 410.8.

1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.84 (dd, J=5.2, 0.9 Hz, 1H), 7.44 (d, J=1, 7 Hz, 1H), 7.43 (d, J=4.6 Hz, 1H), 7.31 (t, J=4.9 Hz, 1H), 7.04 (dd, J=8.8, 2.4Hz, 1H), 4.67(s, 1H), 4.44(s, 1H), 3.89(d, J=9.6Hz, 1H), 3.36(d, J= 9.6 Hz, 1H), 1.42-1.37 (m, 1H), 1.34-1.28 (m, 1H), 0.46-0.40 (m, 1H), 0.24 -0.19 (m, 1H).

Peak 2: SFC Retention time=3.19 min.

Method D: LC-MS: Rt=1.23 min; MS mass/charge [M+H]+ 410.8.

1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 7.84 (dd, J=5.2, 0.9 Hz, 1H), 7.44 (d, J=1, 7 Hz, 1H), 7.43 (d, J=4.6 Hz, 1H), 7.31 (t, J=4.9 Hz, 1H), 7.04 (dd, J=8.8, 2.4Hz, 1H), 4.67(s, 1H), 4.44(s, 1H), 3.89(d, J=9.6Hz, 1H), 3.36(d, J= 9.6 Hz, 1H), 1.42-1.37 (m, 1H), 1.34-1.28 (m, 1H), 0.46-0.40 (m, 1H), 0.24 -0.19 (m, 1H).

Example 32 (1S,2S,4R,5R,6S,7S)-N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide

Method C LC-MS: Rt=1.29 min; MS mass/charge [M+H]+ 411.8.

1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.07 (d, J=2.4 Hz, 1H), 7.84 (d, J=2.4 Hz, 2H ), 7.31 (t, J=4.9 Hz, 1H), 4.70 (s, 1H), 4.44 (s, 1H), 3.90 (d, J=9.6 Hz, 1H ), 3.39 (d, J=9.6 Hz, 1H), 1.43-1.37 (m, 1H), 1.33-1.28 (m, 1H), 0.46-0, 40 (m, 1H), 0.25-0.19 (m, 1H).

Example 33 (1S,2S,4R,5R,6S,7S)-N-(6-methoxypyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LCMS: Rt=0.92 min; MS mass/charge [M+H]+ 338.0.

¹ H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.62 (d, J=5.9 Hz, 2H), 7.76 (dd, J=2.7, 0 .7 Hz, 1H), 7.73 (d, J=5.9 Hz, 2H), 7.31 (dd, J=8.9, 2.7 Hz, 1H), 6.62 (dd, J =8.8, 0.7Hz, 1H), 4.71(s, 1H), 4.40(s, 1H), 3.75(dt, J=9.6, 0.6Hz, 1H) , 3.73 (s, 3H), 3.39 (d, J=9.6 Hz, 1H), 1.40-1.29 (m, 2H), 0.47-0.41 (m, 1H ), 0.25-0.18 (m, 1H).

^Example 34 ⁴ ]octane-6-carboxamide

Method C LC-MS: Rt=0.89 min; MS mass/charge [M+H]+ 373.9.

1H NMR (400 MHz, DMSO-d6) δ 9.70 (s, 1H), 7.85 (d, J=5.2 Hz, 1H), 7.79 (d, J=2.7 Hz, 1H ), 7.33 (t, J=4.9 Hz, 1H), 7.28 (dd, J=8.9, 2.7 Hz, 1H), 6.65 (dd, J=8.9, 0.7 Hz, 1H), 4.67 (s, 1H), 4.42 (s, 1H), 3.88 (d, J=9.6 Hz, 1H), 3.74 (s, 3H) , 3.35 (d, J=9.6 Hz, 1H), 1.42-1.37 (m, 1H), 1.34-1.29 (m, 1H), 0.46-0.40 (m, 1H), 0.23-0.16 (m, 1H).

Example 35 (1S,2S,4R,5R,6S,7S)-N-(6-methoxypyridin-3-yl)-7-(6-(trifluoromethyl)pyridin-2-yl)-8oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide

LC-MS: Rt=1.47 min; MS mass/charge [M+H]+ 406.0.

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1H NMR (400 MHz, DMSO-d ₆ ) δ 9.63 (s, 1H), 7.90 (t, J=7.9 Hz, 1H), 7.76 (d, J=2.1 Hz, 1H), 7.63(d,

J=8.0Hz, 1H), 7.60-7.57(m, 1H), 7.27(dd, J=8.9, 2.7Hz, 1H), 6.59(d, J = 8.9 Hz, 1H), 4.66 (s, 1H), 4.48 (s, 1H),

3.78 (d, J=9.7 Hz, 1H), 3.72 (s, 3H), 3.36 (d, J=9.7 Hz, 1H), 1.42-1.36 (m , 1H), 1.31-1.26 (m, 1H), 0.46-0.41 (m,

1H), 0.23-0.18 (m, 1H).

Example ³⁶ 6-carboxamide

Method B LC-MS: Rt=1.50 min; MS mass/charge [M+H] ⁺ 394.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.57 (d, J=1.5 Hz, 2H), 7.43 (d, J=6.1 Hz, 1H), 7.42 (s, 1H), 7.04 (dd, J=8.8, 2.4 Hz, 1H), 4.66 (s, 1H), 4.42 (s, 1H), 3.66 (d, J=9.5 Hz, 1H), 3.29 (d, J=9.5 Hz, 1H), 1.371.26 (m, 2H), 0.46-0.40 (m , 1H), 0.25-0.17 (m, 1H).

Example 37 (1S,2S,4R,5R,6S,7S)-7-(pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide

LCMS: Rt=1.41 min; MS mass/charge [M+H] ⁺ 376.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.96 (s, 1H), 8.79 (s, 1H), 8.63 (s, 2H), 7.44 (s, 1H), 7, 38 (t, J=8.0 Hz, 1H), 7.29-7.24 (m, 2H), 4.68 (s, 1H), 4.41 (s, 1H), 3.59 (d , J=9.6Hz, 1H), 3.30(s, 1H), 1.40-1.35(m, 1H), 1.341.28(m, 1H), 0.46-0.41( m, 1H), 0.23-0.18 (m, 1H).

Example 38 (1S,2S,4R,5R,6S,7S)-7-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide

LCMS: Rt=1.28 min; MS mass/charge [M+H] ⁺ 375.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.79 (s, 1H), 8.28 (d, J=6.0 Hz, 2H), 7.48 (s, 1H), 7.36 ( t, J=7.9 Hz, 1H), 7.29 (dd, J=4.6, 1.4 Hz, 2H), 7.24 (d, J=8.1 Hz, 2H), 4, 68 (s, 1H), 4.31 (s, 1H), 3.54 (d, J=9.7 Hz, 1H), 3.31 (d, J=9.7 Hz, 1H), 1, 37-1.32(m, 1H), 1.31-1.26(m, 1H), 0.46-0.40(m, 1H), 0.22-0.16(m, 1H).

Example 39 (1S,2S,4R,5R,6S,7S)-7-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LC-MS: Rt=1.24 min; MS mass/charge [M+H]+ 391.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.85 (s, 1H), 8.05 (s, 2H), 7.51 (d, J=2.4 Hz, 1H), 7.42 ( d, J=8.8 Hz, 1H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 6.27 (s, 2H), 4.59 (s, 1H), 4.23 (s, 1H), 3.33 (d, J=9.3 Hz, 1H), 3.15 (d, J=9.5 Hz, 1H), 1.32-1.26 (m , 1H), 1.26-1.20 (m, 1H), 0.42-0.37 (m, 1H), 0.20-0.15 (m, 1H).

Example 40 (1S,2S,4R,5R,6S,7S)-N-(3,4-dichlorophenyl)-7-(2-morpholinopyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LC-MS: Rt=1.55 min; MS mass/charge [M+H] ⁺ 461.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.18 (s, 2H), 7.43-7.39 (m, 2H), 7.04 (dd, J=8.8, 2.4Hz, 1H), 4.60(s, 1H), 4.28(s, 1H), 3.48(s, 8H), 3.39(d, J=9 .4 Hz, 1H), 3.18 (d, J=9.5 Hz, 1H), 1.34-1.28 (m, 1H), 1.28-1.23 (m, 1H), 0 .44-0.38 (m, 1H), 0.21-0.14 (m, 1H).

Example 41 (1S,2S,4R,5R,6S,7S)-7-(2-fluoropyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide

- 27 040531

LC-MS: Rt=1.58 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.92 (d, J=5.2 Hz, 1H), 7.50 (d, J=2.0 Hz, 1H ), 7.38 (t, J=7.9 Hz, 1H), 7.31-7.24 (m, 2H), 7.24-7.18 (m, 1H), 6.96 (d, J=1.4Hz, 1H), 4.69(s, 1H), 4.35(s, 1H), 3.62(d, J=9.6Hz, 1H), 3.33(d, J=9.6 Hz, 1H), 1.39-1.27(m, 2H), 0.46-0.40(m, 1H), 0.23-0.17(m, 1H).

^Example 42 6-carboxamide

Method B LC-MS: Rt=1.35 min; MS mass/charge [M+H] ⁺ 390.0.

1H NMR (400 MHz, DMSO-d6) δ 9.92 (s, 1H), 8.48 (s, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.30 (d , J=2.4Hz, 1H), 6.98(dd, J=8.8, 2.4Hz, 1H), 4.64(s, 1H), 4.36(s, 1H), 3 .53 (d, J=9.5 Hz, 1H), 3.25 (d, J=9.6 Hz, 1H), 2.38 (s, 3H), 1.37-1.31 (m, 1H), 1.30-1.25(m, 1H), 0.46-0.40(m, 1H), 0.23-0.17(m, 1H).

Example 43 rac-(1S,2S,4R,5R,6S,7S)-N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide LC-MS: Rt=1.17 min; MS mass/charge [M+H] ⁺ 376.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 8.50-8.42 (m, 2H), 8.03 (d, J=2.4 Hz, 1H) , 7.85 (d, J=2.4 Hz, 1H), 7.54-7.49 (m, 2H), 4.70 (s, 1H), 4.39 (s, 1H), 3, 68 (d, J=9.6 Hz, 1H), 3.40 (d, J=9.7 Hz, 1H), 1.41-1.29 (m, 2H), 0.46-0.42 (m, 1H), 0.26-0.18 (m, 1H).

Examples 43a and 43b (corresponding to peak 1 and peak 2). (1S,2S,4R,5R,6S,7S)-N-(5,6-dichloropyridin3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6 -carboxamide or (1R,2R,4S,5S,6R,7R)-N-(5,6dichloropyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Chiral resolution rac-(1S,2S,4R,5R,6S,7S)-N-(5,6-dichloropyridin-3-yl)-7-(pyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide (Example 43) was carried out by supercritical liquid chromatography using the following conditions to give the compounds listed below:

Method details:

Column: 30x250 mm IC at 30°C

Mobile phase: 65% CO ₂ /35% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.64 min. LC-MS: Rt=1.17 min; MS mass/charge [M+H] ⁺ 376.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.17 (s, 1H), 8.50-8.42 (m, 2H), 8.03 (d, J=2.4 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.54-7.49 (m, 2H), 4.70 (s, 1H), 4.39 (s, 1H), 3.68 (d, J=9.6 Hz, 1H), 3.40 (d, J=9.7 Hz, 1H), 1.41-1.29 (m, 2H), 0.46-0.42 ( m, 1H), 0.26-0.18 (m, 1H).

Peak 2: SFC Retention time=2.80 min. LC-MS: Rt=1.17 min; MS mass/charge [M+H] ⁺ 376.0.

1H NMR (400 MHz, DMSO-d6) δ 10.17 (s, 1H), 8.50-8.42 (m, 2H), 8.03 (d, J=2.4 Hz, 1H), 7 .85 (d, J=2.4 Hz, 1H), 7.54-7.49 (m, 2H), 4.70 (s, 1H), 4.39 (s, 1H), 3.68 ( d, J=9.6Hz, 1H), 3.40(d, J=9.7Hz, 1H), 1.41-1.29(m, 2H), 0.46-0.42(m , 1H), 0.26-0.18 (m, 1H).

Example ⁴⁴ 6-carboxamide

LCMS: Rt=1.27 min; MS mass/charge [M+H] ⁺ 375.0.

1H NMR (500 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.29-8.25 (m, 2H), 7.41-7.32 (m, 2H), 7.26- 7.21(m, 2H), 7.01-6.96(m, 1H), 4.69-4.62(m, 1H), 4.33-4.27(m, 1H), 3, 53-3.48(m, 1H), 3.30-3.25(m, 1H), 1.37-1.31(m, 1H), 1.31-1.25(m, 1H), 0.45-0.38 (m, 1H), 0.24-0.17 (m, 1H).

Examples 45 and 46 (corresponding to peak 1 and peak 2). (1S,2S,4R,5R,6S,7S)-N-(5,6-dichloropyridin-3yl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide or (1R,2R,4S,5S,6R,7R)-N(5,6-dichloropyridin-3-yl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2. 1.0 ^2,4 ]octane-6-carboxamide

- 28 040531

Chiral resolution of rac-(1S,2S,4R,5R,6S,7S)-N-(5,6-dichloropyridin-3-yl)-7-(2-methyl-pyridin-4yl)-8-oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 21x250 mm IC at 30°C

Mobile phase: 70% CO ₂ /30% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.50 min. LC-MS: Rt=1.19 min; MS mass/charge [M+H]+ 390.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=2.4Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J=5.1, 1.3Hz, 1H), 4, 66 (s, 1H), 4.32 (s, 1H), 3.48 (d, J=9.7 Hz, 1H), 3.31 (d, J=10.1 Hz, 1H), 2, 25 (s, 3H), 1.36-1.26 (m, 2H), 0.45-0.39 (m, 1H), 0.22-0.16 (m, 1H).

Peak 2: SFC Retention time=2.54 min. LC-MS: Rt=1.19 min; MS mass/charge [M+H]+ 390.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (s, 1H), 8.11 (d, J=5.2 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H), 7.79 (d, J=2.4Hz, 1H), 7.10 (s, 1H), 7.01 (dd, J=5.1, 1.3Hz, 1H), 4, 66 (s, 1H), 4.32 (s, 1H), 3.48 (d, J=9.7 Hz, 1H), 3.31 (d, J=10.1 Hz, 1H), 2, 25 (s, 3H), 1.36-1.26 (m, 2H), 0.45-0.39 (m, 1H), 0.22-0.16 (m, 1H).

Example 47 rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2. 1] heptane-2-carboxamide

The title compound was prepared from methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7oxabicyclo[2.2.1]hept-2-en-2-carboxylate and methyl-(1S,4S,6R)- 3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate (intermediate 1e) using steps A-C in Scheme 3.

Step A: Trimethylaluminum in toluene (2 M, 313 ml, 626 mmol) was added to a stirred solution of 3,4-dichloroaniline (44.0 g, 271 mmol) in anhydrous toluene (100 ml) at 0° C. under nitrogen. After 10 min, the ice bath was removed and the mixture was stirred at RT. within 30 min. The reaction mixture was again cooled to 0°C, a mixture of methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7oxabicyclo[2.2.1]hept-2-en-2-carboxylate and methyl-(1S, 4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1e, 26.0 g, 104 mmol) in 600 ml of toluene and the reaction mixture stirred at rt. within 6 hours the Reaction mixture was cooled to 0°and slowly extinguished with saturated aqueous ammonium chloride (500 ml). The suspension was filtered and the precipitate was washed using EtOAc (3x500 ml) and methanol (2x 100 ml). The combined organic layer was washed with sat. aq. NH ₄ Cl (300 ml), water (300 ml), brine (300 ml) and dried over anhydrous sodium sulfate. The crude compound was purified by silica gel column chromatography using PE and EtOAc to give a mixture of (1R,4S,5S)-3-bromo-N-(3,4-dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]hept- 2-en-2-carboxamide and (1S,4S,6R)-3-bromo-N-(3,4-dichlorophenyl)-6-hydroxy-7oxabicyclo[2.2.1]hept-2-en-2-carboxamide in as a 2:1 mixture of alcohol regioisomers with a predominance of the 5-hydroxy product as a light yellow solid.

1H NMR (400 MHz, CDCl3) δ ppm 7.99-7.95 (m, 1H), 7.79-7.78 (m, 1H), 7.43-7.38 (m, 2H), 5 .38-5.36 (m, 0.7H), 5.18-5.17 (m, 0.3H), 5.02-5.01 (m, 0.3H), 4.88-4, 86 (m, 0.7H), 4.29-4.24 (m, 1H), 2.22-2.19 (m, 0.7H), 2.15-2.08 (m, 0.3H ), 1.74-1.69 (m, 1H), 0.89-0.85 (m, 1H).

Stage B:

To a stirred solution of a mixture of (1R,4S,5S)-3-bromo-N-(3,4-dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]hept-2-ene-2-carboxamide and (1S,4S ,6R)-3-bromo-N-(3,4-dichlorophenyl)-6-hydroxy-7oxabicyclo[2.2.1]hept-2-ene-2-carboxamide (14.5 g, 38.3 mmol) in THF (240 ml) and H ₂ O (60 ml) AcOH (18.0 ml) and Zn powder (20.0 g, 306 mmol) were added at 0°C. The reaction suspension was stirred at rt. for 2 hours. The reaction mixture was filtered and neutralized with saturated aqueous sodium bicarbonate to pH 7. The compound was extracted with ethyl acetate (3x200 ml). The organic layer was washed with water (200 ml) and brine (100 ml), dried over anhydrous sodium sulfate and concentrated. The resulting solid was triturated with MTBE (30 mL), then the solid was filtered off to give a mixture of regioisomers (1R,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]hept-2 -en-2-carboxamide and (1S,4S,6R)-N-(3,4-dichlorophenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxamide as a yellow solid substances.

¹ H NMR (400 MHz, DMSO-d6) δ 10.12 (s, 1H), 8.03-8.02 (d, 1H), 7.64-7.57 (m, 2H), 7.09 -7.07 (d, 1H), 5.15-5.08 (m, 2H), 4.87-4.81 (m, 1H), 3.91-3.89 (m, 1H), 1 .76-1.72(m, 1H), 1.44-1.40(m, 1H).

Stage C.

A mixture of (1 R,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo [2.2.1 ]hept-2-en-2-carboxamide and (1S,4S,6R)- N-(3,4-dichlorophenyl)-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxamide (250 mg,

- 29 040531

0.833 mmol), pyridin-4-yl-boronic acid (133 mg, 1.08 mmol), 2,2'-bis(diphenylphosphino)-1,1 binaphthalene (52 mg, 0.083 mmol), chloro-(1.5 -cyclooctadiene)rhodium (I) (21 mg, 0.042 mmol) and potassium carbonate (58.0 mg, 0.416 mmol) in 1,4-dioxane (6 ml) and water (1.5 ml) were heated in a microwave at 100 °C for 1 hour. The reaction mixture was concentrated on celite and purified by silica gel column chromatography to give rac-(1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3( pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide in the form of a mixture of alcohol regioisomers - 2: 1 with a predominance of the 5-hydroxy product. LC-MS: Rt=1.10 min; MS mass/charge [M+H] ⁺ 379.0.

Example 47a (corresponding to peak 1).

(1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2carboxamide or (1S ,2R,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2- carboxamide (Example 47) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 30x250 mm IC at 30°C

Mobile phase: 70% CO ₂ /30% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=3.59 min. LC-MS: Rt=1.10 min; MS mass/charge [M+H] ⁺ 379.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.84 (s, 1H), 8.55-8.52 (m, 2H), 7.65-7.62 (m, 2H), 7, 44 (d, J=2.4Hz, 1H), 7.39 (d, J=8.8Hz, 1H), 7.00 (dd, J=8.8, 2.4Hz, 1H), 5.12-4.96 (m, 1H), 4.91-4.86 (m, 1H), 4.26 (s, 1H), 4.08-4.04 (m, 1H), 3, 53 (d, J=9.7 Hz, 1H), 3.15 (d, J=9.8 Hz, 1H), 2.08-2.00 (m, 1H), 1.54-1.47 (m, 1H).

Examples 48-62 below were synthesized according to the protocol described for Example 47 using methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate (intermediate 1e) and various anilines in step A and various boronic esters/acids in step C.

Example 48 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

393.0.

LC-MS: Rt=1.20 min; MS mass/charge [M+H]+

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.66 (s, 1H), 8.32 (d, J=2.2 Hz, 1H), 7.65-7.59 (m, 1H), 7.38 (d, J=8.8 Hz, 1H), 7.27 (d, J=2.4 Hz, 1H), 7.11-7.06 (m, 1H), 6.95 (dd , J=8.9, 2.4 Hz, 1H), 4.98-4.86 (m, 1H), 4.82 (d, J=5.5, 1.2 Hz, 1H), 4, 17 (s, 1H), 4.05-4.02 (m, 1H), 3.37-3.32 (m, 1H), 3.00 (d, J=9.7 Hz, 1H), 2 .28 (s, 3H), 2.04-1.98 (m, 1H), 1.49-1.43 (m, 1H). -3:1 mixture of alcohol regioisomers.

Example 49 rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7 oxabicyclo[2.2.1 ]heptan-2-carboxamide

LCMS: Rt=1.32 min; MS mass/charge [M+H] ⁺ 409.0.

1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.83 (d, J=5.3 Hz, 1H), 7.39 (d, J=6.0 Hz, 1H ), 7.37 (s, 1H), 6.99 (dd, J=8.8, 2.4Hz, 1H), 6.84 (dd, J=5.4, 1.5Hz, 1H) , 6.68 (s, 1H), 4.96-4.93 (m, 1H), 4.84-4.77 (m, 1H), 4.15 (s, 1H), 4.03-3 .98 (m, 1H), 3.68 (s, 3H), 3.27 (d, J=9.7 Hz, 1H), 3.01 (d, J=9.8 Hz, 1H), 2 .03-1.93(m, 1H), 1.51-1.42(m, 1H). -3:1 mixture of alcohol regioisomers.

Examples 49a and 49b (corresponding to peak 1 and peak 2). (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2R,3R,4S,5R)N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin4-yl)-7-oxabicyclo[2.2.1]heptan- 2-carboxamide (Example 49) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain compounds,

- 30 040531 listed below.

Method details:

Column: 21x250 mm IF at 30°C

Mobile phase: 65% CO ₂ /35% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.10 min. LCMS: Rt=1.23 min; MS mass/charge [M+H] ⁺ 409.0.

1H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 7.83 (d, J=5.3 Hz, 1H), 7.39 (d, J=6.1 Hz, 1H ), 7.37 (s, 1H), 6.99 (dd, J=8.8, 2.4Hz, 1H), 6.84 (dd, J=5.3, 1.4Hz, 1H) , 6.68 (d, J=0.8 Hz, 1H), 4.97-4.92 (m, 1H), 4.86-4.80 (m, 1H), 4.15 (s, 1H ), 4.05-3.97 (m, 1H), 3.68 (s, 3H), 3.27 (d, J=9.7 Hz, 1H), 3.01 (d, J=9, 8 Hz, 1H), 2.02-1.95 (m, 1h), 1.50-1.42 (m, 1H).

Peak 2: SFC Retention time=2.81 min. LCMS: Rt=1.23 min; MS mass/charge [M+H] ⁺ 409.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 7.83 (d, J=5.3 Hz, 1H), 7.39 (d, J=6.1 Hz , 1H), 7.37 (s, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (dd, J=5.3, 1.4 Hz, 1H), 6.68 (d, J=0.8 Hz, 1H), 4.97-4.92 (m, 1H), 4.86-4.80 (m, 1H), 4.15 (s , 1H), 4.05-3.97 (m, 1H), 3.68 (s, 3H), 3.27 (d, J=9.7 Hz, 1H), 3.01 (d, J= 9.8 Hz, 1H), 2.02-1.95(m, 1H), 1.50-1.42(m, 1H).

Example 50 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)7-oxabicyclo [2.2.1 ] heptane-2-carboxamide

LC-MS: Rt=1.57 min; MS mass/charge [M+H] ⁺ 447.0. A mixture of alcohol regioisomers.

Example 51 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyrimidin-5-yl)-7oxabicyclo [2.2.1]heptan-2-carboxamide

LCMS: Rt=1.26 min; MS mass/charge [M+H] ⁺ 380.0. 1H NMR (400 MHz, DMSO-d ₆ ) δ 9.86 (s, 1H), 8.82 (s, 1H), 8.62 (s, 2H), 7.40 (d, J=4.5 Hz, 1H), 7.39 (d, J=1.9 Hz, 1H), 6.99 (dd, J=8.8, 2.4 Hz, 1H), 5.03-4.99 (m , 1H), 4.86-4.82 (m, 1H), 4.28 (s, 1H), 4.07-4.02 (m, 1H), 3.38 (d, J=9.7 Hz, 1H), 3.05 (d, J=9.7 Hz, 1H), 2.07-2.00 (m, 1H), 1.52-1.44 (m, 1H). ~3:1 mixture of alcohol regioisomers.

Example 52 rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7oxabicyclo[2.2.1] heptane-2-carboxamide LC-MS: Rt=1.39 min; MS mass/charge [M+H] ⁺ 397.0.

1H NMR (400 MHz, DMSO-d6) δ 9.74 (s, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H ), 7.40 (d, J=8.8 Hz, 1H), 7.21-7.18 (m, 1H), 7.01 (dd, J=8.8, 2.5 Hz, 1H) , 6.96 (s, 1H), 5.00-4.97 (m, 1H), 4.87-4.83 (m, 1H), 4.21 (s, 1H), 4.05-4 .00 (m, 1H), 3.41 (d, J=9.8 Hz, 1H), 3.07 (d, J=9.8 Hz, 1H), 2.05-1.97 (m, 1H), 1.521.44 (m, 1H). ~3:1 mixture of alcohol regioisomers.

Examples 52a and 52b (corresponding to peak 1 and peak 2). (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2methoxypyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2R,3R,4S,5R)-N(3,4-dichlorophenyl)-3-(2-methoxypyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral resolution of rac-( 1 R,2S,3 S,4R,5S)-N-(3,4-dichlorophenyl)-3 -(2-fluoropyridin-4-yl)-5hydroxy-7-oxabicyclo[2.2.1] heptane-2-carboxamide (Example 52) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm IF at 30°C

Mobile phase: 95-50% CO ₂ /5-50% MeOH + 0.5% isopropylamine in 5 minutes

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=3.15 min. LC-MS: Rt=1.30 min; MS mass/charge [M+H] ⁺ 397.0.

'H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 7.40 (d,

- 31 040531

J=8.8Hz, 1H), 7.20(d, J=4.9Hz, 1H), 7.01(dd, J=8.8, 2.4Hz, 1H), 6.96( s, 1H), 5.04-4.95 (m, 1H), 4.89-4.82 (m, 1H), 4.21 (s, 1H), 4.05-4.00 (m, 1H), 3.41 (d, J=9.7 Hz, 1H), 3.07 (d, J=9.9 Hz, 1H), 2.05-1.96 (m, 1H),

1.52-1.44 (m, 1H).

Peak 2: SFC Retention time=4.12 min. LC-MS: Rt=1.30 min; MS mass/charge [M+H]+ 397.0.

1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 7.95 (d, J=5.2 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H ), 7.40 (d, J=8.8 Hz, 1H), 7.20 (d, J=4.9 Hz, 1H), 7.01 (dd, J=8.8, 2.4 Hz , 1H), 6.96 (s, 1H), 5.04-4.95 (m, 1H), 4.89-4.82 (m, 1H), 4.21 (s, 1H), 4, 05-4.00 (m, 1H), 3.41 (d, J=9.7Hz, 1H), 3.07 (d, J=9.9Hz, 1H), 2.05-1.96 (m, 1H), 1.52-1.44 (m, 1H).

Example 5 3. rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7 oxabicyclo[2.2. 1]heptane-2-carboxamide LC-MS: Rt=1.18 min; MS mass/charge [M+H]+ 393.0. ~3:1 mixture of alcohol regioisomers.

Examples 53a and 53b (corresponding to peak 1 and peak 2) (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5hydroxy-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2R,3R,4S,5R)-N(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7 -oxabicyclo [2.2.1] heptane-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4yl)-7-oxabicyclo[2.2.1]heptane- 2-carboxamide (Example 53) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 21x250 mm IC at 30°C

Mobile phase: 80% CO ₂ /20% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.14 min. LC-MS: Rt=1.10 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.11 (dd, J=5.1, 0.8 Hz, 1H), 7.40-7.36 (m, 2H), 7.11 (s, 1H), 7.03-7.00 (m, 1H), 6.98 (dd, J=8.8, 2.4Hz, 1H), 4.98-4 .91 (m, 1H), 4.86-4.80 (m, 1H), 4.17 (s, 1H), 4.043.99 (m, 1H), 3.25 (d, J=9.7 Hz, 1H), 3.02 (d, J=9.7 Hz, 1H), 2.26 (s, 3H), 2.04-1.95 (m, 1H), 1.50-1.42 (m, 1H).

Peak 2: SFC Retention time=2.79 min. LC-MS: Rt=1.10 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.59 (s, 1H), 8.11 (dd, J=5.1, 0.8 Hz, 1H), 7.40-7.36 (m , 2H), 7.11 (s, 1H), 7.03-7.00 (m, 1H), 6.98 (dd, J=8.8, 2.4Hz, 1H), 4.98- 4.91 (m, 1H), 4.86-4.80 (m, 1H), 4.17 (s, 1H), 4.043.99 (m, 1H), 3.25 (d, J=9, 7 Hz, 1H), 3.02 (d, J=9.7 Hz, 1H), 2.26 (s, 3H), 2.04-1.95 (m, 1H), 1.50-1, 42(m, 1H).

Example 54: rac-(1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4yl)-7-oxabicyclo[2.2. 1]heptane-2-carboxamide LC-MS: Rt=1.48 min; MS mass/charge [M+H]+ 447.0.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 9.70 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.52 (dd, J=5.1, 1.5Hz, 1H), 7.37-7.33 (m, 2H), 6.96 (dd, J=8.8, 2.4Hz, 1H), 4.99-4.97(m, 1H), 4.89-4.86(m, 1H), 4.26(s, 1H), 4.074.03(m, 1H), 3.49(d, J=9.7Hz, 1H), 3.10(d, J=9.9Hz, 1H), 2.06-2.00(m, 1H), 1.52-1.46(m, 1H ). -3:1 mixture of alcohol regioisomers.

Examples 54a and 54b (corresponding to peak 1 and peak 2).

(1 R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide or (1S,2R,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo [2.2.1]heptane-2-carboxamide

Chiral resolution of rac-(1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2 .1]heptane-2-carboxamide (Example 54) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm AD at 30°C

Mobile phase: 80% CO2 / 20% MeOH + 0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=0.80 min. LC-MS: Rt=1.42 min; MS mass/charge [M+H]+ 447.0.

1H NMR (400 MHz, DMSO-d6) δ 9.73 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.52 (dd , J=5.1, 1.6 Hz,

- 32 040531

1H), 7.38-7.34 (m, 2H), 6.96 (dd, J=8.8, 2.4 Hz, 1H), 5.04-4.96 (m, 1H), 4 .90-4.84 (m, 1H), 4.25 (s, 1H), 4.074.00 (m, 1H), 3.49 (d, J=9.8 Hz, 1H), 3.10 ( d, J=9.8 Hz, 1H), 2.06-1.99(m, 1H), 1.54-1.45(m, 1H).

Peak 2: SFC Retention time=1.28 min. LC-MS: Rt=1.42 min; MS mass/charge [M+H]+ 447.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 7.73 (s, 1H), 7.52 (dd, J=5.1, 1.6Hz, 1H), 7.38-7.34 (m, 2H), 6.96 (dd, J=8.8, 2.4Hz, 1H), 5.04-4.96 (m, 1H), 4.90-4.84 (m, 1H), 4.25 (s, 1H), 4.074.00 (m, 1H), 3.49 (d, J=9.8Hz, 1H), 3.10(d, J=9.8Hz, 1H), 2.06-1.99(m, 1H), 1.54-1.45(m, 1H ).

Example 55 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-5-hydroxy-7-oxabicyclo [2.2. 1 ]heptane-2-carboxamide

LCMS: Rt=1.28 min; MS mass/charge [M+H]+ 423.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.71 (s, 1H), 8.15 (s, 2H), 7.40 (d, J=8.8 Hz, 1H), 7.35 ( d, J=2.4Hz, 1H), 7.03 (dd, J=8.9, 2.4Hz, 1H), 4.93-4.89 (m, 1H), 4.80-4 .77 (m, 1H), 4.15 (s, 1H), 4.02-3.97 (m, 1H), 3.16 (d, J=9.5 Hz, 1H), 2.93 ( s, 6H), 2.91 (d, J=9.5 Hz, 1H), 2.01-1.96 (m, 1H), 1.46-1.40 (m, 1H). -3:1 mixture of alcohol regioisomers.

Example 56 (1 R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-5-yl)-7 oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.20 min; MS mass/charge [M+H]+ 394.0.

1H NMR (400 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.49 (s, 2H), 7.41 (d, J=8.8 Hz, 1H), 7.29 (d , J=2.4 Hz, 1H), 6.96 (dd, J=8.8, 2.4 Hz, 1H), 4.85-4.79 (m, 1H), 4.59-4, 53 (m, 1H), 4.24 (s, 1H), 4.06-4.01 (m, 1H), 3.33 (d, J=9.6 Hz, 1H), 3.01 (d , J=9.7 Hz, 1H), 2.38 (s, 3H), 2.05-1.98 (m, 1H), 1.50-1.43 (m, 1H). -3:1 mixture of alcohol regioisomers.

Example 57 (1R,2S,3S,4R,5S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane -2- carboxamide

LC-MS: Rt=1.10 min; MS mass/charge [M+H]+ 394.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.73 (s, 1H), 7.61 (d, J=6.3 Hz, 1H), 7.55 (d, J=2.4 Hz, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.08 (dd, J=8.8, 2.4 Hz, 1H), 6.86 (s, 2H), 6, 64 (s, 1H), 6.58-6.55 (m, 1H), 4.98-4.95 (m, 1H), 4.85-4.82 (m, 1H), 4.16 ( s, 1H), 4.03-3.99 (m, 1H), 3.21 (d, J=9.9 Hz, 1H), 3.04 (d, J=9.8 Hz, 1H), 2.01-1.96(m, 1H), 1.49-1.43(m, 1H). -3:1 mixture of alcohol regioisomers.

Example 58: (1 R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2,5-difluoropyridin-4-yl)-5-hydroxy-7oxabicyclo [2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.38 min; MS mass/charge [M+H]+ 415.0.

1H NMR (400 MHz, DMSO-d6) δ 9.98 (s, 1H), 7.99 (d, J=1.3 Hz, 1H), 7.46-7.41 (m, 2H), 7 .10-7.05 (m, 2H), 5.06-5.01 (m, 1H), 4.85-4.81 (m, 1H), 4.37 (s, 1H), 4.10 -4.03 (m, 1H), 3.63 (d, J=10.0 Hz, 1H), 3.11 (d, J=9.7 Hz, 1H), 2.06-1.99 ( m, 1H), 1.52-1.46 (m, 1H). -2:1 mixture of alcohol regioisomers.

Example 59 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy-7oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.40 min; MS mass/charge [M+H]+ 415.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (s, 1H), 7.84 (d, J=5.2 Hz, 1H), 7.45-7.40 (m, 2H), 7.34 (t, J=4.9 Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H), 5.04-5.01 (m, 1H), 4 .88-4.83 (m, 1H), 4.30 (s, 1H), 4.10-4.05 (m, 1H), 3.70 (d, J=10.0 Hz, 1H), 3.12 (d, J=9.7 Hz, 1H), 2.08-2.00 (m, 1H), 1.53-1.46 (m, 1H). -2:1 mixture of alcohol re- 33 040531 gioisomers.

Example 60 (1R,2S,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]heptan-2 -carboxamide

LC-MS: Rt=1.11 min; MS mass/charge [M+H] ⁺ 395.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.74 (s, 1H), 8.06 (s, 2H), 7.50 (d, J=2.4 Hz, 1H), 7.41 ( d, J=8.8 Hz, 1H), 7.09-7.06 (m, 1H), 6.25 (s, 2H), 4.92-4.89 (m, 1H), 4.81 -4.76 (m, 1H), 4.12 (s, 1h), 4.01-3.97 (m, 1H), 3.13 (d, J=9.6 Hz, 1H), 2, 91 (d, J=9.8 Hz, 1H), 2.00-1.94 (m, 1H), 1.46-1.40 (m, 1H). —3:1 mixture of alcohol regioisomers.

Example 61 (1 R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LCMS: Rt=1.33 min; MS mass/charge [M+H]+ 398.0.

'H NMR (500 MHz, DMSO-d ₆ ) δ 9.91 (s, 1H), 8.57 (d, J=1.5 Hz, 2H), 7.42-7.41 (m, 2H) , 7.03 (dd, J=8.8, 2.5 Hz, 1H), 5.02-4.98 (m, 1H), 4.86-4.82 (m, 1H), 4.30 (s, 1H), 4.06-4.02 (m, 1H), 3.47 (d, J=9.6 Hz, 1H), 3.05 (d, J=9.l Hz, 1H) , 2.07-2.01 (m, 1H), 1.52-1.46 (m, 1H). —2:1 mixture of alcohol regioisomers.

Example 62 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyrimidin-5yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.03 min; MS mass/charge [M+H] ⁺ 448.1.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.90 (s, 1H), 8.83 (s, 2H), 7.38 (d, J=8.8 Hz, 1H), 7.28 ( d, J=2.4Hz, 1H), 6.94 (dd, J=8.8, 2.5Hz, 1H), 5.08-5.03 (m, 1H), 4.89-4 .85 (m, 1H), 4.41 (s, 1H), 4.09-4.05 (m, 1H), 3.53 (d, J=9.6 Hz, 1H), 3.11 ( d, J=9.6 Hz, 1H), 2.09-2.03 (m, 1H), 1.56-1.47 (m, 1H). —3:1 mixture of alcohol regioisomers.

Example 63 (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-methoxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

The described Example 63 was synthesized according to the protocol described for Example 47 using methyl-(1R,4S,5S)-3-bromo-5-methoxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate and methyl (1S,4S,6R)-3-bromo-6-methoxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate (intermediate 1f) and 3,4-dichloroaniline in step A and (2-methylpyridin-4-yl)boronic acid in step C. LC-MS: Rt=1.23 min; MS mass/charge [M+H] ⁺ 407.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 9.61 (s, 1H), 8.11 (d, J=5.1 Hz, 1H), 7.39-7.36 (m, 2H), 7.12 (s, 1H), 7.03 (d, J=5.4Hz, 1H), 6.99 (dd, J=8.9, 2.5Hz, 1H), 4.86-4 .81 (m, 1H), 4.48 (s, 1H), 3.76-3.72 (m, 1H), 3.283.24 (m, 1H), 3.21 (s, 3H), 3. 06 (d, J=9.5 Hz, 1H), 2.27 (s, 3H), 2.03-1.97 (m, 1H), 1.54-1.48 (m, 1H). —4:1 mixture of methoxyregioisomers.

Example 64 (1R,2S,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

The title compound was prepared from (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (intermediate 4a, example 48) using step A in scheme 4.

Step A: To a stirred solution of (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(6methylpyridin-3-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (25 mg, 0.064 mmol) in DCM (1 ml) Xtalfluor-E (36 mg, 0.16 mmol) and Et ₃ N-3HF (0.031 ml, 0.19 mmol) were added at room temperature and

- 34 040531 the reaction mixture was stirred for 16 hours the Reaction mixture was cooled to 0°C and quenched with saturated aqueous sodium bicarbonate. The crude compound was extracted three times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by FCC to give (1R,2S,3S,4R,5R)-N(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2 .1]heptane-2-carboxamide as an unknown mixture of fluorinated regioisomers.

LC-MS: Rt=1.38 min; MS mass/charge [M+H] ⁺ 395.0.

Example 65 (1R,2S,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

Example 65 was synthesized according to the protocol described for example 64 using (1 R,2S,3 S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridine- 4-yl)-7-oxabicyclo[2.2.1]heptan-2-carboxamide (4a, example 49) in step A.

LCMS: Rt=1.53 min; MS mass/charge [M+H] ⁺ 411.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.13 (s, 1H), 7.97-7.94 (m, 1H), 7.77 (d, J=2.5 Hz, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.29 (dd, J=8.8, 2.5 Hz, 1H), 6.69 (dd, J=5.5, 1, 5 Hz, 1H), 6.58 (s, 1H), 5.64 (d, J=72.4 Hz, 1H), 4.854.80 (m, 1H), 3.79 (s, 3H), 3 .70-3.66 (m, 1H), 3.46-3.42 (m, 1H), 3.16-3.13 (m, 1H), 1.99-1.95 (m, 1H) , 1.79

1.75(m, 1H). ~4:1 mixture of fluorinated regiostereomers.

Example 66 (1S,2S,4R,5R,6R,7S)-N-(4-chloro-3-cyanophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

The title compound was prepared from methyl-(1S,2S,4R,5R)-7-bromo-8oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6-carboxylate (Intermediate 1d) using steps A- C and step D in Scheme 2.

Step A: To a stirred solution of methyl-(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0 ^2,4 ]oct6-ene-6-carboxylate (1d, 4.70 g, 19, 2 mmol) in THF (25 ml) and water (6 ml), acetic acid (4.40 ml) was added at 0° C. and Zn (5.00 g, 77.0 mmol) was added in portions. The reaction suspension was stirred until reaching room temperature for 15 minutes. The reaction mixture was filtered and neutralized with saturated aqueous sodium bicarbonate to pH ~7. The compound was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was dried under vacuum. The crude compound (1S,2S,4R,5R)methyl 8oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxylate was used in the next step without further purification. LCMS: Rt=1.16 min; MS mass/charge [M+H] ⁺ 167.1.

Step B: Mixture of (1S,2S,4R,5R)-methyl-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6-carboxylate (800 mg, 4.81 mmol), 2-methyl- 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.27 g, 5.78 mmol), 2,2'bis(diphenylphosphino)-1.1 '-binaphthalene (300 mg, 0.481 mmol), chloro-(1,5-cyclooctadiene)rhodium(I) dimer (119 mg, 0.241 mol) and potassium carbonate (332 mg, 2.41 mmol) in 1,4-dioxane (10 ml) and water (2.5 ml) were heated in a microwave oven at 100° C. for 1 hour. Celite was added to the reaction mixture and the solvent was removed under reduced pressure. The compound was purified by FCC to give (1S,2S,4R,5R,6S,7S)methyl-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxylate (cis) and (1S,2S,4R,5R,6R,7S)methyl-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxylate (trans) , cis LC-MS: Rt=0.88 min; MS mass/charge [M+H] ⁺ 260.1. trans LC-MS: Rt=0.96 min; MS mass/charge [M+H] ⁺ 260.1.

Step C: To a stirred solution of (1S,2S,4R,5R,6R,7S)methyl-7-(2-methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxylate (75, 0 mg, 0.289 mmol) and 5-amino-2-chlorobenzonitrile (44.0 mg, 0.289 mmol) in THF (2 ml) at 0° C. and LiHMDS (1M, 0.434 ml, 0.434 mmol) was added. The reaction mixture was stirred at room temperature for 1 h. LiHMDS (1M, 0.434 mL, 0.434 mmol) was added and the reaction continued to stir at room temperature for 4 h. Celite was added and the solvent was concentrated. The crude compound was purified by FCC to give the title compound (1S,2S,4R,5R,6R,7S)-N-(4-chloro-3-cyanophenyl)-7-(2-methylpyridin-4-yl)- 8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide. Method B LC-MS: Rt=1.11 min; MS mass/charge [M+H] ⁺ 380.1.

1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.22 (d, J=2.5 Hz, 1H ), 7.77 (dd, J=8.9, 2.5 Hz, 1H), 7.69 (d, J=8.9 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=4.0 Hz, 1H), 4.76 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.51 (d, J=4.8 Hz , 1H), 3.09 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.34-1.28 (m, 1H), 1.20-1.15 ( m, 1H), 0.43-35 040531

0.39 (m, 1H), 0.21-0.15 (m, 1H).

Examples 67-76 described below were synthesized according to the protocol described for

Example 66 using methyl-(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-en-6carboxylate (intermediate 1d) and various boronic esters/ boronic acids in step B; and various anilines in step D.

Example 67 (1S,2S,4R,5R,6R,7S)-N-(4-chloro-2-cyanophenyl)-7-(2-methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Method B LC-MS: Rt=1.04 min; MS mass/charge [M+H]+ 380.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.36 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.04 (d, J=2.5 Hz, 1H), 7.77 (dd, J=8.8, 2.5 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.12 (s, 1H), 7, 06 (dd, J=5.1, 1.3Hz, 1H), 4.77 (d, J=4.9Hz, 1H), 4.39 (s, 1H), 3.50 (d,J =4.8Hz, 1H), 3.14(t, J=4.9Hz, 1H), 2.43(s, 3H), 1.42-1.37(m, 1H), 1.33 -1.27 (m, 1H), 0.45-0.40 (m, 1H), 0.21-0.17 (m, 1H).

Example 68 (1S,2S,4R,5R,6R,7S)-N-(4-chloro-3-fluorophenyl)-7-(2-methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Method C LC-MS: Rt=1.47 min; MS mass/charge [M+H] ⁺ 373.1.

1H NMR (400 MHz, DMSC-d6) δ 10.30 (s, 1H), 8.38 (d, J=5.2 Hz, 1H), 7.80 (dd, J=12.0, 2, 3 Hz, 1H), 7.52 (t, J=8.7 Hz, 1H), 7.31-7.28 (m, 1H), 7.19 (s, 1H), 7.12 (d, J=4.9Hz, 1H), 4.76(d, J=4.9Hz, 1H), 4.39(s, 1H), 3.54(d,J=4.8r _y , 1H) , 3.09 (t, J=4.8 Hz, 1H), 2.45 (s, 3H), 1.33-1.28 (m, 1H), 1.18-1.13 (m, 1H ), 0.43-0.39 (m, 1H), 0.21-0.15 (m, 1H).

Example 69 (1S,2S,4R,5R,6R,7S)-7-(2-methyliridin-4-yl)-N-(3-(trifluoromethoxy)phenyl)-8oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide

LC-MS: Rt=1.47 min; MS mass/charge [M+H] ⁺ 405.1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 7.80 (s, 1H), 7.46 -7.41 (m, 2H), 7.12 (s, 1H), 7.08-7.01 (m, 2H), 4.76 (d, J=4.9 Hz, 1H), 4, 38 (s, 1H), 3.51 (d, J=4.8 Hz, 1H), 3.09 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1, 35-1.29(m, 1H), 1.19-1.13(m, 1H), 0.43-0.37(m, 1H), 0.22-0.16(m, 1H).

Example 70 (1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(5-methyltriazol-2-yl)-8oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LC-MS: Rt=1.20 min; MS mass/charge [M+H] ⁺ 342.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 12.12 (s, 1H), 8.55 (d, J=5.9 Hz, 1H), 7.51 (s, 1H), 7.44 ( s, 1H), 7.14 (s, 1H), 4.87 (d, J=4.8 Hz, 1H), 4.48 (d, J=1.8 Hz, 1H), 3.73 ( d, J=4.6 Hz, 1H), 3.21 (d, J=4.9 Hz, 1H), 2.58 (s, 3H), 2.34 (s, 3H), 1.37- 1.32(m, 1H), 1.09-1.03(m, 1H), 0.44-0.38(m, 1H), 0.23-0.17(m, 1H).

Example 71 (1S,2S,4R,5R,6R,7S)-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-7-(2-methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide

LC-MS: Rt=1.50 min; MS mass/charge [M+H] ⁺ 423.1.

1H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.41 (d, J=5.1 Hz, 1H), 7.86 (d, J=12.9 Hz, 1H ), 7.52 (t, J=8.9 Hz, 1H), 7.35 (d, J=8.9 Hz, 1H), 7.25 (s, 1H), 7.19 (d, J =5.4Hz, 1H), 4.78(d, J=4.5Hz, 1H), 4.41(s, 1H), 3.57(d, J=4.4Hz, 1H), 3.11 (t, J=4.3 Hz, 1H), 2.48 (s, 3H), 1.36-1.28 (m, 1H), 1.21-1.13 (m, 1H) , 0.44-0.37 (m, 1H), 0.22-0.16 (m, 1H).

Examples 72 and 73 (corresponding to peak 1 and peak 2).

(1S,2S,4R,5R,6R,7S)-N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide or (1R,2R,4S,5S,6S,7R)-N-(5,6-dichlorophenyl)-7-(2,3-difluoropyridin-4-36 040531 yl)-8 -oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide

Chiral resolution of rac-(1S,2S,4R,5R,6R,7S)-N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin4-yl)-8-oxatricyclo[3.2. 1.0 ^2,4 ]octane-6-carboxamide was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm IA at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.61 min. LC-MS: Rt=1.69 min; MS mass/charge [M+H] ⁺ 412.0.

1H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H ), 8.00 (dd, J=5.2, 1.1Hz, 1H), 7.37 (t, J=4.9Hz, 1H), 4.81 (d, J=5.0Hz , 1H), 4.52 (s, 1H), 3.95 (d, J=4.7 Hz, 1H), 3.20-3.11 (m, 1H), 1.38-1.31 ( m, 1H), 1.26-1.21 (m, 1H), 0.45-0.39 (m, 1H), 0.24-0.16 (m, 1H).

Peak 2: SFC Retention time=3.23 min. LC-MS: Rt=1.69 min; MS mass/charge [M+H] ⁺ 412.0.

1H NMR (500 MHz, DMSO-d6) δ 10.55 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H ), 8.00 (dd, J=5.2, 1.1Hz, 1H), 7.37 (t, J=4.9Hz, 1H), 4.81 (d, J=5.0Hz , 1H), 4.52 (s, 1H), 3.95 (d, J=4.7 Hz, 1H), 3.20-3.11 (m, 1H), 1.38-1.31 ( m, 1H), 1.26-1.21 (m, 1H), 0.45-0.39 (m, 1H), 0.24-0.16 (m, 1H).

Example 74 (1 S,2S,4R,5R,6R,7S)-N-(5,6-dichloropyridin-3-yl)-7-(6-methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide

LCMS: Rt=1.28 min; MS mass/charge [M+H] ⁺ 390.0. 1H NMR (400 MHz, DMSO4) δ 10.51 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.32 (d, J=2.1 Hz, 1H), 7.54 (dd, J=8.0, 2.3 Hz, 1H), 7.19 (d, J=8.0 Hz, 1H ), 4.77 (d, J=4.9 Hz, 1H), 4.32 (s, 1H), 3.54 (d, J=4.7 Hz, lH), 3.10(t, J =4.8 Hz, 1H), 2.42 (s, 3H), 1.35-1.29 (m, 1H), 1.24-1.17 (m, 1H), 0.44-0, 39 (m, 1H), 0.21-0.15 (m, 1H).

Example 75: (1S,2S,4R,5R,6R,7S)-N-(5,6-dichloropyridin-3-yl)-7-(pyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LC-MS: Rt=1.43 min; MS mass/charge [M+H] ⁺ 377.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.52 (s, 1H), 9.06 (s, 1H), 8.69 (s, 2H), 8.49 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H), 4.83 (d, J=4.9 Hz, 1H), 4.43 (s, 1H), 3.62 ( d, J=4.7 Hz, 1H), 3.22 (t, J=4.8 Hz, 1H), 1.37-1.32 (m, 1H), 1.28-1.21 (m , 1H), 0.44-0.40 (m, 1H), 0.22-0.17 (m, 1H).

^Example 76 ⁴ ]octane-6-carboxamide

LC-MS: Rt=1.52 min; MS mass/charge [M+H] ⁺ 406.1.

1H NMR (400 MHz, DMSO-d6) δ 10.52 (s, 1H), 8.49 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H ), 8.07 (d, J=5.3 Hz, 1H), 6.87 (dd, J=5.3, 1.4 Hz, 1H), 6.65 (s, 1H), 4.76 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.81 (s, 3H), 3.52 (d, J=4.8 Hz, 1H), 3.11 (t, J=4.8 Hz, 1H), 1.34-1.27 (m, 1H), 1.23-1.17 (m, 1H), 0.43-0.38 (m, 1H ), 0.19-0.14 (m, 1H).

Example 7 7. rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7 oxabicyclo [2.2. 1] heptane-2-carboxamide

The title compound was prepared from methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7-37 040531 oxabicyclo[2.2.1]hept-2-en-2-carboxylate and methyl-(1S,4S ,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1e) using steps A-B and step D in Scheme 2.

Step A. Solution of methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2carboxylate and methyl-(1S,4S,6R)-3- bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (1e, 1.40 g, 5.62 mmol) and AcOH (1.61 ml, 28.1 mmol) in 1:1 THF:water (15 mL) was treated with Zn powder (735 mg, 11.2 mmol) and stirred at rt. for 1 h. The reaction mixture was diluted with EtOAc and washed with sat. aq. NaHCO ₃ and brine. The aqueous layer was further extracted with EtOAc and the combined EtOAc layers were dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting crude (1R,4S,5S)methyl-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate and (1S,4S,6R)methyl-6-hydroxy7-oxabicyclo[2.2. 1]hept-2-ene-2-carboxylate was used directly from the next step without further purification. LCMS: Rt=0.29 min; MS mass/charge [M+H]+ 171.1.

Step B. Solution of crude (1R,4S,5S)-methyl-5-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2carboxylate and (1S,4S,6R)-methyl-6-hydroxy-7 -oxabicyclo[2.2.1]hept-2-en-2-carboxylate (250 mg, 1.469 mmol) from step A, 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)pyridine (386mg, 1.763mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthalene (91mg, 0.147mmol), chloro(1,5cyclooctadiene)rhodium(I) dimer (36 .2 mg, 0.073 mmol) and potassium carbonate (101 mg, 0.735 mmol) in 1,4-dioxane (15 ml) and water (1.5 ml) in a ratio of 4:1 were heated in a microwave oven at 110°C for 1 h. The reaction was repeated on the same scale for a total of four times under identical conditions. The reactions were combined and concentrated on celite and purified by FCC to give (1R,2S,3S,4R,5S)methyl-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo [2.2. 1 ]heptan-2-carboxylate and (1S,2S,3S,4S,6R)methyl-6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2-carboxylate as a mixture of alcohol regioisomers (cis) and (1R,2R,3S,4R,5S)methyl-5-hydroxy-3-(2-methylpyridin-4yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylate and (1S,2R,3S,4S,6R)methyl-6-hydroxy-3-(2-methylpyridin4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylate as a mixture of alcohol regioisomers (trans). cis: LC-MS: Rt=0.29 min; MS mass/charge [M+H]+ 264.2. trans: LC-MS: Rt=0.33 min; MS mass/charge [M+H]+ 264.2.

Step C. Solution of (1R,2R,3S,4R,5S)methyl-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxylate and (1S, 2R,3S,4S,6R)methyl-6-hydroxy-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2-carboxylate (338 mg, 1.284 mmol) and 3,4-dichloroaniline (416 mg, 2.57 mmol) in THF (volume: 16 mL) at rt. treated with LiHMDS (5.14 ml, 5.14 mmol) and stirred at rt. for 1 h. The reaction mixture was concentrated on celite and purified by FCC to give rac-(1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2- methylpyridin-4-yl)-7-oxabicyclo [2.2.1]heptane-2-carboxamide as a mixture of ~ 8:1 alcohol regioisomers with a predominance of the 5-hydroxy product. LC-MS: Rt=1.20 min; MS mass/charge [M+H]+ 393.1.

1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.34 (d, J=5.0 Hz, 1H), 7.97 (d, J=2.5 Hz, 1H ), 7.55 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 7.11 (s, 1H), 7.05 (dd, J=5.3, 1.7 Hz, 1H), 4.98-4.95 (m, 1H), 4.904.87 (m, 1H), 4.23 (s, 1H), 3, 98-3.95 (m, 1H), 3.18-3.14 (m, 1H), 2.96-2.93 (m, 1H), 2.43 (s, 3H), 2.09- 2.04 (m, 1H), 1.45-1.37 (m, 1H).

Examples 77a and 77c (corresponding to peak 1 and peak 3a).

(1 R,2R,3 S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan- 2-carboxamide or (1S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

Examples 77b and 77d (corresponding to peak 2 and peak 3 b).

(1S,2R,3S,4S,6R)-N-(3,4-dichlorophenyl)-6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2- carboxamide or (1R,2S,3R,4R,6S)-N-(3,4-dichlorophenyl)-6-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan- 2-carboxamide

Chiral resolution of rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide in the form of a mixture of ~ 8:1 alcohol regioisomers (example 77) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm AD-H at 30°C

- 38 040531

Mobile phase: 80% CO ₂ /20% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.14 min. LCMS: Rt=1.16 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.34 (dd, J=5.2, 0.8 Hz, 1H), 7.98 (d, J=2, 4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H) , 7.05 (dd, J=5.2, 1.7 Hz, 1H), 5.00-4.97 (m, 1H), 4.91-4.86 (m, 1H), 4.22 (s, 1H), 3.99-3.94 (m, 1H), 3.19-3.14 (m, 1H), 2.96-2.92 (m, 1H), 2.43 (s , 3H), 2.102.04 (m, 1H), 1.44-1.37 (m, 1H).

Peak 2: SFC Retention time=3.56 min. LCMS: Rt=1.16 min; MS mass/charge [M+H]+ 393.1.

% NMR (400 MHz, DMSO-d ₆ ) δ 10.42 (s, 1H), 8.33 (dd, J=5.2, 0.8 Hz, 1H), 8.00 (d, J=2 .5 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H ), 7.06 (dd, J=5.2, 1.7 Hz, 1h), 4.95-4.90 (m, 1H), 4.64-4.59 (m, 1H), 4, 57-4.51 (m, 1H), 4.02-3.96 (m, 1H), 3.26-3.21 (m, 1H), 3.00-2.95 (m, 1H), 2.42 (s, 3H), 2.10-2.01 (m, 1H), 1.55-1.48 (m, 1H).

Peak 3: SFC retention time=4.22 min. The third eluted peak isolated using supercritical liquid chromatography was concentrated and repurified by supercritical liquid chromatography using the following conditions to give the compounds listed below:

Method details:

Column: 21x250 mm AS-H at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 3a: SFC Retention time=1.44 min. LCMS: Rt=1.16 min; MS mass/charge [M+H]+ 393.1.

% NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.34 (dd, J=5.2, 0.8 Hz, 1H), 7.98 (d, J=2, 4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H) , 7.05 (dd, J=5.2, 1.7 Hz, 1h), 5.00-4.97 (m, 1H), 4.91-4.86 (m, 1H), 4.22 (s, 1H), 3.99-3.94 (m, 1H), 3.19-3.14 (m, 1H), 2.96-2.92 (m, 1H), 2.43 (s , 3H), 2.102.04 (m, 1H), 1.44-1.37 (m, 1H).

Peak 3b: SFC Retention time=2.04 min. LCMS: Rt=1.16 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.33 (dd, J=5.2, 0.8 Hz, 1H), 8.00 (d, J=2, 5 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.5 Hz, 1H), 7.11 (s, 1H) , 7.06 (dd, J=5.2, 1.7 Hz, 1H), 4.95-4.90 (m, 1H), 4.64-4.59 (m, 1H), 4.57 -4.51(m, 1H), 4.02-3.96(m, 1H), 3.26-3.21(m, 1H), 3.00-2.95(m, 1H), 2 .42 (s, 3H), 2.10-2.01 (m, 1H), 1.55-1.48 (m, 1H).

Examples 78-91 below were synthesized according to the protocol described for Example 77 using methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1e) and various boronic acids/esters in step B and various anilines/amines in step D.

Example 78 methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2-carboxamide

LCMS: Rt=0.89 min; MS mass/charge [M+H] ⁺ 453.2.

1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 8.35 (dd, J=5.2, 0.8 Hz, 1H), 7.93 (d, J=2, 1 Hz, 1H), 7.517.45 (m, 2H), 7.38-7.27 (m, 4H), 7.13 (s, 1H), 7.07 (dd, J=5.2, 1 .6 Hz, 1H), 5.00-4.97(m, 1H), 4.94-4.89(m, 1H), 4.24(s, 1H), 4.01-3.95( m, 1H), 3.22-3.19 (m, 1H), 3.00-2.96 (m, 1H), 2.44 (s, 3H), 2.12-2.05 (m, 1H), 1.46-1.41 (m, 1H). ~3:1 mixture of alcohol regioisomers.

Example 79 (1 R,2R,3S,4R,5S)-5-hydroxy-3-(2-methylpyridin-4-yl)-X-(1-(methylsulfonyl)piperidin-4-yl)-7- oxabicyclo [2.2.1 ]heptane-2-carboxamide

LC-MS: Rt=0.20 min; MS mass/charge [M+H]+ 410.2. A mixture of alcohol regioisomers.

Example 80 (1R,2R,3S,4R,5S)-N-(4,5-dichloropyridin-2-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7oxabicyclo [2.2.1 ]heptan-2-carboxamide

- 39 040531

LC-MS: Rt=0.73 min; MS mass/charge [M+H]+ 394.1.

1H NMR (500 MHz, DMSO-d6) δ 11.03 (s, 1H), 8.52 (s, 1H), 8.37-8.32 (m, 2H), 7.10 (s, 1H) , 7.04 (dd,

J=5.3, 1.7 Hz, 1H), 5.00-4.95(m, 1H), 4.95-4.89(m, 1H), 4.24(s, 1H), 4 .00-3.94 (m, 1H), 3.22-3.18 (m, 1H),

3.13-3.09 (m, 1H), 2.43 (s, 3H), 2.07-1.99 (m, 1H), 1.43-1.36 (m, 1H). ~5:1 mixture of alcohol regioisomers.

Example 81: (1R,2R,3S,4R,5S)-N-(5-chloro-6-methylpyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4yl)-7-oxabicyclo [2.2 .1 ]heptane-2-carboxamide

LC-MS: Rt=0.57 min; MS mass/charge [M+H]+ 374.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.37 (s, 1H), 8.45 (d, J=2.2 Hz, 1H), 8.34 (dd, J=5.2, 0 .8 Hz, 1H), 8.17 (d, J=2.2 Hz, 1H), 7.12 (d, J=1.7 Hz, 1H), 7.06 (dd, J=5.3 , 1.7 Hz, 1H), 5.00-4.96 (m, 1H), 4.93-4.87 (m, 1H), 4.22 (s, 1H), 3.99-3, 91 (m, 1H), 3.21-3.15 (m, 1H), 2.99-2.94 (m, 1H), 2.47 (s, 3H), 2.43 (s, 3H) , 2.11-2.04(m, 1H), 1.44-1.36(m, 1H). ~5:1 mixture of alcohol regioisomers.

Example 82 (1 R,2R,3 S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-4-yl)-7 oxabicyclo[2.2.1] heptane-2-carboxamide

T 11 ^N ^N

LCMS: Rt=0.83 min; MS mass/charge [M+H]+ 394.1. A mixture of alcohol regioisomers.

Examples 83 and 84 (corresponding to peak 1 and peak 2A).

(1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide or (1S,2S,3R,4S,5R)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[ 2.2.1 ]heptane-2-carboxamide

Chiral resolution of rac-( 1 R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2 .1]heptane-2-carboxamide as a mixture of alcohol regioisomers was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm IA at 30°C

Mobile phase: 80% CO ₂ /20% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.96 min. LC-MS: Rt=1.05 min; MS mass/charge [M+H]+ 394.2.

1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H ), 8.34 (dd, J=5.2, 0.7Hz, 1H), 7.12 (s, 1H), 7.06 (dd, J=5.2, 1.7Hz, 1H) , 5.02-4.98(m, 1H), 4.94-4.89(m, 1H), 4.23(s, 1H), 4.00-3.94(m, 1H), 3 .19-3.15 (m, 1H), 3.01-2.94 (m, 1H), 2.43 (s, 3H), 2.12-2.03 (m, 1H), 1.45 -1.38 (m, 1H).

Peak 2: The second eluted peak isolated using SLC with retention time=3.03 min was concentrated and repurified by SLC using the following conditions to give the compound below.

Method details:

Column: 21x250 mm AD-H at 30°C

Mobile phase: 80% CO ₂ /20% IPA+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 2A: First eluted peak. SFC Retention time=2.18 min. LC-MS: Rt=1.05 min; MS mass/charge [M+H]+ 394.2.

1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H ), 8.34 (dd,

- 40 040531

J=5.2, 0.7Hz, 1H), 7.12(s, 1H), 7.06(dd, J=5.2, 1.7Hz, 1H), 5.02-4.98 (m, 1H), 4.94-4.89 (m, 1H), 4.23 (s,

1H), 4.00-3.94 (m, 1H), 3.19-3.15 (m, 1H), 3.01-2.94 (m, 1H), 2.43 (s, 3H) , 2.12-2.03 (m, 1H), 1.45-1.38 (m,

1H).

Example 85 (1 R,2R,3S,4R,5S)-5-hydroxy-3-(2-methylpyridin-4-yl)-X-(3-(trifluoromethyl)phenyl)-7oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.13 min; MS mass/charge [M+H]+ 393.3.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.41 (s, 1H), 8.34 (dd, J=5.2, 0.8 Hz, 1H), 8.09 (s, 1H), 7.73-7.69 (m, 1H), 7.57-7.52 (m, 1H), 7.43-7.38 (m, 1H), 7.12 (s, 1H), 7, 07 (dd, J=5.2, 1.7 Hz, 1H), 5.02-4.95 (m, 1H), 4.944.88 (m, 1H), 4.23 (s, 1H), 4 .01-3.94 (m, 1H), 3.22-3.17 (m, 1H), 3.00-2.96 (m, 1H), 2.43 (s, 3H), 2.13 -2.04 (m, 1H), 1.45-1.37 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 86: (1S,2R,3S,4S,6R)-6-hydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7oxabicyclo[2.2.1]heptane- 2-carboxamide

LCMS: Rt=1.12 min; MS mass/charge [M+H]+ 393.3.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.51 (s, 1H), 8.34 (dd, J=5.2, 0.7 Hz, 1H), 8.12 (s, 1H), 7.76-7.72(m, 1H), 7.59-7.53(m, 1H), 7.45-7.40(m, 1H), 7.13-7.10(m, 1H ), 7.07 (dd, J=5.2, 1.7 Hz, 1H), 4.92 (s, 1H), 4.664.61 (m, 1H), 4.58-4.53 (m, 1H), 4.05-3.98 (m, 1H), 3.28-3.23 (m, 1H), 3.03-2.98 (m, 1H), 2.42 (s, 3H) , 2.102.02 (m, 1H), 1.56-1.46 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 87 (1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo [2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=0.84 min; MS mass/charge [M+H]+ 380.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 8.50-8.46 (m, 2H), 8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 7.29-7.25 (m, 2H), 5.04-4.99 (m, 1H), 4.96-4.90 ( m, 1H), 4.25 (s, 1H), 4.02-3.95 (m, 1H), 3.26-3.22 (m, 1H), 3.01-2.96 (m, 1H), 2.12-2.04 (m, 1H), 1.48-1.37 (m, 1H). -5:1 mixture of alcohol regioisomers.

Example 88 (1R,2R,3S,4R,5S)-5-hydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7oxabicyclo[2.2.1]heptan-2- carboxamide

LC-MS: Rt=1.11 min; MS mass/charge [M+H]+ 379.2.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.47 (s, 1H), 8.49-8.46 (m, 2H), 8.09 (s, 1H), 7.74-7, 70 (m, 1H), 7.577.51 (m, 1H), 7.42-7.37 (m, 1H), 7.29-7.25 (m, 2H), 5.01 (s, 1H) , 4.96-4.90(m, 1H), 4.25(s, 1H), 4.02-3.97(m, 1H), 3.27-3.22(m, 1H), 3 .02-2.98 (m, 1H), 2.14-2.04 (m, 1H), 1.46-1.37 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 89 2-carboxamide

LC-MS: Rt=1.08 min; MS mass/charge [M+H]+ 379.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.56 (s, 1H), 8.50-8.45 (m, 2H), 8.12 (s, 1H), 7.77-7.73 (m, 1H), 7.597.53 (m, 1H), 7.44-7.40 (m, 1H), 7.29-7.24 (m, 2H), 4.94 (s, 1H), 4.69-4.62 (m, 1H), 4.61-4.55 (m, 1H), 4.043.97 (m, 1H), 3.32-3.28 (m, 1H), 3, 06-3.00 (m, 1H), 2.13-2.03 (m, 1H), 1.58-1.48 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 90 rac-( 1 R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy7-oxabicyclo[ 2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.30 min; MS mass/charge [M+H]+ 398.1. A mixture of alcohol regioisomers.

Examples 90a and 90b (corresponding to peak 1 and peak 2).

- 41 040531 (1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2 .1]heptan-2-carboxamide or (1S,2S,3R,4S,5R)-N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4yl)-5-hydroxy-7 -oxabicyclo[2.2.1]heptane-2-carboxamide

Chiral resolution of rac-(1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)5-hydroxy-7-oxabicyclo[2.2 .1]heptane-2-carboxamide (Example 90) as a mixture of alcohol regioisomers was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 21x250 mm IF at 30°C

Mobile phase: 70% CO ₂ /30% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.29 min. LC-MS: Rt=1.30 min; MS mass/charge [M+H]+ 398.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.27-7.23 (m, 1H), 7.02 (s, 1H), 5.06-5.02 (m , 1H), 4.97-4.92(m, 1H), 4.28(s, 1H), 4.01-3.96(m, 1H), 3.35-3.33(m, 1H ), 3.04-2.99 (m, 1H), 2.13-2.05 (m, 1H), 1.47-1.38 (m, 1H).

Peak 2: SFC Retention time=1.95 min. LC-MS: Rt=1.30 min; MS mass/charge [M+H]+ 398.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.58 (s, 1H), 8.45 (d, J=2.4 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.27-7.23 (m, 1H), 7.02 (s, 1H), 5.06-5.02 (m , 1H), 4.97-4.92(m, 1H), 4.28(s, 1H), 4.01-3.96(m, 1H), 3.35-3.33(m, 1H ), 3.04-2.99 (m, 1H), 2.13-2.05 (m, 1H), 1.47-1.38 (m, 1H).

Example 91 (1R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy7-oxabicyclo [2.2 .1 ]heptane-2-carboxamide

LC-MS: Rt=1.35 min; MS mass/charge [M+H]+ 416.1.

1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 8.44 (d, J=2.4 Hz, 1H), 8.39 (d, J=2.4 Hz, 1H ), 8.01 (dd, J=5.2, 1.2 Hz, 1H), 7.42-7.37 (m, 1H), 5.11-5.08 (m, 1H), 4, 96-4.93 (m, 1H), 4.36 (s, 1H), 4.02-3.97 (m, 1H), 3.64-3.60 (m, 1H), 3.05- 3.02 (m, 1H), 2.15-2.07 (m, 1H), 1.49-1.40 (m, 1H). ~5:1 mixture of alcohol regioisomers.

Examples 92-102 below were synthesized according to the protocol described for example 77 using methyl-(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1 ]hept-2-ene-2-carboxylate (intermediate 1g) and various boronic acids/ esters in step B and various anilines in step D. Examples 92 and 94 (corresponding to peak 1 and peak 3) 3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2S,3R,4S,5S)-N-(3,4-dichlorophenyl)-5fluoro-3- (2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2-carboxamide

Examples 93 and 95 (corresponding to peak 2 and peak 4) oxabicyclo[2.2.1]heptane-2-carboxamide or (1R,2S,3R,4R,6R)-N-(3,4dichlorophenyl)-6-fluoro-3-(2-methylpyridin-4-yl)-7- oxabicyclo [2.2.1 ]heptane-2-carboxamide

Chiral resolution of rac-(1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)7-oxabicyclo[2.2.1]heptane -2-carboxamide as a mixture of fluorinated regioisomers was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm IF at 30°C

- 42 040531

Mobile phase: 95-50% CO2/5-50% MeOH+0.5% isopropylamine in 5 minutes

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.45 min. LC-MS: Rt=1.35 min; MS mass/charge [M+H] ⁺ 395.1.

1H NMR (400 MHz, acetonitrile-d3) δ 8.50 (s, 1H), 8.36 (dd, J=5.2, 0.8 Hz, 1H), 7.88 (dd, J=2, 3, 0.6Hz, 1H), 7.46-7.39(m, 2H), 7.16(s, 1H), 7.10(dd, J=5.2, 1.7Hz, 1H ), 5.24-5.02 (m, 1H), 4.92-4.87 (m, 1H), 4.654.58 (m, 1H), 4.09-4.02 (m, 1H), 3.18-3.11(m, 1H), 2.46(s, 3H), 2.23-2.16(m, 1H), 1.91-1.79(m, 1H).

Peak 2: SFC Retention time=2.75 min. LC-MS: Rt=1.35 min; MS mass/charge [M+H] ⁺ 395.1.

1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.61 (s, 1H), 8.36 (dd, J=5.2, 0.7 Hz, 1H), 7.87 (d, J=2 .4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.40-7.37 (m, 1H), 7.13 (s, 1H), 7.07 (dd , J=5.2, 1.7 Hz, 1H), 5.12-4.97 (m, 1H), 4.974.95 (m, 1H), 4.68-4.62 (m, 1H), 3.26-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.46 (s, 3H), 2.41-2.29 (m, 1H), 1.831, 68(m, 1H).

Peak 3: SFC Retention time=2.85 min. LC-MS: Rt=1.35 min; MS mass/charge [M+H] ⁺ 395.1.

1H NMR (400 MHz, acetonitrile^) δ 8.50 (s, 1H), 8.36 (dd, J=5.2, 0.8 Hz, 1H), 7.88 (dd, J=2.3 , 0.6 Hz, 1H), 7.46-7.39 (m, 2H), 7.16 (s, 0H), 7.10 (dd, J=5.2, 1.7 Hz, 1H) , 5.24-5.02(m, 1H), 4.92-4.87(m, 1H), 4.654.58(m, 1H), 4.09-4.02(m, 1H), 3 .18-3.11(m, 1H), 2.46(s, 3H), 2.23-2.16(m, 1H), 1.91-1.79(m, 1H).

Peak 4: SFC Retention time=3.12 min. LC-MS: Rt=1.35 min; MS mass/charge [M+H] ⁺ 395.1. 1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.61 (s, 1H), 8.36 (dd, J=5.2, 0.7 Hz, 1H), 7.87 (d, J=2 .4 Hz, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.40-7.37 (m, 1H), 7.13 (s, 1H), 7.07 (dd , J=5.2, 1.7 Hz, 1H), 5.12-4.97 (m, 1H), 4.97-4.95 (m, 1H), 4.68-4.62 (m , 1H), 3.26-3.20 (m, 1H), 2.97-2.91 (m, 1H), 2.46 (s, 3H), 2.41-2.29 (m, 1H ), 1.83-1.68 (m, 1H).

Example 96 2-carboxamide

LC-MS: Rt=1.29 min; MS mass/charge [M+H] ⁺ 395.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.38 (s, 1H), 8.37 (dd, J=5.1, 0.8 Hz, 1H), 8.10 (s, 1H), 7.75-7.71 (m, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.45-7.39 (m, 1H), 7.16 (s, 1H) , 7.10 (dd, J=5.2, 1.7 Hz, 1H), 5.25-5.03 (m, 1H), 5.01-4.95 (m, 1H), 4.74 -4.68 (m, 1H), 4.06-3.98 (m, 1H), 3.25-3.20 (m, 1H), 2.44 (s, 3H), 2.25-2 .10 (m, 1H), 1.82-1.70 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 97: (1 R,2R,3 S,4R,5R)-5-fluoro-N-(6-methoxypyridin-3-yl)-3-(2-methylpyridin-4-yl)-7 oxabicyclo[2.2. 1]heptane-2-carboxamide

LCMS: Rt=0.92 min; MS mass/charge [M+H] ⁺ 358.2.

1H NMR (400 MHz, DMSO-d6) δ 10.06 (s, 1H), 8.37 (d, J=5.2 Hz, 1H), 8.31 (dd, J=2.7, 0, 7 Hz, 1H), 7.87 (dd, J=8.9, 2.7 Hz, 1H), 7.15 (s, 1H), 7.09 (dd, J=5.2, 1.7 Hz, 1H), 6.79 (dd, J=8.8, 0.7 Hz, 1H), 5.24-5.04 (m, 1H), 4.97-4.91 (m, 1H) , 4.71-4.66 (m, 1H), 4.02-3.98 (m, 1H), 3.80 (s, 3H), 3.22-3.15 (m, 1H), 2 .44 (s, 3H), 2.24-2.09 (m, 1H), 1.82-1.70 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 98 (1R,2R,3S,4R,5R)-N-(5,6-dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1 ]heptan-2-carboxamide

LCMS: Rt=1.21 min; MS mass/charge [M+H] ⁺ 396.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.59 (s, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H), 8.37 (d, J=5.1 Hz, 1H), 7.17-7.14 (m, 1H), 7.09 (dd, J=5.2, 1.7 Hz, 1H ), 5.26-5.05 (m, 1H), 5.01-4.94 (m, 1H), 4.75-4.67 (m, 1H), 4.03-3.97 (m , 1H), 3.27-3.21(m, 1H), 2.44(s, 3H), 2.24-2.11(m, 1H), 1.81-1.67(m, 1H ). >20:1 mixture of fluorinated regioisomers.

Example 99 2-carboxamide

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LC-MS: Rt=1.30 min; MS mass/charge [M+H]+ 411.2.

1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.38 (dd, J=5.2, 0.8 Hz, 1H), 7.78 (s, 1H), 7 .49-7.41 (m, 2H), 7.19-7.15 (m, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 7.08-7 .04 (m, 1H), 5.26-5.04 (m, 1H), 4.99-4.94 (m, 1H), 4.75-4.66 (m, 1H), 4.04 -4.00 (m, 1H), 3.25-3.20 (m, 1H), 2.45 (s, 3H), 2.24-2.09 (m, 1H), 1.81-1 .68 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 100 (1R,2R,3S,4R,5R)-5-fluoro-N-(3-fluoro-4-(trifluoromethoxy)phenyl)-3-(2-methylpyridin-4yl)-7-oxabicyclo[2.2. 1]heptane-2-carboxamide

LC-MS: Rt=1.36 min; MS mass/charge [M+H]+ 429.2.

1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.37 (d, J=0.7 Hz, 1H), 7.84 (dd, J=12.9, 2, 5 Hz, 1H), 7.55-7.50 (m, 1H), 7.36-7.32 (m, 1H), 7.15 (s, 1H), 7.09 (dd, J=5 .2, 1.7 Hz, 1H), 5.25-5.04 (m, 1H), 4.99-4.93 (m, 1H), 4.74-4.68 (m, 1H), 4.03-3.99 (m, 1H), 3.25-3.17 (m, 1H), 2.44 (s, 3H), 2.23-2.10 (m, 1h), 1, 79-1.65 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 101 (1 R,2R,3S,4R,5R)-5-fluoro-Na(1-methyl-1H-pyrazol-3-yl)-3-(2-methylpyridin-4-yl)-7 oxabicyclo [2.2.1 ]heptane-2-carboxamide

LC-MS: Rt=0.43 min; MS mass/charge [M+H]+ 331.3.

1H NMR (400 MHz, DMSO-d6) δ 10.54 (s, 1H), 8.36 (dd, J=5.1, 0.8 Hz, 1H), 7.55 (d, J=2, 3Hz, 1H), 7.12(s, 1H), 7.06(dd, J=5.2, 1.7Hz, 1H), 6.46(d, J=2.2Hz, 1H) , 5.22-5.01 (m, 1H), 4.95-4.89 (m, 1H), 4.70-4.65 (m, 1H), 4.03-3.98 (m, 1H), 3.71 (s, 3H), 3.20-3.15 (m, 1H), 2.44 (s, 3H), 2.19-2.06 (m, 1H), 1.75 -1.61 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 102 (1R,2R,3S,4R,5R)-5-fluoro-3-(2-methylpyridin-4-yl)-N-(5-methylthiazol-2-yl)-7-oxabicyclo [2.2.1 ] heptane-2-carboxamide

LC-MS: Rt=1.04 min; MS mass/charge [M+H]+ 348.2.

¹ H NMR (400 MHz, DMSO-d6) δ 12.11 (s, 1H), 8.37 (dd, J=5.1, 0.7 Hz, 1H), 7.16-7.11 (m , 2H), 7.08 (dd, J=5.3, 1.7 Hz, 1H), 5.25-5.04 (m, 1H), 5.02-4.97 (m, 1H), 4.75-4.69 (m, 1H), 4.06-4.00 (m, 1H), 3.33-3.27 (m, 1H), 2.44 (s, 3H), 2, 34 (s, 3H), 2.24-2.10 (m, 1H), 1.68-1.53 (m, 1H). -8:1 mixture of fluorinated regioisomers.

Examples 103-116 below were synthesized according to the protocol described for example 77 using methyl-(1R,4S,5S)-3-bromo-5-fluoro-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-fluoro-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1j) and various boronic acids/esters in stage B and various anilines in stage D.

Example 103 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7 oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.54 min; MS mass/charge [M+H]+ 411.2.

1H NMR (500 MHz, DMSO-d6) δ 10.37 (s, 1H), 8.10 (dd, J=5.3, 0.7 Hz, 1H), 7.97 (d, J=2, 4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.4 Hz, 1H), 6.88 (dd, J= 5.4, 1.5 Hz, 1H), 6.66 (s, 1H), 5.16-5.01 (m, 1H), 5.01-4.98 (m, 1H), 4.67 (d, J=10.6 Hz, 1H), 3.83 (s, 3H), 3.24-3.19 (m, 1H), 3.02-2.96 (m, 1H), 2, 30-2.20 (m, 1H), 1.79-1.64 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 104 (1S,2R,3S,4S,6R)-N-(3,4-dichlorophenyl)-6-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.55 min; MS mass/charge [M+H]+ 411.1.

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1H NMR (400 MHz, acetonitrile-d3) δ 8.55 (s, 1H), 8.07 (dd, J=5.4, 0.7 Hz, 1H), 7.86 (d, J=2, 4Hz, 1H),

7.43 (d, J=8.7 Hz, 1H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 6.87 (dd, J=5.3, 1, 5 Hz, 1H), 6.67 (dd, J=1.5, 0.7 Hz, 1H),

5.11-4.92 (m, 2H), 4.67-4.59 (m, 1H), 3.86 (s, 3H), 3.27-3.21 (m, 1H), 2, 97-2.90(m, 1H), 2.43-2.31(m, 1H),

1.84-1.65 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 105: (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.31 min; MS mass/charge [M+H]+ 395.2.

¹ H NMR (400 MHz, α-cetonitrile-dh) δ 8.56 (s, 1H), 8.36 (dd, J=5.2, 0.8 Hz, 1H), 7.87 (d, J=2 .4 Hz, 1H), 7.45-7.38(m, 2H), 7.13(s, 1H), 7.08-7.06(m, 1H), 5.13-4.93( m, 2H), 4.68-4.63 (m, 1H), 3.26-3.22 (m, 1H), 2.96-2.91 (m, 1H), 2.46 (s, 3H), 2.40-2.30 (m, 1H), 1.85-1.77 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 106 (1 S,2R,3S,4S,6R)-N-(3,4-dichlorophenyl)-6-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.31 min; MS mass/charge [M+H]+ 395.2.

1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.52 (s, 1H), 8.36 (dd, J=5.2, 0.8 Hz, 1H), 7.89 (d, J=2 .0 Hz, 1H), 7.45-7.38 (m, 2H), 7.18-7.15 (m, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 5.23-5.03 (m, 1H), 4.91-4.86 (m, 1H), 4.644.59 (m, 1H), 4.08-4.05 (m, 1H) , 3.19-3.13(m, 1H), 2.46(s, 3H), 2.20-2.11(m, 1H), 1.91-1.79(m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 107 2-carboxamide

LC-MS: Rt=1.29 min; MS mass/charge [M+H]+ 395.2.

1H NMR (400 MHz, acetonitrile^) δ 8.72 (s, 1H), 8.35 (dd, J=5.2, 0.8 Hz, 1H), 8.02 (s, 1H), 7, 68-7.62(m, 1H), 7.52-7.46(m, 1H), 7.42-7.36(m, 1H), 7.14(s, 1H), 7.07( dd, J=5.2, 1.7 Hz, 1H), 5.13-4.95(m, 2H), 4.70-4.63(m, 1H), 3.29-3.23( m, 1H), 2.99-2.92 (m, 1H), 2.45 (s, 3H), 2.43-2.34 (m, 1H), 1.86-1.67 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 108 2-carboxamide

LC-MS: Rt=1.29 min; MS mass/charge [M+H]+ 395.2.

1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.59 (s, 1H), 8.37 (dd, J=5.2, 0.8 Hz, 1H), 8.03 (s, 1H), 7.71-7.67(m, 1H), 7.53-7.47(m, 1H), 7.42-7.37(m, 1H), 7.18(s, 1H), 7, 11 (dd, J=5.3, 1.7 Hz, 1H), 5.24-5.03 (m, w), 4.94-4.89 (m, 1H), 4.66-4, 60 (m, 1H), 4.12-4.07 (m, 1H), 3.21-3.16 (m, 1H), 2.46 (s, 3H), 2.24-2.14 ( m, 1H), 1.90-1.81 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 109: (1 R,2R,3S,4R,5S)-N-(5,6-dichloropyridin-3-yl)-5-fluoro-3-(2-methylpyridin-4-yl)-7 oxabicyclo[2.2 .1 ]heptane-2-carboxamide

LCMS: Rt=1.22 min; MS mass/charge [M+H]+ 396.2.

1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.73 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 8.36 (dd, J=5.2, 0 .8 Hz, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.14-7.13 (m, 1H), 7.07 (dd, J=5.3, 1, 7 Hz, 1H), 5.13-4.94 (m, 2H), 4.69-4.62 (m, 1H), 3.27-3.21 (m, 1H), 3.00-2 .94 (m, 1H), 2.46 (s, 3H), 2.40-2.30 (m, 1H), 1.86-1.67 (m, 1H). >20:1 mixture of fluorinated regioisomers.

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Example 110 (1S,2R,3S,4S,6R)-N-(5,6-dichloropyridin-3-yl)-6-fluoro-3-(2-methylpyridin-4-yl)-7oxabicyclo [2.2.1 ] heptane-2-carboxamide

LCMS: Rt=1.22 min; MS mass/charge [M+H]+ 396.2. 1H NMR (400 MHz, Acetonitrile^) δ 8.69 (s, 1H), 8.42 (d, J=2.4 Hz, 1H), 8.37 (dd, J=5.2, 0.8 Hz, 1H), 8.31 (d, J=2.4 Hz, 1H), 7.17 (s, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 5.24-5.04(m, 1H), 4.93-4.89(m, 1H), 4.64-4.60(m, 1H), 4.09-4.05(m, 1H ), 3.22-3.18 (m, 1H), 2.46 (s, 3H), 2.25-2.14 (m, 1H), 1.90-1.78 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 111 (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.59 min; MS mass/charge [M+H]+ 399.1.

1H NMR (400 MHz, acetonitrile^) δ 8.55 (s, 1H), 8.13 (d, J=5.2 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H) , 7.44 (d, J=8.8 Hz, 1H), 7.37 (dd, J=8.8, 2.4 Hz, 1H), 7.23-7.20 (m, 1H), 6.97-6.93 (m, 1H), 5.13-4.95 (m, 2H), 4.704.65 (m, 1H), 3.39-3.34 (m, 1H), 2, 99-2.94 (m, 1H), 2.41-2.30 (m, 1H), 1.85-1.69 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 112 (1S,2R,3S,4S,6R)-N-(3,4-dichlorophenyl)-6-fluoro-3-(2-fluoropyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.59 min; MS mass/charge [M+H]+ 399.1.

1H NMR (400 MHz, acetonitrile^) δ 8.50 (s, 1H), 8.13 (dd, J=5.2, 0.7 Hz, 1H), 7.88 (d, J=2.2 Hz, 1H), 7.45-7.39 (m, 2H), 7.27-7.23 (m, 1H), 6.99-6.97 (m, 1H), 5.25-5, 04 (m, 1H), 4.94-4.89 (m, 1H), 4.68-4.65 (m, 1H), 4.21-4.17 (m, 1H), 3.20- 3.15 (m, 1H), 2.25-2.17 (m, 1H), 1.91-1.80 (m, 1H). ~5:1 mixture of fluorinated regioisomers.

Example 113 (1R,2R,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-fluoro-7-oxαbicyclo[2.2.1]heptane -2-carboxamide

LCMS: Rt=1.33 min; MS mass/charge [M+H]+ 397.2.

1H NMR (400 MHz, acetonitrile-d3) δ 8.57 (s, 1H), 8.18 (s, 2H), 7.85 (d, J=2.4 Hz, 1H), 7.43 (d , J=8.8Hz, 1H), 7.37(dd, J=8.8, 2.4Hz, 1H), 5.37(s, 2H), 5.10-4.92(m, 2H), 4.56-4.51(m, 1H), 3.11-3.07(m, 1H), 2.93-2.89(m, 1H), 2.44-2.33( m, 1H), 1.81-1.65 (m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 114 (1S,2R,3S,4S,6R)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-6-fluoro-7oxabicyclo[2.2.1]heptan-2 -carboxamide

LCMS: Rt=1.33 min; MS mass/charge [M+H]+ 397.2. ¹ H NMR (400 MHz, Acetonitrile-d ₃ ) δ 8.50 (s, 1H), 8.22 (s, 2H), 7.87 (dd, J=2.2, 0.6 Hz, 1H) , 7.44-7.39(m, 2H), 5.36(s, 2H), 5.20-5.01(m, 1H), 4.89-4.84(m, 1H), 4 .54-4.50 (m, 1H), 3.94-3.90 (m, 1H), 3.14-3.07 (m, 1H), 2.21-2.10 (m, 1H) , 1.93-1.83 (m, 1H). -5:1 mixture of fluorinated regioisomers.

Example 115 (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

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LCMS: Rt=1.32 min; MS mass/charge [M+H]+ 395.2.

1H NMR (400 MHz, acetonitrile^) δ 8.55 (s, 1H), 8.37-8.34 (m, 1H), 7.86 (d, J=2.4 Hz, 1H), 7, 57 (dd, J=8.1, 2.4Hz, 1H), 7.43 (d, J=8.8Hz, 1H), 7.37 (dd, J=8.8, 2.4Hz , 1H), 7.16 (d, J=8.0 Hz, 1H), 5.14-4.93 (m, 2H), 4.61-4.55 (m, 1H), 3.27- 3.23 (m, 1H), 2.97-2.92 (m, 1H), 2.45 (s, 3H), 2.44-2.33 (m, 1H), 1.83-1, 67(m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 116 (1S,2R,3S,4S,6R)-N-(3,4-dichlorophenyl)-6-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LCMS: Rt=1.32 min; MS mass/charge [M+H] ⁺ 395.2.

1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.57 (s, 1H), 8.39 (d, J=2.4 Hz, 1H), 7.86 (d, J=2.1 Hz, 1H), 7.60 (dd, J=8.1, 2.4 Hz, 1H), 7.43-7.36 (m, 2H), 7.16 (d, J=8.0 Hz, 1H ), 5.21-5.01 (m, 1H), 4.91-4.86 (m, 1H), 4.584.54 (m, 1H), 4.12-4.06 (m, 1H), 3.18-3.11(m, 1H), 2.45(s, 3H), 2.21-2.10(m, 1H), 1.92-1.81(m, 1H). >20:1 mixture of fluorinated regioisomers.

Example 117 (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

The title compound was prepared from methyl-(1S,2S,4R,5R)-7-bromo-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxylate (intermediate 1d) using the steps A-C in diagram 3.

Step A: To a stirred solution of 3,4-dichloroaniline (568 mg, 3.51 mmol) in anhydrous toluene (10 mL) at 0°C under N2 was added trimethylaluminum in toluene (2 M, 3.9 mL, 7.79 mmol). After 10 minutes, the ice bath was removed and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was again cooled to 0°C and 1d (955 mg, 3.90 mmol, dissolved in 2 ml toluene) was added and the reaction mixture was stirred at room temperature for 6 h. The reaction was cooled to 0°C and quenched with a solution of saturated aqueous NH ₄ Cl and methanol. The suspension was filtered and the solid washed with EtOAc. The organic layer was separated and washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography using DCM and EtOAc to give (1S,2S,4R,5R)-7bromo-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]oct-6 -en-6-carboxamide. LC-MS: Rt=1.63 min; MS mass/charge [M+H] ⁺ 373.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.10 (s, 1H), 8.04 (d, J=2.3 Hz, 1H), 7.65 (dd, J=8.9, 2 .3 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 5.15 (s, 1H), 4.87 (s, 1H), 1.70-1.66 (m , 1H), 1.60-1.55 (m, 1H), 1.42-1.39 (m, 1H), 1.02-0.98 (m, 1H).

Step B: To a stirred solution of (1S,2S,4R,5R)-7-bromo-N-(3,4-dichlorophenyl)-8oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6-carboxamide (525 mg, 1.40 mmol) in THF (10 ml) and water (2.5 ml) at 0°C was added acetic acid (0.321 ml) and Zn powder (366 mg, 5.60 mmol) was added in portions. The reaction suspension was stirred until reaching room temperature for 15 minutes. The reaction mixture was filtered and neutralized with saturated sodium bicarbonate to pH ~7. The compound was extracted with ethyl acetate. The organic layer was washed with water and brine and dried over anhydrous sodium sulfate and concentrated. The crude compound was purified by silica gel column chromatography (hexanes:EtOAc) to give (1S,2S,4R,5R)-N-(3,4-dichlorophenyl)-8oxatricyclo[3.2.1.0 ^2.4 ]oct-6-ene-6 -carboxamide. LC-MS: Rt=1.54 min; MS mass/charge [M+H] ⁺ 296.0.

1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 1H), 8.05 (d, J=2.3 Hz, 1H), 7.64 (dd, J=8.9, 2, 4 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.37 (d, J=1.7 Hz, 1H), 4.98 (s, 1H), 4.89 (d, J=1.7 Hz, 1H), 1.42-1.36 (m, 3H), 0.96-0.90 (m, 1H).

Step C: Mixture of (1S,2S,4R,5R)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2,4 ]oct-6-ene-6carboxamide (150 mg, 0.507 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (133mg, 0.608mmol), 2,2-bis(diphenylphosphino)-1.1 -binaphthalene (32 mg, 0.051 mmol), chlor(1,5-cyclooctadiene)rhodium(1) dimer (12 mg, 0.025 mmol) and potassium carbonate (35.0 mg, 0.253 mmol) in 1,4dioxane (2 ml) and water (0.5 ml) was heated in a microwave oven at 100°C for 1 h. The crude reaction mixture was passed through celite and the solvent was evaporated to dryness. The crude compound was purified by silica gel column chromatography to give (1S,2S,4R,5R6S,7S)-N-(3,4-dichlorophenyl)-7-(2methylpyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide (cis) and (1S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2-methylpyridin-4-yl)-8-oxatricyclo[3.2 .1.0 ^2,4 ]octane-6-carboxamide (Example 117). Method B LC-MS: Rt=1.33 min; MS mass/charge [M+H] ⁺ 389.0.

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1H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 8.33 (d, J=5.1 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.57(d,

J=8.8Hz, 1H), 7.45(dd, J=8.8, 2.4Hz, 1H), 7.12-7.10(m, 1H), 7.05(dd, J =5.2, 1.6Hz, 1H), 4.75 (d, J=4.9Hz,

1H), 4.38 (s, 1H), 3.50 (d, J=4.8 Hz, 1H), 3.07 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.33-1.28(m, 1H), 1.18-1.13(m,

1H), 0.43-0.39 (m, 1H), 0.21-0.15 (m, 1H).

Examples 118-137 below were synthesized according to the protocol described for Example 117 using methyl-(1S,2S,4R,5R)-7-bromo-8-oxαtricyclo[3.2.1.0 ^2.4 ]oct 6-ene-6carboxylate (intermediate 1d) and various anilines in step A and various boronic esters/boronic acids in step C.

Example 118 (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2-methoxypyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Method B LC-MS: Rt=1.59 min; MS mass/charge [M+H] ⁺ 405.1.

1H NMR (400 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.07 (d, J=5.3 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H ), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 6.87 (dd, J=5.3, 1.4Hz, 1H), 6.47-6.45(m, 1H), 4.75(d, J=4.9Hz, 1H), 4.38(s, 1H), 3.81( s, 3H), 3.51 (d, J=4.8 Hz, 1H), 3.07 (t, J=4.9 Hz, 1H), 1.33-1.28 (m, 1H), 1.19-1.13(m, 1H), 0.42-0.39(m, 1H), 0.20-0.15(m, 1H).

Example ¹¹⁹ octane-6-carboxamide

Method B LC-MS: Rt=1.71 min; MS mass/charge [M+H] ⁺ 393.0.

1H NMR (400 MHz, DMSC-d6) δ 10.27 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H ), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.23 (dt, J=5.2, 1.8Hz, 1H), 7.00(s, 1H), 4.79(d, J=4.9Hz, 1H), 4.44(s, 1H), 3.65(d, J= 4.8 Hz, 1H), 3.12 (t, J=4.8 Hz, 1H), 1.34-1.30 (m, 1H), 1.20-1.16 (m, 1H), 0.43-0.40 (m, 1H), 0.19-0.17 (m, 1H).

Example 120 (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(6-(trifluoromethyl)pyridin-2-yl)-8oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide

Method B LC-MS: Rt=1.84 min; MS mass/charge [M+H]+ 443.0.

¹ H NMR (400 MHz, DMSO-d6) δ 10.38 (s, 1H), 8.06 (t, J=7.8 Hz, 1H), 8.02 (d, J=2.4 Hz, 1H), 7.76 (d, J=7.4Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.57 (d, J=8.8Hz, 1H) , 7.48 (dd, J=8.8, 2.4 Hz, 1H), 4.77 (d, J=5.0 Hz, 1H), 4.50 (s, 1H), 3.87 ( d, J=4.8 Hz, 1H), 3.68 (t, J=4.9 Hz, 1H), 1.41-1.37 (m, 1H), 1.19-1.14 (m , 1H), 0.420.40 (m, 1H), 0.21-0.16 (m, 1H).

Example 121 rac-(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide

Method B LC-MS: Rt=1.30 min; MS mass/charge [M+H] ⁺ 389.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.74 ( d, J=8.4 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J=5.1 Hz, 1H), 4.77 (d, J=4.9 Hz, 1H), 4.39 (s, 1H), 3.52 (d, J=4.8 Hz, 1H), 3.10 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.33-1.28 (m, 1H), 1, 21-1.16 (m, 1H), 0.43-0.38 (m, 1H), 0.21-0.15 (m, 1H).

Examples 121a and 121b (corresponding to peak 1 and peak 2).

(1S,2S,4R,5R,6R,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane- 6-carboxamide or (1R,2R,4S,5S,6S,7R)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

Chiral resolution rac-(1S,2S,4R,5R,6S,7S)-7-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide (Example 121) was carried out by supercritical liquid chromatography using the following conditions, which gave the compounds listed below:

Method details:

- 48 040531

Column: 21x250 mm IB at 30°C

Mobile phase: 90% CO ₂ /10% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.28 min. LC-MS: Rt=1.43 min; MS mass/charge [M+H]+ 389.1.

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.74 (d , J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.12 (s, 1H ), 7.06 (dd, J=5.1, 1.4Hz, 1H), 4.77 (d, J=4.9Hz, 1H), 4.39 (s, 1H), 3.52 (d, J=4.8 Hz, 1H), 3.10 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.34-1.28 (m, 1H) , 1.21-1.15 (m, 1H), 0.43-0.38 (m, 1H), 0.22-0.15 (m, 1H).

Peak 2: SFC Retention time=1.66 min. LC-MS: Rt=1.43 min; MS mass/charge [M+H]+ 389.1.

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.34 (d, J=5.1 Hz, 1H), 8.13 (s, 1H), 7.74 (d , J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.12 (s, 1H ), 7.06 (dd, J=5.1, 1.4Hz, 1H), 4.77 (d, J=4.9Hz, 1H), 4.39 (s, 1H), 3.52 (d, J=4.8 Hz, 1H), 3.10 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.34-1.28 (m, 1H) , 1.21-1.15 (m, 1H), 0.43-0.38 (m, 1H), 0.22-0.15 (m, 1H).

Example 122 rac-(1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

Method B LC-MS: Rt=1.73 min; MS mass/charge [M+H]+ 411.0.

1H NMR (400 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.01 (d, J=2.4 Hz, 1H), 8.00 (d, J=5.2 Hz, 1H ), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 7.36 (t, J=4.9 Hz , 1H), 4.79 (d, J=4.9 Hz, 1H), 4.51 (s, 1H), 3.94 (d, J=4.7 Hz, 1H), 3.12 (t , J=4.8 Hz, 1H), 1.36-1.31 (m, 1H), 1.21-1.16 (m, 1H), 0.44-0.40 (m, 1H), 0.22-0.17 (m, 1H).

Examples 122a and 122b (corresponding to peak 1 and peak 2). (1S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6 -carboxamide or (1R,2R,4S,5S,6S,7R)-N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6carboxamide

Chiral resolution rac-(1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2,3-difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide (Example 122) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 21x250 mm IB at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.86 min. Method D LC-MS: Rt=1.79 min; MS mass/charge [M+H]+ 411.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 8.03-7.97 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4Hz, 1H), 7.36 (t, J=4.9Hz, 1H), 4.79 (d, J=4.9Hz, 1H ), 4.51 (s, 1H), 3.94 (d, J=4.7 Hz, 1H), 3.12 (t, J=4.8 Hz, 1H), 1.37-1.31 (m, 1H), 1.22-1.17 (m, 1H), 0.45-0.39 (m, 1H), 0.22-0.17 (m, 1H).

Peak 2: SFC Retention time=2.43 min. LCMS: Rt=1.79 min; MS mass/charge [M+H]+ 410.8.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.29 (s, 1H), 8.03-7.97 (m, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4Hz, 1H), 7.36 (t, J=4.9Hz, 1H), 4.79 (d, J=4.9Hz, 1H ), 4.51 (s, 1H), 3.94 (d, J=4.7 Hz, 1H), 3.12 (t, J=4.8 Hz, 1H), 1.37-1.31 (m, 1H), 1.22-1.17 (m, 1H), 0.45-0.39 (m, 1H), 0.22-0.17 (m, 1H).

^Example 123 ⁴ ]octane-6-carboxamide

LC-MS: Rt=1.03 min; MS mass/charge [M+H]+ 352.0.

1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 8.34-8.32 (m, 1H), 8.31 (d, J=2.1 Hz, 1H), 7 .87 (dd, J=8.9, 2.7Hz, 1H), 7.53 (dd, J=8.0, 2.4Hz, 1H), 7.19 (d, J=8.0 Hz, 1H), 6.79 (dd, J=8.9, 0.5 Hz, 1H), 4.74 (d, J=4.9 Hz, 1H), 4.29 (s, 1H), 3.80 (s, 3H), 3.53 (d, J=4.8 Hz, 1H), 3.05 (t, J=4.8 Hz, 1H), 2.42 (s, 3H), 1.33-1.27(m, 1H), 1.22-1.16(m, 1H), 0.44-0.39(m, 1H), 0.21-0.15(m, 1H ).

Example 124 (1S,2S,4R,5R,6R,7S)-N-(5,6-dichloropyridin-3-yl)-7-(2,3-difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide

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NCl

IX

IN^CI

Method C LC-MS: Rt=1.49 min; MS mass/charge [M+H]+ 411.8.

1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz, 1H ), 8.00 (d,

J=5.1Hz, 1H), 7.36(t, J=4.9Hz, 1H), 4.81(d, J=4.9Hz, 1H), 4.52(s, 1H) , 3.94 (d, J=4.7 Hz, 1H), 3.17 (t, J=4.8

Hz, 1H), 1.36-1.30 (m, 1H), 1.26-1.20 (m, 1H), 0.45-0.39 (m, 1H), 0.23-0, 18(m, 1H).

Example 125 (1S,2S,4R,5R,6R,7S)-N-(6-methoxypyridin-3-yl)-7-(pyridin-4-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LC-MS: Rt=1.01 min; MS mass/charge [M+H] ⁺ 338.0.

1H NMR (400 MHz, DMSO-d6) δ 10.00 (s, 1H), 8.48 (d, J=5.3 Hz, 2H), 8.35-8.32 (m, 1H), 7 .87 (dd, J=8.9, 2.7 Hz, 1H), 7.28-7.24 (m, 2H), 6.82-6.77 (m, 1H), 4.76 (d , J=4.9 Hz, 1H), 4.39 (s, 1H), 3.81 (s, 3H), 3.56 (d, J=4.8 Hz, 1H), 3.08 (t , J=4.8 Hz, 1H), 1.34-1.28 (m, 1H), 1.21-1.16 (m, 1H), 0.44-0.39 (m, 1H), 0.21-0.15 (m, 1H).

Example 126 rac-(1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Method B LC-MS: Rt=1.46 min; MS mass/charge [M+H] ⁺ 376.0.

1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 9.06 (s, 1H), 8.68 (s, 2H), 8.02 (d, J=2.4 Hz , 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (d, J=4, 9 Hz, 1H), 4.42 (s, 1H), 3.61 (d, J=4.7 Hz, 1H), 3.17 (t, J=4.8 Hz, 1H), 1.36 -1.30(m, 1H), 1.21-1.16(m, 1H), 0.45-0.39(m, 1H), 0.22-0.17(m, 1H).

Examples 126a and 126b (corresponding to peak 1 and peak 2). (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide or (1R,2R,4S,5S,6S,7R)-N-(3,4dichlorophenyl)-7-(pyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2,4 ]octane-6-carboxamide

Chiral resolution of rac-(1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(pyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ^2,4 ]octane-6 α-carboxamide (Example 126) was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below:

Method details:

Column: 21x250 mm IB at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.88 min. Method B LC-MS: Rt=1.44 min; MS mass/charge [M+H] ⁺ 375.8.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.06 (s, 1H), 8.68 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (d, J=4 .9 Hz, 1H), 4.42(s, 1H), 3.61 (d, J=4.7 Hz, 1H), 3.18 (t, J=4.8 Hz, 1H), 1, 36-1.29(m, 1H), 1.22-1.17(m, 1H), 0.44-0.39(m, 1H), 0.23-0.17(m, 1H).

Peak 2: SFC Retention time=2.43 min. Method B LC-MS: Rt=1.44 min; MS mass/charge [M+H] ⁺ 375.9.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.26 (s, 1H), 9.06 (s, 1H), 8.68 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (d, J=4 .9 Hz, 1H), 4.42 (s, 1H), 3.61 (d, J=4.7 Hz, 1H), 3.18 (t, J=4.8 Hz, 1H), 1, 36-1.29(m, 1H), 1.22-1.17(m, 1H), 0.44-0.39(m, 1H), 0.23-0.17(m, 1H).

Example 127 (1S,2S,4R,5R,6R,7S)-7-(2,3-difluoropyridin-4-yl)-N-(6-methoxypyridin-3-yl)-8oxatricyclo[3.2.1.0 ^{2, 4} ]octane-6-carboxamide

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LC-MS: Rt=1.44 min; MS mass/charge [M+H] ⁺ 374.0.

1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.35-8.32 (m, 1H), 8.00 (dd, J=5.0, 0.9 Hz, 1H), 7.88 (dd, J=8.9, 2.7 Hz, 1H), 7.36 (t, J=4.9 Hz, 1H), 6.80 (dd, J=8.9 , 0.5 Hz, 1H), 4.78 (d, J=4.9 Hz, 1H), 4.49 (s, 1H), 3.94 (d, J=4.7 Hz, 1H), 3.81 (s, 3H), 3.12 (t, J=4.8 Hz, 1H), 1.36-1.30 (m, 1H), 1.24-1.19 (m, 1H) , 0.44-0.38(m, 1H), 0.23-0.17(m, 1H).

Example 128 (1S,2S,4R,5R,6R,7S)-N-(6-methoxypyridin-3-yl)-7-(6-(trifluoromethyl)pyridin-2-yl)-8oxatricyclo[3.2.1.0 ^{2 ,4} ]octane-6-carboxamide

LC-MS: Rt=1.76 min; MS mass/charge [M+H] ⁺ 406.1.

1H NMR (400 MHz, DMSO-d6) δ 10.10 (s, 1H), 8.36 (d, J=2.7 Hz, 1H), 8.06 (t, J=7.8 Hz, 1H ), 7.89 (dd, J=8.9, 2.7Hz, 1H), 7.76 (d, J=7.7Hz, 1H), 7.72 (d, J=8.0Hz , 1H), 6.80 (d, J=8.9 Hz, 1H), 4.77 (d, J=5.0 Hz, 1H), 4.49 (s, 1H), 3.87 (d , J=4.8 Hz, 1H), 3.81 (s, 3H), 3.66 (t, J=4.9 Hz, 1H), 1.40-1.35 (m, 1H), 1 .22-1.16 (m, 1H), 0.44-0.39 (m, 1H), 0.22-0.16 (m, 1H).

Example 129 (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2-fluoropyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Method B LC-MS: Rt=1.65 min; MS mass/charge [M+H] ⁺ 394.0.

1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.64 (d, J=1.6 Hz, 2H), 8.02 (d, J=2.4 Hz, 1H ), 7.57 (d, J=8.8 Hz, 1H), 7.46 (dd, J=8.8, 2.4 Hz, 1H), 4.82 (d, J=4.9 Hz , 1H), 4.41 (s, 1H), 3.68 (d, J=4.6 Hz, 1H), 3.17 (t, J=4.8 Hz, 1h), 1.35-1 .29 (m, 1H), 1.22-1.16 (m, 1H), 0.45-0.39 (m, 1H), 0.23-0.18 (m, 1H).

Example 130 (1S,2S,4R,5R,6R,7S)-7-(pyrimidin-5-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide

LC-MS: Rt=1.56 min; MS mass/charge [M+H] ⁺ 376.1.

1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.06 (s, 1H), 8.69 (s, 2H), 8.13 (s, 1H), 7.74 (d, J=8.5 Hz, 1H), 7.55 (t, J=8.0 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 4.84 (d , J=4.9Hz, 1H), 4.43(s, 1H), 3.63(d, J=4.7Hz, 1H), 3.20(t, J=4.8Hz, 1H ), 1.37-1.32 (m, 1H), 1.24-1.18 (m, 1H), 0.45-0.39 (m, 1H), 0.23-0.17 (m , 1H).

Example 131 (1S,2S,4R,5R,6R,7S)-7-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane -6-carboxamide

LC-MS: Rt=1.40 min; MS mass/charge [M+H] ⁺ 375.1.

1H NMR (400 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.48 (d, J=5.8 Hz, 2H), 8.13 (s, 1H), 7.74 (d , J=8.5 Hz, 1H), 7.55 (t, J=7.9 Hz, 1H), 7.41 (d, J=7.7 Hz, 1H), 7.27 (d, J =6.1 Hz, 2H), 4.79 (d, J=4.9 Hz, 1H), 4.41 (s, 1H), 3.58 (d, J=4.8 Hz, 1H), 3.11 (t, J=4.8 Hz, 1H), 1.36-1.30 (m, 1H), 1.20-1.15 (m, 1H), 0.44-0.40 ( m, 1H), 0.220.17 (m, 1H).

Example 132 (1S,2S,4R,5R,6R,7S)-7-(2-aminopyridin-5-yl)-N-(3,4-dichlorophenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

LC-MS: Rt=1.46 min; MS mass/charge [M+H]+ 391.0.

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Ή NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 8.10 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.56 ( d, J=8.8 Hz,

1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 6.52 (s, 2H), 4.73 (d, J=4.9 Hz, 1H), 4, 25 (s, 1H), 3.34 (d, J=4.0 Hz, 1H), 3.03 (t, J=4.8 Hz, 1H), 1.29-1.24 (m, 1H ), 1.17-1.11 (m, 1H), 0.41-0.36 (m, 1H), 0.18-0.13 (m, 1H).

Example ¹³³ 6-carboxamide __ ⁰ ίι Τ ^d. HD <Ί ο| η'ο

LCMS: Rt=1.72 min; MS mass/charge [M+H]+ 461.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.24 (s, 1H), 8.26 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.56 ( d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.75 (d, J=4.9 Hz, 1H), 4, 27 (s, 1H), 3.64 (s, 8H), 3.41 (d, J=4.6 Hz, 1H), 3.05 (t, J=4.8 Hz, 1H), 1, 31-1.25(m, 1H), 1.18-1.13(m, 1H), 0.43-0.38(m, 1H), 0.20-0.14(m, 1H).

Example 134 (1S,2S,4R,5R,6R,7S)-7-(2-fluoropyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-8-oxatricyclo[3.2.1.0 ^2.4 ]octane-6-carboxamide

LC-MS: Rt=1.73 min; MS mass/charge [M+H] ⁺ 393.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.16 (d, J=5.2 Hz, 1H), 8.13 (s, 1H), 7.74 ( d, J=8.5Hz, 1H), 7.56(t, J=8.0Hz, 1H), 7.44-7.35(m, 1H), 7.27-7.21(m , 1H), 7.01(s, 1H), 4.81(d, J=4.9Hz, 1H), 4.45(s, 1H), 3.67(d, J=4.8Hz , 1H), 3.14 (t, J=4.8 Hz, 1H), 1.36-1.30 (m, 1H), 1.21-1.16 (m, 1H), 0.45- 0.38 (m, 1H), 0.22-1.16 (m, 1H).

Example 135 (1S,2S,4R,5R,6R,7S)-N-(3,4-dichlorophenyl)-7-(2-methylpyrimidin-5-yl)-8-oxatricyclo[3.2.1.0 ^2.4 ] octane-6-carboxamide

Method B LC-MS: Rt=1.53 min; MS mass/charge [M+H] ⁺ 390.0.

1H NMR (400 MHz, DMSO-d6) δ 10.26 (s, 1H), 8.55 (s, 2H), 8.02 (d, J=2.4 Hz, 1H), 7.57 (d , J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.4 Hz, 1H), 4.80 (d, J=4.9 Hz, 1H), 4.37 (s, 1H), 3.56 (d, J=4.7 Hz, 1H), 3.13 (t, J=4.8 Hz, 1H), 2.58 (s, 3H), 1.35 -1.29(m, 1H), 1.20-1.15(m, 1H), 0.44-0.38(m, 1H), 0.22-0.16(m, 1H).

^Example 136 ⁴ ]octane-6-carboxamide

LCMS: Rt=1.28 min; MS mass/charge [M+H] ⁺ 376.0.

1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 8.67 (d, J=5.7 Hz, 2H), 8.50 (d, J=2.4 Hz, 1H ), 8.41 (d, J=2.4 Hz, 1H), 7.61 (d, J=5.9 Hz, 2H), 4.87-4.83 (m, 1H), 4.48 (s, 1H), 3.76-3.71 (m, 1H), 3.21-3.17 (m, 1H), 1.38-1.33 (m, 1H), 1.28-1 .22 (m, 1H), 0.45-0.40 (m, 1H), 0.24-0.17 (m, 1H).

Example ¹³⁷ 6-carboxamide

LCMS: Rt=1.41 min; MS mass/charge [M+H] ⁺ 375.0.

1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.47 (d, J=6.1 Hz, 2H), 8.01 (d, J=2.5 Hz, 1H ), 7.56 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.5 Hz, 1H), 7.25 (d, J=6.2 Hz , 2H), 4.77 (d, J=4.9 Hz, 1H), 4.40 (s, 1H), 3.56 (d, J=4.8 Hz, 1H), 3.09 (t , J=4.9 Hz, 1H), 1.35-1.29 (m, 1H), 1.21-1.14 (m, 1H), 0.45-0.40 (m, 1H), 0.21-0.16 (m, 1H).

Examples 138-154 below were synthesized following the protocol described for Example 117 using methyl-(1R,4S,5S)-3-bromo-5-hydroxy-7-oxabicyclo[2.2.1]hepta-2-ene -2-carboxylate and methyl-(1S,4S,6R)-3-bromo-6-hydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate (intermediate 1e) and various anilines in step A and various harrow complex

- 52 040531 esters/acids in step C.

Example 138 -2-carboxamide

LC-MS: Rt=1.17 min; MS mass/charge [M+H]+ 393.0.

1H NMR (400 MHz, DMSO-d6) δ 10.30 (s, 1H), 8.31 (dd, J=2.5, 0.8 Hz, 1H), 7.98 (d, J=2, 4 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.54-7.52 (m, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 4.96 (d, J=4.7 Hz, 1H), 4.91-4.87 (m, 1H), 4.16 (s, 1H), 4.00-3.96 (m, 1H), 3.20 (d, J=5.3 Hz, 1H), 2.94-2.91 (m, 1H) , 2.12-2.05(m, 1H), 1.43-1.36(m, 1H). —4:1 mixture of alcohol regioisomers.

Example 139 rac-(1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.46 min; MS mass/charge [M+H]+ 409.0. —4:1 mixture of alcohol regioisomers.

Examples 139a and 139b (corresponding to peak 1 and peak 2). (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2S,3R,4S,5R)-N(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2-carboxamide

Chiral resolution of rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide (Example 139) as a mixture of -4:1 alcohol regioisomers was carried out by supercritical liquid chromatography using the following conditions, which allowed the compounds listed below to be obtained.

Method details:

Column: 21x250 mm IB at 30°C

Mobile phase: 85% CO ₂ /15% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=2.40 min. LC-MS: Rt=1.38 min; MS mass/charge [M+H]+ 409.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.08 (dd, J=5.3, 0.7 Hz, 1H), 7.97 (d, J=2 .5 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 6.87 (dd, J =5.3, 1.5 Hz, 1H), 6.64 (s, 1H), 5.01-4.94 (m, 1H), 4.92-4.84 (m, 1H), 4, 21 (s, 1H), 4.00-3.94 (m, 1H), 3.82 (s, 3H), 3.20-3.16 (m, 1H), 2.97-2.91 ( m, 1H), 2.102.03 (m, 1H), 1.43-1.36 (m, 1H).

Peak 2: SFC Retention time=3.59 min. LC-MS: Rt=1.38 min; MS mass/charge [M+H]+ 409.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.08 (dd, J=5.3, 0.7 Hz, 1H), 7.97 (d, J=2 .5 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 6.87 (dd, J =5.3, 1.5 Hz, 1H), 6.64 (s, 1H), 5.01-4.94 (m, 1H), 4.92-4.84 (m, 1H), 4, 21 (s, 1H), 4.00-3.94 (m, 1H), 3.82 (s, 3H), 3.20-3.16 (m, 1H), 2.97-2.91 ( m, 1H), 2.102.03 (m, 1H), 1.43-1.36 (m, 1H).

Example 140 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(6-(trifluoromethyl)pyridin-2-yl)7-oxabicyclo[2.2. 1]heptane-2-carboxamide

LC-MS: Rt=1.69 min; MS mass/charge [M+H]+ 447.0. A mixture of alcohol regioisomers.

Example 141 2-carboxamide

LC-MS: Rt=1.37 min; MS mass/charge [M+H]+ 380.0.

1H NMR (400 MHz, DMSO-d6) δ 10.31 (s, 1H), 9.07 (s, 1H), 8.69 (s, 2H), 7.98 (d, J=2.5 Hz , 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 5.05-4.99 (m, 1H), 4.98-4.93(m, 1H), 4.27(s, 1H), 4.03-3.97(m, 1H), 3.31-3.28(m, 1H) , 3.05-3.01 (m, 1H), 2.13-2.04 (m, 1H), 1.46-1.35 (m, 1H). —6:1 mixture of alcohol regioisomers.

- 53 040531

Example 142 rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.54 min; MS mass/charge [M+H]+ 397.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.17 (d, J=5.1 Hz, 1H), 7.98 (d, J=2.4 Hz , 1H), 7.58-7.54 (m, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 7.25-7.22 (m, 1H), 7.01 (s, 1H), 5.03-5.01 (m, 1H), 4.94-4.90 (m, 1H), 4.27 (s, 1H), 3.99-3, 95 (m, 1H), 3.35-3.31 (m, 1H), 3.00-2.95 (m, 1H), 2.10-2.02 (m, 1H), 1.46- 1.37(m, 1H). —4:1 mixture of alcohol regioisomers.

Examples 142a and 142b (corresponding to peak 1 and peak 2A). (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane-2-carboxamide or (1S,2S,3R,4S,5R)-N(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptan-2- carboxamide

Chiral resolution of rac-(1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5hydroxy-7-oxabicyclo[2.2.1]heptan- 2-carboxamide (Example 142) as a mixture of -4:1 alcohol regioisomers was carried out by supercritical liquid chromatography using the following conditions, which gave the compounds listed below.

Method details:

Column: 21x250 mm AD-H at 30°C

Mobile phase: 75% CO ₂ /25% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.30 min. LC-MS: Rt=1.46 min; MS mass/charge [M+H] ⁺ 397.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 7.26-7.22 (m, 1H ), 7.01 (d, J=1.5 Hz, 1H), 5.05-5.00 (m, 1H), 4.954.89 (m, 1H), 4.27 (s, 1H), 4 .01-3.95 (m, 1H), 3.33-3.30 (m, 1H), 3.01-2.96 (m, 1H), 2.11-2.03 (m, 1H) , 1.461.39 (m, 1H).

Peak 2: The second eluted peak isolated using SLC with retention time=4.22 min was concentrated and repurified by SLC using the following conditions to give the compound below:

Method details:

Column: 21x250 mm IC at 30°C

Mobile phase: 80% CO ₂ /20% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 2A: First eluted peak. SFC Retention time=1.21 min. LC-MS: Rt=1.46 min; MS mass/charge [M+H] ⁺ 397.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.32 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 7.26-7.22 (m, 1H ), 7.01 (d, J=1.5 Hz, 1H), 5.05-5.00 (m, 1H), 4.954.89 (m, 1H), 4.27 (s, 1H), 4 .01-3.95 (m, 1H), 3.33-3.30 (m, 1H), 3.01-2.96 (m, 1H), 2.11-2.03 (m, 1H) , 1.461.39 (m, 1H).

Example 143 (1 R,2R,3S,4R,5S)-3-(2-aminopyrimidin-5-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7 oxabicyclo[2.2.1 ]heptane-2-carboxamide ⁰ ίι G

Jo Ih

LCMS: Rt=1.27 min; MS mass/charge [M+H] ⁺ 395.0.

1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.10 (s, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.55 (d , J=8.8Hz, 1H), 7.42(dd, J=8.8, 2.4Hz, 1H), 6.48(s, 2H), 4.93-4.90(m, 1H), 4.88-4.83(m, 1H), 4.11(s, 1H), 3.96-3.93(m, 1H), 3.03-2.99(m, 1H) , 2.91-2.88 (m, 1H), 2.09-2.04 (m, 1H), 1.42-1.34 (m, 1H). —5:1 mixture of alcohol regioisomers.

Example 144 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-(dimethylamino)pyrimidin-5-yl)-5hydroxy-7-oxabicyclo[2.2. 1]heptane-2-carboxamide

- 54 040531

LCMS: Rt=1.39 min; MS mass/charge [M+H]+ 423.0.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.27 (s, 1H), 8.22 (s, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.55 (d, J=8.8 Hz,

1H), 7.42 (dd, J=8.8, 2.4 Hz, 1H), 4.94-4.91 (m, 1H), 4.89-4.86 (m, 1H), 4 .12 (s, 1H), 3.97-3.93 (m, 1H), 3.08 (s,

6H), 3.06-3.04 (m, 1H), 2.91-2.88 (m, 1H), 2.11-2.06 (m, 1H), 1.41-1.35 ( m, 1H). -4:1 mixture of alcohol regioisomers.

Example 145 rac-( 1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4yl)-7-oxabicyclo[2.2 .1]heptane-2-carboxamide

LC-MS: Rt=1.63 min; MS mass/charge [M+H]+ 447.0.

¹ H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.68 (d, J=5.0 Hz, 1H), 7.97 (d, J=2.4 Hz, 1H), 7.73 (s, 1H), 7.61-7.59 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J=8 .8, 2.5 Hz, 1H), 5.01-4.99 (m, 1H), 4.97-4.93 (m, 1H), 4.28 (s, 1H), 4.04- 3.98 (m, 1H), 3.42-3.39 (m, 1H), 3.05-2.99 (m, 1H), 2.13-2.05 (m, 1H), 1, 47-1.39 (m, 1H). -5:1 mixture of alcohol regioisomers.

Examples 145a and 145b (corresponding to peak 1 and peak 2).

(1 R,2R,3 S,4R,5 S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2. 1]heptane-2-carboxamide or (1 S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2(trifluoromethyl)pyridin-4-yl)-7 -oxabicyclo [2.2.1 ]heptane-2-carboxamide ^{but H0} Vq fCf fTf g OR G

Chiral resolution of rac-(1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyridin-4-yl)-7-oxabicyclo[2.2 .1]heptane-2-carboxamide (Example 145) as a 5:1 mixture of alcohol regioisomers was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm AD-H at 30°C

Mobile phase: 90% CO ₂ /10% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=3.44 min. LC-MS: Rt=1.71 min; MS mass/charge [M+H]+ 447.1.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 7.98 (d, J=2.4 Hz , 1H), 7.73 (s, 1H), 7.61-7.59 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J= 8.8, 2.4 Hz, 1H), 5.03-4.99(m, 1H), 4.97-4.93(m, 1H), 4.27(s, 1H), 4.04 -3.98 (m, 1H), 3.43-3.39 (m, 1H), 3.05-2.99 (m, 1H), 2.12-2.05 (m, 1H), 1 .47-1.39 (m, 1H).

Peak 2: SFC Retention time=4.56 min. LC-MS: Rt=1.71 min; MS mass/charge [M+H]+ 447.0.

¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 8.68 (d, J=5.1 Hz, 1H), 7.98 (d, J=2.4 Hz , 1H), 7.73 (s, 1H), 7.61-7.59 (m, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.41 (dd, J= 8.8, 2.4 Hz, 1H), 5.03-4.99(m, 1H), 4.97-4.93(m, 1H), 4.27(s, 1H), 4.04 -3.98 (m, 1H), 3.44-3.38 (m, 1H), 3.05-2.99 (m, 1H), 2.12-2.05 (m, 1H), 1 .48-1.39 (m, 1H).

Example 146 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2,3-difluoropyridin-4-yl)-5-hydroxy-7oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.58 min; MS mass/charge [M+H]+ 415.0.

¹ H NMR (500 MHz, DMSO-d6) δ 10.32 (s, 1H), 8.01 (d, J=5.2, Hz, 1H), 7.97 (d, J=2.4 Hz , 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 7.38 (t, J=4, 9 Hz, 1H), 5.09-5.04(m, 1H), 4.96-4.90(m, 1H), 4.36(s, 1H), 4.02-3.96(m , 1H), 3.63-3.58 (m, 1H), 3.02-2.96 (m, 1H), 2.13-2.05 (m, 1H), 1.47-1.40 (m, 1H). -5:1 mixture of alcohol regioisomers.

Example 147 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2,5-difluoropyridin-4-yl)-5-hydroxy-7oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.57 min; MS mass/charge [M+H]+ 415.0.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.30 (s, 1H), 8.18 (d, J=1.3 Hz, 1H), 7.97 (d, J=2.4 Hz , 1H), 7.57 (d,

- 55 040531

J=8.8Hz, 1H), 7.42 (dd, J=8.8, 2.5Hz, 1H), 7.14 (dd, J=4.7, 2.1Hz, 1H), 5.08-5.01 (m, 1H), 4.94-4.88 (m, 1H),

4.41 (s, 1H), 4.01-3.97 (m, 1H), 3.54-3.50 (m, 1H), 3.02-2.98 (m, 1H), 2, 13-2.07 (m, 1H), 1.46-1.37 (m, 1H).

—4:1 mixture of alcohol regioisomers.

Example 148 (1 R,2R,3 S,4R,5 S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyrimidin-5-yl)-7 oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.37 min; MS mass/charge [M+H] ⁺ 394.0.

1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.56 (s, 2H), 7.97 (dd, J=2.6, 1.0 Hz, 1H), 7 .55 (dd, J=8.8, 1.0Hz, 1H), 7.41 (ddd, J=8.8, 2.5, 1.0Hz, 1H), 4.99-4.96 (m, 1H), 4.94-4.91 (m, 1H), 4.22 (s, 1H), 4.02-3.97 (m, 1H), 3.26-3.22 (m , 1H), 3.01-2.97 (m, 1H), 2.57 (s, 3H), 2.12-2.06 (m, 1H), 1.44-1.38 (m, 1H ). —4:1 mixture of alcohol regioisomers.

Example 149 (1 R,2R,3 S,4R,5 S)-3-(2-aminopyridin-4-yl)-N-(3,4-dichlorophenyl)-5-hydroxy-7 oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.29 min; MS mass/charge [M+H] ⁺ 394.0.

1H NMR (500 MHz, DMSO-d6) δ 10.31 (s, 1H), 7.98-7.96 (m, 1H), 7.80 (d, J=5.2 Hz, 1H), 7 .56 (d, J=8.9 Hz, 1H), 7.44-7.40 (m, 1H), 6.37-6.30 (m, 2H), 5.84 (s, 2H), 4.95-4.91(m, 1H), 4.85-4.81(m, 1H), 4.20(s, 1H), 3.95-3.91(m, 1H), 3, 01-2.98 (m, 1H), 2.90-2.86 (m, 1H), 2.07-2.00 (m, 1H), 1.41-1.35 (m, 1H). —4:1 mixture of alcohol regioisomers.

Example 150 (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1]heptan-2 -carboxamide

LC-MS: Rt=1.25 min; MS mass/charge [M+H] ⁺ 379.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.31 (s, 1H), 8.50-8.47 (m, 2H), 7.97 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.42 (dd, J=8.9, 2.5 Hz, 1H), 7.28-7.24 (m, 2H), 4 .99-4.96(m, 1H), 4.93-4.86(m, 1H), 4.25(s, 1H), 4.04-3.97(m, 1H), 3.25 -3.20 (m, 1H), 2.99-2.95 (m, 1H), 2.11-2.04 (m, 1H), 1.45-1.38 (m, 1H). —4:1 mixture of alcohol regioisomers.

Example 151 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyrimidin-5-yl)-5-hydroxy-7-oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.44 min; MS mass/charge [M+H] ⁺ 398.0.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.34 (s, 1H), 8.65 (d, J=1.7 Hz, 2H), 7.99 (d, J=2.4 Hz, 1H), 7.58-7.54 (m, 1H), 7.42 (dd, J=8.8, 2.5 Hz, 1H), 5.04-5.01 (m, 1H), 4 .97-4.92(m, 1H), 4.27(s, 1H), 4.02-3.95(m, 1H), 3.39-3.36(m, 1H), 3.06 -3.02(m, 1H), 2.12-2.04(m, 1H), 1.46-1.38(m, 1H). —2:1 mixture of alcohol regioisomers.

Example 152 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(1-methyl-1H-pyrazol-4-yl)-7 oxabicyclo[ 2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.95 min; MS mass/charge [M+H]+ 382.1. A mixture of alcohol regioisomers.

Example 153 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(1-methyl-1H-pyrazol-3-yl)-7 oxabicyclo[ 2.2.1]heptane-2-carboxamide

- 56 040531

LC-MS: Rt=0.97 min; MS mass/charge [M+H]+ 382.1.

¹ H NMR (500 MHz, DMSO-d6) δ 10.40 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.58-7.55 (m, 2H), 7.46 (dd, J=8.8,

2.4 Hz, 1H), 6.06 (d, J=2.2 Hz, 1H), 4.95-4.86 (m, 1H), 4.81-4.76 (m, 1H), 4.20 (s, 1H), 3.97-3.90 (m, 1H), 3.75 (s, 3H), 3.27-3.22 (m, 1H), 3.21-3, 17(m, 1H), 2.04-1.97(m, 1H), 1.38-1.32(m, 1H). -4:1 mixture of alcohol regioisomers.

Example 154 (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-(trifluoromethyl)pyrimidin-5yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.13 min; MS mass/charge [M+H]+ 448.1.

¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.33 (s, 1H), 8.93 (s, 2H), 7.98 (d, J=2.4 Hz, 1H), 7.55 (d, J=8.9 Hz, 1H), 7.41 (dd, J=8.8, 2.5 Hz, 1H), 5.09-5.02 (m, 1H), 5.02- 4.95 (m, 1H), 4.36 (s, 1H), 4.05-3.98 (m, 1H), 3.473.42 (m, 1H), 3.12-3.07 (m, 1H), 2.15-2.06(m, 1H), 1.50-1.40(m, 1H). -5:1 mixture of alcohol regioisomers.

Example 155 (1 R,2R,3 S,4R,5S)-N-(3,4-dichlorophenyl)-5-methoxy-3-(2-methylpyridin-4-yl)-7 oxabicyclo[2.2.1] heptane-2-carboxamide

Example 155 described below was synthesized according to the protocol described for Example 117 using methyl-(1R,4S,5S)-3-bromo-5-methoxy-7-oxabicyclo[2.2.1]hept-2-en-2- carboxylate and methyl-(1S,4S,6R)-3-bromo-6-methoxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (intermediate 1f and dichloroaniline in step A and (2- methylpyridin-4-yl)boronic acid in step C.

LCMS: Rt=1.39 min; MS mass/charge [M+H]+ 407.0. -4:1 mixture of alcohol regioisomers.

Examples 156 and 157 (corresponding to peak 1 and peak 2).

(1S,2R,3S,4R,6R)-N-(3,4-dichlorophenyl)-5,6-fluoro-3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1]heptan- 2-carboxamide or (1R,2S,3R,4S,6S)-N-(3,4-dichlorophenyl)-5,6-fluoro-3-(2-methylpyridin4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide

The title compound was prepared from methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (Intermediate 1c) using steps A-E and step G in Scheme 5, followed by separation enantiomers using chiral chromatography.

Step A: To a solution of methyl 3-bromo-7-oxabicyclo[2.2.1]hepta-2,5-diene-2-carboxylate (10.0 g, 43.3 mmol) in 1:1 acetone/water (200 ml) was added NMO (5.85 g, 43.3 mmol) at 0°C, and then osmium tetroxide (0.220 g, 0.866 mmol) in acetone (15 ml) was added dropwise at 0°C. The resulting mixture was slowly heated to rt. And then stirred overnight at rt. The solvent was evaporated and the resulting residue was extracted using DCM (3x100 ml). The combined DCM layers were dried over anhydrous Na ₂ SO ₄ , filtered and concentrated. The resulting residue was purified by FCC to give methyl 3-bromo-5,6-dihydroxy-7-oxabicyclo[2.2.1]hept-2-en-2-carboxylate (6.5 g, 54%).

¹ H NMR (400 MHz, CDCl ₃ ) δ 5.01 (d, J=1.4 Hz, 1H), 4.75 (d, J=1.4 Hz, 1H), 4.18-3.91 (m, 2H), 3.83 (s, 3H), 3.19 (d, J=6.4 Hz, 1H), 3.03 (d, J=6.3 Hz, 1H).

Step B. To a suspension of methyl 3-bromo-5,6-dihydroxy-7-oxabicyclo[2.2.1]hept-2-ene-2-carboxylate (3.81 g, 14.4 mmol) in toluene (150 ml ) was added (dimethoxymethyl)benzene (2.63 g, 17.3 mmol) and pTsOH (137 mg, 0.719 mmol). The resulting reaction mixture was heated at 70°C for 30 min. The reaction mixture was concentrated and purified by FCC to give methyl 6-bromo-2-phenyl-3a,4,7,7atetrahydro-4,7-epoxybenzo[d][1,3]dioxol-5-carboxylate as 2: 1 mixture of diastereomers.

L NMR (400 MHz, CDCl ₃ ) δ 7.58 (m, 1H), 7.51-7.35 (m, 6.5H), 6.37 (s, 1H), 6.04 (s, 0 .5H), 5.32 (d, J=1.2Hz, 1H), 5.22 (d, J=1.2Hz, 0.5H), 5.05 (d, J=1.2Hz , 1H), 4.95 (d, J=1.2 Hz, 0.5H), 4.77-4.68 (m, 2H), 4.68-4.63 (m, 1H), 3, 85(s, 4.5H). 2:1 mixture of diastereomers:

Step C: To a solution of 3,4-dichloroaniline (0.628 g, 3.87 mmol) in toluene (30 ml) was added 2.0 M Me ₃ Al in toluene (2.10 ml, 4.20 mmol) at 0°C . The reaction mixture was stirred for 1 h and then a solution of methyl 6-bromo-2-phenyl-3a,4,7,7a-tetrahydro-4,7epoxybenzo[d][1,3]dioxol- 5-carboxylate (1.14 g, 3.23 mmol) in toluene (20 ml). The resulting reaction mixture was allowed to warm to rt. and stirred at room temperature. during the night. The reaction mixture was quenched

- 57 040531 with saturated aqueous NH4C1 and diluted with EtOAc and water. The aqueous layer was extracted using

EtOAc and the combined organic solutions were washed with water and brine, dried over anhydrous Na2SO4, filtered and concentrated. The resulting residue was purified by FCC to give (3aS,4S,7S,7aS)-6-bromo-N-(3,4-dichlorophenyl)-2-phenyl-3a,4,7,7a-tetrahydro-4,7- epoxybenzo[d][1,3]dioxol-5carboxamide (450 mg, 26%).

LC-MS: Rt=1.76 min; MS mass/charge [M+H]+ 482.0.

Step D: To a stirred solution of (3aS,4S,7S,7aS)-6-bromo-N-(3,4-dichlorophenyl)-2-phenyl3a,4,7,7a-tetrahydro-4,7-epoxybenzo^][ 1,3]dioxol-5-carboxamide (650 mg, 1.307 mmol) in THF (40 mL) and water (10 mL) acetic acid (0.299 mL, 5.23 mmol) was added at 0°C and then the powder was added in portions zinc (342 mg, 5.23 mmol). The reaction suspension was allowed to warm up to rt. and stirred for 15 min. The reaction mixture was filtered and neutralized with saturated aqueous sodium bicarbonate to pH 7. The mixture was extracted with ethyl acetate and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting crude mixture was purified by RP-HPLC to give (3aS,4S,7R,7aR)-N-(3,4-dichlorophenyl)-2-phenyl3a,4,7,7a-tetrahydro-4,7-epoxybenzo[4 ] [ 1,3]dioxol-5-carboxamide, which was directly used in the next step.

LC-MS: Rt=1.62 and 1.66 min; MS mass/charge [M+H]+ 404.1.

Step E: To a mixture of (3aS,4S,7R,7aR)-N-(3,4-dichlorophenyl)-2-phenyl-3a,4,7,7a-tetrahydro-4,7epoxybenzo[b][1,3] dioxol-5-carboxamide (180 mg, 0.445 mmol), 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)pyridine (117 mg, 0.534 mmol), dimer chlorine(1,5-cyclooctadiene)rhodium(I) (11.0 mg, 0.022 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (28 mg, 0.045 mmol) and potassium carbonate (30 .8 mg, 0.223 mmol) was charged with 1,4-dioxane/H ₂ O (3:1) (16 ml) and purged with nitrogen. The resulting reaction mixture was heated in a microwave at 100° C. for 1 hour. The reaction mixture was filtered and purified by RP-HPLC to give (4S,5R,6S,7R)-N-(3,4-dichlorophenyl)-6- (2-methylpyridin-4-yl)2-phenylhexahydro-4,7-epoxybenzo[d][1,3]dioxol-5-carboxamide.

LC-MS: Rt=1.43 min; MS mass/charge [M+H]+ 497.2.

Step G: To a solution of (4S,5R,6S,7R)-N-(3,4-dichlorophenyl)-6-(2-methylpyridin-4-yl)-2phenylhexahydro-4,7-epoxybenzo[d][1, 3]dioxol-5-carboxamide (133 mg, 0.267 mmol) and 1,2,3,4,5 pentamethylbenzene (119 mg, 0.802 mmol) in DCM (3.0 ml) were added dropwise 1.0 M BCl ₃ in DCM (1.34 ml, 1.34 mmol) at 0°C. The resulting reaction mixture was stirred for 1 hour at 0° C. and then allowed to warm to rt. and stirred for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO ₃ and the aqueous layer was extracted using DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated to give the crude product which was purified by HPLC to give rac-(1S,2R,3S,4R,5S,6R)-N-(3,4-dichlorophenyl)-5, 6-dihydroxy-3-(2-methylpyridin4-yl)-7-oxabicyclo[2.2.1]heptane-2-carboxamide as a mixture of enantiomers.

LC-MS: Rt=1.06 min; MS mass/charge [M+H]+ 409.1.

Chiral resolution of rac-(1S,2R,3S,4R,5S,6R)-N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2. 1 ]heptane-2-carboxamide was carried out by supercritical liquid chromatography using the following conditions, which made it possible to obtain the compounds listed below.

Method details:

Column: 21x250 mm IA at 30°C

Mobile phase: 75% CO ₂ /25% MeOH+0.5% isopropylamine

Detection: UV at 220 nm

Flow rate: 2 ml/min

Peak 1: SFC Retention time=1.47 min. LC-MS: Rt=1.07 min; MS mass/charge [M+H]+ 409.1.

1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 8.40 (d, J=5.3 Hz, 1H), 8.01 (d, J=2.4 Hz, 1H ), 7.59 (d, J=8.8 Hz, 1H), 7.48 (dd, J=8.8, 2.5 Hz, 1H), 7.23 (d, J=1.7 Hz , 1H), 7.16 (dd, J=5.5, 1.7 Hz, 1H), 4.98 (brs, 1H), 4.83 (brs, 1H), 4.61 (dd, J= 5.6, 1.6 Hz, 1H), 4.23 (d, J=1.5 Hz, 1H), 3.92 (q, J=4.6 Hz, 2H), 3.00 (t, J=5.5 Hz, 1H), 2.47 (s, 3H).

Peak 2: SFC Retention time=2.54 min. LC-MS: Rt=1.07 min; MS mass/charge [M+H]+ 409.2.

Examples 158-163 below were synthesized according to the protocol described for Example 156 using methyl 3-bromo-7-oxatricyclo[2.2.1]hepta-2,5-diene-2-carboxylate (Intermediate 1c) and various anilines in step C and various boronic esters/boronic acids in step E.

Example 158 (1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-3-(2-methylpyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7-oxabicyclo [ 2.2.1] heptane-2-carboxamide

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LC-MS: Rt=1.05 min; MS mass/charge [M+H]+ 409.2.

Example 159 (1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-3-(pyridin-4-yl)-N-(3-(trifluoromethyl)phenyl)-7oxabicyclo[2.2.1] heptane-2-carboxamide

LC-MS: Rt=1.07 min; MS mass/charge [M+H] ⁺ 395.2.

Example 160 (1R,2R,3S,4R,5S,6R)-N-(3,4-dichlorophenyl)-5,6-dihydroxy-3-(pyridin-4-yl)-7-oxabicyclo[2.2.1 ]heptan-2-carboxamide

LC-MS: Rt=1.08 min; MS mass/charge [M+H] ⁺ 395.1.

Example 161 7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=0.85 min; MS mass/charge [M+H] ⁺ 410.2.

Example 162 (1S,2R,3S,4R,5S,6R)-N-(5,6-dichloropyridin-3-yl)-5,6-dihydroxy-3-(2-methylpyridin4-yl)-7-oxabicyclo [2.2.1] heptane-2-carboxamide

LCMS: Rt=0.96 min; MS mass/charge [M+H] ⁺ 410.1.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.73 (s, 1H), 8.48 (d, J=2.4 Hz, 1H), 8.40-8.36 (m, 2H), 7.18 (s, 1H), 7.12 (dd, J=5.3, 1.7 Hz, 1H), 4.94 (s, 2H), 4.63-4.58 (m, 1H) , 4.24-4.21(m, 1H), 3.96-3.90(m, 2H), 3.35-3.28(m, 1H), 3.03-2.97(m, 1H), 2.45 (s, 3H).

Example 163 (1S,2R,3S,4R,5S,6R)-5,6-dihydroxy-N-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2methylpyridin-4-yl) )-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LCMS: Rt=0.92 min; MS mass/charge [M+H] ⁺ 424.2.

1H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 8.78 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.5 Hz, 1H ), 8.39 (d, J=5.5 Hz, 1H), 7.22 (s, 1H), 7.16(dd, J=5.4, 1.7 Hz, 1H), 4.94 (s, 1H), 4.85 (s, 1H), 4.63-4.58 (m, 1H), 4.24-4.21 (m, 1H), 3.97-3.90 (m , 2H), 3.36-3.32 (m, 1H), 3.05-2.99 (m, 1H), 2.59-2.56 (m, 3H), 2.46 (s, 3H ).

164.

Example (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7 oxabicyclo[2.2.1]heptan-2- carboxamide

The title compound was prepared from (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy3-(6-methylpyridin-3-yl)-7-oxabicyclo[2.2.1] heptan-2-carboxamide (5a, where R ₂ =3,4-dichlorophenyl and Ar=6-methylpyridin-3-yl, example 138) following step A in scheme 6.

Step A: To a stirred solution of (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(6methylpyridin-3-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (25 mg, 0.064 mmol) in DCM (1 ml) Xtalfluor-E (22 mg, 0.095 mmol) and triethylamine trihydrofluoride (0.021 ml, 0.127 mmol) were added at room temperature. The reaction mixture was stirred for 16 hours. The reaction mixture was cooled to 0° C. and quenched with saturated aqueous sodium bicarbonate. The crude mixture was extracted three times with dichloromethane. The combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The crude compound was purified by FCC to give (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(6-methylpyridin-3-yl)-7-oxabicyclo[ 2.2.1]heptane-2carboxamide.

LC-MS: Rt=1.46 min; MS mass/charge [M+H] ⁺ 395.0.

- 59 040531

1H NMR (500 MHz, DMSO-d6) δ 10.62 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.99 (d, J=2.4 Hz, 1H ), 7.59-7.56 (m, 2H), 7.49 (dd, J=8.8, 2.4Hz, 1H), 7.24 (d, J=8.1Hz, 1H) , 5.27 (d, J=71.0 Hz, 1H), 4.85-4.77 (m, 1H), 3.813.76 (m, 1H), 3.15-3.13 (m, 1H ), 3.12-3.09 (m, 1H), 2.44 (s, 3H), 1.99-1.91 (m, 2H). >20:1 mixture of alcohol regioisomers.

Example 165 (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-fluoro-3-(2-methoxypyridin-4-yl)-7-oxabicyclo[2.2.1]heptane -2-carboxamide

Example 165 was synthesized according to the protocol described for example 164 using (1R,2S,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methoxypyridin-4-yl )-7-oxαbicyclo[2.2.1]heptane-2-carboxamide (5a, where R ₂ =3,4-dichlorophenyl and Ar=2-methoxypyridin-4-yl, example 139) in step A. LC-MS: Rt =1.74 min; MS mass/charge [M+H]+ 411.0.

1H NMR (500 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.13-8.12 (m, 1H), 7.99 (d, J=2.4 Hz, 1H), 7.58 (d, J=8.8 Hz, 1H), 7.49 (dd, J=8.8, 2.4 Hz, 1H), 6.95-6.92 (m, 1H), 6 .75 (s, 1H), 5.31-5.13 (m, 1H), 4.84-4.81 (m, 1H), 3.85 (s, 3H), 3.80-3.76 (m, 1H), 3.25-3.21 (m, 1H), 3.11-3.08 (m, 1H), 1.97-1.91 (m, 2H). -2:1 mixture of alcohol regiostereomers.

Example 166 (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-(dimethylamino)-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane -2-carboxamide

The title compound was prepared from (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptan-2-carboxamide (5a, where R ₂ =3,4-dichlorophenyl and Ar=2-methylpyridin-4-yl, example 77) following steps B and C in scheme 6.

Step B: To a stirred solution of (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (200 mg, 0.509 mmol) in THF (5 mL) at RT and the Dess-Martin reagent (431 mg, 1.02 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by FCC to give (1R,2R,3S,4R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo7-oxabicyclo[2.2.1] heptane-2-carboxamide.

LCMS: Rt=1.22 min; MS mass/charge [M+H]+ 391.0.

Step C: To a stirred solution of (1R,2R,3S,4R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4yl)-5-oxo-7-oxabicyclo[2.2.1]heptane- 2-carboxamide (20 mg, 0.051 mmol) in DCM (2 ml) was added one drop of acetic acid and dimethylamine in THF (0.153 ml, 0.307 mmol). The reaction mixture was cooled to 0° C. and sodium borohydride (4 mg, 0.102 mmol) was added. The reaction mixture was stirred at rt. for 30 min, then heated at 50° C. for 2 h. The reaction mixture was cooled to room temperature and filtered, and the filtrate was concentrated. The crude compound was purified by RP-HPLC to give (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-(dimethylamino)-3-(2methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2-carboxamide. LCMS: Rt=1.12 min; MS mass/charge [M+H]+ 420.1.

1H NMR (400 MHz, DMSO-d6) δ 10.21 (s, 1H), 8.35 (d, J=5.1 Hz, 1H), 8.00 (d, J=2.5 Hz, 1H ), 7.55 (d, J=8.8 Hz, 1H), 7.43 (dd, J=8.8, 2.5 Hz, 1H), 7.12 (s, 1H), 7.06 (d, J=5.3Hz, 1H), 4.94-4.87(m, 1H), 4.48-4.42(m, 1H), 4.13-4.08(m, 1H ), 3.10-3.04 (m, 1H), 2.43 (s, 3H), 2.42-2.35 (m, 1H), 2.12 (s, 6H), 1.89- 1.79 (m, 1H), 1.48-1.40 (m, 1H). >20:1 mixture of alcohol regioisomers.

Examples 167-177 below were synthesized according to the protocol described for example 166 using intermediate 5a and various amines in step C.

Example 167 (1 R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-(methylamino)-3-(2-methylpyridin-4-yl)-7 oxabicyclo [2.2.1 ] heptane-2-carboxamide

LC-MS: Rt=1.10 min; MS mass/charge [M+H]+ 406.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.44 (s, 1H), 8.37-8.32 (m, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (s, 1H), 7.08 (dd , J=5.2, 1.7 Hz, 1H), 4.90-4.84 (m, 1H), 4.49-4.44 (m, 1H), 3.99-3.95 (m , 1H), 3.16 (s, 1H), 3.15-3.11 (m, 1H), 3.09-3.02 (m, 1H), 2.43 (s, 3H), 2, 28 (s, 3H), 1.99-60 040531

1.89 (m, 1H), 1.28-1.20 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 168 (1 R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-((2-hydroxyethyl)amino)-3-(2-methylpyridin4-yl)-7-oxabicyclo [2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.06 min; MS mass/charge [M+H]+ 436.2.

1H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 8.35 (dd, J=5.1, 0.7 Hz, 1H), 8.01 (d, J=2, 4 Hz, 1H), 7.56 (d, J=8.8 Hz, 1H), 7.45 (dd, J=8.8, 2.5 Hz, 1H), 7.14 (d, J= 1.7 Hz, 1H), 7.08 (dd, J=5.2, 1.7 Hz, 1H), 4.87-4.84 (m, 1H), 4.60-4.54 (m , 1H), 4.48-4.44 (m, 1H), 4.01-3.97 (m, 1H), 3.50-3.43 (m, 2H), 3.22-3.11 (m, 3H), 2.592.53 (m, 2H), 2.44 (s, 3H), 2.02-1.93 (m, 1H), 1.28-1.20 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 169 (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-((tetrahydro-2Hpyran-4-yl)amino )-7-oxabicyclo[2.2.1 ]heptane-2-carboxamide

LCMS: Rt=1.16 min; MS mass/charge [M+H]+ 476.2. A mixture of alcohol regioisomers.

Example 170 (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-(((1r,3R)-3-hydroxycyclobutyl)amino)-3-(2methylpyridin-4-yl )-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.07 min; MS mass/charge [M+H] ⁺ 462.2. A mixture of alcohol regioisomers.

Example 171 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-(methylamino)-7 oxabicyclo[2.2.1 ]heptan-2-carboxamide

LCMS: Rt=1.26 min; MS mass/charge [M+H]+ 410.2.

1H NMR (400 MHz, DMSO-d6) δ 10.33 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H ), 7.57 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.4 Hz, 1H), 7.28-7.25 (m, 1H) , 7.03 (s, 1H), 4.93-4.86 (m, 1H), 4.56-4.51 (m, 1H), 4.14-4.09 (m, 1H), 3 .33-3.30 (m, 1H), 3.16-3.12 (m, 1H), 3.10-3.02 (m, 1H), 2.28 (s, 3H), 1.98 -1.90(m, 1H), 1.27-1.21(m, 1H). >20:1 mixture of alcohol regioisomers.

Example 172 (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-(dimethylamino)-3-(2-fluoropyridin-4-yl)-7oxabicyclo[2.2.1]heptane -2-carboxamide

LC-MS: Rt=1.25 min; MS mass/charge [M+H]+ 424.2.

1H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.17 (d, J=5.3 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H ), 7.56 (d, J=8.8 Hz, 1H), 7.46-7.42 (m, 1H), 7.25-7.21 (m, 1H), 7.00 (s, 1H), 4.97-4.92 (m, 1H), 4.55-4.51 (m, 1H), 4.254.18 (m, 1H), 3.13-3.08 (m, 1H) , 2.43-2.37(m, 1H), 2.12(s, 6H), 1.90-1.81(m, 1H), 1.47-1.39(m, 1H). >20:1 mixture of alcohol regioisomers.

Example 173 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-fluoropyridin-4-yl)-5-((2-hydroxyethyl)amino)-7 -oxabicyclo [2.2.1 ]heptane-2-carboxamide

LCMS: Rt=1.21 min; MS mass/charge [M+H]+ 440.2.

¹ H NMR (400 MHz, DMSO-d6) δ 10.36 (s, 1H), 8.18 (d, J=5.2 Hz, 1H), 8.00 (d, J=2.4 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.44 (dd, J=8.8, 2.4 Hz, 1H), 7.28-7.24 (m, 1H ), 7.03 (d, J=1.4 Hz, 1H), 4.91-4.84 (m, 1H), 4.594.55 (m, 1H), 4.53 (d, J=4, 6 Hz, 1H), 4.13 (d, J=5.5 Hz, 1H), 3.50-3.43 (m, 2H), 3.36-3.31 (m, 1H), 3, 22-3.13(m, 2H), 2.62-2.52(m, 2H), 2.04-1.94(m, 1H), 1.29-1.22(m, 1H). >20:1 mixture of alcohol regioisomers.

Example 174 (1 R,2R,3S,4R,5R)-N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-(methylamino)-7- oxabicyclo[2.2.1] heptane-2-carboxamide

- 61 040531

LC-MS: Rt=1.11 min; MS mass/charge [M+H]+ 411.2.

1H NMR (400 MHz, DMSO-06) δ 10.60 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.40 (d, J=2.4 Hz, 1H ), 8.17 (d,

J=5.2Hz, 1H), 7.29-7.25(m, 1H), 7.04(s, 1H), 4.94-4.90(m, 1H), 4.58-4 .51 (m, 1H), 4.17-4.12 (m, 1H), 3.33

3.29 (m, 1H), 3.20-3.16 (m, 1H), 3.10-3.04 (m, 1H), 2.27 (s, 3H), 1.99-1, 91 (m, 1H), 1.29-1.22 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 175 (1R,2R,3S,4R,5R)-N-(5,6-dichloropyridin-3-yl)-5-(dimethylamino)-3-(2-fluoropyridin-4yl)-7-oxabicyclo [2.2 .1]heptane-2-carboxamide

LC-MS: Rt=1.13 min; MS mass/charge [M+H] ⁺ 425.2.

1H NMR (400 MHz, DMSO-d6) δ 10.46 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.41 (d, J=2.4 Hz, 1H ), 8.18 (d, J=5.2 Hz, 1H), 7.26-7.24 (m, 1H), 7.02-7.00 (m, 1H), 4.98-4, 94 (m, 1H), 4.57-4.53 (m, 1H), 4.25-4.19 (m, 1H),

3.17-3.11 (m, 1H), 2.44-2.36 (m, 1H), 2.12 (s, 6H), 1.91-1.81 (m, 1H), 1, 48-1.38 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 176 (1R,2R,3S,4R,5R)-N-(5,6-dichloropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-5-((2-hydroxyethyl)amino )-7-oxabicyclo[2.2.1]heptane-2-carboxamide

LC-MS: Rt=1.08 min; MS mass/charge [M+H] ⁺ 441.2.

1H NMR (400 MHz, DMSO-d ₆ ) δ 10.64 (s, 1H), 8.47 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.3 Hz, 1H), 8.18 (d, J=5.2 Hz, 1H), 7.28-7.25 (m, 1H), 7.03 (s, 1H), 4.92-4.86 (m , 1H), 4.60-4.53 (m, 2H), 4.15 (d, J=5.6 Hz, 1H), 3.50-3.43 (m, 2H), 3.35- 3.29 (m, 1H), 3.24-3.15 (m, 2H), 2.63-2.52 (m, 2H), 2.04-1.94 (m, 1H), 1, 26 (dd, J=12.8, 4.7 Hz, 1H). >20:1 mixture of alcohol regioisomers.

Example 177 (1 R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-morpholino-7 oxabicyclo[2.2.1]heptane -2-carboxamide

LCMS: Rt=1.15 min; MS mass/charge [M+H] ⁺ 462.1. A mixture of alcohol regioisomers.

Example 178 (1 R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-5-methyl-3-(2-methylpyridin-4-yl)7-oxabicyclo[2.2 .1]heptane-2-carboxamide

The title compound was prepared from (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (5a, where R ₂ =3,4-dichlorophenyl and Ar=2-methylpyridin-4-yl, example 77a), following steps B and D in scheme 6.

Step B: To a stirred solution of (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (200 mg, 0.509 mmol) in THF (5 mL) at RT and the Dess-Martin reagent (431 mg, 1.017 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by FCC to give (1R,2R,3S,4R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo7-oxabicyclo[2.2.1] heptane-2-carboxamide.

LCMS: Rt=1.22 min; MS mass/charge [M+H] ⁺ 391.0.

Step D: Solution of (1R,2R,3S,4R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7oxabicyclo[2.2.1]heptan-2 - carboxamide (10.4 mg, 0.027 mmol) in THF (0.5 ml) at RT was treated with 3.0 M MeMgBr in diethyl ether (35.4 μl, 0.106 mmol) and stirred for 2 h. Additional 3.0 M MeMgBr in diethyl ether (35.4 μl, 0.106 mmol) was added and the reaction mixture was stirred at k.t. within 16 hours the Reaction mixture was quenched sat. aq. NH ₄ Cl, diluted

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EtOAc, washed with water and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by FCC to give (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-hydroxy5-methyl-3-(2-methylpyridin-4-yl)-7- oxabicyclo[2.2.1]heptane-2-carboxamide.

Example 179 (1S,2S,3R,4S,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-5-methyl-3-(2-methylpyridin-4-yl)-7oxabicyclo [2.2.1 ]heptan-2-carboxamide

Example 179 was synthesized according to the protocol described for example 178 using (1S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl )-7-oxabicyclo[2.2.1]heptane2-carboxamide (Example 77c).

LCMS: Rt=1.27 min; MS mass/charge [M+H]+ 407.2. >20:1 mixture of alcohol regioisomers.

Example 180 (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2 -carboxamide

The title compound was prepared from (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy3-(2-methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptan-2-carboxamide (5a, where R ₂ =3,4-dichlorophenyl and Ar=2-methylpyridin-4-yl, example 77a), following steps B and E in scheme 6.

Step B: To a stirred solution of (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2methylpyridin-4-yl)-7-oxabicyclo[2.2.1] heptane-2-carboxamide (200 mg, 0.509 mmol) in THF (5 mL) at RT and the Dess-Martin reagent (431 mg, 1.017 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc, washed with sat. aq. NaHCO ₃ and brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by FCC to give (1R,2R,3S,4R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo7-oxabicyclo[2.2.1] heptane-2-carboxamide.

LCMS: Rt=1.22 min; MS mass/charge [M+H]+ 391.0.

Step E: Solution of (1R,2R,3S,4R)-N-(3,4-dichlorophenyl)-3-(2-methylpyridin-4-yl)-5-oxo-7oxabicyclo[2.2.1]heptan-2- carboxamide (18 mg, 0.046 mmol) in THF (1 ml) at RT Work up using NaBH ₄ (6.96 mg, 0.184 mmol) and stir at rt. within 18 hours the Reaction mixture was diluted with sat. aq. NaHCO ₃ and extracted using EtOAc. The organic layer was washed with brine, dried (Na ₂ SO ₄ ), filtered and concentrated. The resulting residue was purified by FCC to give (1R,2R,3S,4R,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2. 1]heptane-2-carboxamide.

LC-MS: Rt=1.20 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, acetonitrile^) δ 8.59 (s, 1H), 8.35 (dd, J=5.2, 0.8 Hz, 1H), 7.89 (dd, J=2.2 , 0.6 Hz, 1H), 7.46-7.38 (m, 2H), 7.18-7.16 (m, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 4.87-4.79 (m, 1H), 4.42-4.34 (m, 1H), 4.33-4.24 (m, 1H), 4.17-4, 13 (m, 1H), 3.65-3.55 (m, 1H), 3.15-3.07 (m, 1H), 2.46 (s, 3H), 2.12-2.02 ( m, 1H),

1.54-1.46 (m, 1H). >20:1 mixture of alcohol regioisomers.

Example 181 (1S,2S,3R,4S,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2 -carboxamide

Example 181 was synthesized according to the protocol described for example 180 using (1S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3-(2-methylpyridin-4-yl )-7-oxabicyclo[2.2.1]heptane2-carboxamide (Example 77c). LC-MS: Rt=1.20 min; MS mass/charge [M+H]+ 393.1.

1H NMR (400 MHz, acetonitrile-d ₃ ) δ 8.60 (s, 1H), 8.36-8.34 (m, 1H), 7.89 (dd, J=2.2, 0.6 Hz , 1H), 7.467.39 (m, 2H), 7.17 (s, 1H), 7.10 (dd, J=5.2, 1.7 Hz, 1H), 4.86-4.81 ( m, 1H), 4.42-4.37(m, 1H), 4.31-4.24(m, 1H), 4.17-4.11(m, 1H), 3.63-3, 57 (m, 1H), 3.15-3.09 (m, 1H), 2.46 (s, 3H), 2.11-2.01 (m, 1H), 1.54-1.45 ( m, 1H). >20:1 mixture of alcohol regioisomers.

Example 182 The incorporation of a 58-hydroxyl group into the oxabicyclic core reduces CYP3A4 inhibition and intrinsic clearance of compounds in microsomes in both rats and humans, as shown in Table 1. 1.

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Table 1

⁰ II ϊ Example 47а . .,-¾% ^{1 0} ίι N „ ,¾ %ι %G Example 149 CL _co g _CTB (µl/min/mg) in rat liver microsomes 466 7 243 AND CL _co g _CTB (µl/min/mg) in human liver microsomes 202 7 38 7 CYP3A4 ING. (µM) 6 >25 5 20

Biological analyzes

Compounds of the present invention were evaluated using the following assays: (1) type II collagen assay to measure chondrogenic differentiation; (2) alkaline phosphatase (ALP) activity assay to determine the ability of compounds to prevent chondrocyte hypertrophy in normal human articular chondrocytes (NHAC) and C3H10T1/2 cell line; and (3) calcium flux assay.

Table 2. Reagents used for experiments

Description Manufacturer Number no catalog Dilution/Concentration Collagenase type II Worthington Biochemicals CLS-2 0.2 mg/ml Antibody to type II collagen Abeam 3092 1:500 Anti-mouse 647 Life Technologies A-21235 1:5000 Bovine serum albumin (BSA) Triton X-100 Hoescht 33342 Life Technologies H3570 1:1000 Durable blue RR salt Sigma F0500-25G 0.024% w/v Naphthol AS-MX phosphate alkaline solution Sigma 855-20ML 4%(v/v) Dye "Calcium 5" Molecular Devices R8186 100 ml/bottle probenecid Sigma P8761-100G 5mM HEPES Hyclone SH30237.01 10mM

cell culture

Normal human articular chondrocytes (NHAC) were purchased from PromoCell (Heidelberg, Germany) and grown in chondrocyte growth medium (CGM; Lonza, Walkersville, MD). Cell line C3H10T1/2 (clone 8) was purchased from ATCC (Manassas, Virginia) and grown in high glucose DMEM supplemented with 10% FBS and antibiotic/antifungal (ThermoFisher Scientific, Waltham, MA). Human chondrogenic progenitor cells (CPCs) were derived from primary human articular chondrocytes (Lonza, Walkersville, MD) that were separated into individual cells, grown by cloning in mesenchymal stem cell growth medium (MSCGM; Lonza, Walkersville, MD) and confirmed as mesenchymal cells. -predecessors through chondrogenic, osteogenic and adipogenic differentiation. Cells were sorted by FACS and confirmed to be >98% positive for CD166 and CD105. CPC were cultured up to 20 passages without changing the cell profile, growth rate or cell differentiation.

Type II Collagen Analysis and Quantification

To initiate chondrogenesis in primary CPCs, 8,000 cells were plated/well in a 96-well Costar plate in MSCGM. After 24 hours MSCGM was removed and replaced with DMEM containing 1% FBS. The test compound was then added to each well at the indicated dose. Cultures were grown at 37°C for 18 days. 10 days after the induction of chondrogens, additional medium was added in the amount of an additional 50 μl of DMEM containing 1% FBS.

To detect the presence of type II collagen, hCPCs were fixed with 10% formalin for 20 min, permeable using PBS containing 0.1% Triton X-100, 0.2 mg/ml collagenase 2 for 10 min, blocked using PBS containing 5% BSA for 1 hour at room temperature and then incubated with the primary antibody (anti-collagen

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type II) in PBS containing 1% BSA overnight at 4°C. Cells were washed 3 times with PBS and incubated with fluorophore-conjugated secondary antibody and Hoechst dye for 1 hour at room temperature, followed by washing 3 times with PBS.

The overall intensity of staining was observed using fluorescence microscopy and/or quantified using simultaneous multi-parameter analysis on ImageXpress Micro Confocal (Molecular Devices, Sunnyvale, CA). Data analysis was performed using a dedicated multi-wavelength cell counting application.

Staining and quantification of alkaline phosphatase in NHAC

To initiate differentiation in NHAC, 16,000 cells/well were plated in a 96-well Costar plate in CGM medium (Lonza). After 24 h MSCGM was removed and replaced with DMEM containing 1% FBS. The test compound was then added to each well at the indicated dose. Cultures were grown at 37°C for 10 days.

To detect the presence of hypertrophied cells, NHAC was fixed with 10% formalin and Hoeschst stain for 20 minutes, washed in PBS, then stained with RR fast blue salt with AS-MX naphthol alkaline phosphate solution. After observing blue staining of the cells after about 2 hours at 37°C, they were washed three times using PBS.

Overall staining intensity was observed by fluorescent microscopy at 651 wavelength and/or quantified by simultaneous multiparameter analysis on an ImageXpress Micro Confocal (Molecular Devices, Sunnyvale, CA). Data analysis was performed using a dedicated multi-wavelength cell counting application.

Staining and quantification of alkaline phosphatase in C3H10T1/2

To initiate differentiation into C3H10T1/2, clone 8 (ATCC cat. no. CCL-226), 4000 cells per well were plated in a 384 Perkin Elmer CellCarrier Ultra plate in DMEM/c high glucose (HyClone cat # SH30022.01) containing 10 % FBS and 1x Antibiotic/Anti-fungal (HyClone cat. no. SV30079.01). After 24 hours, the test compound at the indicated dose was added to each well. Cultures were grown at 37°C for 6 days.

To detect the presence of hypertrophied cells, C3H10T1/2 was fixed with 4% paraformaldehyde and Hoeschst stain for 20 min, washed in PBS, then stained with RR fast blue salt with AS-MX naphthol alkaline phosphate solution. By observing blue staining of the cells after about 3 hours at 37°C, they were washed six times using PBS.

ALP staining was recorded using fluorescence microscopy at a wavelength of 561 and/or quantified using simultaneous multi-parameter analysis on ImageXpress Micro Confocal (Molecular Devices, Sunnyvale, CA). Data analysis was performed using a specialized multi-wavelength cell counting application based on the number of ALP positive cells per well.

Calcium Flux Analysis and Quantification

NHAC was seeded on a Greiner 1536 plate at 2000 cells/well and a volume of 4 μl. After 24 h, 4 μl of calcium dye solution 5 (Hank's balanced salt solution/HEPES buffer containing 5 mM probenecid) was added and incubated for 1 h at room temperature. Fluorescence readings at an excitation wavelength of 470-495 nm and an emission wavelength of 515-575 nm were taken using a FLIPR high throughput screening system (Molecular Devices, Sunnyvale, CA). The test compound was then added to each well at the indicated dose. The signal was measured before and after compound dosing using a first interval of 1 second for 60 readings and a second interval of 3 seconds for 20 readings. Data was analyzed using Molecular Devices ScreenWorks® software.

The activity of the compounds of the present invention in the following assays are shown in table. 3. Legend: (A) calcium flow analysis; (B) type II collagen analysis; (C) NHAC alkaline phosphatase analysis; and (D) C3H10T1/2 alkaline phosphatase analysis.

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Table 3

Etc. No. (A) EC ₅₀ µM (% potency) (IN) EC so µM (% potency) (C) 1C ₅₀ µM (% potency) (D) 1C ₅₀ µM (% potency) 1 (1 S,2S,4R,5R,6S,7S)-N-(5,6dichloropyridin-3-yl)-7-(2methoxypyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 3.4 (164) 2 rac-(\S,2S,4R,5R,6S,7S)-N-(6methoxypyridin-3-yl)-7-(6methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) 3 (1 S,2S,4R,5R,6S,7S)-N-(6methoxypyridin-3-yl)-7-(6methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 0.30 (45) 4 (lR,2R,4S,5S,6R,7R)-N-(6methoxypyridin-3-yl)-7-(6methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) 5 (lR,2R,3S,4R,5S)-N-(4,5dichloropyridin-2-yl)-5hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (28) 6 (lR,2R,3S,4R,5S)-N-(5-xaop-6methylpyride in-3-yl)-5 hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50(18) 7 (lR,2R,3S,4R,5S)-N-(5,6dichloropyridin-3-yl)-5 hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50(17) 8 (lR,2R,3S,4S,5R)-N-(5,6dichloropyridin-3-yl)-5 hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (0)

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9 (1R,2S,3S,4R,5S)-5-^pokch3 -(2-methylpyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (50) >31 (62) >20 (16) 10 (lS,2S,3S,4S,6R)-6-nmpoKCH-3(2-methyl pyride and n-4-yl)-N-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptan- 2carboxamide >50 (0) eleven rac-(lR,2R,3S,4R,5S)-N-(5,6d ichloropyridin-3-yl)-5 hydroxy-3-(pyridin-4-yl)-7 oxabicyclo[2.2.1]heptan- 2carboxamide >50 (0) Pa (lR,2R,3S,4R,5S)-N-(5,6d ichloropyridin-3-yl)-5 hydroxy-3-(pyridin-4-yl)-7 oxabicyclo[2.2.1]heptan-2carboxamide >50 (55) 12 rac-(lR,2S,3S,4R,5S)-5hydroxy-3-(pyridin-4-yl)-M[3-(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (27) 12a (lR,2S,3S,4R,5S)-5-hydropoκci3 -(pyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide 0.27 (98) 2.9(91) 48 (65) >20 (6) 13 (lS,2S,3S,4S,6R)-6-hydroxy-3(pyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (22) 14 (lR,2S,3S,4R,5R)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 4.5 (68) 15 (lR,2S,3S,4R,5R)-5^ _T op-N-(6methoxypyride in-3-yl)-3 -(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 8.3 (115) 16 (lR,2S,3S,4R,5R)-5-φτop-3-(2methylpyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicycloG2.2.1]heptan-2- >50 (0)

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carboxamide 17 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 21 (105) 18 (1R,2S,3S,4R,5S)-5^to _P -3-(2methylpyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 19 (lR,2R,3S,4R,5S)-N-(5,6dichloropyridin-3-yl)-5-fluoro3 -(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (0) 20 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 25 (258) 21 (lR,2S,3S,4R,5S)-3-(2- aminopyrimidin-5-yl)-M-(3,4dichlorophenyl)-5-fluoro-7oxabicyclo [2.2.1]heptane-2carboxamide >50 (5) 22 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(6methylpyridin-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 27(159) 23 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(2fluoropyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 4.2 (128) 24 gas-(1 S,2S,4R,5R,6S,7S)-N(3,4-dichlorophenyl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ² ' ⁴ ]octane6-carboxamide >50 (54) 24a (1 S,2S,4R,5R,6S,7S)-N-(3,4dichlorophenyl)-7-(2methylpyride in-4-yl)-8 oxatricyclo[3.2.1.0 ² ' ⁴ ]octane 6-carboxamide 6.1 (99) 0.78 (29) 30(100) >20 (28)

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24b (lR,2R,4S,5S,6R,7R)-N-(3,4dichlorophenyl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) 25 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichloroφenyl)-7-(2methoκcipyridin-4-yl)-8oxatricyclo[ ^{3.2.1.0 2'4} ]octane6-carboxamide I(71) 26 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichlorophenyl)-7-( ^{2fluoropyridin} -4-yl)-8oxatricyclo[3.2.1.0 ^2'4 ]octane6-carboxamide 17(52) 27 (1 S,2S,4R,5R,6S,7S)-7-(2methyl pyride and n-4-yl)-N-[3 (trifluoromethyl)phenyl] - 8 oxatricyclo[3.2.1.0 ² ' ⁴ ]octane6-carboxamide 23 (54) 28 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichlorophenyl)-7-(πirimide in5-yl)-8oxatricyclo[3.2.1.0 ² ' ⁴ ]octane6-carboxamide 13 (120) 34(71) >20 (48) 29 (lR,2R,4S,5S,6R,7R)-N-(3,4dichlorophenyl)-7-(in5-yl pyrimide)-8oxatricyclo[3.2.1.0 ² ' ⁴ ]octane 6-carboxamide 23 (167) thirty (1 S,2S,4R,5R,6S,7S)-N-(3,4dichlorophenyl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[ ^{3.2.1.0 2'4} ]octane6-carboxamide >50 (6) 31 (lR,2R,4S,5S,6R,7R)-N-(3,4dichlorophenyl)-7-(2,3 ^{difluoropyridin} -4-yl)-8oxatricyclo[3.2.1.0 ^2'4 ]octane6-carboxamide 10(133) 32 (lS,2S,4R,5R,6S,7S)-N-(5,6dichl op pyridin-3-yl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ² ' ⁴ ]octane6-carboxamide 13 (143)

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33 (lS,2S,4R,5R,6S,7S)-N-(6methoxypyridin-3-yl)-7(pyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 4.6 (49) 34 (lS,2S,4R,5R,6S,7S)-7-(2,3difluoropyridin-4-yl)-X-(6methoxypyridin-3-yl)-8oxatricyclo[ ^{3.2.1.0 2'4 ]} octane6-carboxamide >50(3) 35 (1 S,2S,4R,5R,6S,7S)-N-(6methoxypyridin-3-yl)-7-[6(trifluoromethyl)pyridin-2-yl]8oxatricyclo[ ^{3.2.1.0 2'4} ]octane6-carboxamide >50 (0) 36 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichlorophenyl)-7-(2fluoropyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ²⁴ }]octane -6-carboxamide 8.6 (124) 37 (lS,2S,4R,5R,6S ^, 7S)-7(pyrimidin-5-yl)-M-[3(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1.0 ^2'4 ]octane6-carboxamide >50 (26) 38 (lS,2S,4R,5R,6S ^, 7S)-7-(pyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1.0 ^2'4 ]octane6-carboxamide 9.9 (36) 39 (lS,2S,4R,5R ^, 6S,7S)-7-(2aminopyrimidin-5-yl)-M-(3,4dichlorophenyl)-8oxatricyclo[3.2.1.0 ^2'4 ]octane6-carboxamide 0.53 (40) 40 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichloropφenyl)-7 - [2(morpholin-4-yl)pyrimidin-5yl]-8oxatricyclo[3.2.1.0 ² ' ⁴ ]octane6- carboxamide >50 (37) 41 (lS,2S,4R,5R,6S,7S)-7-(2fluoropyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1.0 ² > ⁴ ]octane6-carboxamide 24(121) 42 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichlorophenyl)-7-(2- 18 (57)

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methylpyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane 6-carboxamide 43 gas-(1 S,2S,4R,5R,6S,7S)-N(5,6-dichloroπiridin-3-yl)-7(πiridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50(168) 43a (1 S,2S,4R,5R,6S,7S)-N-(3,4dichloroφenyl)-7-(πiridin-4yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) 43b (lR,2R,4S,5S,6R,7R)-N-(5,6dichloropyridine-3-yl)-7(pyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50(3) 44 (1 S,2S,4R,5R,6S,7S)-N-(3,4dichloroφenyl)-7-(πiridin-4yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) 45 (1 S,2S,4R,5R,6S,7S)-N-(5,6dichloropyridin-3-yl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 14 (32) 46 (lR,2R,4S,5S,6R,7R)-N-(5,6dichloropyridin-3-yl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) 47 rac-(lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(pyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 7.8 (38) 47a (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(pyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (68) 2.1 (82) 33 (88) >20 (23) 48 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(6-methylpyridin-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 22 (80)

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49 rac-(lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 11(77) 49a (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 0.84 (53) 49b (lS,2R,3R,4S,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50(31) 50 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[6-(trifluoromethyl)pyridin-2yl]-7oxabicyclo[2.2.1]heptane-2carboxamide 21 (308) 51 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(pyrimide in-5-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 52 rac-(lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (4) 52a (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (96) 0.49 (80) 17(71) >20 (36) 52b (lS,2R,3R,4S,5R)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50(1) 53 rac-(lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (43)

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53a (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50(12) 13 (44) 31(83) >20 (0) 53b (lS,2R,3R,4S,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50(119) 54 rac-(lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyridin-4yl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (22) >20 (35) 54a (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyridin-4yl]-7oxabicyclo[2.2.1]heptane-2carboxamide 3.5 (45) >20 (35) 54b (lS,2R,3R,4S,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyridin-4yl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50(16) >20 (46) 55 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-3 - [2(d-imethylamino)pyrimidin-5yl]-5-hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 56 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyrimidin-5-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 57 (lR,2S,3S,4R,5S)-3-(2aminopyridin-4-yl)-M-(3,4dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (56) 58 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2,5difluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptan-2- >50 (0)

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carboxamide 59 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2,3difluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 1.2 (254) 60 (lR,2S,3S,4R,5S)-3-(2- aminopyrimidin-5-yl)-X-(3,4dichlorophenyl)-5-hydroxy-7 oxabicyclo [2.2.1]heptane-2carboxamide >50 (2) 61 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyrimidin-5-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (24) 62 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyrimidin5-yl]-7oxabicyclo[2.2.1]heptan-2carboxamide 8.2 (61) 63 (lR,2S,3S,4R,5S)-N-(3,4dichlorophenyl)-5-methoxy-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (9) 64 (lR,2S,3S,4R,5R)-N-(3,4dichlorophenyl)-5-fluoro-3-(6methylpyridin-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 21 (253) 65 (lR,2S,3S,4R,5R)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 18(169) 66 (1 S,2S,4R,5R,6R,7S)-N-(4chloro-3-cyanophenyl)-7-(2methylpyridin-4-yl)-8oxatricyclo[ ^{3.2.1.0 2'4 ]} octane6-carboxamide 20 (179) 67 (1 S,2S,4R,5R,6R,7S)-N-(4chloro-2-cyanoφenyl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ² ' ⁴ ]octane- >50 (39)

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6-carboxamide 68 (1 S,2S,4R,5R,6R,7S)-N-(4chloro-3-fluorophenyl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 15 (306) 69 (lS,2S,4R,5R,6R,7S)-7-(2methyl pyride and n-4-yl)-N-[3(trifluoromethoxy)phenyl]-8 oxatricyclo[3.2.1.0 ²⁴ ]octane6- carboxamide 21 (180) >20 (63) 70 (1 S,2S,4R,5R,6R,7S)-N-(5methyl-1,3-thiazol-2-yl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6- carboxamide >50 (25) >20 (1) 71 (lS,2S,4R,5R,6R,7S)-N-[3fluoro-4(trifluoromethoxy)phenyl]-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 6.2 (250) 72 (1 S,2S,4R,5R,6R,7S)-N-(5,6dichl op pyridin-3-yl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ] octane6-carboxamide 7.7 (208) 73 (lR,2R,4S,5S,6S,7R)-N-(5,6dichl op pyridin-3-yl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6 -carboxamide 16(127) 74 (1 S,2S,4R,5R,6R,7S)-N-(5,6dichloropyridin-3-yl)-7-(6methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 7.7 (90) >20 (83) 75 (1 S,2S,4R,5R,6R,7S)-N-(5,6dichloropyridine-3-yl)-7(pyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 4.4 (73) >20 (45) 76 (1 S,2S,4R,5R,6R,7S)-N-(5,6dichloropyridin-3-yl)-7-(2methoxypyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 5.8 (123)

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77 rac-(lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 26 (49) 77a (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 26(182) 0.69 (120) 3.5 (114) >20 (45) 77b (lS,2R,3S,4S,6R)-N-(3,4dichlorophenyl)-6-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 20(157) >20 (47) 77c (lS,2S,3R,4S,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 13 (72) 3.9 (72) 77d (lR,2S,3R,4R,6S)-N-(3,4dichlorophenyl)-6-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 33 (92) >20 (54) 78 (lR,2R,3S,4R,5S)-N-[3-chloro-4(2-fluorophenyl)phenyl]-5hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (70) 79 (lR,2R,3S,4R,5S)-5-hydropoκc and N-(lmethanesulfonylpiperidin-4yl)-3-(2-methylpyridin-4-yl)7-oxabicyclo[2.2.1]heptan-2carboxamide >50(113) >20 (34) 80 (lR,2R,3S,4R,5S)-N-(4,5dichloropyridin-2-yl)-5hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (32) 81 (lR,2R,3S,4R,5S)-N-(5-chloro-6methylpyride in-3-yl)-5 hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 2.7 (34)

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82 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyrimidin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (74) 83 (lR,2R,3S,4R,5S)-N-(5,6dichloropyridin-3-yl)-5 hydroxy-3-(2-methylpyridin4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (38) 1.5 (150) 12(106) >20 (34) 84 (lS,2S,3R,4S,5R)-N-(5,6- dichloropyridin-3 -yl)-5 hydroxy-3 -(2-methylpyridin- 4-yl)-7- oxabicyclo[2.2.1] heptane-2carboxamide >50(61) >20 (31) 85 (1R,2R,3S,4R,5S)-5-^pokch3 -(2-methylpyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (56) 86 (lS,2R,3S,4S,6R)-6-nmpoKCH- 3-(2-methylpyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (38) 87 (lR,2R,3S,4R,5S)-N-(5,6dichloropyr idin-3-yl)-5 hydroxy-3-(pyridin-4-yl)-7 oxabicyclo[2.2.1]heptan-2carboxamide >50(14) 88 (1R,2R,3S,4R,5S)-5-^pokch3 -(pyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (27) 89 (lS,2R,3S,4S,6R)-6-nmpoKCH- 3-(pyridine in-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 90 rac-(lR,2R,3S,4R,5S)-N-(5,6dichloropyridin-3-yl)-3-(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (45)

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90a (lR,2R,3S,4R,5S)-N-(5,6dichloropyridin-3-yl)-3-(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptan-2carboxamide >50(101) 2.3 (65) >50 (98) >20 (48) 90b (lS,2S,3R,4S,5R)-N-(5,6d ichloropyride in-3-yl)-3-(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (44) >20 (45) 91 (lR,2R,3S,4R,5S)-N-(5,6dichl op pyridin-3 -yl)-3 -(2,3 difluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptan- 2carboxamide 4.4 (66) 92 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (57) 93 (lS,2R,3S,4S,6S)-N-(3,4d ichlorophenyl)-6-fluoro-3 -(2methylpyride in-4-yl)-7oxabicyclo[2.2.1] heptane-2carboxamide >50 (7) 94 (lS,2S,3R,4S,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 18 (157) >20 (0) 95 (lR,2S,3R,4R,6R)-N-(3,4d ichlorophenyl)-6-fluoro-3 -(2methylpyride in-4-yl)-7oxabicyclo[2.2.1] heptane-2carboxamide 11(113) 96 (1R,2R,3S,4R,5R)-5^to _P -3-(2methyl and iride and n-4-yl)-N-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane- 2carboxamide 14(281) 97 (lR,2R,3S,4R,5R)-5-φτop-N-(6methoxypyride in-3-yl)-3-(2methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (2)

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98 (1R,2R,3 S,4R,5R)-N-(5,6dichloropyridin-3-yl)-5-fluoro3 -(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 21 (404) 99 (lR,2R,3S,4R,5R)-5^ _T op-3-(2methylpyridin-4-yl)-I-[3(trifluoromethoxy)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide 18 (383) 100 (lR,2R,3S,4R,5R)-5-φτop-N-[3fluoro-4(trifluoromethoxy)phenyl)]-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 18(310) 101 (lR,2R,3S,4R,5R)-5-φτop-N-(lmethyl-1 H-pyrazol-3 -yl)-3 -(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan- 2carboxamide 29 (62) 102 (lR,2R,3S,4R,5R)-5-φτop-N-(5methyl-1,3-thiazol-2-yl)-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptane -2 carboxamide 2.1 (84) 103 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 24(153) 10 (79) 104 (lS,2R,3S,4S,6R)-N-(3,4d ichlorophenyl)-6-fluoro-3 -(2methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 14 (96) 105 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 8.2 (106) 1.7 (68) 106 (lS,2R,3S,4S,6R)-N-(3,4d ichlorophenyl)-6-fluoro-3 -(2methylpyride in-4-yl)-7oxabicyclo[2.2.1] heptane-2carboxamide 24 (84) 107 (1R,2R,3S,4R,5S)-5^to _P -3-(2methylpyridin-4-yl)-I-[3(trifluoromethyl)phenyl]-7- 12(139)

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oxabicyclo[2.2.1] heptane-2carboxamide 108 (18.2K,38.48.6K)-6-fluoro-3-(2methylpyridin-4-yl)-X-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide 27(137) 109 (lR,2R,3S,4R,5S)-N-(5,6dichloropyridin-3-yl)-5-fluoro3 -(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 28 (164) 110 (lS,2R,3S,4S,6R)-N-(5,6dichloropyride in-3-yl)-6-fluoro3-(2-methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 28 (199) 111 (lR,2R,3S,4R,5S)-N-(3,4d ichlorophenyl)-5-fluoro-3-(2fluoropyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 28 (87) 112 (lS,2R,3S,4S,6R)-N-(3,4d ichlorophenyl)-6-fluoro-3 -(2fluoropyridin-4-yl)-7oxabicyclo[2.2.1] heptane-2carboxamide 28 (99) FROM (1R,2R,3S,4R,58)-3-(2- aminopyrimidin-5-yl)-M-(3,4dichlorophenyl)-5-fluoro-7oxabicyclo [2.2.1]heptane-2carboxamide 30(103) 114 (lS,2R,3S,4S,6R)-3-(2- aminopyrimidin-5-yl)-M-(3,4dichlorophenyl)-6-fluoro-7oxabicyclo [2.2.1]heptane-2carboxamide 30(127) 115 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-fluoro-3-(6methylpyridin-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 33 (49) 116 (lS,2R,3S,4S,6R)-N-(3,4d ichlorophenyl)-6-fluoro-3 -(6methylpyride in-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 23 (58)

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117 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2methylpyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 3.0 (177) 7.0 (59) 118 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2methoxypyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 8.2(118) 119 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2fluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 25 (149) 120 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7 - [6(trifluoromethyl)pyridin-2-yl]8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 20 (102) 4.4(119) 121 rac-(\S,2S,4R,5R,6R,7S)-7-(2methyl pyride and n-4-yl)-N-[3(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1, 0 ² > ⁴ ]octane 6-carboxamide 26 (353) 121a (lS,2S,4R,5R,6R,7S)-7-(2methyl and irid and n-4-yl)-N-[3 (trifluoromethyl)phenyl] - 8 oxatricyclo[3.2.1.0 ²⁴ ]octane6- carboxamide 2.7(231) 4.5 (80) 121b (lR,2R,4S,5S,6S,7R)-7-(2methyl pyride and n-4-yl)-N- [3 (trifluoromethyl)phenyl] - 8 oxatricyclo[3.2.1.0 ²⁴ ]octane6- carboxamide 22 (92) 122 gas-(1 S,2S,4R,5R,6R,7S)-N(3,4-dichlorophenyl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 5.0 (32) 122a (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 25 (160) 122b (lR,2R,4S,5S,6S,7R)-N-(3,4dichlorophenyl)-7-(2,3 difluoropyridin-4-yl)-8- 17(217)

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oxatricyclo[3.2.1.0 ²⁴ ]octane 6-carboxamide 123 (1 S,2S,4R,5R,6R,7S)-N-(6methoxypyridin-3-yl)-7-(6methylpyridin-3-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (0) >20 (48) 124 (1 S,2S,4R,5R,6R,7S)-N-(5,6d ichlor pyridin-3-yl)-7-(2,3 difluoropyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 2.8 (160) 17 (59) 125 (1 S,2S,4R,5R,6R,7S)-N-(6methoκcipyridin-3-yl)-7(pyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 17(162) 126 gas-(1 S,2S,4R,5R,6R,7S)-N(3,4-dichlorophenyl)-7(pyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 10 (212) 126a (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(pyrimide in5-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 5.4 (233) 126b (lR,2R,4S,5S,6S,7R)-N-(3,4dichlorophenyl)-7-(in5-yl pyrimide)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 5.6(103) >20 (42) 127 (1 S,2S,4R,5R,6R,7S)-7-(2,3difluoropyridin-4-yl)-Н-(6methoxypyridin-3-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (62) 128 (lS,2S,4R,5R,6R,7S)-N-(6methoxypyridin-3-yl)-7-[6(1fluoromethyl)pyridin-2-yl]8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide >50 (27) >20 (39) 129 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2fluoropyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 10(146)

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130 (lS,2S,4R,5R,6R,7S)-7(pyrimidin-5-yl)-M-[3(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 10 (237) 131 (lS,2S,4R,5R,6R,7S)-7-(pyridin-4-yl)-X-[3-(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 19 (360) 132 (1 S,2S,4R,5R,6R,7S)-7-(2aminopyrimidin-5-yl)-M-(3,4dichlorophenyl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 18(321) 133 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7 - [2(morpholin-4-yl)pyrimidin-5yl]-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 25 (158) 134 (lS,2S,4R,5R,6R,7S)-7-(2fluoropyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-8 oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 19 (249) 135 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(2methylpyrimidin-5-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 16 (237) 136 (1 S,2S,4R,5R,6R,7S)-N-(5,6dichloropyridin-3-yl)-7(pyridin-4-yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 17 (254) 137 (1 S,2S,4R,5R,6R,7S)-N-(3,4dichlorophenyl)-7-(pyridin-4yl)-8oxatricyclo[3.2.1.0 ²⁴ ]octane6-carboxamide 21 (202) 138 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(6-methylpyridin-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) >20 (24) 139 rac-(lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methoxypyridin-4-yl)-7- 21 (223)

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oxabicyclo[2.2.1] heptane-2carboxamide 139a (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 25 (275) 1.8 (54) 139b (lS,2S,3R,4S,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 26(141) 7.7 (82) 140 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[6-(trifluoromethyl)pyridin-2yl]-7oxabicyclo[2.2.1]heptane-2carboxamide 15 (292) 141 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3 (pyrimide in-5-yl)-7 oxabicyclo[2.2.1] heptane-2carboxamide 13 (43) 142 rac-(lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 28 (142) 142a (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 22 (68) 1.2 (83) 33 (93) 6.6(81) 142b (lS,2S,3R,4S,5R)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 0.79 (54) 143 (lR,2R,3S,4R,5S)-3-(2aminopyrimidin-5-yl)-M-(3,4dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 144 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -[2(dimethylamino)pyrimidine-5 - 30 (183)

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yl]-5-hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 145 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyridin-4yl]-7oxabicyclo[2.2.1]heptane-2carboxamide 17 (246) 145a (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyridin-4yl]-7oxabicyclo[2.2.1]heptane-2carboxamide 1.2(100) 145b (lS,2S,3R,4S,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-(trifluoromethyl)pyridin-4yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 11(83) 146 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2,3 difluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 20 (150) 147 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2,5difluoropyridin-4-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 28 (284) 148 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyrimidin-5-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 7.8 (51) 18 (58) 149 (lR,2R,3S,4R,5S)-3-(2aminopyridin-4-yl)-M-(3,4dichlorophenyl)-5-hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide 26(112) 8.3 (58) 150 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(pyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50(5)

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151 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3-(2fluoropyrimidin-5-yl)-5hydroxy-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 152 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(1-methyl-1H-pyrazol-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 12 (44) 2.0(61) 153 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(1-methyl-1H-pyrazol-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 19(121) >20 (46) 154 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3[2-(trifluoromethyl)pyrimidin5-yl]-7oxabicyclo[2.2.1]heptan-2carboxamide 26 (236) 4.0 (75) 155 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-5-methoxy-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 26 (262) 156 (lR,2R,3S,4R,5S,6R)-N-(3,4dichlorophenyl)-5,6-d ihydroxy3-(2-methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 18(28) 0.95 (99) 15 (103) >20 (42) 157 (lR,2R,3R,4S,5R,6S)-N-(3,4dichlorophenyl)-5,6-d ihydroxy3-(2-methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 29 (57) 2.1 (59) 32 (84) >20(15) 158 (lS,2R,3S,4R,5S,6R)-5,6dihydroxy-3-(2methylpyridin-4-yl)-M-[3(trifluoromethyl)phenyl]-7oxabicyclo[2.2.1]heptane-2carboxamide >50(31) 159 (lS,2R,3S,4R,5S,6R)-5,6dihydroxy-3 -(pyridin-4-yl)X-[3-(trifluoromethyl)phenyl]7-oxabicyclo[2.2.1]heptane-2carboxamide >50(11)

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160 (lR,2R,3S,4R,5S,6R)-N-(3,4dichlorophenyl)-5,6-d ihydroxy3-(pyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (32) 161 (lS,2R,3S,4R,5S,6R)-5,6dihydroxy-3-(2methylpyridin-4-yl)-M-[2(trifluoromethyl)pyridin-4-yl]7-oxabicyclo[2.2.1]heptane -2 carboxamide >50 (29) 162 (lS,2R,3S,4R,5S,6R)-N-(5,6dichloropyridin-3-yl)-5,6dihydroxy-3-(2methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (25) 163 (lS,2R,3S,4R,5S,6R)-5,6dihydroxy-M-[6-methyl-5(trifluoromethyl)pyridin-3-yl]3-(2-methylpyride in-4-yl)-7oxabicyclo [2.2.1] heptane-2carboxamide >50 (23) 164 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5-fluoro-3-(6methylpyridin-3-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (0) 165 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5-fluoro-3-(2methoxypyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 6.0(110) >20 (59) 166 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5(dimethylamino)-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 24 (68) >20 (0) 167 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5(methylamino)-3-(2methylpyride in-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 6.9 (83) 168 (lR,2R,3S,4R,5R)-N-(3,4d ichlorophenyl)-5 - [(2hydroxyethyl)amino]-3-(2methylpyridin-4-yl)-7- 0.32(114) >20 (0)

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oxabicyclo[2.2.1] heptane-2carboxamide 169 (lR,2R,3S,4R,5R)-N-(3,4- dichlorophenyl)-3 -(2methylpyridin-4-yl)-5 - [(ohap4-yl)amino]-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (69) >20 (54) 170 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-3 -(2methylpyridin-4-yl)-5{[(1g,3g)-3dihydroxycyclobutyl]amino }-7-oxabicyclo[2.2. 1] heptane2-carboxamide >50 (37) 171 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyridin-4-yl)-5(methylamino)-7oxabicyclo[2.2.1]heptane-2carboxamide 24 (237) 172 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5(dimethylamino)-3-(2fluoropyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 16 (177) 173 (lR,2R,3S,4R,5S)-N-(3,4dichlorophenyl)-3 -(2fluoropyride in-4-yl)-5 - [(2hydroxyethyl)amino]-7oxabicyclo[2.2.1]heptane-2carboxamide 27 (54) 174 (lR,2R,3S,4R,5R)-N-(5,6dichloropyridin-3-yl)-3-(2fluoropyridin-4-yl)-5(methylamino)-7oxabicyclo[2.2.1]heptan-2carboxamide >50 (37) 175 (lR,2R,3S,4R,5R)-N-(5,6dichloropyridin-3-yl)-5(dimethylamino)-3-(2fluoropyridin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 29 (186) 176 (1R,2R,3 S,4R,5R)-N-(5,6d ichloropyride in-3-yl)-3-(2fluoropyridin-4-yl)-5-[(2hydroxyethyl)amino]-7- 25 (51)

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oxabicyclo[2.2.1 ]heptane-2carboxamide 177 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-3 -(2methylpyridin-4-yl)-5(morpholin-4-yl)-7oxabicyclo[2.2.1]heptan-2carboxamide 22 (211) 1.5 (34) >50 (33) 1.5 (103) 178 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5-hydroxy-5methyl-3-(2-methylpyridin-4yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50(1) 179 (lS,2S,3R,4S,5S)-N-(3,4dichlorophenyl)-5-hydroxy-5methyl-3-(2-methylpyridin-4yl)-7oxabicyclo[2.2.1]heptane-2carboxamide >50 (22) 180 (lR,2R,3S,4R,5R)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 30(113) 11 (69) 181 (lS,2S,3R,4S,5S)-N-(3,4dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7oxabicyclo[2.2.1]heptane-2carboxamide 27(243) >20 (28)

It should be understood that the examples and embodiments described herein are for illustrative purposes only, and that various modifications or changes in light thereof will be understood by those skilled in the art and are to be included within the spirit and scope of this application and the scope of the appended invention formulas. All publications, patents, and patent applications cited in this document are incorporated herein by reference for all purposes.

Claims (8)

CLAIM 1. The compound of formula (2A) or (2G) or its pharmaceutically acceptable salt o o Where R ^1a is hydroxyl; R ² is phenyl substituted with 1-2 substituents independently selected from chlorine, fluorine, trifluoromethyl, trifluoromethoxy, cyano and halogenated phenyl; R ³ is pyridyl, unsubstituted or substituted with 1-2 substituents independently selected from fluorine, trifluoromethyl, methyl and methoxy. 2. The compound according to claim 1, which is (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7-oxabicyclo [2.2.1]heptan-2-carboxamide or a pharmaceutically acceptable salt thereof. 3. The compound according to claim 1, which is (1S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3(2-methylpyridin-4-yl)-7-oxabicyclo [2.2.1]heptan-2-carboxamide or a pharmaceutically acceptable salt thereof. 4. The compound according to claim 1, which is (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-3-(2fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[ 2.2.1]heptan-2-carboxamide or a pharmaceutically acceptable salt thereof. 5. The compound according to claim 1, which is (1S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-3-(2fluoropyridin-4-yl)-5-hydroxy-7-oxabicyclo[ 2.2.1]heptan-2-carboxamide or a pharmaceutically acceptable salt thereof. 6. The compound according to claim 1, which is (1R,2R,3S,4R,5S)-N-(3,4-dichlorophenyl)-5-hydroxy-3(2-(trifluoromethyl)pyridin-4-yl)- 7-oxabicyclo[2.2.1]heptane-2-carboxamide or a pharmaceutically acceptable salt thereof. 7. The compound according to claim 1, which is (1S,2S,3R,4S,5R)-N-(3,4-dichlorophenyl)-5-hydroxy-3(2-(trifluoromethyl)pyridin-4-yl)- 7-oxabicyclo[2.2.1]heptane-2-carboxamide or its pharmaceutical - 89 040531 acceptable salt. 8. A pharmaceutical composition for treating, alleviating or preventing arthritis or joint damage in a mammal, or for restoring cartilage, comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers.