Modulators of TNF alpha activity and uses thereof

Abstract

Described herein are modulators of TNF alpha activity and pharmaceutical compositions comprising said inhibitors. The subject compounds and compositions are useful for the treatment of TNF alpha-mediated disorders or diseases.

Description

WSGR Docket No. 66412-713.601MODULATORS OF TNF ALPHA ACTIVITY AND USES THEREOFCROSS-REFERENCE

[0001] This application claims the benefit of U. S. Provisional Application Serial No. 63 / 760,335 filed February 19, 2025; which is hereby incorporated by reference in its entirety.BACKGROUND OF THE INVENTION

[0002] TNF alpha is the prototypical member of the Tumor Necrosis Factor (TNF) superfamily of proteins that share a primary' function of regulating cell survival and cell death. One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors. By way of example, TNF alpha exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.

[0003] TNF superfamily members, including TNF alpha itself, are implicated in a variety' of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance. Various products capable of modulating TNF alpha activity are already commercially available. All currently approved products are macromolecular and act by inhibiting the binding of human TNF alpha to its receptor. Typical macromolecular TNF alpha inhibitors include anti- TN F alpha antibodies and soluble TNF alpha receptor fusion proteins. All are approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis and Crohn’s disease.

[0004] As such there is a need for new potent small molecule modulators of human TNF alpha activity beneficial in the treatment of various disorders including autoimmune and inflammatory' disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.SUMMARY OF THE INVENTION

[0005] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, that is selected from the group consisting of:WSGR Docket No. 66412-713.601WSGR Docket No. 66412-713.601

[0006] Also disclosed herein is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

[0007] Also disclosed herein is a method for the treatment of disorders for which the administration of a modulator of TNF alpha function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.WSGR Docket No. 66412-713.601

[0008] Also disclosed herein is a method for the treatment of an inflammatory or autoimmune disorder, a neurological, a neuro-degenerative disorder, pain, a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt or solvate thereof.INCORPORATION BY REFERENCE

[0009] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0010] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments. However, one skilled in the art will understand that the invention may be practiced without these details. In other instances, well-known structures have not been shown or described in detail to avoid unnecessarily obscuring descriptions of the embodiments. Unless the context requires otherwise, throughout the specification and claims which follow, the word “comprise” and variations thereof, such as, “comprises” and “comprising” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” Further, headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed invention.

[0011] Reference throughout this specification to “some embodiments” or “an embodiment” means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. Thus, the appearances of the phrases “in one embodiment” or “in an embodiment” in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments. Also, as used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. It should also be noted that the term “or” is generally employed in its sense including “and / or” unless the content clearly dictates otherwise.

[0012] The terms below, as used herein, have the following meanings, unless indicated otherwise:

[0013] “oxo” refers to =0.

[0014] “Amine” refers to -NH2.

[0015] “hydroxy” refers to -OH.

[0016] “Carboxyl” refers to -COOH.

[0017] “Alkyl” refers to a straight-chain or branched-chain saturated hydrocarbon monoradical having from one to about ten carbon atoms, more preferably one to six carbon atoms. Examples include, but are not limited to methyl, ethyl, n-propyl, isopropyl, 2 -methyl- 1 -propyl, 2 -methyl -2 -propyl, 2-methyl-l-WSGR Docket No. 66412-713.601butyl, 3 -methyl- 1 -butyl, 2-methyl-3 -butyl, 2,2-dimethyl-l -propyl, 2 -methyl- 1 -pentyl, 3 -methyl- 1 -pentyl, 4-methyl-l -pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-l -butyl, 3,3-dimethyl-1 -butyl, 2-ethyl-l -butyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, tert-amyl and hexyl, and longer alkyl groups, such as heptyl, octyl and the like. Whenever it appears herein, a numerical range such as “Ci-Cg alkyl”, means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, the alkyl is a Ci-Cio alkyl. In some embodiments, the alkyl is a Ci-Cg alkyl. In some embodiments, the alkyl is a C1-C5 alkyl. In some embodiments, the alkyl is a C1-C4 alkyl. In some embodiments, the alkyl is a C1-C3 alkyl. Unless stated otherwise specifically in the specification, an alkyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkyl is optionally substituted with halogen.

[0018] “Alkenyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon double-bonds and having from two to about ten carbon atoms, more preferably two to about six carbon atoms. The group may be in either the cis or trans or Z or E conformation about the double bond(s) and should be understood to include both isomers. Examples include, but are not limited to, ethenyl (-CH=CH2), 1 -propenyl (-CH2CH=CH2), isopropenyl [-C(CH3)=CH2], butenyl, 1,3-butadienyl and the like. Whenever it appears herein, a numerical range such as “C2-Ce alkenyl”, means that the alkenyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, an alkenyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkenyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkenyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkenyl is optionally substituted with halogen.

[0019] “Alkynyl” refers to a straight-chain or branched-chain hydrocarbon monoradical having one or more carbon-carbon triple-bonds and having from two to about ten carbon atoms, more preferably from two to about six carbon atoms. Examples include, but are not limited to ethynyl, 2-propynyl, 2-butynyl, 1,3-butadiynyl and the like. Whenever it appears herein, a numerical range such as “C2-Ce alkynyl”, means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. Unless stated otherwise specifically in the specification, anWSGR Docket No. 66412-713.601alkynyl group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkynyl is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkynyl is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkynyl is optionally substituted with halogen.

[0020] “Alkylene” refers to a straight or branched divalent hydrocarbon chain. Unless stated otherwise specifically in the specification, an alkylene group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkylene is optionally substituted with one or more oxo, halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkylene is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkylene is optionally substituted with halogen.

[0021] “Alkoxy” refers to a radical of the formula -Oalkyl where alkyl is defined as above. Unless stated otherwise specifically in the specification, an alkoxy group may be optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -COOH, -COOMe, -OH, -OMe, -NH2, or -NO2. In some embodiments, the alkoxy is optionally substituted with one or more halogen, -CN, -OH, or -OMe. In some embodiments, the alkoxy is optionally substituted with halogen.

[0022] “Aryl” refers to a radical derived from a hydrocarbon ring system comprising 6 to 30 carbon atoms and at least one aromatic ring. The aryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the aryl is bonded through an aromatic ring atom) or bridged ring systems. In some embodiments, the aryl is a 6- to 10-membered aryl. In some embodiments, the aryl is a 6-membered aryl (phenyl). Aryl radicals include, but are not limited to anthracenyl, naphthyl, phenanthrenyl, azulenyl, phenyl, chrysenyl, fluoranthenyl, fluorenyl, as-indacenyl, s-indacenyl, indanyl, indenyl, phenalenyl, phenanthrenyl, pleiadenyl, pyrenyl, and triphenylenyl. Unless stated otherwise specifically in the specification, an aryl may be optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the aryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the aryl is optionally substituted with halogen.

[0023] “Cycloalkyl” refers to a partially or fully saturated, monocyclic, or polycyclic carbocyclic ring, which may include fused (when fused with an aryl or a heteroaryl ring, the cycloalkyl is bonded through a non-aromatic ring atom), spiro, and / or bridged ring systems. In some embodiments, the cycloalkyl is fully saturated. Representative cycloalkyls include, but are not limited to, cycloalkyls having from threeWSGR Docket No. 66412-713.601to fifteen carbon atoms (e.g., C3-C15 fully saturated cycloalkyl or C3-C15 cycloalkenyl), from three to ten carbon atoms (e.g., C3-C10 fully saturated cycloalkyl or C3-C10 cycloalkenyl), from three to eight carbon atoms (e.g., C3-C8 fully saturated cycloalkyl or C3-C8 cycloalkenyl), from three to six carbon atoms (e.g., C3-C6 fully saturated cycloalkyl or C3-C6 cycloalkenyl), from three to five carbon atoms (e.g., C3-C5 fully saturated cycloalkyl or C3-C5 cycloalkenyl), or three to four carbon atoms (e.g., C3-C4 fully saturated cycloalkyl or C3-C4 cycloalkenyl). In some embodiments, the cycloalkyl is a 3 - to 10 -membered fully saturated cycloalkyl or a 3- to 10-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 3 - to 6-membered fully saturated cycloalkyl or a 3- to 6-membered cycloalkenyl. In some embodiments, the cycloalkyl is a 5- to 6-membered fully saturated cycloalkyl or a 5- to 6-membered cycloalkenyl.Monocyclic cycloalkyls include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyls include, for example, adamantyl, norbomyl, decalinyl, bicyclo[3.3.0]octyl, bicyclo[4.3.0]nonyl, cis-decalinyl, trans-decalinyl, bicyclo [2. l.l]hexyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.2.2]nonyl, and bicyclo[3.3.2]decyl, bicyclo [1.1. IJpentyl, bicyclo[3. I.0]hexyl, bicyclo[3.1.1]heptyl, 7,7-dimethyl-bicyclo[2.2. I]heptanyl, Spiro[4.2]heptyl, spiro[4.3]octyl, spiro[5.2]octyl, spiro[3.3]heptyl, and spiro[5.3]nonyl. Partially saturated cycloalkyls include, for example cyclopentenyl, cyclohexenyl, cycloheptenyl, and cyclooctenyl. Unless stated otherwise specifically in the specification, a cycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a cycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the cycloalkyl is optionally substituted with halogen.

[0024] “Halo” or “halogen” refers to bromo, chloro, fluoro or iodo. In some embodiments, halogen is fluoro or chloro. In some embodiments, halogen is fluoro.

[0025] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 2-fluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0026] “Haloalkoxy” refers to -O-haloalkyl, with haloalkyl as defined above.

[0027] “Hydroxyalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more hydroxyls. In some embodiments, the alkyl is substituted with one hydroxyl. In some embodiments, the alkyl is substituted with one, two, or three hydroxyls. Hydroxyalkyl includes, for example, hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, or hydroxypentyl. In some embodiments, the hydroxyalkyl is hydroxymethyl.

[0028] “Aminoalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more amines. In some embodiments, the alkyl is substituted with one amine. In some embodiments, the alkyl is substituted with one, two, or three amines. Aminoalkyl includes, for example, aminomethyl, aminoethyl, aminopropyl, aminobutyl, or aminopentyl. In some embodiments, the aminoalkyl is aminomethyl.WSGR Docket No. 66412-713.601

[0029] “Deuteroalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more deuteriums. In some embodiments, the alkyl is substituted with one deuterium. In some embodiments, the alkyl is substituted with one, two, or three deuteriums. In some embodiments, the alkyl is substituted with one, two, three, four, five, or six deuteriums. Deuteroalkyl includes, for example, CDs, CH2D, CHD2, CH2CD3, CD2CD3, CHDCDs, CH2CH2D, or CH2CHD2. In some embodiments, the deuteroalkyl is CDs.

[0030] “Heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or more atoms other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus, or combinations thereof wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a Ci-Ce heteroalkyl wherein the heteroalkyl is comprised of 1 to 6 carbon atoms and one or two atoms selected from the group consisting of oxygen, nitrogen, and sulfur wherein the heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. Examples of such heteroalkyl are, for example, -CH2OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, -CH(CH3)OCH3, -CH2NHCH3, -CH2N(CH3)2, -CH2CH2NHCH3, or -CH2CH2N(CH3)2. Unless stated otherwise specifically in the specification, a heteroalkyl is optionally substituted for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, a heteroalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroalkyl is optionally substituted with halogen.

[0031] “Heterocycloalkyl” refers to a 3- to 24-membered partially or fully saturated ring radical comprising 2 to 23 carbon atoms and from one to 8 heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, silicon, and sulfur. In some embodiments, the heterocycloalkyl is fully saturated. In some embodiments, the heterocycloalkyl is C-linked. In some embodiments, the heterocycloalkyl is N-linked. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heterocycloalkyl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heterocycloalkyl comprises one to three nitrogens. In some embodiments, the heterocycloalkyl comprises one or two nitrogens. In some embodiments, the heterocycloalkyl comprises one nitrogen. In some embodiments, the heterocycloalkyl comprises one nitrogen and one oxygen. Unless stated otherwise specifically in the specification, the heterocycloalkyl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with an aryl or a heteroaryl ring, the heterocycloalkyl is bonded through a non-aromatic ring atom), spiro, or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycloalkyl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. RepresentativeWSGR Docket No. 66412-713.601heterocycloalkyls include, but are not limited to, heterocycloalkyls having from two to fifteen carbon atoms (e.g., C2-C15 fully saturated heterocycloalkyl or C2-C15 heterocycloalkenyl), from two to ten carbon atoms (e.g., C2-C10 fully saturated heterocycloalkyl or C2-C10 heterocycloalkenyl), from two to eight carbon atoms (e.g., C2-C8 fully saturated heterocycloalkyl or C2-C8 heterocycloalkenyl), from two to seven carbon atoms (e.g., C2-C7 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to six carbon atoms (e.g., C2-C6 fully saturated heterocycloalkyl or C2-C7 heterocycloalkenyl), from two to five carbon atoms (e.g., C2-C5 fully saturated heterocycloalkyl or C2-C5 heterocycloalkenyl), or two to four carbon atoms (e.g., C2-C4 fully saturated heterocycloalkyl or C2-C4 heterocycloalkenyl). Examples of such heterocycloalkyl radicals include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, dioxolanyl, thienyl[l,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, 1,3-dihydroisobenzofuran-l-yl, 3-oxo-l,3-dihydroisobenzofuran-l-yl, methyl-2-oxo-l,3-dioxol-4-yl, and 2-oxo-l,3-dioxol-4-yl. The term heterocycloalkyl also includes all ring forms of the carbohydrates, including but not limited to the monosaccharides, the disaccharides, and the oligosaccharides. In some embodiments, heterocycloalkyls have from 2 to 10 carbons in the ring. It is understood that when referring to the number of carbon atoms in a heterocycloalkyl, the number of carbon atoms in the heterocycloalkyl is not the same as the total number of atoms (including the heteroatoms) that make up the heterocycloalkyl (i.e., skeletal atoms of the heterocycloalkyl ring). In some embodiments, the heterocycloalkyl is a 3- to 8-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 5- to 6-membered heterocycloalkyl. In some embodiments, the heterocycloalkyl is a 3 - to 8-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 7-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 3- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 4- to 6-membered heterocycloalkenyl. In some embodiments, the heterocycloalkyl is a 5 - to 6-membered heterocycloalkenyl. Unless stated otherwise specifically in the specification, a heterocycloalkyl is optionally substituted, for example, with one or more oxo, halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, heteroaryl, and the like. In some embodiments, the heterocycloalkyl is optionally substituted with one or more oxo, halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CF3, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heterocycloalkyl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heterocycloalkyl is optionally substituted with halogen.WSGR Docket No. 66412-713.601

[0032] “Heteroaryl” refers to a 5 - to 14-membered ring system radical comprising one to thirteen carbon atoms, one to six heteroatoms selected from the group consisting of nitrogen, oxygen, phosphorous, and sulfur, and at least one aromatic ring. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. In some embodiments, the heteroaryl comprises one to three heteroatoms selected from the group consisting of nitrogen and oxygen. In some embodiments, the heteroaryl comprises one to three nitrogens. In some embodiments, the heteroaryl comprises one or two nitrogens. In some embodiments, the heteroaryl comprises one nitrogen. In some embodiments, the heteroaryl is C-linked. In some embodiments, the heteroaryl is N-linked. The heteroaryl radical may be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused (when fused with a cycloalkyl or heterocycloalkyl ring, the heteroaryl is bonded through an aromatic ring atom) or bridged ring systems; and the nitrogen, carbon, or sulfur atoms in the heteroaryl radical may be optionally oxidized; the nitrogen atom may be optionally quatemized. In some embodiments, the heteroaryl is a 5- to 10-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5- to 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 6-membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. In some embodiments, the heteroaryl is a 5 -membered heteroaryl comprising 1, 2, or 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. Examples include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzodioxolyl, benzofuranyl, benzoxazolyl, benzothiadiazolyl, benzo[b][l,4]dioxepinyl, 1,4-benzodioxanyl, benzonaphthofuranyl, benzodioxinyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[l,2-a]pyridinyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl,, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1 -oxidopyrazinyl, 1-oxidopyridazinyl, 1-phenyl-lH-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl, triazinyl, and thiophenyl (i.e., thienyl). Unless stated otherwise specifically in the specification, a heteroaryl is optionally substituted, for example, with one or more halogen, amino, nitrile, nitro, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, carboxyl, carboxylate, aryl, cycloalkyl, heterocycloalkyl, or heteroaryl, and the like. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -COOH, -COOMe, -CFs, -OH, -OMe, -NH2, or -NO2. In some embodiments, the heteroaryl is optionally substituted with one or more halogen, methyl, ethyl, -CN, -CF3, -OH, or -OMe. In some embodiments, the heteroaryl is optionally substituted with halogen.

[0033] The term “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event orWSGR Docket No. 66412-713.601circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means either “alkyl” or “substituted alkyl” as defined above. Further, an optionally substituted group may be un-substituted (e.g., -CH2CH3), fully substituted (e.g., -CF2CF3), mono-substituted (e.g., -CH2CH2F) or substituted at a level anywhere in-between fully substituted and mono-substituted (e.g., -CH2CHF2, -CH2CF3, -CF2CH3, -CFHCHF2, etc ).

[0034] The term “one or more” when referring to an optional substituent means that the subject group is optionally substituted with one, two, three, or four, or more substituents. In some embodiments, the subject group is optionally substituted with one, two, three, or four substituents. In some embodiments, the subject group is optionally substituted with one, two, or three substituents. In some embodiments, the subject group is optionally substituted with one or two substituents. In some embodiments, the subject group is optionally substituted with one substituent. In some embodiments, the subject group is optionally substituted with two substituents. In some embodiments, the subject group is optionally substituted with three substituents.

[0035] An “effective amount” or “therapeutically effective amount” refers to an amount of a compound administered to a mammalian subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0036] “Treatment” of an individual (e.g., a mammal, such as a human) or a cell is any type of intervention used in an attempt to alter the natural course of the individual or cell. In some embodiments, treatment includes administration of a pharmaceutical composition subsequent to the initiation of a pathologic event or contact with an etiologic agent and includes stabilization of the condition (e.g., condition does not worsen) or alleviation of the condition.

[0037] “Synergy” or “synergize” refers to an effect of a combination that is greater than additive of the effects of each component alone at the same doses.

[0038] As used herein, a “disease or disorder associated with TNF alpha” or, alternatively, “a TNF alpha-mediated disease or disorder” means any disease or other deleterious condition in which TRPML1, or a mutant thereof, is known or suspected to play a role.Compounds

[0039] Described herein are compounds, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof useful in the treatment of a TNF alpha-mediated disease or disorder.

[0040] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are more potent than corresponding compounds with a benzimidazole core. In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, are 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% more potent than corresponding compounds with a benzimidazole core.

[0041] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have less cardiac toxicity than corresponding compounds with aWSGR Docket No. 66412-713.601benzimidazole core. In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% less cardiac toxicity than corresponding compounds with a benzimidazole core.

[0042] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have better cell permeability than corresponding compounds with a benzimidazole core. In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have 5%, 6%, 7%, 8%, 9%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, or 80% better cell permeability than corresponding compounds with a benzimidazole core.

[0043] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have better physical properties than corresponding compounds with a benzimidazole core.

[0044] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have better pharmacokinetic properties than corresponding compounds with a benzimidazole core.

[0045] In some embodiments, the compounds described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, have better pharmacodynamic properties than corresponding compounds with a benzimidazole core.f pH

[0046] The compounds with a benzimidazole core comprise the following ring system:in their central core.

[0047] Disclosed herein is a compound of Formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (I);wherein:Ring B is phenyl or a 6-membered heteroaryl comprising one or two nitrogen;each R1is independently halogen, -CN, -NO2, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R1on the same atom are taken together to form an oxo;n is 0, 1, 2, 3, or 4;WSGR Docket No. 66412-713.601R2is hydrogen, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cedeuteroalkyl, or cycloalkyl;X is N or CRX;Rxis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, heterocycloalkyl;Y is N or CRY;RYis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; Z is N or CRZ;Rzis hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, Ci-Cealkyl, Ci-Cehaloalkyl, Ci-Cehydroxyalkyl, Ci-Ceaminoalkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, cycloalkyl, or heterocycloalkyl; Ring A is cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each R3is independently halogen, -L-CN, -L-NO2, -L-OH, -L-ORa, -L-OC(=O)Ra, -L-OC(=O)ORb, -L- OC(=O)NRcRd, -L-SH, -L-SRa, -L-S(=O)Ra, -L-S(=O)2Ra, -L-S(=O)(=NH)Ra, -L-S(=O)2ORb, -L- S(=O)2NRcRd, -L-NRcRd, -L-NRbC(=O)NRcRd, -L-NRbC(=O)Ra, -L-NRbC(=O)ORb, -L- NRbS(=O)2Ra, -L-C(=O)Ra, -L-C(=O)ORb, -L-C(=O)NRcRd, -L-P(=O)RcRd, -L-P(=O)ORcORd, Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L-heterocycloalkyl, -L- aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or two R3on the same atom are taken together to form an oxo;or two R3on adjacent atoms are taken together to form a cycloalkyl, heterocycloalkyl, aryl, or heteroaryl;each independently optionally substituted with one or more R;m is 0, 1, 2, 3, or 4;each Rais independently Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L-cycloalkyl, -L- heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rbis independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, -L- cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;each Rcand Rdare independently hydrogen, Ci-Cealkyl, Ci-Ceheteroalkyl, C2-Cealkenyl, C2-Cealkynyl, - L-cycloalkyl, -L-heterocycloalkyl, -L-aryl, or -L-heteroaryl; wherein each alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more R;or Rcand Rdare taken together with the atom to which they are attached to form a heterocycloalkyl independently optionally substituted with one or more R; andL is absent or Ci-Csalkylene optionally substituted with one or more R;WSGR Docket No. 66412-713.601each R is independently halogen, -CN, -OH, -OCi-C8alkyl, -S(=O)Ci-C3alkyl, -S(=O)2Ci-C3alkyl, - S(=O)2NH2, -S(=O)2NHCi-C3alkyl, -S(=O)2N(Ci-C3alkyl)2, -NH2, -NHCi-C3alkyl, -N(Ci-C3alkyl)2, - NHC(=O)OCi-C3alkyl, -C(=O)Ci-C3alkyl, -C(=O)OH, -C(=O)OCi-C3alkyl, -C(=O)NH2, - C(=O)N(Ci-C3alkyl)2, -C(=O)NHCi-C3alkyl, -P(=O)(Ci-C3alkyl)2, -P(=O)(OCi-C3alkyl)2,Ci-C8alkyl, Ci-C8haloalkyl, Ci-C8hydroxyalkyl, Ci-C8aminoalkyl, Ci-C8heteroalkyl, Ci-C8cycloalkyl, or 3- to 6-membered heterocycloalkyl;or two R on the same atom are taken together to form an oxo.

[0048] Disclosed herein is a compound of Formula (la), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (la).

[0049] Disclosed herein is a compound of Formula (lb), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Id).

[0050] Disclosed herein is a compound of Formula (Ic), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (Ic).

[0051] Disclosed herein is a compound of Formula (Id), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:WSGR Docket No. 66412-713.601Formula (Id);wherein Rlais hydrogen or R1.

[0052] Disclosed herein is a compound of Formula (le), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (le);wherein Rlais hydrogen or R1.

[0053] Disclosed herein is a compound of Formula (If), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof:Formula (If);wherein Rlais hydrogen or R1.

[0054] Disclosed herein is a compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, selected from a compound found in Table 1.Table 1WSGR Docket No. 66412-713.601Ex. StructureEx. Structure 30 °Q° J / \ ° ° J / X? Q\ ^^x z\ Z\K^^ / Q \^ “Q29 j Y r Zo\ FZA 0 "4 \Z^ w wr^N'N X ^DO oz z—30 H2N T M zZ=ZJ \ )^O \nVA z* ONI I A \ \ _ VMM C C’" A \\' z z""NC" \ F0F -X= / '- N°N oIC- T H? b bz X / \= / z 5 f O / 1II o310 o°F J / Q \^V Z^6r^N'N kDN^N-N. vN^XX^»X” < YL IJ \ 0o 32 jl J \ Z^o w “■ H2N-V^N1 o— (zy H2N^JXJ _ \ y F FF— < \= / F0 C7Z 1 \xCM LL II338FV"N'VDkD34H2IM T || X >=o 0ny H9‘V'N-V VNX > cH2N T J \ 0o35H2NT 1] \ 00 rjny_H°w x A OH1000 kDX 0N'V V HO T JJ \ 00DH2N H \ X 0o 36Jy" °M / N°NC" \ F0 6HWSGR Docket No. 66412-713.601Ex. Structure Ex. Structure11"o Y"-v V AA% / \ °dq7 HO H \ X J J! Q Q\ v \IC^ / / JI\\ o ^ 3 > \= ° °q°qQONjj Y r r JO5 XX°iz XX^12 > Vi Y1l Q / -- X Y o z—^j \ O m \ / =O1~>r 'hr 0 zH. 38 H2N YA^- AH % _ / / Y OCM CM bZ. ' - X \ - ''z / z I XOL 713 ° Yi l °° cQO °QQ39JI JI \ J / Y / Q \\ ° °QQOO ZX\X^^ □A Qj V r> Z^} r V14 YYy W XX°Lw YN'VNk o jwD° 40 JL IJ \ Y° CY H2NX 1 00 7 XL \ - \««V o"^3i Nll MC4 CM b z z / / z X X15I YN'VDy° 41H2^-YLY V_ / 00 F 0—H0C / '"\FY FX= / 16YYV. X 42 H2M 7 || \ / Yfco < 730NVH 1743WSGR Docket No. 66412-713.601Ex. StructureEx. Structure18f^N'VDxDNIT / \ °qT J \f U JIq440HAT O4 r YiJ F19Jy-Nn A45S r yU L T Y JX A YY AJ I F21II0 J46JI JI JIjjJ T T T r r r21 tYwY H HYX^N'N kD47 T \\ \ / ^o H2N yJf 'N v^7 \ w X2248 H2N 1 l| \ >o NC" yYnF— ( xX= / 23Nn 'I1f^N'V kDN Y YN D49H2M 7 \ \ y^o oN°YF24XYVNn NAAAT T 'I1^ XNAJAN'VANAkD\DH2NX^N50 Jj \> ^ H2NA^N\= / FWSGR Docket No. 66412-713.601Further Forms of Compounds Disclosed HereinIsomers / Stereoisomers

[0055] In some embodiments, the compounds described herein exist as geometric isomers. In some embodiments, the compounds described herein possess one or more double bonds. The compounds presented herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the corresponding mixtures thereof. In some situations, the compounds described herein possess one or more chiral centers and each center independently exists in the R configuration or S configuration. The compounds described herein include all diastereomeric, enantiomeric, and epimeric forms as well as the corresponding mixtures thereof. In additional embodiments of the compounds and methods provided herein, mixtures of enantiomers and / or diastereoisomers, resulting from a single preparative step, combination, or interconversion are useful for the applications described herein. In some embodiments, the compounds described herein are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds, separating the diastereomers and recovering the optically pure enantiomers. In some embodiments, dissociable complexes are preferred. In some embodiments, the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities. In some embodiments, the diastereomers are separated by chiral chromatography, or preferably, by separation / resolution techniques based upon differences in solubility. In some embodiments, the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.Labeled compounds

[0056] In some embodiments, the compounds described herein exist in their isotopically -labeled forms. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically -labeled compounds. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such isotopically-labeled compounds as pharmaceutical compositions. Thus, in some embodiments, the compounds disclosed herein include isotopically-labeled compounds, which are identical to those recited herein, but for the fact that one orWSGR Docket No. 66412-713.601more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds disclosed herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine, and chlorine, such as2H,3H,13C,14C,15N,180,170,31P,32P,35S,18F, and36C1, respectively. Compounds described herein, and the pharmaceutically acceptable salts, solvates, or stereoisomers thereof which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.,3H and carbon- 14, i.e.,14C, isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e.,2H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. In some embodiments, one or more hydrogen in a compound disclosed herein has been replaced by a deuterium atom. In some embodiments, one or more alkyl substituents in a compound disclosed herein has been replaced by a deuteroalkyl substituents. In some embodiments, -CH3is -CD3.

[0057] In some embodiments, the compounds described herein are labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.Pharmaceutically acceptable salts

[0058] In some embodiments, the compounds described herein exist as their pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts. In some embodiments, the methods disclosed herein include methods of treating diseases by administering such pharmaceutically acceptable salts as pharmaceutical compositions.

[0059] In some embodiments, the compounds described herein possess acidic or basic groups and therefore react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt. In some embodiments, these salts are prepared in situ during the final isolation and purification of the compounds disclosed herein, or a solvate, or stereoisomer thereof, or by separately reacting a purified compound in its free form with a suitable acid or base, and isolating the salt thus formed.

[0060] Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, but not limited to, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, gluconate, dihydrogenphosphate, dinitrobenzoate, dodecylsulfate, ethane sulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne- 1,6-dioate, hydroxybenzoate, y-hydroxybutyrate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethane sulfonate, iodide, isobutyrate, lactate,WSGR Docket No. 66412-713.601maleate, malonate, methanesulfonate, mandelate metaphosphate, methoxybenzoate, methylbenzoate, monohydrogenphosphate, 1-napthalenesulfonate, 2-napthalenesulfonate, nicotinate, nitrate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, pyrosulfate, pyrophosphate, propiolate, phthalate, phenylacetate, phenylbutyrate, propane sulfonate, salicylate, succinate, sulfate, sulfite, succinate, suberate, sebacate, sulfonate, tartrate, thiocyanate, tosylate, undecanoate, and xylene sulfonate.

[0061] Further, the compounds described herein can be prepared as pharmaceutically acceptable salts formed by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid metaphosphoric acid, and the like; and organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, p-toluenesulfonic acid, tartaric acid, trifluoroacetic acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, arylsulfonic acid, methanesulfonic acid, ethanesulfonic acid, 1,2 -ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-naphthalenesulfonic acid, 4-methylbicyclo-[2.2.2]oct-2-ene-l-carboxylic acid, glucoheptonic acid, 4,4 ’-methylenebis-(3 -hydroxy-2 -ene-1-carboxylic acid), 3 -phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid and muconic acid. In some embodiments, other acids, such as oxalic, while not in themselves pharmaceutically acceptable, are employed in the preparation of salts useful as intermediates in obtaining the compounds disclosed herein, solvate, or stereoisomer thereof and their pharmaceutically acceptable acid addition salts.

[0062] In some embodiments, those compounds described herein which comprise a free acid group react with a suitable base, such as the hydroxide, carbonate, bicarbonate, sulfate, of a pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable organic primary, secondary, tertiary, or quaternary amine. Representative salts include the alkali or alkaline earth salts, like lithium, sodium, potassium, calcium, and magnesium, and aluminum salts and the like. Illustrative examples of bases include sodium hydroxide, potassium hydroxide, choline hydroxide, sodium carbonate, N+(C1-C4alkyl)4hydroxide, and the like.

[0063] Representative organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like. It should be understood that the compounds described herein also include the quatemization of any basic nitrogen-containing groups they contain. In some embodiments, water or oil-soluble or dispersible products are obtained by such quatemization.Solvates

[0064] In some embodiments, the compounds described herein exist as solvates. The invention provides for methods of treating diseases by administering such solvates. The invention further provides for methods of treating diseases by administering such solvates as pharmaceutical compositions.WSGR Docket No. 66412-713.601

[0065] Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and, in some embodiments, are formed with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of the compounds described herein can be conveniently prepared or formed during the processes described herein. By way of example only, hydrates of the compounds described herein can be conveniently prepared from an aqueous / organic solvent mixture, using organic solvents including, but not limited to, dioxane, tetrahydrofuran or methanol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.Method of Treatment

[0066] Disclosed herein are methods of treating diseases or disorders in a subject in need thereof, the method comprising administering a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In some embodiments, the diseases or disorders include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

[0067] Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders, and organ-specific autoimmune disorders. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, inflammatory myopathy (including polymyositis, dermatomyositis and inclusion body myositis), scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis juvenile idiopathic arthritis (including oligoarticular and polyarticular forms thereof), anemia of chronic disease (ACD), Still’s disease (juvenile and / or adult onset), Behcet’s disease and Sjogren’s syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison’s disease, hemolytic or pernicious anemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin- induced obstructive uropathy), glomerulonephritis (including Goodpasture’s syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)- associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves’ disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn’s disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility, osteoporosis, osteopenia, erosive bone disease, chondritis, cartilage degeneration and / or destruction, fibrosing disorders (including various forms of hepatic and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy), organ transplant rejection (including kidney allograft rejection), scleritis (including giant cell arteritis scleritis), Takayasu arteritis, hidradenitis suppurativa, pyoderma gangrenosum, sarcoidosis, polymyalgia rheumatic and axial spondylarthritis.WSGR Docket No. 66412-713.601

[0068] Neurological and neurodegenerative disorders include Alzheimer’s disease, Parkinson's disease, Huntington’s disease, ischemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures, and epilepsy.

[0069] Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g., during heart failure), and sexual disorders (including erectile dysfunction and female sexual dy sfunction). Modulators of INF alpha function may also be of use in the treatment of myocardial infarction (see J. J. Wu et al, JAMA, 2013, 309, 2043-2044).

[0070] Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.

[0071] Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy, and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularization (including comeal vascularization and neovascularization), retinal vein occlusion, and various forms of uveitis (including iritis) and keratitis.

[0072] Oncological disorders, which may be acute or chronic, include proliferative disorders, especially cancer, and cancer-associated complications (including skeletal complications, cachexia, and anemia). Particular categories of cancer include hematological malignancy (including leukemia and lymphoma) and non-hematological malignancy (including solid tumor cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma, and renal cell carcinoma.) Chronic leukemia may be myeloid or lymphoid. Varieties of leukemia include lymphoblastic T cell leukemia, chronic myelogenous leukemia (CML), chronic lymphocytic / lymphoid leukemia (CLL), hairycell leukemia, acute lymphoblastic leukemia (ALL.), acute myelogenous leukemia (AML), myelodysplastic syndrome, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, irnmunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, acute megakaryoblastic leukemia, acute megakaryocytic leukemia, promyelocytic leukemia, and erythroleukemia. Varieties of lymphoma include malignant lymphoma, Hodgkin’s lymphoma, non¬ Hodgkin’s lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, MALT1 lymphoma, and marginal zone lymphoma. Varieties of non-hematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach, and muscle. Modulators of TNF alpha function may also be used to increase the safety of the potent anticancer effect of TNF (see F. V. Hauwermeiren et al, J Clin. Invest., 2013, 123, 2590-2603).Dosing

[0073] In certain embodiments, the compositions containing the compound(s) described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition.WSGR Docket No. 66412-713.601Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0074] When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drugs, and the judgment of the treating physician. In one aspect, prophylactic treatments include administering to a mammal, who previously experienced at least one symptom of or risk factor for the disease being treated and is currently in remission, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0075] In certain embodiments wherein the patient’s condition does not improve, upon the doctor’s discretion the compounds are administered chronically, that is, for an extended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0076] Once improvement of the patient’s conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage, or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent or daily treatment on a long-term basis upon any recurrence of symptoms.

[0077] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity (e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.Routes of Administration

[0078] Suitable routes of administration include, but are not limited to, oral, intravenous, rectal, aerosol, parenteral, ophthalmic, pulmonary, transmucosal, transdermal, vaginal, otic, nasal, and topical administration. In addition, by way of example only, parenteral delivery includes intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intralymphatic, and intranasal injections.Pharmaceutical Compositions / Formulations

[0079] The compounds described herein are administered to a subject in need thereof, either alone or in combination with pharmaceutically acceptable carriers, excipients, or diluents, in a pharmaceutical composition, according to standard pharmaceutical practice. In one embodiment, the compounds disclosed herein may be administered to animals. The compounds can be administered orally orWSGR Docket No. 66412-713.601parenterally, including the intravenous, intramuscular, intraperitoneal, subcutaneous, rectal, and topical routes of administration.

[0080] In another aspect, provided herein are pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and at least one pharmaceutically acceptable excipient. Pharmaceutical compositions are formulated in a conventional manner using one or more pharmaceutically acceptable excipients that facilitate processing of the active compounds into preparations that can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions described herein can be found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N. Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins 1999), herein incorporated by reference for such disclosure.Combination

[0081] Disclosed herein are methods of treating a TNF alpha-mediated disorder or disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

[0082] In some embodiments, the additional therapeutic agent is administered at the same time as the compound disclosed herein. In some embodiments, the additional therapeutic agent and the compound disclosed herein are administered sequentially. In some embodiments, the additional therapeutic agent is administered less frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered more frequently than the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered prior than the administration of the compound disclosed herein. In some embodiments, the additional therapeutic agent is administered after the administration of the compound disclosed herein.WSGR Docket No. 66412-713.601ExampleIntermediate 1 and 2H2SO4, MeOH 1. NaNO2, 15% H2SO4NaOH 2. KI, MeCN KOH, MeCN, H2O THF, MeOH, H2O Step 1Step 2 Step 3 Step 4Pd(OAc)2, PPh3NaH, Mel, THF HATU, DIEA, DMF Et3N, toluene Step7 Step 5 Step 6BH3-THF, THF 3 M NaOH, H2O2Step 8

[0083] Step 1: To a stirred solution of 3-hydroxyanthranilic acid (175 g, 1.14 mol, 1.0 equiv) in MeOH (1 L) was added H2SO4 (150 mL) dropwise at room temperature. The resulting mixture was stirred for 24 hr at 80°C. The resulting mixture was cooled and concentrated in vacuo to remove most of the solvent. The residue was basified with NaHCO3 solution until pH = 8-9 and then extracted with DCM (500 mL x 3). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (3:1) to afford methyl 2-amino-3-hydroxybenzoate (150 g, 78.%) as a yellow solid. LC-MS: (M+H)+found: 168.10. 'HNMR (400 MHz, DMSO-d6) 59.69 (s, 1H), 7.22 (dd, J = 8.2, 1.4 Hz, 1H), 6.83 (dd, J = 7.6, 1.5 Hz, 1H), 6.44 - 6.36 (m, 1H), 6.12 (br, 2H), 3.78 (s, 3H).

[0084] Step 2: A solution of methyl 2-amino-3-hydroxybenzoate (150 g, 0.89 mol, 1.0 equiv) in 15% H2SO4 (a solution of H2SO4 (450 mL) in H2O (2.5 L)) was treated with NaNO2(68.10 g, 0.98 mol, 1.1 equiv) at 0°C. Then the mixture was stirred for 1 hr at room temperature. The resulting mixture was diluted with MeCN (1.5 L) followed by the addition of KI (1.19 kg, 7.18 mol, 8.0 equiv). The final reaction mixture was stirred overnight at 80°C. The resulting mixture was cooled and concentrated in vacuo to remove most of the solvent. The residue was basified with sat. Na2CO3solution until pH = 6-7 and extracted with EtOAc (2 L x 3). The combined organic layers were washed with Na2SO3aq. (2 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM (100%) to afford methyl 3 -hydroxy -2 -iodobenzoate (180 g, 72%) as a brown solid. LC-MS: (M+H)+found: 276.90. ’HWSGR Docket No. 66412-713.601NMR (400 MHz, CDC13) 57.41 (dd, J = 7.6, 1.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 1H), 7.19 (dd, J = 8.0, 1.6 Hz, 1H), 5.99 (br, 1H), 3.96 (s, 3H).

[0085] Step 3: A solution of methyl 3 -hydroxy-2 -iodobenzoate (180 g, 0.65 mol, 1.0 equiv) in MeCN (1.8 L) was treated with 5 M KOH (a solution of KOH (182 g, 3.2 mol, 5.0 equiv) in H2O (500 mL)) followed by the addition of diethyl bromodifluoromethylphosphonate (230 mL, 1.3 mol, 2.0 equiv) dropwise at 0°C. The final reaction mixture was stirred overnight at room temperature. The desired product was detected by TLC (PE: EA=10: l). The resulting mixture was extracted with tert-butyl methyl ether (2 L x 3). The combined organic layers were washed with brine (800 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (100: 1) to afford methyl 3-(difluoromethoxy)- 2-iodobenzoate (136 g, 64%) as a yellow oil. LC-MS: (M+H)+found: 328.85. 'H NMR (400 MHz, CDCh) 57.55 (dd, J = 7.7, 1.5 Hz, 1H), 7.42 (t, J = 7.9 Hz, 1H), 7.34 - 7.26 (m, 1H), 6.56 (t, J = 73.1Hz, 1H), 3.98 (s, 3H).

[0086] Step 4: To a stirred solution of methyl 3 -(difluoromethoxy) -2-iodobenzoate (137 g, 0.42 mol, 1.0 equiv) in THF (500 mL) were added MeOH (500 mL) and H2O (500 mL) at room temperature under air atmosphere. To the above mixture was added NaOH (50 g, 1.25 mol, 3.0 equiv) at room temperature. The resulting mixture was stirred for an additional 30 min at 50°C. The resulting mixture was cooled and concentrated in vacuo to remove most of the solvent. The aqueous was acidified with 6 M HC1 until pH = 3-4 and extracted with EtOAc (2 x 1 L). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 3 -(difluoromethoxy) -2 -iodobenzoic acid (120 g, 92%) as a light yellow solid. LC-MS: (M-H)+found: 312.90. 'HNMR (400 MHz, CDC13) 57.78 (dd, J = 7.7, 1.5 Hz, 1H), 7.46 (t, J = 7.9 Hz, 1H), 7.40 - 7.34 (m, 1H), 6.58 (t, J = 73.0 Hz, 1H).

[0087] Step 5: To a stirred solution of 3 -(difluoromethoxy) -2 -iodobenzoic acid (120 g, 0.38 mol, 1.00 equiv) and cyclopent-3-en-l -amine hydrochloride (50.3 g, 0.42 mol, 1.1 equiv) in DMF (1 L) was added DIEA (148.2 g, 1.14 mmol, 3.0 equiv) at room temperature under air atmosphere. To the above mixture was added HATU (188.9 g, 496.8 mmol, 1.30 equiv) at room temperature. The resulting mixture was stirred for 30 min at room temperature. The reaction was poured into water (4 L) at room temperature. The resulting mixture was extracted with EtOAc (3 x 1 L). The combined organic layers were washed with brine (2 x 1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE: EA (5:1) to afford N-(cyclopent-3-en-l-yl)-3-(difluoromethoxy)-2-iodobenzamide (126 g, 87%) as a white solid. LC-MS: (M+H)+found: 379.80.1H NMR (400 MHz, CDC13) 57.39 (t, J = 7.9 Hz, 1H), 7.27 - 7.16 (m, 2H), 6.54 (t, J = 73.1Hz, 1H), 5.91 (br, 1H), 5.79 (s, 2H), 4.81 (qt, J = 7.5, 3.3 Hz, 1H), 2.89 (dd, J = 15.9, 7.4 Hz, 2H), 2.46 - 2.37 (m, 2H).

[0088] Step 6: A solution of N-(cyclopent-3-en-l-yl)-3-(difluoromethoxy)-2-iodobenzamide (126 g, 332.3 mmol, 1.0 equiv) in toluene (1.8 L) was added EtsN (139 mL, 997 mmol, 3.0 equiv) and PPh3(17.4 g, 66.5 mmol, 0.2 equiv) followed by Pd(OAc)2 (7.5 g, 33.2 mmol, 0.1 equiv) under nitrogen atmosphere.WSGR Docket No. 66412-713.601Then the mixture was degassed with N2 for 3 times and stirred overnight at 110°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford 7-(difluoromethoxy)-3,6-dihydro- 3.6-methanobenzo[c]azocin-l(2H)-one (81 g, 97%) as awhite solid. LC-MS: (M+H)+found: 252.05. ’H NMR(400 MHz, CDC13) 58.47 (dd, J = 7.8, 1.9 Hz, 1H), 7.36 - 7.29 (m, 2H), 6.79 (s, 1H), 6.58 (t, J = 73.6 Hz, 1H), 6.05 (dd, J = 5.5, 3.0 Hz, 1H), 5.92 (dd, J = 5.7, 2.5 Hz, 1H), 4.58 (dd, J = 7.1, 3.0 Hz, 1H), 4.22 (td, J = 6.5, 2.5 Hz, 1H), 2.52 (dt, J = 13.4, 6.9 Hz, 1H), 2.02 (d, J = 12.8 Hz, 1H).

[0089] Step 7: A solution of 7-(difluoromethoxy)-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (81 g, 322.41 mmol, 1.0 equiv) in THF (1 L) was treated with NaH (16.8 g, 419.13 mmol, 1.3 equiv, 60%) at 0°C. The mixture was allowed to stir at 0°C for 0.5 hr. To the above mixture was added Mel (30 mL, 483.62 mmol, 1.5 equiv) dropwise at 0°C under nitrogen atmosphere. The final reaction mixture was stirred for 3.5 hr at room temperature under nitrogen atmosphere. The reaction was quenched with water (500 mL) at room temperature. The resulting mixture was extracted with EtOAc (1 L x 2). The combined organic layers were washed with brine (1 L) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-1(2H)-one (75 g, 88%) as awhite solid. LC-MS: (M+H)+found: 266.00. ’H NMR(400 MHz, CDCh) 58.53 (dd, J = 8.2, 1.5 Hz, 1H), 7.30 (t, J = 8.1Hz, 1H), 7.22 (ddt, J = 8.1, 1.6, 0.9 Hz, 1H), 6.56 (t, J = 73.6 Hz, 1H), 6.05 (dd, J = 5.5, 2.9 Hz, 1H), 5.99 - 5.93 (m, 1H), 4.47 (ddd, J = 7.0, 2.9, 1.0 Hz, 1H), 4.33 (dd, J = 7.3, 2.5 Hz, 1H), 3.29 (s, 3H), 2.52 (dt, J = 13.0, 7.1Hz, 1H), 2.05 (d, J = 13.0 Hz, 1H).

[0090] Step 8: To a stirred solution of 7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-1(2H)-one (66 g, 0.25 mol, 1.0 equiv) in THF (660 mL) was added BH3-THF (498 mL, 0.5 mol, 2.0 equiv) at 0°C under N2 atmosphere. The resulting mixture was stirred for 3 hr at 0 °C under N2 atmosphere. To the above mixture was added NaOH (290 mL, 0.87 mol, 3.5 equiv) and H2O2 (116 mL, 1.24 mol, 5.0 equiv, 25%) at 0°C. The resulting mixture was stirred for an additional 30 min at 0°C. TLC (PE / EA = 1 / 1) showed the reaction was complete. The reaction was quenched with MeOH (300 mL) followed by Na2SO3 solution (500 mL) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with brine (500 mL) and dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with MeOH / DCM (0 to 5%) to afford 7-(difluoromethoxy)-4-hydroxy-2-methyl-3,4,5,6-tetrahydro-3,6-methanobenzo[c]azocin-l(2H)-one and 7 -(difluoromethoxy) -5 -hydroxy-2 -methyl-3,4,5,6-tetrahydro-3,6-methanobenzo [c]azocin- 1 (2H)-one (43 g, 58%) as a light yellow solid. The mixture was used in the next step directly without further separation. LC-MS: (M+H)+found: 283.90.

[0091] Step 9: To a stirred solution of 7-(difluoromethoxy)-4-hydroxy-2 -methyl-3, 4,5, 6-tetrahydro- 3.6-methanobenzo [c]azocin- 1 (2H)-one and 7 -(difluoromethoxy) -5 -hydroxy -2 -methyl-3,4,5,6-tetrahydro- 3.6-methanobenzo[c]azocin-l(2H)-one (15 g, 59.25 mmol, 1.0 equiv) in DCM (300 mL) was added silicaWSGR Docket No. 66412-713.601gel (6.36 g, 105.90 mmol, 2 equiv) followed by PCC (22.8 g, 105.90 mmol, 2.0 equiv) at 0°C under N2 atmosphere. The resulting mixture was stirred for 12 hr at 25 °C under N2 atmosphere. The reaction mixture was filtered through a pad of celite. The filter cake was washed with DCM (200 mL x 3). The combined organic phase was washed with sat. NaHCO3solution (500 mL), brine (200 mL) and dried over Na2SO4. Filtered and the filtrate was concentrated in vacuo to give a crude product. The crude product was purified by prep-Achiral SFC (Column: Viridis BEH Prep 2-EP OBD Column 5* 15 cm, 5um; Mobile Phase A: CO2, Mobile Phase B: IPA (l%-2M-NH3-MeOH); Flow rate: 120 mL / min;Gradient: isocratic 30% B; Column Temperature (°C): 35; Back Pressure(bar): 100; Wave Length: 220 nm; RTl(min): 3.9; RT2(min): 5.33; Sample Solvent: MeOH; Injection Volume: 3 mL) to give Intermediate 1: 7 -(difluoromethoxy)-2-methyl-2,3,5,6-tetrahydro-3,6-methanobenzo [c] azocine- 1,4-dione (3.9 g, 26%) as an off-white solid. LC-MS: (M+H)+found: 282.10. 'HNMR (400 MHz, DMSO-d6) 5 8.26 (dd, J = 7.9, 1.7 Hz, 1H), 7.46 - 7.04 (m, 3H), 4.16 (t, J = 7.2Hz, 1H), 4.05 (d, J = 8.6 Hz, 1H), 3.20 (s, 3H), 2.98 (ddd, J = 18.0, 8.1, 0.9 Hz, 1H), 2.76 (ddd, J = 14.2, 8.7, 6.5 Hz, 1H), 2.25 (ddd, J = 18.1, 3.1, 1.3 Hz, 1H), 2.07 (dd, J = 14.2, 3.1Hz, 1H).

[0092] Intermediate 2: 7 -(difluoromethoxy)-2-methyl-3,4-dihydro-3,6-methanobenzo [c]azocine- l,5(2H,6H)-dione (5.8 g, 39%) as an off-white solid with a total yield of 65%. LC-MS: (M+H)+found: 282.10. 'H NMR (400 MHz, CDC13) 58.53 (dd, J = 7.1, 2.5 Hz, 1H), 7.41 - 7.31 (m, 2H), 6.64 (dd, J = 79.6, 69.8 Hz, 1H), 4.50 (d, J = 8.6 Hz, 1H), 4.29 (t, J = 5.9 Hz, 1H), 3.27 (s, 3H), 2.87 - 2.65 (m, 3H), 2.40 (dd, J = 14.2, 2.7 Hz, 1H).Intermediate 3 and 4

[0093] Intermediate 1 (250 g) was purified by chiral SFC with the following conditions (Column: DAICELCHIRALPAK®AD; 250*40 mm 10 pm; Mobile Phase A: Supercritical CO2, Mobile Phase B: IPA(+0.1% 7.0mol / l Ammonia in MEOH); Flow rate: 150 mL / min; Gradient: 25% B to 25% B; Wave Length: 220 / 214 nm; RTl(min): 4.30; RT2(min): 5.60; Sample Solvent: IPA: DCM=1: 1; Injection Volume: 3 mL; Number Of Runs: 540) to afford:

[0094] Intermediate 3. (3S,6R)-7-(difluoromethoxy)-2-methyl-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azocine-1,4-dione (114.7 g, 45.9%) as a yellow oil. LCMS (ESI, m / z): 282.10 [M+H]+. ’HNMR (400 MHz, CDCh) 58.46 (d, J = 7.4 Hz, 1H), 7.35 (t, J = 8.1Hz, 1H), 7.25 - 7.23 (m, 1H), 6.56 (t, J = 73.4 Hz, 1H), 4.33 (t, J = 7.6 Hz, 1H), 3.81 (d, J = 8.1Hz, 1H), 3.34 (s, 3H), 2.80 (q, J = 8.4 Hz, 1H), 2.68 - 2.61 (m, 1H), 2.49 - 2.43 (m, 1H), 2.25 (dd, J = 14.5, 2.7 Hz, 1H).

[0095] Intermediate 4. (3R,6S)-7-(difluoromethoxy)-2-methyl-2,3,5,6-tetrahydro-3,6-methanobenzo[c]azocine-1,4-dione (115.3 mg, 46.1%) as ayellow oil. LCMS (ESI, m / z): 282.15WSGR Docket No. 66412-713.601[M+H]+. ’H NMR (400 MHz, CDC13) 58.46 (d, J = 8.8 Hz, 1H), 7.35 (t, J = 8.2Hz, 1H), 7.25 - 7.23 (m, 1H), 6.56 (t, J = 73.3 Hz, 1H), 4.33 (t, J = 7.6 Hz, 1H), 3.81 (d, J = 8.1Hz, 1H), 3.34 (s, 3H), 2.80 (q, J = 8.5 Hz, 1H), 2.68 - 2.61 (m, 1H), 2.46 (dd, J = 18.9, 2.5 Hz, 1H), 2.26 (dd, J = 14.4, 2.7 Hz, 1H).Intermediate 5 and 6

[0096] Intermediate 2 (240 g) was purified by chiral SFC with the following conditions (Column: DAICELCHIRALPAK®AD; 250*50 mm 10 pm; Mobile Phase A: Supercritical CO2, Mobile Phase B: IPA(+0.1% 7.0mol / l Ammonia in MeOH); Flow rate: 140 mL / min; Gradient: 25% B to 25% B; Wave Length: 220 / 214 nm; RTl(min): 6.70; RT2(min): 8.60; Sample Solvent: IPA: DCM=1: 1; Injection Volume: 8 mL; Number Of Runs: 125) to afford:

[0097] Intermediate 5: ((3S,6S)-7-(difluoromethoxy)-2-methyl-3,4-dihydro-3,6-methanobenzo[c]azocine-l,5(2H,6H)-dione (89.5 g, 43.8%) as a white solid. LCMS (ESI, m / z): 282.1 [M+H]+. ’H NMR (400 MHz, CDC13) 58.51 (dd, J = 5.9, 2.6 Hz, 1H), 7.34 (t, J = 4.9 Hz, 1H), 6.62 (dd, J = 79.6, 69.7 Hz, 1H), 4.48 (d, J = 8.7 Hz, 1H), 4.27 (t, J = 5.2Hz, 1H), 3.42 (s, 3H), 2.83 -2.76 (m, 1H), 2.72 - 2.65 (m, 2H), 2.39 (dd, J = 14.2, 2.6 Hz, 1H).

[0098] Intermediate 6. ((3R,6R)-7-(difluoromethoxy)-2-methyl-3,4-dihydro-3,6-methanobenzo[c]azocine-l,5(2H,6H)-dione (86.4 g, 42.3%) as a white solid. LCMS (ESI, m / z): 282.1 [M+H]+. H NMR (400 MHz, CDC13) 58.51 (d, J = 5.8 Hz, 1H), 7.35 - 7.33 (m, 1H), 6.56 (dd, J = 79.4, 69.7 Hz, 1H), 4.48 (d, J = 8.5 Hz, 1H), 4.27 (s, 1H), 3.25 (s, 3H), 2.83 - 2.76 (m, 1H), 2.71 - 2.65 (m, 2H), 2.38 (d, J= 14.2Hz, 1H).

[0099] Step 1: A solution of Intermediate 4 (750 mg, 2.7 mmol, 1 equiv) in THF (20 mL) was treated with LiHMDS (3.2 mL, 3.2 mmol, 1.2 equiv) for lOmin at -78°C under nitrogen atmosphere. TheWSGR Docket No. 66412-713.601mixture was warmed to -10°C. The resulting mixture was stirred for 15 min at -10°C under nitrogen atmosphere. The mixture was then cooled to -78°C. A solution of 4-methylbenzenesulfonyl cyanide (725 mg, 4.0 mmol, 1.5 equiv) in THF (10 mL) was added quickly(<lmin) to the cool reaction mixture. The resulting mixture was stirred for 5min at -78°C under nitrogen atmosphere. The resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (10 mL) at 0°C. The resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (1 x 60 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 1% NH3. H2O, 4: 1, ref=0.2) to afford (3R,6R)-7-(difluoromethoxy)-4-hydroxy-2-methyl-l-oxo-l,2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-carbonitrile (300 mg, 36.7%) as a yellow oil. LCMS (ESI, m / z): 306.9 [M+H]+.

[0100] Step 2: A solution of (3R,6R)-7-(difluoromethoxy)-4-hydroxy-2-methyl-l-oxo-l, 2,3,6-tetrahydro-3,6-methanobenzo[c]azocine-5-carbonitrile (320 mg, 1.1 mmol, 1 equiv) in EtOH (30 mL) was treated with NH2NH2. H2O (115 mg, 2.30 mmol, 2.2 equiv) for 5 min at room temperature under nitrogen atmosphere followed by the addition ofHCl(gas)in dioxane (0.1 mL, 3.1 mmol, 3 equiv) at room temperature. The resulting mixture was stirred for 3 hr at 85°C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10: 1) to afford (4R,1 lS)-l-amino-10-(difluoromethoxy)-5-methyl-2,4,5,ll-tetrahydro-6H-4,1 l-methanobenzo[c]pyrazolo[4,3-f]azocin-6-one (120 mg, 35.9%) as a yellow solid. LCMS (ESI, m / z): 320.90 [M+H]+.

[0101] Step 3: A solution of (4R,1 lS)-l-amino-10-(difluoromethoxy)-5-methyl-2, 4,5,11-tetrahydro-6H-4,1 l-methanobenzo[c]pyrazolo[4,3-f]azocin-6-one (120 mg, 0.4 mmol, 1 equiv) in DMF (2 mL) was treated with Cs₂CO₃ (195 mg, 0.6 mmol, 1.6 equiv) for 1 min at room temperature under nitrogen atmosphere followed by the addition of ethyl 3-ethoxy-2-propenoate (64.8 mg, 0.5 mmol, 1.2 equiv) at room temperature. The resulting mixture was stirred for 2 hr at 110 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 10: 1) to afford (7R,14S)-l-(difluoromethoxy)-6-methyl-6,7,13,14-tetrahydro-7,14-methanobenzo[c]pyrimido[l',2': l,5]pyrazolo[4,3-f]azocine-5, 12-dione (98 mg, 70.3%) as a yellow solid. LCMS (ESI, m / z): 373.00 [M+H]+.

[0102] Step 4: A solution of (7R,14S)-l-(difluoromethoxy)-6-methyl-6,7,13,14-tetrahydro-7,14-methanobenzo[c]pyrimido[l',2':l,5]pyrazolo[4,3-f]azocine-5, 12-dione (98 mg, 0.3 mmol, 1 equiv) in DCM (4 mL) was treated with DMAP (8. mg, 0.1 mmol, 0.25 equiv) and 2,6-lutidine (14.10 mg, 0.13 mmol, 0.5 equiv) for 1 min at 0 °C under nitrogen atmosphere followed by the addition of (trifluoromethane)sulfonyl trifluoromethanesulfonate (223 mg, 0.8 mmol, 3 equiv) at 0°C. The resulting mixture was stirred for 1 hr at room temperature under nitrogen atmosphere. The mixture was acidified to pH 8 with saturated NH4CI (aq.). The resulting mixture was extracted with DCM (3 x 30 mL). The combined organic layers were washed with brine (2 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLCWSGR Docket No. 66412-713.601(PE / EA 1:10) to afford Intermediate 7: (7R,14S)-l-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7, 14-methanobenzo [c]pyrimido [ l',2': 1,5]pyrazolo [4,3 -f] azocin- 12-yl trifluoromethanesulfonate (84 mg, 63.3%) as a yellow solid. LCMS (ESI, m / z): 505.05 [M+H]+.Intermediate 8

[0103] Step 1: NaH (60% suspension in mineral oil, 15.6 g, 0.39 mole) was washed with and suspended in ether (300 mL). To this suspension, ethyl formate (29.1 mb, 0.36 mole, 1.2 eq) was added and the mixture was cooled in an ice bath. Ethyl fluoroacetate (29.0 mL, 0.3 mole) was added slowly over 1 hr. After 2 hr, the ice bath was removed, and the reaction was stirred for another 2 hr. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification.

[0104] Step 2: The residue was re-dissolved in 350 mL of dry DMF and cooled in an ice bath, and ethyl iodide (48 mL, 0.6 mole) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight, then quenched with saturated aqueous solution of NH4CI (lOOmL). The mixture was diluted with ether and extracted with water. The separated ether layer was washed with sodium thiosulfate, brine and dried over MgSO₄. After concentration under vacuum, the residue was distilled to give ethyl 3 -ethoxy-2 -fluoroacrylate (6 g, 73°- 85° C / 14 mmHg) as a colorless oil. ’H NMR (300 MHz, CDCh): 5 1.35 (t, 3H), 1.39 (t, 3H), 4.10 (q, 2H), 4.30 (q, 2H), 6.95 (d, 1H).

[0105] Step 3: A solution of (lS,10R)-14-amino-3-(difluoromethoxy)-9-methyl-9,12,13-triazatetracyclo[8.5.1.0A{2,7}.0A{ll,15}]hexadeca-2,4,6,ll,14-pentaen-8-one (500 mg, 1.56 mmol, 1 equiv) in DMF (1 mL) was treated with Cs₂CO₃ (1.12 g, 3.43 mmol, 2.2 equiv) at room temperature for 1 min under nitrogen atmosphere followed by the addition of ethyl (2Z)-3-ethoxy-2-fluoroprop-2 -enoate (60.75 mg, 0.38mmol, 4 equiv) at room temperature. The resulting mixture was stirred at 110 °C for 3 hr under nitrogen atmosphere. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (lOmmol / L NH4HCO3), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (lS, HR)-18-(difluoromethoxy)-6-fluoro-12-methyl-4,8,9,12-tetraazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa-2,6,9,14,16,18-hexaene -5, 13 -dione (140 mg, 22.97%) as ayellow solid. LCMS (ESI, m / z): 391.10 [M+H]+.WSGR Docket No. 66412-713.601

[0106] Step 4: A solution of rel-(lR,llS)-18-(difluoromethoxy)-6-fluoro-12-methyl-4,8,9,12-tetraazapentacyclo[9.8.1.0A{2,10}.0A{3,8}.0A{14,19}]icosa-2,6,9,14,16,18-hexaene-5,13-dione (130 mg, 0.33 mmol, 1 equiv) in DCM (4 mL) was treated with DMAP (20.35 mg, 0.17 mmol, 0.5 equiv) at room temperature for 1 min under nitrogen atmosphere followed by the addition of 2,6-lutidine (53.53 mg, 0.50 mmol, 1.5 equiv) at room temperature. To the above mixture was added trifluoromethanesulfonic anhydride (281.90 mg, 1.00 mmol, 3 equiv) over 1 min at 0 °C. The resulting mixture was stirred at 0 °C for 1 hr. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:2) to afford Intermediate 8 (110 mg, 63.22%) as a yellow solid. LCMS (ESI, m / z): 523.15 [M+H]+.Intermediate 9

[0107] Step 1: To a stirred solution of Intermediate 6 (2.0 g, 7.1 mmol, 1 equiv) in THF (40 mL) was added LiHMDS (11.4 mL, 11.4 mmol, 1.6 equiv) dropwise at -78°C under nitrogen atmosphere. The resulting mixture was stirred at -78°C for 1 hr. To the above mixture was added 1,1,1-trifluoro-N-phenyl-N-(trifhioromethane)sulfonylmethanesulfonamide (3.8 g, 10.7 mmol, 1.5 equiv) in THF(40 mL) dropwise at -78°C. The resulting mixture was stirred at 78°C to RT for 2 hr. The reaction was quenched by the addition of sat. NH4CI (aq.) (50 mL) at 0 °C. The aqueous layer was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8: 1) to afford (3R,6R)-7-(difluoromethoxy)-2-methyl-1 -oxo-1, 2, 3, 6-tetrahydro-3,6-methanobenzo[c]azocin-5-yl trifluoromethanesulfonate (1.7 g, 57.8%) as light yellow oil. LCMS (ESI, m / z): 413.90 [M+H]+.

[0108] Step 2: To a stirred mixture of (3R,6R)-7-(difluoromethoxy)-2-methyl-l-oxo-l, 2,3,6-tetrahydro-3,6-methanobenzo[c]azocin-5-yl trifluoromethanesulfonate (1.7 g, 4.1 mmol, 1 equiv) and 4-chloro-2-(tributylstannyl)pyridine (2.5 g, 6.2 mmol, 1.5 equiv) in toluene (34 mL) was added Pd(PPh₃)₄ (475.3 mg, 0.41 mmol, 0.1 equiv) and CuCl (407.2 mg, 4.1 mmol, 1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 100°C for 4 hr. The resulting mixture wasWSGR Docket No. 66412-713.601filtered, the filter cake was washed with DCM (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (600 mg, 38.7%) as a light yellow solid. LCMS (ESI, m / z): 376.95 [M+H]+.

[0109] Step 3: To a stirred mixture of (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (5.0 g, 13.3 mmol, 1 equiv) and 2, 2,6,6-tetramethylpiperidin-l-olate (0.41 g, 2.7 mmol, 0.2 equiv) in DCE (100 mL) was added iron(III) nitrate nonahydrate (10.7 g, 26.5 mmol, 2.0 equiv) and 4A-MS (15 g) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 80°C for 2 hr. The resulting mixture was filtered, the filter cake was washed with DCE (3 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (2.2 g, 39.3%) as a light yellow solid. LCMS (ESI, m / z): 421.90 [M+H]+.

[0110] Step 4: A solution of (3R,6S)-5-(4-chloropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (2.2 g, 13.5 mmol, 1 equiv) in toluene (44 mL) was treated with triphenyl phosphite (4.9 g, 40.5 mmol, 3 equiv) at 100°C for 3 hr under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford Intermediate 9 (1.0 g, 50%) as a yellow solid. LCMS (ESI, m / z): 390.05 [M+H]+.Intermediate 10Pd(PPh3)4, CuCI Step 2

[0111] Step 1: A solution of 2-bromo-4-chloro-5 -fluoropyridine (1 g, 4.8 mmol, 1.0 equiv), hexamethyldistannane (7.8 g, 23.8 mmol, 5.0 equiv) and Pd(PPh₃)₄ (549 mg, 0.48 mmol, 0.1 equiv) in dioxane (15 mL) was stirred at 120 °C for 1 hr under nitrogen atmosphere. The reaction was quenched with H2O (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 4-chloro-5-fluoro-2-(trimethylstannyl)pyridine (1 g, crude) as a black solid. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 293.90 [M+H]+.WSGR Docket No. 66412-713.601

[0112] Step 2: A solution of 4-chloro-5-fluoro-2-(trimethylstannyl) pyridine (925 mg, 3.2 mmol, 2.0 equiv) and Intermediate 6 (650 mg, 1.6 mmol, 1.0 equiv), CuCl (234 mg, 2.4 mmol, 1.5 equiv) and Pd(PPh₃)₄ (272.6 mg, 0.24 mmol, 0.15 equiv) in toluene (15 mL) was stirred at 100°C for 1 hr under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford (3R,6S)-5-(4-chloro-5-fhioropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c] azocin- l(2H)-one (300 mg, 48.32%) as a white solid. LCMS (ESI, m / z): 395.10 [M+H]+.

[0113] Step 3: A solution of molecular sieves 4A (960 mg), (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (320 mg, 0.8 mmol, 1.0 equiv), iron(III) nitrate nonahydrate (660 mg, 1.6 mmol, 2.0 equiv) and TEMPO (25 mg, 0.16 mmol, 0.2 equiv) in DCE (10 mL) was stirred at 80°C for 2 hr under nitrogen atmosphere. The resulting mixture was filtered; the filter cake was washed with DCM (2 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzofc] azocin- l(2H)-one (220 mg, 61.7%) as a yellow solid. LCMS (ESI, m / z): 440.05 [M+H]+.

[0114] Step 4: To a stirred solution of (3R,6S)-5-(4-chloro-5-fluoropyridin-2-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (500 mg, 1.1 mmol, 1 equiv) and triphenyl phosphite (1.76 mg, 5.7 mmol, 5 equiv) in toluene (10 mL) was stirred at 100°C for 1 hr under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / EA (1: 1) to afford Intermediate 10 (150 mg, 32.4%) as a yellow solid. LCMS (ESI, m / z): 408.15 [M+H]+.WSGR Docket No. 66412-713.601Intermediate 11— Sn Sn— BnOH, NaH / \ THF Pd(PPh3)4, DMF Pd(PPH3)4, CuC Step 1 Step 2 Step 3Triphenyl phosphite Toluene Step 5

[0115] Step 1: A solution of benzyl alcohol (39.9 g, 369.2 mmol, 1.1 equiv) in THF (250 mL) was treated with NaH (16.1 g, 402.8 mmol, 1.2 equiv, 60%) at 0°C for 30min followed by the addition of 4,6-dichloropyrimidine (50 g, 335.6 mmol, 1.0 equiv) in portions at 0°C. The resulting mixture was stirred at room temperature for 2 hr under air atmosphere. The reaction was quenched by the addition of sat.NH4CI (5 mL) at 0°C. The reaction mixture was diluted with water (100 mL), and the aqueous phase was extracted with EA (3 x 100 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography (column, C18 silica gel; mobile phase, MeCN in water (TFA,0.1%), 50% to 90% gradient in lOmin; detector, UV 220 nm) to afford 4-(benzyloxy)-6-chloropyrimidine (30 g, 40.5%) as yellow oil. LCMS (ESI, m / z): 220.95 [M+H]+.

[0116] Step 2: A solution of 4-(benzyloxy)-6-chloropyrimidine (24 g, 108.8 mmol, 1 equiv), hexamethyldistannane (35.6 g, 108.8 mmol, 1 equiv) in toluene (150 mL) was treated with Pd(PPh₃)₄ (12.6 g, 10.9 mmol, 0.1 equiv) at room temperature under nitrogen atmosphere. The resulting mixture was stirred at 120°C for 2 hr under nitrogen atmosphere. The reaction mixture was diluted with water (40 mL), and the aqueous phase was extracted with EA (3 x 60 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 4-(benzyloxy)-6-(trimethylstannyl)pyrimidine (23 g) as a brown semi-solid. LCMS (ESI, m / z): 349.05 / 351.05 [M+H]+.

[0117] Step 3: A solution of Intermediate 6 (15 g, 12.1 mmol, 1 equiv), Pd(PPh3)4(4.2 g, 1.2 mmol, 0.1 equiv), CuCl (3.6 g, 12.1 mmol, 1.0 equiv) and 4-(benzyloxy)-6-(trimethylstannyl)pyrimidine (25.3 g, 24.2 mmol, 2 equiv) in toluene (300 mL) was stirred at 100°C for overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was dissolvedWSGR Docket No. 66412-713.601in DCM (500 mL). The resulting mixture was filtered, the filter cake was washed with DCM (3 x 500 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:2) to afford 12-[6-(benzyloxy)pyrimidin-4-yl]-3-(difluoromethoxy)-9-methyl-9-azatricyclo[8.2.1.0A{2,7}]trideca-2,4,6,l l-tetraen-8-one (11.5 g, 32.9%) as a light yellow solid. LCMS (ESI, m / z): 350.25 [M+H]+.

[0118] Step 4: A solution of (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (11.5 g, 25.6 mmol, 1 equiv) in DCE (230 mL) was treated with iron(III) nitrate nonahydrate (20.7 g, 51.2 mmol, 2 equiv) at room temperature for 1 min under nitrogen atmosphere followed by the addition of 2,2,6,6-tetramethylpiperidin-l-olate (799.6 mg, 5.1mmol, 0.2 equiv) and 4A-MS (34.5 g) in portions at room temperature. The resulting mixture was stirred at 80°C for 16 hr. The resulting mixture was filtered, the filter cake was washed with DCM (3 x 200 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (13:7) to afford (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (6.2 g, 49 %) as a light yellow solid. LCMS (ESI, m / z): 495.25 [M+H]+.

[0119] Step 5: A solution of (3R,6S)-5-(6-(benzyloxy)pyrimidin-4-yl)-7-(difluoromethoxy)-2-methyl-4-nitro-3,6-dihydro-3,6-methanobenzo[c]azocin-l(2H)-one (6.2 g, 12.5 mmol, 1 equiv) in toluene (124 mL) was treated with triphenyl phosphite (11.7 g, 37.6 mmol, 3 equiv) at 100°C for 1 hr under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (7R,14S)-12-(benzyloxy)-l-(difluoromethoxy)-6-methyl-6, 7-dihydro-7,14-methanobenzo[c]pyrimido[r, 6': l,5]pyrazolo[4,3-f] azocin-5(14H)-one (2.0 g, 35.5%) as a light brown solid. LCMS (ESI, m / z): 463.20 [M+H]+.

[0120] Step 6: A solution of (7R,14S)-12-(benzyloxy)-l-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[r,6':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (2 g, 4.3 mmol, 1 equiv) and Pd / C (920.5 mg, 0.87 mmol, 0.2 equiv, 10%) in ethyl acetate (100 mL) was stirred at room temperature for 2 hr under hydrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with MeOH: DCM=l: 1 (3 x 50 mL). The filtrate was concentrated under reduced pressure to afford (7R,14S)-l-(difluoromethoxy)-12-hydroxy-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[T,6':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (1.4 g, 86.9%) as a dark yellow solid. LCMS (ESI, m / z): 373.15 [M+H]+.

[0121] Step 7: To a stirred mixture of (7R,14S)-l-(difluoromethoxy)-12-hydroxy-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrimido[T,6':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (1.3 g, 3.5 mmol, 1 equiv) and DIEA (1.4 g, 10.5 mmol, 3 equiv) in DCM (26 mL) was added (trifluoromethane)sulfonyl trifluoromethane sulfonate (2.0 g, 7.0 mmol, 2 equiv) at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for 2 hr. The aqueous layer was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (1 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford (7R,14S)-l-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-WSGR Docket No. 66412-713.601methanobenzo[c]pyrimido[r,6': l,5]pyrazolo[4,3-f]azocin-12-yl trifluoromethanesulfonate (700 mg, 40%) as a light brown solid. LCMS (ESI, m / z): 505.15 [M+H]+.Table 2. Intermediate 12 - 25 prepared using similar procedure.Intermediate Structure Intermediate Structure12 1913 20 YrV^ 'CD3\ / =00\ \= / / jMJ / F14 21ZCD3CiA>=<r NFYYNX'. 'CD3\ / =0 O Q Q O o — — CO mA Y JsJ Ji T OIJI CF F Y z\Aj15 j r Y r V22 oyY M X trAwh ro o o16 23 XYO'X xzx^^ ZCD3 TfO N \y / =I o I °° O o w X AXF17 24V 'CD3 X ZCD3Tfo'XX%Y^n\ 2=° y X0=MXo—AYF18 25ZCD3, CD3Tfo'X / XY''N\ / =0 \ / =0FM 7 y_^A>F X= / WSGR Docket No. 66412-713.601Intermediate 24 and 25o

[0122] Step 1: A solution of cyclobutanone (20 g, 285.3 mmol, 1.0 equiv) and tert-butanesulfinamide (34.6 g, 285.3 mmol, 1.0 equiv) in THF (540 mL) was stirred with Ti(Oi-Pr)4 (128.1 mb, 428.0 mmol, 1.5 equiv) for overnight at 60°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The residue was dissolved in EtOAc (100 mL). The reaction was quenched by the addition of saturated Na₂CO₃ (aq.) (50 mL) at 0°C. The resulting mixture was filtered, the filter cake was washed with EtOAc (3x400 mL). The filtrate was concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (2 x 1000 mL). The combined organic layers were dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford N-cyclobutylidene-2-methylpropane-2-sulfinamide (34.5 g, 70%) as a light yellow liquid. LCMS (ESI, m / z): 174.10 [M+H]+.

[0123] Step 2: A solution of 5 -bromo-2 -iodopyrimidine (57.3 g, 201.1 mmol, 1.01 equiv) in DCM (1225 mL) was treated with n-BuLi in hexanes (81.3 mL, 203.1 mmol, 1.02 equiv) for lOmin at -78°C under nitrogen atmosphere followed by the addition ofN-cyclobutylidene-2-methylpropane-2-sulfinamide (34.5 g, 199.1 mmol, 1 equiv) dropwise at -78°C. The resulting mixture was stirred overnight at -20°C under nitrogen atmosphere. The reaction was quenched with Water / Ice at 0°C. The resulting mixture was extracted with DCM (3 x 500mL). The combined organic layers were washed dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford N-[l-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (23.2 g, 35.1%) as a yellow solid. LCMS (ESI, m / z): 334.00 [M+H]+.

[0124] Step 3: A mixture of N-[l-(5-bromopyrimidin-2-yl)cyclobutyl]-2-methylpropane-2-sulfinamide (23 g, 69.2 mmol, 1 equiv) and HCl(g) in MeOH (23 mL, 757 mmol, 10.9 equiv) in MeOH (230 mL) was stirred for 30min at room temperature under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The crude product was used in the next step directly without further purification. This resulted in l-(5-bromopyrimidin-2-yl)cyclobutan-l -amine (15.7 g, 99%) as a yellow oil. LCMS (ESI, m / z): 229.90 [M+H]+.

[0125] Step 4: A solution of l-(5-bromopyrimidin-2-yl)cyclobutan-l-amine (15.7 g, 68.8 mmol, 1 equiv) and TEA (28.7 mL, 206.5 mmol, 3 equiv) in DCM (158 mL) was stirred with BOC2O (22.5 g, 103.2 mmol, 1.5 equiv) for 1 hr at room temperature under air atmosphere. The resulting mixture wasWSGR Docket No. 66412-713.601extracted with DCM (3 x lOOmL). The combined organic layers were washed with NaHCO3.aq (3 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford tertbutyl N-[l-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (14.7 g, 65.1%) as a light yellow solid. LCMS (ESI, m / z): 329.90 [M+H]+.

[0126] Step 5: To a stirred solution of tert-butyl N-[l-(5-bromopyrimidin-2-yl)cyclobutyl]carbamate (1 g, 3.1 mmol, 1 equiv) and bis(pinacolato)diboron (1.2 g, 4.6 mmol, 1.5 equiv) in dioxane (15 mL) were added KO Ac (898 mg, 9.1 mmol, 3 equiv) and Pd(dppf)C12. DCM (248 mg, 0.31 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for an additional 2 hr at 100°C. The resulting mixture was diluted with H2O (30 mL). The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (DCM / MeOH 25:1) to afford tert-butyl N-{ l-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclobutyl}carbamate (650 mg, 57%) as a light yellow solid. LCMS (ESI, m / z): 376.10 [M+H]+.Intermediate 26 - 28Br

[0127] Step 1: l-methyl-3-oxocyclobutane-l-carbonitrile (1 g, 9.2 mmol, 1 equiv) was dissolved DCM (50 mL) and cooled under nitrogen to -78 °C, n-BuLi (4.40 mL, 11 mmol, 1.2 equiv) was added dropwise. The resulting mixture was stirred for 5min at -78 °C under nitrogen atmosphere. To the above mixture was added 5-bromo-2-iodopyrimidine (3.1 g, 11 mmol, 1.2 equiv) in DCM (50 mL) dropwise at -78°C. The resulting mixture was stirred for an additional 2 hr at -78°C. Then the resulting mixture was stirred overnight at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0°C. The aqueous layer was extracted with EtOAc (3 x 20 mL). The residue was purified by Prep-TLC (PE / EA 2: 1) to afford (3r)-3-(5-bromopyrimidin-2-yl)-3-hydroxy-l-methylcyclobutane-l-carbonitrile (800 mg, 32.6%) as an off-white solid. LCMS (ESI, m / z): 269.95 [M+H]+.

[0128] Step 2: 3-(5-bromopyrimidin-2-yl)-3-hydroxy-l-methylcyclobutane-l-carbonitrile (1g) was purified by prep chiral HPLC with the following conditions (Column: JW-CHIRAL ART Cellulose-SC, 20*250mm, 5um; Mobile Phase A: EtOH, Mobile Phase B: Hex(0.5% 2M NH₃-MeOH); Plow rate: 20WSGR Docket No. 66412-713.601mL / min; Gradient: 70% B to 70% B in 10min; Wave Length: 220 / 254 nm; RTl(min): 5.03; RT2(min): 7.78; Sample Solvent: EtOH: DCM=1: 1; Injection Volume: 1.4 mL; Number Of Runs: 10) to afford Intermediate 26. ( 1 r,3r)-3 -(5 -bromopyrimidin-2-yl)-3 -hydroxy- 1 -methylcyclobutane- 1 -carbonitrile (trans) (420 mg, 42.0%) as a yellow solid. 'H NMR (400 MHz, DMSO-d6) 59.07 (s, 2H), 6.16 (s, 1H), 3.27 - 3.19 (m, 2H), 2.42 - 2.34 (m, 2H), 1.65 (s, 3H).

[0129] Intermediate 27'. (( 1 s,3 s)-3 -(5 -bromopyrimidin-2-yl)-3 -hydroxy- 1 -methylcyclobutane- 1 -carbonitrile (cis) (220 mg, 22.0%) as a yellow solid. ’H NMR (400 MHz, DMSO-de) 59.04 (s, 2H), 6.19 (s, 1H), 2.86 - 2.79 (m, 2H), 2.75 - 2.68 (m, 2H), 1.40 (s, 3H).

[0130] Step 3: A solution of Intermediate 27 (100 mg, 0.37 mmol, 1 equiv), KO Ac (109.8 mg, 1.1 mmol, 3 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (189.4 mg, 0.75 mmol, 2 equiv) in dioxane (3 mL) was stirred for 1 hr at 100°C under nitrogen atmosphere. The reaction was monitored by TLC. TLC (DCM: MeOH=8: 1, Rf=0.3). The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Intermediate 28 (50 mg, 57.5%) as a yellow solid. LCMS (ESI, m / z): 234.20 [M+H]+.Intermediate 29 - 31

[0131] Step 1: A mixture of 3 -methylidenecyclobutane- 1 -carbonitrile (6.5 g, 69.8 mmol, 1 equiv) in THF (100 mL) was added LDA (38.4 mL, 76.8 mmol, 1.1 equiv) at -78 °C under nitrogen atmosphere. The resulting mixture was stirred at -78 °C for 1Hr prior addition of morpholine-4-carbonitrile (8.6 g, 76.8 mmol, 1.1 equiv). The mixture was stirred for 1 hr at -78 °C. The reaction was diluted with water (300 mL) and extracted with EA (3 x 300 mL). The combined organic layers were washed with brine (2 xWSGR Docket No. 66412-713.601400 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM / MeOH (30 / 1) to afford l-(imino(morpholino)methyl)-3-methylenecyclobutane-l-carbonitrile (5.0 g, 41%) as lightyellow oil. LCMS (ESI, m / z): 206.15 [M+H]+.

[0132] Step 2: A mixture of 5 -bromo- 1,2, 3 -triazine (3 g, 18.8 mmol, 1.0 equiv) in can (100 mL) was added l-(imino(morpholino)methyl)-3-methylenecyclobutane-l-carbonitrile (4.2 g, 20.6 mmol, 1.1 equiv) at 0 °C. The resulting mixture was stirred at 0°C for 10 min. To the above mixture was stirred for 6 hr at 80°C. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (30 / 1) to afford l-(5-bromopyrimidin-2-yl)-3-methylidenecyclobutane-1 -carbonitrile (2.7 g, 58%) as an off-white solid. LCMS (ESI, m / z): 250.95 [M+H]+.

[0133] Step 3: A mixture of 1 -(5 -bromopyrimidin-2-yl)-3 -methylidenecyclobutane- 1 -carbonitrile (1.7 g, 6.8 mmol, 1 equiv) in fluoroboric acid (20 mL) at room temperature. The resulting mixture was stirred at 70 °C for 7 hr. The reaction was quenched with saturated sodium bicarbonate solution (200 mL) and extracted with EA (3 x 200 mL). The combined organic layers were washed with brine (2 x 200 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA=1 / 1) to afford l-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane- 1 -carbonitrile (1.3 g, 71.3%) as yellow oil. LCMS (ESI, m / z): 270.00 [M+H]+.

[0134] Step 4: l-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-l-carbonitrile (1 g) was separated by prep chiral HPLC (Column: JW-CHIRAL ART Cellulose-SC, 20*250mm, 5um; Mobile Phase A: IPA, Mobile Phase B: Hex (0.5% 2M NH₃-MeOH); Plow rate: 20 mL / min; Gradient: 70% B to 70% B in 15min; Wave length: 220 / 254 nm; RTl(min): 6.21; RT2(min): 12.05; Sample Solvent: EtOH; Injection Volume: 2.2 mL; Number Of Runs: 8) to afford Intermediate 29: (ls,3s)-I-(5-bromopyrimidin-2-yl)-3 -hydroxy-3 -methylcyclobutane- 1 -carbonitrile (trans) (503 mg) as an off-white solid. ’HNMR (400 MHz, DMSO-d6) 59.10 (s, 2H), 2.99 - 2.87 (m, 2H), 2.82 - 2.72 (m, 2H), 1.56 (s, 3H).

[0135] Intermediate 30: ( 1 r,3r)- 1 -(5 -bromopyrimidin-2-yl)-3 -hydroxy-3 -methylcyclobutane- 1 -carbonitrile (cis) (384 mg) as an off-white solid. ’H NMR (400 MHz, DMSO-de) 59.10 (s, 2H), 2.93 -2.85 (m, 2H), 2.83 - 2.76 (m, 2H), 1.21 (s, 3H).

[0136] Step 5: A solution of (lr,3r)-l-(5-bromopyrimidin-2-yl)-3-hydroxy-3-methylcyclobutane-I-carbonitrile (100 mg, 0.37 mmol, 1 equiv) Pd(dppf)C12. DCM (30 mg, 0.04 mmol, 0.1 equiv) 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (189 mg, 0.75 mmol, 2 equiv), KO Ac (110 mg, 1.2 mmol, 3 equiv) in dioxane (3 mL) was stirred for 1 hr at 100°C under nitrogen atmosphere. The reaction was monitored by LCMS. The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by re versed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Intermediate 31: ( 1 r,3r)-3 -hydroxy-3 -methyl- 1 -(5 -(4,4,5,5 -tetramethyl- 1,3,2-dioxaborolan-2-WSGR Docket No. 66412-713.601yl)pyrimidin-2-43yclobuteneane-l -carbonitrile (30 mg, 26%) as a white solid. LCMS (ESI, m / z): 234.05 [M+H]+.Intermediate 32 - 34Brcis3334

[0137] Step 1: A solution of l-methyl-3 -oxocyclobutane- 1 -carbonitrile (3 g, 27.5 mmol, 1 equiv) and (R)-2-methyl -propane-2-sulfinamide (3 g, 27.5 mmol, 1 equiv) in THF (180 mL) was stirred with Ti(Oi-Pr)4 (12 mL, 41.2 mmol, 1.5 equiv) overnight at 75°C under nitrogen atmosphere. The resulting mixture was concentrated under vacuum. The reaction was quenched by the addition of water (200 mL) at room temperature. The residue was dissolved in EtOAc (250 mL). The resulting mixture was filtered, the fdter cake was washed with EtOAc (5 x 100 mL). The fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (5 g, 85.7%) as a white solid. LCMS (ESI, m / z): 213.10 [M+H]+.

[0138] Step 2: A solution of 5 -bromo-2 -iodopyrimidine (5 g, 19.8 mmol, 1.2 equiv) in DCM (400 mL) was treated with butyllithium (8 mL, 19.8 mmol, 1.2 equiv) for 10 min at -78 °C under nitrogen atmosphere followed by the addition of (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (4 g, 16.5 mmol, 1 equiv) for 10 min at -78 °C. The resulting mixture was stirred for 2 hr at -78 °C. The resulting mixture was stirred for 3 hr at room temperature under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (500 mL) at 0°C. The resulting mixture was extracted with DCM (3 x 400 mL). The combined organic layers were washed with brine (2 x 400 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% NH3. H2O), 10% to 60% gradient in 10 min; detector, UV 254 nm. This resulted in (R)-N-[I-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl]-2-methylpropane-2-sulfinamide) (700 mg, 8.0%) as a yellow oil. LCMS (ESI, m / z): 373.05 [M+H]+.

[0139] Step 3: The crude product (700 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAKIA3; Mobile Phase A: Hex(0.1%DEA): (IPA: MeOH=l: l)=90: 10; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: 2ul mL) to afford Intermediate 33: (R)-N-((Ir,3R)-l-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (320 mg, 45.7%) as a white solid.WSGR Docket No. 66412-713.601

[0140] Intermediate 32 (trans): 1H NMR (400 MHz, DMSO-d6) 59.08 (d, J= 1.6 Hz, 2H), 6.08 (s, 1H), 3.35 - 3.31 (m, 2H), 2.74 - 2.55 (m, 2H), 1.60 (s, 3H), 1.06 (s, 9H). LCMS (ESI, m / z): 373.05 [M+H]+.

[0141] Intermediate 33 (cis): ((R)-N-((ls,3S)-l-(5-bromopyrimidin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (180 mg, 25.7%). ’H NMR (400 MHz, DMSO-de) 5 9.02 (s, 2H), 6.10 (s, 1H), 3.02 - 2.99 (m, 1H), 2.92 (d, J = 1.9 Hz, 2H), 2.78 (d, J = 12.6 Hz, 1H), 1.37 (s, 3H), 1.12 (s, 9H).

[0142] Step 4: To a stirred solution of Intermediate 34 (100 mg, 0.27 mmol, 1 equiv) and 4, 4, 5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (137 mg, 0.538 mmol, 2 equiv) in dioxane (2 mL) were added KOAc (80 mg, 0.81 mmol, 3 equiv) and Pd(dppf)C12. DCM (22 mg, 0.027 mmol, 0.1 equiv) in portions at room temperature under nitrogen atmosphere. The resulting mixture was stirred for 2 hr at 110°C under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with brine (1 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford Intermediate 34 (60 mg, 54.8%) as a black solid. LCMS (ESI, m / z): 419.22 [M+H]+.Intermediate 35 - 37Br3637

[0143] Step 1: A solution of 5 -bromo-2 -iodopyrimidine (1.38 g, 4.9 mmol, 1.1 equiv) in Toluene (30 mL) was treated with n-butyllithium (310. mg, 4.7 mmol, 1.1 equiv) for 20 min at -50 °C under nitrogen atmosphere. To the above mixture was added (S)-N-(3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (1.4 g, 4.4 mmol, 1 equiv) in toluene (30 mL) over 5 min at -50°C. The resulting mixture was stirred for an additional 2 hr at room temperature. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (2 x 20 mb), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% PA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in (S)-N-(l-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (270 mg, 12.9%) as a yellow solid. LCMS (ESI, m / z): 476.10 [M+H]+.WSGR Docket No. 66412-713.601

[0144] Step 2: (S)-N-(l-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (270 mg) was purified by Prep-HPLC with the following conditions (Column: CHIRALPAKIG3; Mobile Phase A: Hex(0.1%DEA): IPA=95: 5; Flow rate: ImL / min mL / min; Gradient: isocratic; Injection Volume: 2ul mL) to afford:

[0145] Intermediate 35 (trans): ((S)-N-((lr,3S)-l-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (64 mg, 23.7%) as a white solid. 'HNMR (400 MHz, DMSO-d6) 58.98 (s, 2H), 5.78 (s, 1H), 3.03 (d, J = 12.7 Hz, 1H).

[0146] Intermediate 36 (cis): ((S)-N-((ls,3R)-l-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (110 mg, 40.7%) as a white solid. ’HNMR (400 MHz, DMSO-d6) 59.02 (s, 2H), 5.83 (s, 1H), 3.17 - 3.09 (m, 1H), 2.96 -2.88 (m, 1H), 2.65 (d, J = 12.2Hz, 1H), 2.60 (d, J = 12.2Hz, 1H), 1.04 (d, J = 3.5 Hz, 12H), 0.87 (s, 9H), 0.08 (s, 6H).

[0147] Step 3: A solution of Intermediate 37 (60 mg, 0.13 mmol, 1 equiv) and 4,4,5,5-tetramethyl-2-(tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (63.94 mg, 0.25 mmol, 2 equiv) in dioxane (1 mL) was treated with KOAc (37.07 mg, 0.38 mmol, 3 equiv) for 1 hr at room temperature under nitrogen atmosphere followed by the addition of Pd(dppf)Ch DCM (20.51 mg, 0.03 mmol, 0.2 equiv) at room temperature. The resulting mixture was stirred for 2 hr at 110°C under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EtOAc (3 x 5 mL). The filtrate was concentrated under reduced pressure to afford Intermediate 37 (60 mg, 91.0%) as a black solid. LCMS (ESI, m / z): 524.30 [M+H]+.Intermediate 38 - 40Dess-Martin TBSCI MeMgBr Step 2 Step 3o, P^L- B-B r o' 'o^y~ Pd(dppf)CI2, KOAc Step 5

[0148] Step 1: A solution ofl-(5-bromopyrimidin-2-yl) cyclobutane - 1,3-diol (200 mg, 0.82 mmol, 1 equiv) in DCM (5 mL) was treated with Dess-Martin (415.4 mg, 0.98 mmol, 1.20 equiv) for 10 min at 0°C under nitrogen atmosphere. The resulting mixture was stirred for 2 hr at room temperature under nitrogen atmosphere. The reaction was quenched with sat. Na2SOs (aq.) at 0°C. The resulting mixtureWSGR Docket No. 66412-713.601was extracted with DCM (3 x 10 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 3-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutan-l-one (150 mg, 75.6%) as a yellow solid. LCMS (ESI, m / z): 243 [M+H]+.

[0149] Step 2: A solution of 3-(5-bromopyrimidin-2-yl)-3-hydroxycyclobutan-l-one (2.2 g, 9.1 mmol, 1 equiv) in DMF (30 mL) was treated with Imidazole (1.4 g, 19.9 mmol, 2.2 equiv) at 0°C under nitrogen atmosphere followed by the addition of TBSC1 (3.0 g, 19.9 mmol, 2.2 equiv) in dropwise at 0°C. The resulting mixture was stirred for 2 hr at room temperature under nitrogen atmosphere. The reaction was quenched with sat. Na2SOs (aq.) at 0°C. The resulting mixture was extracted with DCM (3 x 10 mL). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-l-one (2 g, 61.8%) as a yellow oil. LCMS (ESI, m / z): 359.00 [M+H]+.

[0150] Step 3: In a 250mL round bottom flask, to a solution of 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]cyclobutan-l-one (1.8 g, 5.0 mmol, 1 equiv) in THF (40 mL) was added dropwise chloro(methyl)magnesium (0.38 g, 5.0 mmol, 1 equiv) at -78°C under N2 atmosphere. The reaction mixture was stirred at -78°C for 3 mins. The mixture was stirred for another 4 hr. The reaction was quenched with sat. NH4CI (4 mL), and then the mixture was extracted with ether / EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was purified by Prep-TLC (PE / EA 10: 1) to afford 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-l-methylcyclobutan-l-ol (1.7 g, 90.4%) as a yellow oil. LCMS (ESI, m / z): 375.10 [M+H]+.

[0151] Step 4: 3-(5-bromopyrimidin-2-yl)-3-[(tert-butyldimethylsilyl)oxy]-l-methylcyclobutan-l-ol (1.7 g) was purified by Prep Chiral HPLC with the following conditions (Column: JW-CHIRAL ART Cellulose-SC, 20*250mm, 5um; Mobile Phase A: EtOH— HPLC, Mobile Phase B: Hex(0.5% 2M NH3-MeOH)— HPLC; Flow rate: 45 mL / min; Gradient: 70% B to 70% B in 1 Imin; Wave Length: 220 / 254 nm; RTl(min): 5.21; RT2(min): 9.36; Sample Solvent: EtOH: DCM=1: 1; Injection Volume: 2.0 mL; Number Of Runs: 9) to afford Intermediate 39 (ls,3s)-3-(5-bromopyrimidin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-l-methylcyclobutan-l-ol (1.4 g, 82.4%) as ayellow solid. ’HNMR (400 MHz, DMSO-d6) 59.05 (s, 2H), 5.05 (s, 1H), 3.03 - 2.92 (m, 2H), 2.48 - 2.38 (m, 2H), 0.89 (s, 3H), 0.79 (s, 9H), 0.19 (s, 6H).

[0152] Step 5: A solution of Intermediate 44 (100 mg, 0.4 mmol, 1 equiv) Pd(dppf)C12. DCM (31.4 mg, 0.4 mmol, 0.1 equiv), KOAc (113.6 mg, 1.2 mmol, 3 equiv), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-l,3,2-dioxaborolane (196.0 mg, 0.8 mmol, 2 equiv) in dioxane (2 mL) was stirred for 2 hr at 80°C under nitrogen atmosphere. The reaction was monitored by LCMS. TLC (DCM: MeOH = 8: 1, Rf=0.3). The resulting mixture was concentrated under reduced pressure. The resulting mixture was concentrated under vacuum. The residue was purified by reversed-phase flash chromatography with the following conditions: column, Cl 8 silica gel; mobile phase, MeCN in WaterWSGR Docket No. 66412-713.601(0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in Intermediate 40 (80 mg, 92.53%) as a black solid. LCMS (ESI, m / z): 339.10 [M+H]+.Intermediate 41 and 42OTi(O-iPr)4, THF n-BuLi, DCM Step 1 Step 242

[0153] Step 1: To a stirred solution of l-methyl-3 -oxocyclobutane- 1 -carbonitrile (3.5 g, 32.07 mmol, 1 equiv) and (R)-2-methylpropane-2-sulfinamide (3.89 g, 32.07 mmol, 1 equiv) in THF (200 mL) was added Ti(OEt)4 (13 mL, 32.07 mmol, 1 equiv) dropwise at room temperature under nitrogen atmosphere. The resulting mixture was stirred overnight at 75 °C under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. To the above mixture was added H2O (200 mL) dropwise at 0°C. The precipitated solids were collected by filtration and washed with ethyl acetate (3 x 40 mL). The resulting mixture was concentrated under reduced pressure and purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (5.7 g, 83.7%) as an off-white solid. LCMS (ESI, m / z): 213.05 [M+H]+.

[0154] Step 2: A solution of 5-bromo-3-fluoro-2-iodopyridine (1.64 g, 5.42 mmol, 1.15 equiv) in DCM (250 mL) was treated with butyllithium (328.86 mg, 5.13 mmol, 1.09 equiv) for 5 min at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 min at -78 °C under nitrogen atmosphere. To the above mixture was added (R)-N-(3-cyano-3-methylcyclobutylidene)-2-methylpropane-2-sulfinamide (1 g, 4.71 mmol, 1 equiv) over 2 min at -78 °C. The resulting mixture was stirred for 2 hr at -78 °C. The resulting mixture was stirred for 2 hr at 0 °C under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of sat. NH4Cl (aq.) (125 mL) at 0 °C. The resulting mixture was extracted with DCM (3 x 200 mL). The combined organic layers were washed with brine (2 x 10 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:2) to afford Intermediate 41 (trans): (R)-N-((lr,3R)-l-(5-bromo-3-fluoropyridin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (200 mg, 10.9%) as a white solid and Intermediate 42 (cis): (R)-N-((ls,3S)-l-(5-bromo-3-fhioropyridin-2-yl)-3-cyano-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (150 mg, 8.2%) as a white solid. LCMS (ESI, m / z):388.05 [M+H] +.WSGR Docket No. 66412-713.601

[0155] Intermediate 41 (trans): 'HNMR (400 MHz, CDCL) 58.54 - 8.48 (m, 1H), 7.67 - 7.59 (m, 1H), 3.91 (s, 1H), 3.74 (d, J = 13.0 Hz, 1H), 3.35 (d, J = 12.8 Hz, 1H), 2.78 - 2.57 (m, 2H), 1.74 (d, J = 3.9 Hz, 3H), 1.20 (d, J = 2.4 Hz, 9H).

[0156] Intermediate 42 (cis): ’H NMR (400 MHz, CDCL) 58.46 (s, 1H), 7.63 - 7.56 (m, 1H), 4.04 (s, 1H), 3.15 (d, J = 13.1Hz, 1H), 3.08 - 2.96 (m, 2H), 2.65 (d, J = 12.7 Hz, 1H), 1.59 - 1.49 (m, 3H), 1.44 -1.12 (s, 9H).Intermediate 43 and 44MeMgBr, THF Step 1Dess-Martin Step 4

[0157] Step 1: A solution of 3-(benzyloxy)cyclobutan-l-one (10 g, 56.8 mmol, 1 equiv) in THF (100 mL) was treated with MeMgBr (20.3 g, 170.3 mmol, 3 equiv) for 15 min at -78 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hr at room temperature under nitrogen atmosphere. The reaction was quenched with sat. NH4CI (aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 50% to 100% gradient in 10 min; detector, UV 254 nm. This resulted in 3 -(benzyloxy)- 1-methylcyclobutan-l-ol (4 g, 36.7%) as a colorless oil. LCMS (ESI, m / z):175.10 [M+H-0H]+. 'HNMR (400 MHz, CDCL) 57.39 - 7.27 (m, 5H), 4.44 (s, 2H), 3.80 - 3.68 (m, 1H), 2.52 - 2.41 (m, 2H), 2.18 - 2.05 (m, 2H), 1.33 (t, J = 1.0 Hz, 3H).

[0158] Step 2: A solution of 3-(benzyloxy)-l-methylcyclobutan-l-ol (4 g, 20.8 mmol, 1 equiv) in DCM (50 mL) was treated with Imidazole (7.1 g, 104.0 mmol, 5 equiv) for 5 min at 0 °C under nitrogen atmosphere followed by the addition of TBSC1 (9.4 g, 62.4 mmol, 3 equiv) at 0 °C. The resulting mixture was stirred for 5 hr at room temperature under nitrogen atmosphere. The resulting mixture was extracted with DCM (3 x 100 mL). The combined organic layers were washed with brine (2 x 100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (40: 1) to afford [3 -(benzyloxy)- 1-WSGR Docket No. 66412-713.601mcthylcyclobutoxy |(tcrt-butyl)dimcthylsilanc (5 g, 78.4%) as a colorless oil. ’H NMR (400 MHz, CDCh) 57.42 - 7.28 (m, 5H), 4.44 (s, 2H), 3.75 - 3.64 (m, 1H), 2.41 (ddt, J = 11.8, 6.9, 2.5 Hz, 2H), 2.24 - 2.10 (m, 2H), 1.32 (t, J = 1.0 Hz, 3H), 0.91 (s, 9H), 0.10 (s, 6H).

[0159] Step 3: To a solution of [3 -(benzyloxy)- 1 -methylcyclobutoxy] (tert-butyl)dimethylsilane (5.3 g, 17.3 mmol, 1 equiv) in EtOH (60 mL) was added Pd / C (184.0 mg, 1.7 mmol, 0.1 equiv) under nitrogen atmosphere in a 250 mL round-bottom flask. The mixture was hydrogenated at room temperature for 1 day under hydrogen atmosphere using a hydrogen balloon, filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was filtered, the fdter cake was washed with EtOH (60 mb) (2 x 10 mb). The fdtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (9: 1) to afford 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-ol (3.5 g, 94.3%) as a yellow oil. 'H NMR (400 MHz, CDCh) 53.99-3.88 (m, 1H), 2.53 - 2.41 (m, 2H), 2.13 - 2.01 (m, 2H), 1.86 (s, 1H), 1.30 (d, J = 1.0 Hz, 3H), 0.90 (s, 9H), 0.09 (s, 6H).

[0160] Step 4: A solution of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-ol (2.5 g, 11.7 mmol, 1 equiv) in DCM (26 mL) was treated with Dess-Martin (6.0 g, 14.0 mmol, 1.2 equiv) for 10 min at 0 °C under nitrogen atmosphere. The resulting mixture was stirred for 2 hr at room temperature under nitrogen atmosphere. The reaction was quenched with sat. Na2SOs (aq.) at 0 °C. The resulting mixture was extracted with DCM (3 x 10 mb). The combined organic layers dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-one (2 g, 79.8%) as a yellow oil. 'H NMR (400 MHz, CDCI3) 53.28 - 3.16 (m, 2H), 3.05 - 2.95 (m, 2H), 1.66 - 1.56 (m, 3H), 0.91 (s, 9H), 0.14 (s, 6H).

[0161] Step 5: A solution of 3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutan-l-one (2.2 g, 10.4 mmol, 1 equiv) and (S)-2-methylpropane-2-sulfinamide (2.0 g, 16.6 mmol, 1.6 equiv) in THF (23 mL) was treated with Ti(Oi-Pr)4 (11.8 g, 41.6 mmol, 4 equiv) for 10 min at room temperature. The resulting mixture was stirred overnight at 70 °C under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with ACN (23 mL). The reaction was quenched with water (10 mL) at 0 °C. The resulting mixture was filtered, the filter cake was washed with MeCN (3 x 20 mL). The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10:1) to afford (S)-N-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutylidene}-2-methylpropane-2-sulfinamide (2.5 g, 74.5%) as a yellow oil. 'HNMR (400 MHz, CDC13) 53.63 - 3.47 (m, 1H), 3.41 - 3.17 (m, 2H), 3.09 - 2.99 (m, 1H), 1.52 (d, J = 7.4 Hz, 3H), 1.26 (d, J = 1.0 Hz, 9H), 0.90 (s, 9H), 0.12 (s, 6H).

[0162] Step 6: A solution of 5 -bromo-3-fluoro-2 -iodopyridine (1.9 g, 6.2 mmol, 1.1 equiv) in THF (50 mL) was treated with n-BuLi in hexanes (435.7 mg, 6.8 mmol, 1.2 equiv) for 30 min at -70 °C under nitrogen atmosphere. To the above mixture was added (S)-N-{3-[(tert-butyldimethylsilyl)oxy]-3-methylcyclobutylidene}-2-methylpropane-2-sulfinamide (1.8 g, 5.7 mmol, 1 equiv) over 10 min at -66 °C. The resulting mixture was stirred for 2 hr at -70 °C. The reaction was quenched with sat. NH4CIWSGR Docket No. 66412-713.601(aq.) at 0 °C. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (2 x 50 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (2: 1) to afford Intermediate 43 (trans): (S)-N-((lr,3S)-l-(5-bromo-3-fluoropyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (560 mg, 20.02%) as a yellow oil. LCMS (ESI, m / z):494.85 [M+H]+.1H NMR (400 MHz, CDC13) 5 8.47 - 8.40 (m, 1H), 7.58 - 7.50 (m, 1H), 3.86 (s, 1H), 3.19 (d, J = 13.2Hz, 1H), 2.76 - 2.52 (m, 3H), 1.58 (s, 3H), 1.18 (s, 9H), 0.79 (s, 9H), 0.04 (d, J = 7.2Hz, 6H).

[0163] Intermediate 44 (cis): (S)-N-((ls,3R)-l-(5-bromo-3-fluoropyridin-2-yl)-3-((tert-butyldimethylsilyl)oxy)-3-methylcyclobutyl)-2-methylpropane-2-sulfinamide (540 mg, 19.30%) as a yellow oil. 'HNMR (400 MHz, CDC13) 58.48 - 8.44 (m, 1H), 7.62 - 7.52 (m, 1H), 3.99 - 3.89 (m, 1H), 3.38 - 3.32 (m, 1H), 2.97 - 2.91 (m, 1H), 2.74 (d, J = 12.6 Hz, 1H), 2.56 (d, J = 12.7 Hz, 1H), 1.16 (s, 9H), 1.12 (s, 3H), 0.91 (s, 9H), 0.11 (s, 6H).Intermediate 45B2pin2n-BuLi, DCM Pd(dppf)CI2, KOAc, dioxaneStep 1 Step 2

[0164] Step 1: To a mixture of 5 -bromo-3-fluoro-2 -iodopyridine (10 g, 33.13 mmol, 1 equiv) in DCM (100 mL) was added n-BuLi (13.25 mL, 33.12 mmol, 1 equiv) drop wise at -78 °C under nitrogen atmosphere. The mixture was stirred for 1 hr at -78°C. And then (S)-2-methyl-N-(propan-2-ylidene) propane-2-sulfinamide (10.68 g, 66.25 mmol, 2 equiv) was added at -78°C. The mixture was stirred for 1 hr at -65°C. The mixture was quenched with saturated NH4Cl(aq.), and the aqueous phase was extracted with EA (500 mL) three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by reverse flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in water, 40% to 70% gradient in 10 min; detector, UV 220 nm to afford (S)-N-[2-(5-bromo-3-fluoropyridin-2-yl) propan-2 -yl]-2-methylpropane-2-sulfinamide (5 g, 44.8% yield, 99.6% purity) as yellow oil. LCMS (ESI, m / z): 337.00 [M+H]+.

[0165] Step 2: A mixture of (S)-N-[2-(5-bromo-3-fluoropyridin-2-yl) propan-2 -yl]-2-methylpropane-2-sulfinamide (100 mg, 0.30 mmol, 1 equiv) and bis(pinacolato)diboron (113 mg, 0.45 mmol, 1.5 equiv), Pd(dppf)C12-CH2C12 (13.3 mg, 33.13 mmol, 0.1 equiv), AcOK (87.3 mg, 0.89 mmol, 3 equiv) in dioxane (5 mL) was stirred at 100°C for Ihr under nitrogen atmosphere. The resulting mixture was filtered, the filter cake was washed with EA (10 mL x 3). The filtrate was concentrated under reduced pressure to afford (S)-N-{2-[3-fluoro-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl) pyridin-2-yl] propan-2-yl}-2-methylpropane-2-sulfinamide (150 mg) as black oil. The resulting mixture was used in the next step directly without further purification. LCMS (ESI, m / z): 303.15 [M+H-81]+.WSGR Docket No. 66412-713.601Intermediate 46

[0166] Step 1: A solution of (S)-2-methylpropane-2-sulfinamide (15 g, 123.8 mmol, 1.0 equiv) in THF (500 mL) was treated with acetone (35.9 g, 618.8 mmol, 5.0 equiv) at room temperature for 5 min under nitrogen atmosphere followed by the addition of tetrakis(propan-2-yloxy)titanium (175.9 g, 618.8 mmol, 5.0 equiv) dropwise at room temperature. The final reaction mixture was stirred at 60 °C for overnight. The reaction was quenched by the addition of water (300 mL) at room temperature and filtered through a Celite pad and concentrated under reduced pressure. The resulting mixture was extracted with EtOAc (3 x 800 mL). The combined organic layers were washed with water (3x300 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:1) to afford (S)-2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (5.5 g) as ayellow oil. LCMS (ESI, m / z): 162.10 [M+H]+.

[0167] Step 2: A solution of 5-bromo-2-iodo-4-methylpyrimidine (11.1 g, 37.2 mmol, 1.5 equiv) in DCM (15 mL) was treated with butyllithium (1.6 M in n-hexane) (23.3 mL, 37.2 mmol, 1.5 equiv) at -50 °C for 30 min under nitrogen atmosphere followed by the addition of (S)-2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (4 g, 24.8 mmol, 1 equiv) dropwise at -50°C. The final reaction mixture was stirred at room temperature for overnight. The reaction was quenched by the addition of sat. NELCl (aq.) (50 mL) at room temperature. The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (10 mmol / L NH4HCO3), 40% to 95% gradient in 20 min; detector, UV 254 nm. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford (S)-N-[2-(5-bromo-4-methylpyrimidin-2-yl)propan-2-yl]-2-methylpropane-2-sulfinamide (1.3 g) as ayellow solid. LCMS (ESI, m / z): 334.20 / 336.10[M+H]+.WSGR Docket No. 66412-713.601Intermediate 471aq.48%HBr, Br2, NaNO2N|T ° Step 3 Br'^^Y n-BuLi, DCMF Step 4

[0168] Step 1: A solution of 2-bromo-3-fluoro-6-methylpyridine (10 g, 52.627 mmol, 1 equiv) and (2-aminoethyl)dimethylamine (0.46 g, 5.263 mmol, 0.1 equiv), K2CO3 (1.09 g, 7.894 mmol, 0.15 equiv), Cu2O (0.75 g, 5.263 mmol, 0.1 equiv) in NH3. H2O (100 mL) and ethylene glycol (100 mL) was stirred at 80 °C for overnight under nitrogen atmosphere in pressure tank. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with CH2C12 (3 x 300 mL). The combined organic layers were washed with brine (1x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (4: 1) to afford 3-fluoro-6-methylpyridin-2 -amine (4.5 g, 67.79%yield, 92%purity) as an off-white solid. LCMS (ESI, m / z): 127.05 [M+H]+.

[0169] Step 2: A solution of 3-fhioro-6-methylpyridin-2-amine (4.5 g, 35.676 mmol, 1 equiv) and NBS (6.35 g, 35.676 mmol, 1 equiv) in MeCN (60 mL) was stirred at room temperature for 2 h under nitrogen atmosphere. Desired product could be detected by LCMS. The reaction was quenched by the addition of water (300 mL) at room temperature. The resulting mixture was extracted with CH2C12 (3 x 300 mL). The combined organic layers were washed with brine (1x300 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (7: 1) to afford 5-bromo-3-fluoro-6-methylpyridin-2 -amine (4.5 g, 61.52%yield, 92%purity) as an off-white solid. LCMS (ESI, m / z): 204.95 [M+H]+.

[0170] Step 3: A solution of 5-bromo-3-fluoro-6-methylpyridin-2-amine (1 g, 4.877 mmol, 1 equiv) in Hydrobromic acid (48% solution in water) (6 mL) was treated with Br2 (1.56 g, 9.754 mmol, 2 equiv) at 0°C for 1 h under nitrogen atmosphere followed by the addition of NaNO2 (0.67 g, 9.754 mmol, 2 equiv) in H2O (6 mL) dropwise at 0°C. The resulting mixture was stirred at 0 °C for 1 h under nitrogen atmosphere. The reaction was quenched by the addition of ice water ( 50 mL) at 0°C. The mixture / residue was basified to pH 9 with NaOH. The resulting mixture was extracted with CH2C12 (3 x 50 mL). The combined organic layers were washed with brine (1x50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (8: 1) to afford 2,5-dibromo-3-fluoro-6-WSGR Docket No. 66412-713.601methylpyridine (850 mg, 64.81%yield, 93%purity) as an off-white solid. LCMS (ESI, m / z): 269.80 [M+H]+.

[0171] Step 4: In a 50-mL round bottom flask, to a solution of 2,5-dibromo-3-fluoro-6-methylpyridine (400 mg, 1.487 mmol, 1 equiv) in DCM (7 mL) was added dropwise n-butyllithium solution (2.5 M in hexane, 0.6544 mL, 1.636 mmol) at -78 degrees C under N2 atmosphere. The reaction mixture was stirred at -78 degrees C for 30 mins. Then a solution of 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (287.85 mg, 1.784 mmol, 1.2 equiv) in 3 mL DCM was added dropwise and the mixture was stirred for another 40 mins. The reaction was quenched with water / sat. NH4Cl(100 mL), and then the mixture was extracted with ether / EtOAc (2* lOOmL). The combined organic extracts were washed with brine (lOmL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (PE: EA:3: 1) mixture to yield.to afford N-[2-(5-bromo-3-fluoro-6-methylpyridin-2-yl)propan-2-yl]-2-methylpropane-2-sulfinamide (120 mg, 22.97%yield, 92%purity) as an off-white solid. LCMS (ESI, m / z): 351.00 [M+H]+.Intermediate 48LDA, Mel THF n-BuLi, DCMStep 1Step 2

[0172] Step 1: To a solution of 2,5-dibromo-3-fluoropyridine (6 g, 23.5 mmol, 1 equiv) in THE (90 mL) was added dropwise LDA(2 M in THF / heptane / ethylbenzene) (17.7 mL, 35.3 mmol, 1.5 equiv) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 15 mins. Then a solution of Mel (6.7 g, 47.1 mmol, 2 equiv) in 10 mL of THF was added dropwise and the mixture was stirred for another 30 mins. The reaction was quenched with sat. NH4CI (30 mL), and then the mixture was extracted with EtOAc (2 x150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (PE: EA 4:1) mixture to yield. This resulted in 2,5-dibromo-3-fluoro-4-methylpyridine (6 g) as a yellow oil. LC-MS: (M+H)+ found: 269.85.

[0173] Step 2: To a solution of 2,5-dibromo-3-fluoro-4-methylpyridine (3 g, 11.1 mmol, 1 equiv) in DCM (30 mL) was added dropwise butyllithium (1.6 M in n-hexane) (5.4 mL, 13.4 mmol, 1.2 equiv) at -78 °C under N2 atmosphere. The reaction mixture was stirred at -78 °C for 10 mins. Then a solution of 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (2.2 g, 13.4 mmol, 1.2 equiv) in 10 mL of DCM was added dropwise and the mixture was stirred for another 10 mins. The reaction was quenched with sat. NH4CI (100 mL), and then the mixture was extracted with EtOAc (2 x 150 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under vacuum to yield a crude product which was directly purified by flash chromatography (PE: EA 1:1) mixture to yield. This resulted in N-[2-(5-bromo-3-fluoro-4-methylpyridin-2-yl)propan-2-yl]-2-methylpropane-2-sulfinamide; ethane (1.2 g) as a yellow solid. LC-MS: (M+H)+ found: 353.00.WSGR Docket No. 66412-713.601Table 3. Intermediate 49 - 55 prepared using similar procedure.Intermediate Structure Intermediate Structure49 53N<-yBrH2N tjT H2NA'' 4<d " F^FHO^\50 54M CX51 5552 CIyrH2N<NExample 2. (7R,14S)-l-(difluoromethoxy)-12-((l-(2-hydroxyethyl)-lH-pyrazol-4-yl)ethynyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[l',2':l,5]pyrazolo[4,3-f|azocin-5(14H)-one X N)Z / ' uo

[0174] Step 1: A mixture of (7R,14S)-l-(difluoromethoxy)-12-iodo-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[r,2':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (140 mg, 0.3 mmol, 1 equiv) and tert-butyl 4-ethynylpyrazole-l -carboxylate (112 mg, 0.6 mmol, 2 equiv), Cui (12 mg, 0.06 mmol, 0.2 equiv), EtsN (90 mg, 0.9 mmol, 3 equiv), Pd(PPh3)2C12 (20 mg, 0.03 mmol, 0.1 equiv) in MeCN (4 mL) was stirred at 80°C for 2 hr under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was filtered, the filter cake was washed with CH2Q2 (2 x 5 mL). The filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford tert-butyl 4-(((7R, 14S)- l-(difluoromethoxy)-6-methyl-5-oxo-5,6,7, 14-tetrahydro-7, 14-WSGR Docket No. 66412-713.601methanobenzo[c]pyrido[r,2':l,5]pyrazolo[4,3-f]azocin-12-yl)ethynyl)-lH-pyrazole-l-carboxylate (120 mg, 75.6% yield, 90% purity) as an off-white solid. LCMS (ESI, m / z): 546.15 [M+H]+.

[0175] Step 2: To a stirred solution of tert-butyl tert-butyl 4-(((7R,14S)-l-(difluoromethoxy)-6-methyl-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[T,2':l,5]pyrazolo[4,3-f]azocin-12-yl)ethynyl)-lH-pyrazole-l -carboxylate (120 mg, 0.22 mmol, 1 equiv) in DCM (4 mL) was added HC1 in 1,4-dioxane (4.0 M) (2 mL) dropwise at 0°C under nitrogen atmosphere. The resulting mixture was stirred at room temperature for overnight under nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The residue was basified to pH 9 with saturated NaHCO₃ (aq.). The resulting mixture was extracted with CH2Q2 (2 x 20 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure to afford (7R,14S)-12-((lH-pyrazol-4-yl)ethynyl)-l-(difluoromethoxy)-6-methyl-6,7-dihydro-7, 14-methanobenzo[c]pyrido[r,2':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (80 mg, 81.7% yield, 90% purity) as an off-white solid. LCMS (ESI, m / z): 446.10 [M+H]+.

[0176] Step 3: A mixture of (7R,14S)-12-((lH-pyrazol-4-yl)ethynyl)-l-(difluoromethoxy)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[T,2':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (80 mg, 0.18 mmol, 1 equiv) and 2-bromoethanol (45 mg, 0.36 mmol, 2 equiv) in DME (2 mL) was stirred at 80°C for overnight under air atmosphere. The mixture was allowed to cool down to room temperature. The reaction was quenched by the addition of water (30 mL) at room temperature. The resulting mixture was extracted with EtOAc (3 x 30 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product (80 mg) was purified by Prep-HPLC with the following conditions(Column: XBridge Prep OBD C18 Column, 30* 150 mm, 5pm; Mobile Phase A: Water(10mmol / L NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL / min mL / min; Gradient: 36% B to 56% B in 10 min; Wave Length:254nm / 220nm nm; RTl(min): 8.48) to afford (7R,14S)-l-(difluoromethoxy)-12-((l-(2-hydroxyethyl)-lH-pyrazol-4-yl)ethynyl)-6-methyl-6,7-dihydro-7,14-methanobenzo[c]pyrido[r,2':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (48.3 mg, 55% yield, 98.8% purity) as an off-white solid. LCMS (ESI, m / z): 490.25 [M+H]+. 'H NMR (400 MHz, DMSO-d6) 58.66 (dd, J = 7.3, 1.0 Hz, 1H), 8.22 (dd, J = 8.1, 1.4 Hz, 1H), 8.12 (d, J = 0.7 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.57 - 7.23 (m, 4H), 6.83 (dd, J = 7.3, 1.9 Hz, 1H), 5.06 (d, J = 6.9 Hz, 1H), 4.99 - 4.89 (m, 2H), 4.16 (t, J = 5.5 Hz, 2H), 3.73 (q, J = 5.5 Hz, 2H), 3.26 (s, 4H), 2.47 (s, 1H).WSGR Docket No. 66412-713.601Example 13. (lS,3s)-3-(5-((7R,14R)-l-acetyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [c] pyrimido[l ',2': l,5]pyrazolo [4,3-f] azocin-12-yl)pyrimidin-2-yl)-3-hydroxy-l-methylcyclobutane-l-carbonitrileHCI in dioxane Pd(PPh3)4, LiCI, dioxane DCM Step 3 Step 4

[0177] Step 1: A solution of (7R,14S)-12-bromo-l-hydroxy-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[c]pyrimido[r,2':l,5]pyrazolo[4,3-f]azocin-5(14H)-one (339 mg, 0.87 mmol, 1 equiv) and 2 (2-((ls,3s)-l-((tert-butyldimethylsilyl)oxy)-3-cyano-3-methylcyclobutyl)pyrimidin-5-yl)boronic acid (349 mg, 1.0 mmol, 1.15 equiv) in dioxane (5 mL) and H2O (1 mL) was treated with Pd(dppf)C12-CH2C12 (72 mg, 0.087 mmol, 0.1 equiv) and Na2CO3(278 mg, 2.62 mmol, 3 equiv) at 80°C for 1 h under nitrogen atmosphere. The mixture was allowed to cool down to room temperature. The resulting mixture was extracted with EtOAc (3 x 10 mL). The combined organic layers were washed with water (30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:3) to afford (lR,3s)-3-((tert-butyldimethylsilyl)oxy)-3-(5-((7R,14S)-l-hydroxy-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo [c]pyrimido [ 1 ',2': 1,5]pyrazolo [4,3-f] azocin- 12-yl)pyrimidin-2-yl)- 1 -methylcyclobutane- 1 -carbonitrile (400 mg, 75% yield, 94% purity) as a yellow solid. LC-MS: (M+H)+ found: 611.35.

[0178] Step 2: A solution of (lR,3s)-3-((tert-butyldimethylsilyl)oxy)-3-(5-((7R,14S)-l-hydroxy-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[l',2':l,5]pyrazolo[4,3-f]azocin- 12-yl)pyrimidin-2-yl)-l-methylcyclobutane-l-carbonitrile (300 mg, 0.49 mmol, 1 equiv) in DCM (30 mL) was treated with pyridine (195 mg, 2.46 mmol, 5 equiv) at 0°C for 2 min under nitrogen atmosphere followed by the addition of trifluoromethanesulfonic anhydride (416 mg, 1.47 mmol, 3 equiv) dropwise at 0°C. The resulting mixture was stirred at room temperature for 1 hr under air atmosphere. The resulting mixture was extracted with CH2Q2 (3 x 30 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:3) to afford (7R,14S)-12-(2-((ls,3R)-l-((tert-butyldimethylsilyl)oxy)-3-cyano-3-methylcyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-5-oxo-5, 6, 7, 14-tetrahydro-7, 14-methanobenzo[c]pyrimido[l',2': l,5]pyrazolo[4,3-f]azocin-l-ylWSGR Docket No. 66412-713.601trifluoromethane sulfonate (280 mg, 76.7% yield, 95% purity) as a yellow solid. LC-MS: (M+H)+ found: 743.30.

[0179] Step 3: A mixture of (7R,14S)-12-(2-((ls,3R)-l-((tert-butyldimethylsilyl)oxy)-3-cyano-3-methylcyclobutyl)pyrimidin-5-yl)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[r,2': l,5]pyrazolo[4,3-f]azocin-l-yl trifluoromethanesulfonate (10 mg, 0.015 mmol, 1 equiv) and tributyl(l-ethoxyethenyl)stannane (73 mg, 0.203 mmol, 1.5 equiv), Pd(PPh3)4(156 mg, 0.135 mmol, 1 equiv), LiCl (86 mg, 2.025 mmol, 15 equiv) in dioxane (3 mL) was stirred at 95°C for 2 hr under nitrogen atmosphere. The resulting mixture was extracted with EtOAc (3 x 5 mL). dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford ((lS,3s)-3-((tert-butyldimethylsilyl)oxy)-3-(5-((7R,14R)-l-(l-ethoxyvinyl)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7, 14-methanobenzo[c]pyrimido [ l',2': 1,5]pyrazolo [4,3 -f] azocin- 12-yl)pyrimidin-2-yl)- 1 -methylcyclobutane- 1 -carbonitrile (70 mg, 78.2% yield, 95% purity) as a yellow solid. LC-MS: (M+H)+ found: 665.40.

[0180] Step 4: To a solution of (lS,3s)-3-((tert-butyldimethylsilyl)oxy)-3-(5-((7R,14R)-l-(l-ethoxyvinyl)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrimido[ 1 ',2': 1,5]pyrazolo[4,3 -f] azocin- 12-yl)pyrimidin-2-yl)- 1 -methylcyclobutane- 1 -carbonitrile (60 mg, 0.09 mmol, 1 equiv) in DCM (2 mL) was treated with HC1 in dioxane (4 M, 0.5 mL) at room temperature overnight under nitrogen atmosphere. The resulting mixture was extracted with CH2CI2 (3 x 5 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. The aqueous layer was extracted with EtOAc (2 x 10 mL). Then concentrated under reduced pressure. The crude product (25 mg) was purified by Prep-HPLC with the following conditions (Column: YMC-Actus Triart C18 ExRS 250*20mm; Mobile Phase A:Water(10mmol / L NH4HCO3), Mobile Phase B: MEOH; Flow rate: 20 mL / min mL / min; Wave Length: 220 / 254 nm; RT1(min): 8.97) to afford (lS,3s)-3-(5-((7R,14R)-l-acetyl-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7, 14-methanobenzo [c]pyrimido [ 1 ',2': 1,5]pyrazolo [4,3 -f] azocin- 12-yl)pyrimidin-2-yl)-3 -hydroxy- 1 -methylcyclobutane- 1 -carbonitrile (9.2 mg, 19.5% yield, 99.4% purity) as a light yellow solid. LC-MS: (M+H)+ found: 550.30.1H NMR (400 MHz, DMSO-d6) 59.52 (s, 2H), 9.29 (d, J = 7.4 Hz, 1H), 8.40 (dd, J = 8.2, 1.4 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 6.24 (s, 1H), 5.09 (d, J = 6.9 Hz, 1H), 4.94 (d, J = 6.9 Hz, 1H), 3.30 - 3.21 (m, 1H), 2.95 (s, 3H), 2.90 (d, J = 13.2 Hz, 2H), 2.79 - 2.74 (m, 2H), 1.44 (s, 3H).WSGR Docket No. 66412-713.601Example 40. 2-(2-aminopropan-2-yl)-5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo- 5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[l',2':l,5]pyrazolo[4,3-f|azocin-12-yl)nicotinonitrile

[0181] Step 1: A solution of 5-bromo-2-iodopyridin-3-ol (5 g, 16.7 mmol, 1 equiv) in DMF (75 mL) was treated with K2CO3 (3.5 g, 25.0 mmol, 1.5 equiv) at room temperature for 3 min under nitrogen atmosphere followed by the addition of (bromomethyl)benzene (3.1 mL, 26.4 mmol, 1.6 equiv) dropwise at room temperature. The final reaction mixture was stirred at room temperature overnight. The reaction was poured into water at room temperature. The resulting mixture was extracted with EtOAc (200 mL). The combined organic layers were washed with brine (3 x 50 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (10: 1) to afford 3 -(benzyloxy)-5-bromo-2 -iodopyridine (5.9 g, 90.7% yield, 98% purity) as a white solid. LCMS (ESI, m / z): 389.90 [M+H]+.

[0182] Step 2: A solution of 3-(benzyloxy)-5-bromo-2 -iodopyridine (2 g, 5.1 mmol, 1 equiv) in THF (60 mL) was treated with n-BuLi (2.67 mL, 6.666 mmol, 1.3 equiv) at -78°C for Ih under nitrogen atmosphere followed by the addition of 2-methyl-N-(propan-2-ylidene)propane-2-sulfinamide (1.7 g, 10.3 mmol, 2 equiv) dropwise at -78°C. A solution was stirred at -78°C for 2 hr under nitrogen atmosphere. The reaction was quenched by the addition of sat. NH4CI (aq.) (100 mL) at room temperature. The resulting mixture was extracted with EtOAc (100 mL). The combined organic layers were washed with brine (3 x 30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reversed-phase flash chromatography with the following conditions: column, C18 silica gel; mobile phase, MeCN in Water (0.1% TFA), 10% to 50% gradient in 10 min; detector, UV 254 nm. This resulted in N-(2-(3-(benzyloxy)-5-bromopyridin-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (800 mg, 36.7% yield, 91% purity) as a yellow liquid. LCMS (ESI, m / z): 427.20 [M+H]+.WSGR Docket No. 66412-713.601

[0183] Step 3: To a solution of N-(2-(3-(benzyloxy)-5-bromopyridin-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (500 mg, 1.2 mmol, 1 equiv) and Pin2B2 (448 mg, 1.8 mmol, 1.5 equiv) in dioxane (10 mL) were added Pd(dppf)C12-CH2C12 (96 mg, 0.12 mmol, 0.1 equiv) and AcOK (289 mg, 2.9 mmol, 2.5 equiv). After stirring for 2 hr at 100°C under a nitrogen atmosphere. The resulting mixture was concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 453.30 [M+H],

[0184] Step 4: To a solution of (7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[T,2':l,5]pyrazolo[4,3-f]azocin-12-yl trifluoromethane sulfonate (200 mg, 0.4 mmol, 1 equiv) and N-(2-(3-(benzyloxy)-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-yl)pivalamide (243 mg, 0.5 mmol, 1.3 equiv) in dioxane (5 mL) and H2O (0.6 mL) were added Pd(dppf)C12-CH2C12 (64.5 mg, 0.08 mmol, 0.2 equiv) and K3PO4 (210 mg, 0.99 mmol, 2.5 equiv). After stirring for 2 hr at 80°C under a nitrogen atmosphere, the resulting mixture was concentrated under reduced pressure. The resulting mixture was extracted with CH2Q2 (50 mL). The combined organic layers were washed with water (3 x 30 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1:2) to afford N-(2-(3-(benzyloxy)-5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[T,2':l,5]pyrazolo[4,3-f]azocin-12-yl)pyridin-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (200 mg, 72.1% yield, 91% purity) as a brown solid. LCMS (ESI, m / z): 703.30 [M+H]+.

[0185] Step 5: To a solution of N-(2-(3-(benzyloxy)-5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[T,2':l,5]pyrazolo[4,3-f]azocin-12-yl)pyridin-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (500 mg, 0.7 mmol, 1 equiv) in MeOH (20 mL) was added Pd(OH)2 / C (10%, 0.5 g) under nitrogen atmosphere. The mixture was hydrogenated at room temperature overnight under hydrogen atmosphere using a balloon, filtered through a Celite pad and concentrated under reduced pressure. The crude product was used in the next step directly without further purification. LCMS (ESI, m / z): 613.25 [M+H]+.

[0186] Step 6: A solution ofN-(2-(5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[l',2':l,5]pyrazolo[4,3-f]azocin-12-yl)-3-hydroxypyridin-2-yl)propan-2-yl)-2-methylpropane-2-sulfinamide (80 mg, 0.13 mmol, 1 equiv) in DCM (5 mL) was treated with DMAP (3.2 mg, 0.03 mmol, 0.2 equiv) at room temperature under nitrogen atmosphere followed by the addition of l,l,l-trifluoro-N-phenyl-N-(trifluoromethane)sulfonylmethanesulfonamide (93 mg, 0.26 mmol, 2.0 equiv) at room temperature. The final reaction mixture was stirred at room temperature for 2 hr. The resulting mixture was concentrated under reduced pressure. The residue was purified by Prep-TLC (PE / EA 1: 1) to afford 2-(2-((tert-butylsulfmyl)amino)propan-2-yl)-5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[r,2':l,5]pyrazolo[4,3-f]azocin-12-yl)pyridin-3-yl trifluoromethanesulfonate (80 mg, 82.3% yield, 98% purity) as a white solid. LCMS (ESI, m / z): 745.20 [M+H]+.WSGR Docket No. 66412-713.601

[0187] Step 7: A solution of2-(2-((tert-butylsulfmyl)amino)propan-2-yl)-5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7, 14-tetrahydro-7, 14-methanobenzo [c]pyrido [ l',2': 1,5]pyrazolo [4,3 -f] azocin- 12-yl)pyridin-3-yl trifluoromethanesulfonate (60 mg, 0.08 mmol, 1 equiv) in DMF (1 mL) was treated with Pd(PPh₃)₄ (9.3 mg, 0.008 mmol, 0.1 equiv) at 100°C for 1 hr under nitrogen atmosphere. The crude product (50 mg) was purified by Prep-HPLC with the following conditions (Column: xBridge Prep Shield RP185pm OBD 30* 150mm; Mobile Phase A: Water (lOmmol / L NH4HCO3), Mobile Phase B: ACN;; Flow rate: 60 mL / min mL / min; Wave Length: 220 / 254 nm; RTl(min): 9.53) to afford 2-(2-aminopropan-2-yl)-5-((7R,14S)-l-(difluoromethoxy)-6-(methyl-d3)-5-oxo-5,6,7,14-tetrahydro-7,14-methanobenzo[c]pyrido[r,2':l,5]pyrazolo[4,3-f]azocin-12-yl)nicotinonitrile (12.4 mg, 29.7% yield, 98.6% purity) as a white solid. LCMS (ESI, m / z): 518.20 [M+H]+.1H NMR (400 MHz, DMSO-d6) 58.99 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 7.4 Hz, 1H), 8.61 (d, J = 2.3 Hz, 1H), 8.32 (s, 1H), 8.23 (dd, J = 8.1, 1.5 Hz, 1H), 7.81 - 7.54 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.16 (dd, J = 7.4, 2.1 Hz, 1H), 5.06 (dd, J = 24.9, 6.8 Hz, 2H), 3.30 (dt, J = 13.5, 6.8 Hz, 1H), 2.53 (s, 1H), 1.46 (s, 6H).

[0188] The following compounds were prepared as described above.Ex. LCMS ¹H NMR (ppm)[M+H]+1 460.20 ’H NMR (400 MHz, DMSO-d6) 58.66 (dd, J = 7.2, 1.0 Hz, 1H), 8.23 (dd, J = 8.1, 1.4Hz, 1H), 8.13 (s, 1H), 7.72 (d, J = 6.4 Hz, 1H), 7.59 - 7.27 (m, 4H), 6.83 (dd, J = 7.3, 1.9 Hz, 1H), 5.06 (d, J = 6.9 Hz, 1H), 4.96 (d, J = 6.6 Hz, 1H), 3.87 (s, 3H), 3.42 - 3.36 (m, 1H), 3.27 (s, 3H), 2.48 (s, 1H)2 490.25 ’H NMR (400 MHz, DMSO-d6) 58.66 (dd, J = 7.3, 1.0 Hz, 1H), 8.22 (dd, J = 8.1, 1.4Hz, 1H), 8.12 (d, J = 0.7 Hz, 1H), 7.76 - 7.69 (m, 1H), 7.57 - 7.23 (m, 4H), 6.83 (dd, J = 7.3, 1.9 Hz, 1H), 5.06 (d, J = 6.9 Hz, 1H), 4.99 - 4.89 (m, 2H), 4.16 (t, J = 5.5 Hz, 2H), 3.73 (q, J = 5.5 Hz, 2H), 3.26 (s, 4H), 2.47 (s, 1H)3 531.25 ’H NMR (400 MHz, DMSO-d6) 59.53 (s, 2H), 9.30 (d, J = 7.4 Hz, 1H), 8.25 (dd, J =7.9, 1.7 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.57 - 7.29 (m, 3H), 6.28 (t, J = 56.4 Hz, 1H), 5.13 (dd, J = 6.8, 1.4 Hz, 2H), 3.35 - 3.30 (m, 1H), 2.54 - 2.50 (m, 1H), 2.44 - 2.33 (m, 2H), 1.54 (d, J = 1.7 Hz, 3H)4 598.35 ’H NMR (400 MHz, DMSO-d6) 59.20 (s, 2H), 8.87 (d, J = 7.4 Hz, 1H), 8.26 - 8.16(m, 1H), 7.89 - 7.20 (m, 5H), 5.07 (dd, J = 27.6, 6.8 Hz, 2H), 3.31 (d, J = 14.5 Hz, 5H), 2.67 (d, J = 26.3 Hz, 4H), 2.55 (s, 1H), 1.39 (d, J = 7.3 Hz, 12H)5 531.25 ’H NMR (400 MHz, DMSO-d6) 59.52 (s, 2H), 9.30 (d, J = 7.4 Hz, 1H), 8.25 (dd, J =7.9, 1.7 Hz, 1H), 7.78 - 7.70 (m, 1H), 7.59 - 7.29 (m, 3H), 6.28 (t, J=56.4 Hz, 1H), 5.14 (d, J = 1.2 Hz, 2H), 3.35 - 3.30 (m, 1H), 2.54 - 2.50 (m, 1H), 2.44 - 2.33 (m, 2H), 1.54 (d, J= 1.8 Hz, 3H)6 530.30 ’H NMR (400 MHz, DMSO-d6) 59.19 (s, 2H), 8.85 (d, J = 7.4 Hz, 1H), 8.22 (dd, J =8.0, 1.5 Hz, 1H), 7.84 - 7.25 (m, 5H), 6.26 (t, J = 56.4 Hz, 1H), 5.06 (dd, J = 23.0, 6.8 Hz, 2H), 3.31 - 3.20 (m, 1H), 2.54 (s, 1H), 2.40 (s, 1H), 1.53 (s, 3H)7 530.30 ’H NMR (400 MHz, DMSO-d6) 59.20 (s, 2H), 8.85 (d, J= 1A Hz, 1H), 8.22 (dd, J =7.9, 1.5 Hz, 1H), 7.82 - 7.27 (m, 5H), 6.27 (t, J= 56.3 Hz, 1H), 5.06 (dd, J= 22.6, 6.8 Hz, 2H), 3.33 - 3.24 (m, 1H), 2.79 (s, 1H), 2.54 (s, 1H), 1.54 (d, J= 1.7 Hz, 3H) 8 542.25 ’H NMR (400 MHz, DMSO-d6) 58.87 (d, J = 6.5 Hz, 1H), 8.75 (d, J = 7.3 Hz, 1H),8.69 (s, 1H), 8.20 (dd, J = 7.9, 1.6 Hz, 1H), 7.69 - 7.29 (m, 4H), 6.97 (dd, J = 7.3, 2.0Hz, 1H), 5.04 (d, J = 6.6 Hz, 1H), 4.79 (t, J = 6.6 Hz, 1H), 3.28 - 3.23 (m, 1H), 3.09WSGR Docket No. 66412-713.601Ex. LCMS ¹H NMR (ppm)[M+H]+- 2.76 (m, 4H), 2.64 - 2.56 (m, 2H), 2.51 - 2.47 (m, 3H), 2.43 (d, J = 12.9 Hz, 1H), 1.47 (s, 3H)9 512.35 ’H NMR (400 MHz, DMSO-d6) 59.11 (s, 2H), 8.82 (d, J = 7.3 Hz, 1H), 8.48 - 8.40(m, 2H), 8.28 (s, 1H), 7.90 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.30 (dd, J = 7.4, 2.2 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 6.8 Hz, 1H), 3.18 (s, 1H), 2.84 (d, J = 12.1 Hz, 2H), 2.78 (s, 3H), 2.41 (s, 1H), 2.24 (d, J = 11.4 Hz, 2H), 1.18 (d, J = 2.0 Hz, 3H)10 513.30 ’H NMR (400 MHz, DMSO-d6) 59.14 (s, 2H), 8.83 (dt, J = 7.4, 0.9 Hz, 1H), 8.49 - 8.42 (m, 2H), 7.91 (dd, J = 7.6, 1.4 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.32 (ddd, J = 7.4, 2.2, 0.9 Hz, 1H), 5.64 (s, 1H), 5.03 (d, J = 6.8 Hz, 1H), 4.98 (s, 1H), 4.75 (d, J = 6.9 Hz, 1H), 3.22 (dt, J = 13.6, 7.0 Hz, 1H), 2.95 - 2.87 (m, 2H), 2.80 (s, 3H), 2.47 - 2.38 (m, 3H), 1.09 (s, 3H)11 521.30 ’H NMR (400 MHz, DMSO-d6) 59.12 (s, 2H), 8.82 (dd, J = 7.4, 0.9 Hz, 1H), 8.48 - 8.40 (m, 2H), 7.90 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.28 (dd, J = 7.4, 2.2 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 6.9 Hz, 1H), 3.23 - 3.15 (m, 1H), 2.86 - 2.75 (m, 5H), 2.65 - 2.57 (m, 2H), 2.42 (d, J = 13.5 Hz, 1H), 1.45 (s, 3H) 12 483.25 ¹H NMR (400 MHz, DMSO-d6) δ8.80 - 8.74 (m, 1H), 8.63 (t, J = 2.2 Hz, 1H), 8.44(dt, J = 8.0, 1.3 Hz, 1H), 8.11 (q, J = 1.3 Hz, 1H), 7.88 (dt, J = 7.7, 1.4 Hz, 1H), 7.40 (td, J = 7.9, 1.3 Hz, 1H), 7.00 (dt, J = 7.3, 1.8 Hz, 1H), 5.03 (d, J = 6.7 Hz, 1H), 4.70 (d, J = 6.9 Hz, 1H), 3.23 - 3.15 (m, 1H), 2.73 (d, J = 1.3 Hz, 3H), 2.49 - 2.42 (m, 3H), 2.40 (s, 1H), 1.46 (t, J = 2.4 Hz, 6H)13 550.30 ’H NMR (400 MHz, DMSO-d6) 59.52 (s, 2H), 9.29 (d, J = 7.4 Hz, 1H), 8.40 (dd, J =8.2, 1.4 Hz, 1H), 7.74 (d, J = 7.5 Hz, 1H), 7.64 (dd, J = 7.6, 1.5 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 6.24 (s, 1H), 5.09 (d, J = 6.9 Hz, 1H), 4.94 (d, J = 6.9 Hz, 1H), 3.30 - 3.21 (m, 1H), 2.95 (s, 3H), 2.90 (d, J = 13.2 Hz, 2H), 2.79 - 2.74 (m, 2H), 1.44 (s, 3H)14 527.15 ¹H NMR (400 MHz, DMSO-d6) δ8.76 (dd, J = 7.3, 0.9 Hz, 1H), 8.23 (dd, J = 7.6, 1.9Hz, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.79 (d, J = 7.9 Hz, 1H), 7.67 - 7.27 (m, 4H), 6.97 (dd, J = 7.3, 2.0 Hz, 1H), 5.08 (d, J = 6.9 Hz, 1H), 4.99 (d, J = 6.6 Hz, 1H), 3.31 - 3.26 (m, 1H), 2.12 (s, 2H), 1.41 (s, 6H)15 435.05 ¹H NMR (400 MHz, DMSO-d6) δ8.79 (d, J = 7.3 Hz, 1H), 8.71 (d, J = 1.8 Hz, 1H),8.47 - 8.40 (m, 2H), 8.01 (d, J = 13.1 Hz, 1H), 7.89 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.4, 2.1 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.72 (d, J = 6.9 Hz, 1H), 3.23 - 3.15 (m, 1H), 2.78 (s, 3H), 2.42 (d, J = 13.5 Hz, 1H), 1.64 - 1.37 (m, 6H)16 561.20 ’H NMR (400 MHz, DMSO-d6) 59.24 (d, J = 7.4 Hz, 1H), 8.94 (s, 1H), 8.25 (dd, J =7.1, 2.4 Hz, 1H), 7.83 - 7.01 (m, 4H), 6.16 (s, 1H), 5.12 (dd, J = 17.4, 6.8 Hz, 2H), 3.30 (d, J = 7.2 Hz, 1H), 2.90 (d, J = 12.9 Hz, 2H), 2.76 (d, J = 12.8 Hz, 2H), 2.68 (s, 3H), 2.54 (s, 1H), 1.46 (s, 3H)17 561.20 ’H NMR (400 MHz, DMSO-d6) 59.24 (d, J = 7.4 Hz, 1H), 8.94 (s, 1H), 8.25 (dd, J =7.1, 2.4 Hz, 1H), 7.83 - 7.01 (m, 4H), 6.16 (s, 1H), 5.12 (dd, J = 17.4, 6.8 Hz, 2H), 3.30 (d, J = 7.2 Hz, 1H), 2.90 (d, J = 12.9 Hz, 2H), 2.76 (d, J = 12.8 Hz, 2H), 2.68 (s, 3H), 2.54 (s, 1H), 1.46 (s, 3H)18 472.30 ’H NMR (400 MHz, DMSO-d6) 59.17 (s, 2H), 8.82 (dd, J = 7.4, 0.9 Hz, 1H), 8.22(dd, J = 8.1, 1.5 Hz, 1H), 7.98 (dd, J = 2.2, 0.9 Hz, 1H), 7.69 (dd, J = 7.7, 1.6 Hz, 1H), 7.33 - 7.24 (m, 2H), 5.71 - 5.61 (m, 1H), 5.56 (d, J = 4.7 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.90 (d, J = 7.1 Hz, 1H), 3.29 - 3.24 (m, 1H), 2.45 (d, J = 13.3 Hz, 1H), 1.57 (d, J = 6.2 Hz, 3H), 1.47 (s, 6H)19 480.30 ’H NMR (400 MHz, DMSO-d6) 58.79 (d, J = 7.1 Hz, 2H), 8.35 - 8.21 (m, 1H), 7.58- 7.42 (m, 2H), 7.24 (t, J = 7.9 Hz, 1H), 7.00 (t, J = 8.3 Hz, 1H), 5.22 (d, J = 6.5 Hz, 1H), 5.12 - 5.03 (m, 1H), 4.98 - 4.53 (m, 2H), 3.86 - 3.67 (m, 3H), 3.28 - 3.18 (m, 1H), 2.54 (s, 1H), 2.20 (s, 3H), 1.58 (s, 6H)20 494.25 ¹H NMR (400 MHz, DMSO-d6) δ8.87 (d, J = 6.6 Hz, 1H), 8.80 - 8.70 (m, 2H), 8.20(dd, J = 8.0, 1.5 Hz, 1H), 8.01 (dd, J = 13.3, 2.0 Hz, 1H), 7.66 (dd, J = 15.9, 1.8 Hz,WSGR Docket No. 66412-713.601Ex. LCMS ¹H NMR (ppm)[M+H]+2H), 7.48 - 7.37 (m, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.25 (dd, J = 7.4, 2.1 Hz, 1H), 5.08 (d, J = 6.6 Hz, 1H), 4.79 (t, J = 6.6 Hz, 1H), 3.29 - 3.20 (m, 1H), 2.44 (d, J = 12.9 Hz, 1H), 1.48 (d, J = 1.7 Hz, 6H)21 483.25 ’H NMR (400 MHz, DMSO-d6) 58.72 (d, J = 7.3 Hz, 1H), 8.45 (dd, J = 8.1, 1.4 Hz,1H), 8.07 (d, J = 2.0 Hz, 1H), 7.88 (dd, J = 7.7, 1.4 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 7.3, 2.1 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 6.9 Hz, 1H), 3.31 (s, 1H), 3.21 (dt, J = 13.8, 7.1 Hz, 1H), 2.73 (s, 3H), 2.46 (s, 3H), 2.41 (d, J = 13.5 Hz, 1H), 1.43 (s, 6H)22 492.25 ’H NMR (400 MHz, DMSO-d6) 58.85 - 8.71 (m, 1H), 8.60 (s, 1H), 8.48 (d, J = 8.1Hz, 1H), 7.90 - 7.55 (m, 2H), 7.50 - 7.37 (m, 2H), 7.01 (dd, J = 7.3, 2.0 Hz, 1H), 5.07 (d, J = 6.8 Hz, 1H), 4.95 (d, J = 6.7 Hz, 1H), 3.35 - 3.30 (m, 1H), 2.54 (s, 1H), 2.45 (s, 3H), 1.47 (s, 6H)23 525.30 ’H NMR (400 MHz, DMSO-d6) 58.76 (dd, J = 7.3, 0.9 Hz, 1H), 8.23 (dd, J = 7.8, 1.7Hz, 1H), 7.73 - 7.47 (m, 2H), 7.41 - 7.29 (m, 3H), 6.96 (dd, J = 7.3, 2.0 Hz, 1H), 5.08 (d, J = 6.9 Hz, 1H), 4.99 (d, J = 6.7 Hz, 1H), 3.28 (q, J = 6.8 Hz, 1H), 2.53 (s, 1H), 2.44 (d, J = 1.0 Hz, 3H), 2.25 (s, 2H), 1.46 (d, J = 1.6 Hz, 6H)24 491.20 ¹H NMR (400 MHz, DMSO-d6) δ8.87 (d, J = 6.6 Hz, 1H), 8.74 (d, J = 7.4 Hz, 1H),8.64 (s, 1H), 8.20 (dd, J = 7.8, 1.6 Hz, 1H), 7.73 - 7.26 (m, 4H), 6.98 (dd, J = 7.4, 2.0 Hz, 1H), 5.05 (d, J = 6.5 Hz, 1H), 4.79 (t, J = 6.5 Hz, 1H), 3.31 - 3.20 (m, 1H), 2.48 (s, 3H), 2.43 (d, J = 13.0 Hz, 1H), 2.19 (s, 1H), 1.45 (s, 6H)25 469.25 ¹H NMR (400 MHz, DMSO-d6) δ8.93 (s, 1H), 8.81 (d, J = 7.5 Hz, 1H), 8.45 (dd, J =6.1, 2.2 Hz, 4H), 8.31 - 8.13 (m, 1H), 7.89 (dd, J = 7.6, 1.5 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 7.28 (dd, J = 7.4, 2.2 Hz, 1H), 5.03 (d, J = 6.8 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 3.32 - 3.30 (m, 1H), 2.92 (s, 3H), 2.68 (s, 1H), 2.31 (s, 1H), 1.66 (d, J = 5.2 Hz, 6H)26 550.25 ’H NMR (400 MHz, DMSO-d6) 58.78 (dd, J = 7.3, 0.9 Hz, 1H), 8.65 (s, 1H), 8.22 (dd, J = 7.7, 1.8 Hz, 1H), 7.72 - 7.25 (m, 4H), 7.00 (dd, J = 7.3, 2.0 Hz, 1H), 5.08 (d, J = 6.9 Hz, 1H), 4.99 (d, J = 6.6 Hz, 1H), 4.85 (s, 1H), 3.28 (dd, J = 13.5, 6.8 Hz, 1H), 2.69 (d, J = 11.3 Hz, 2H), 2.53 (s, 1H), 2.48 (s, 3H), 2.35 - 2.32 (m, 1H), 2.11 (s, 2H), 1.54 (s, 3H)27 483.20 ¹H NMR (400 MHz, DMSO-d6) δ8.73 (dd, J = 7.3, 0.9 Hz, 1H), 8.44 (dd, J = 8.1, 1.5Hz, 1H), 8.35 (s, 1H), 8.07 (dd, J = 2.1, 1.0 Hz, 1H), 7.87 (dd, J = 7.7, 1.5 Hz, 1H), 7.61 (s, 1H), 7.39 (t, J = 7.9 Hz, 1H), 6.93 (dd, J = 7.3, 2.1 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.69 (d, J = 6.9 Hz, 1H), 3.21 (dt, J = 13.8, 7.0 Hz, 1H), 2.72 (s, 3H), 2.41 (d, J = 13.4 Hz, 1H), 2.30 (s, 3H), 1.44 (s, 6H)28 525.20 ’H NMR (400 MHz, DMSO-d6) 58.77 (dd, J = 7.3, 1.0 Hz, 1H), 8.29 - 8.19 (m, 2H),7.71 - 7.22 (m, 4H), 6.93 (dd, J = 7.3, 2.0 Hz, 1H), 5.08 (d, J = 6.9 Hz, 1H), 4.99 (d, J = 6.6 Hz, 1H), 3.32 - 3.23 (m, 1H), 2.53 (s, 1H), 2.32 (d, J = 6.0 Hz, 2H), 2.21 (d, J = 2.5 Hz, 3H), 1.46 (d, J = 1.6 Hz, 6H)29 529.25 ’H NMR (400 MHz, DMSO-d6) 58.79 (dd, J = 7.4, 0.9 Hz, 1H), 8.68 (t, J = 1.7 Hz,1H), 8.44 (dd, J = 8.2, 1.5 Hz, 2H), 7.98 (dd, J = 12.2, 1.9 Hz, 1H), 7.90 (dd, J = 7.6, 1.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.26 (dd, J = 7.4, 2.2 Hz, 1H), 5.02 (d, J = 6.8 Hz, 2H), 4.72 (d, J = 6.9 Hz, 1H), 3.23 - 3.16 (m, 1H), 2.88 (d, J = 11.8 Hz, 2H), 2.79 (s, 3H), 2.42 (d, J = 13.5 Hz, 1H), 2.24 (d, J = 12.2 Hz, 2H), 0.99 (s, 3H) 30 538.25 ’H NMR (400 MHz, DMSO-d6) 58.79 (d, J = 7.4 Hz, 1H), 8.67 (t, J = 1.8 Hz, 1H),8.52 - 8.37 (m, 2H), 8.01 (dd, J = 12.0, 1.9 Hz, 1H), 7.90 (dd, J = 7.7, 1.5 Hz, 1H), 7.40 (t, J = 7.9 Hz, 1H), 7.25 (dd, J = 7.4, 2.2 Hz, 1H), 5.02 (d, J = 6.8 Hz, 1H), 4.72 (d, J = 6.9 Hz, 1H), 3.26 - 3.17 (m, 1H), 2.88 - 2.80 (m, 2H), 2.79 (s, 3H), 2.68 - 2.62 (m, 2H), 2.41 (s, 3H), 1.34 (s, 3H)31 575.25 ¹H NMR (400 MHz, DMSO-d6) δ8.81 - 8.67 (m, 2H), 8.23 (dd, J = 8.0, 1.6 Hz, 1H),7.81 - 7.29 (m, 4H), 7.12 (dd, J = 7.4, 2.0 Hz, 1H), 5.04 (dd, J = 31.4, 6.7 Hz, 2H), 4.05 (s, 3H), 3.31 - 3.18 (m, 1H), 2.82 (d, J = 12.3 Hz, 2H), 2.64 - 2.53 (m, 2H),2.50 - 2.48 (m, 1H), 1.50 (s, 3H)WSGR Docket No. 66412-713.601Ex. LCMS ¹H NMR (ppm)[M+H]+32 488.20 ¹H NMR (400 MHz, DMSO-d6) δ9.61 (d, J = 1.5 Hz, 1H), 8.90 (t, J = 1.8 Hz, 1H),8.54 - 8.41 (m, 2H), 8.09 - 7.89 (m, 2H), 7.43 (t, J = 7.9 Hz, 1H), 5.09 (d, J = 6.9 Hz, 1H), 4.76 (d, J = 6.9 Hz, 1H), 3.25 - 3.17 (m, 1H), 2.81 (s, 3H), 2.44 (s, 1H), 2.25 (s, 2H), 1.46 (d, J = 1.6 Hz, 6H)33 579.15 ’H NMR (400 MHz, DMSO-d6) 58.92 (s, 1H), 8.83 (dd, J = 7.3, 1.0 Hz, 1H), 8.23 (dd, J = 7.7, 1.8 Hz, 1H), 7.70 - 7.23 (m, 4H), 7.04 (dd, J = 7.3, 2.0 Hz, 1H), 5.05 (dd, J = 38.0, 6.8 Hz, 2H), 3.33 - 3.22 (m, 2H), 2.81 - 2.73 (m, 2H), 2.64 - 2.56 (m, 2H), 1.48 (s, 3H)34 500.15 ’H NMR (400 MHz, DMSO-d6) 59.23 (d, J = 6.1 Hz, 1H), 9.00 (d, J = 1.5 Hz, 2H),8.45 (dd, J = 8.2, 1.4 Hz, 1H), 8.30 (d, J = 8.0 Hz, 1H), 7.91 (dd, J = 7.6, 1.5 Hz, 1H), 7.41 (t, J = 7.9 Hz, 1H), 5.05 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 6.8 Hz, 1H), 3.22 (dt, J = 13.6, 7.0 Hz, 1H), 2.77 (s, 3H), 2.63 (m, 3H), 2.42 (d, J = 13.5 Hz, 1H), 2.13 (ddd, J = 11.3, 9.1, 6.7 Hz, 2H), 2.07 - 1.92 (m, 1H), 1.90 - 1.75 (m, 1H)35 512.20 ¹H NMR (400 MHz, DMSO-d6) δ8.90 (s, 2H), 8.58 (s, 1H), 8.44 (dd, J = 8.1, 1.4 Hz,1H), 8.10 (s, 1H), 7.88 (dd, J = 7.6, 1.5 Hz, 1H), 7.39 (t, J = 7.9 Hz, 1H), 5.00 (d, J = 6.7 Hz, 1H), 4.68 (d, J = 6.8 Hz, 1H), 3.84 (s, 3H), 3.20 (dt, J = 13.6, 7.0 Hz, 1H), 2.74 (s, 3H), 2.68 - 2.57 (m, 2H), 2.40 (d, J = 13.4 Hz, 1H), 2.16 - 2.05 (m, 2H), 2.05 - 1.93 (m, 1H), 1.88 - 1.73 (m, 1H)36 575.25 ’H NMR (400 MHz, DMSO-d6) 58.72 (s, 2H), 8.33 - 8.07 (m, 1H), 7.75 (s, 1H),7.33 (t, J = 73.5 Hz, 4H), 5.02 (d, J = 28.2 Hz, 2H), 4.08 (s, 3H), 3.28 (s, 1H), 2.54 (s, 2H), 2.28 (s, 3H), 1.70 (d, J = 17.7 Hz, 3H)37 576.25 ’H NMR (400 MHz, DMSO-d6) 58.76 (d, J = 9.2 Hz, 2H), 8.23 (dd, J = 8.0, 1.5 Hz,1H), 7.85 - 7.48 (m, 2H), 7.41 - 7.29 (m, 2H), 7.15 (dd, J = 7.4, 2.1 Hz, 1H), 6.01 (s, 1H), 5.08 (d, J = 6.8 Hz, 1H), 5.00 (d, J = 6.6 Hz, 1H), 4.09 (s, 3H), 3.32 (s, 3H), 2.53-2.51(m, 1H), 2.40 (d, J = 13.2 Hz, 2H), 1.68 (s, 3H)38 576.25 ’H NMR (400 MHz, DMSO-d6) 58.54 (s, 1H), 8.46 (ddd, J = 7.4, 4.6, 1.2 Hz, 2H),7.75 (dd, J = 2.1, 0.9 Hz, 1H), 7.23 (s, 1H), 7.21 (s, 1H), 6.97 - 6.56 (m, 2H), 5.12 (d, J = 6.6 Hz, 1H), 5.03 (s, 1H), 4.92 (d, J = 6.9 Hz, 1H), 4.13 (s, 3H), 3.31 (dt, J = 13.5, 6.9 Hz, 1H), 3.04 (d, J = 13.7 Hz, 2H), 2.93 (d, J = 13.4 Hz, 2H), 2.67 (d, J = 13.3 Hz, 1H), 1.80 (s, 3H)39 526.20 ¹H NMR (400 MHz, DMSO-d6) δ9.61 (d, J = 1.5 Hz, 1H), 8.41 (s, 1H), 8.24 (dd, J =7.8, 1.7 Hz, 1H), 7.68 - 7.31 (m, 4H), 5.15 (d, J = 7.0 Hz, 1H), 5.02 (d, J = 6.7 Hz, 1H), 3.27 (d, J = 6.8 Hz, 1H), 2.58 (s, 1H), 2.31 (d, J = 2.5 Hz, 3H), 2.20 (s, 2H), 1.46 (d, J = 1.5 Hz, 6H)40 518.20 ’H NMR (400 MHz, DMSO-d6) 58.99 (d, J = 2.0 Hz, 1H), 8.87 (d, J = 7.4 Hz, 1H),8.61 (d, J = 2.3 Hz, 1H), 8.32 (s, 1H), 8.23 (dd, J = 8.1, 1.5 Hz, 1H), 7.81 - 7.54 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.16 (dd, J = 7.4, 2.1 Hz, 1H), 5.06 (dd, J = 24.9, 6.8 Hz, 2H), 3.30 (dt, J = 13.5, 6.8 Hz, 1H), 2.53 (s, 1H), 1.46 (s, 6H)41 567.25 ’H NMR (400 MHz, DMSO-d6) 58.75 (d, J = 7.3 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H),7.69 - 7.47 (m, 2H), 7.40 - 7.29 (m, 3H), 6.95 (dd, J = 7.4, 2.0 Hz, 1H), 5.08 (d, J = 6.8 Hz, 1H), 4.98 (d, J = 8.0 Hz, 2H), 3.31 - 3.24 (m, 1H), 2.85 (d, J = 11.7 Hz, 2H), 2.68 (s, 1H), 2.42 (s, 3H), 2.32 -2.17 (m, 4H), 1.03 (s, 3H)42 505.30 ’H NMR (400 MHz, DMSO-d6) 59.10 (s, 2H), 8.81 (d, J = 7.3 Hz, 1H), 8.35 (d, J =2.1 Hz, 1H), 8.31 (dd, J = 8.1, 1.4 Hz, 1H), 7.87 (dd, J = 7.7, 1.5 Hz, 1H), 7.37 (t, J = 7.9 Hz, 1H), 7.28 (dd, J = 7.4, 2.2 Hz, 1H), 5.08 (d, J = 7.0 Hz, 1H), 4.75 (d, J = 6.7 Hz, 1H), 3.24 - 3.19 (m, 1H), 2.98 (m, 1H), 2.78 (s, 3H), 2.62 (m, 2H), 2.38 (d, J = 13.5 Hz, 2H), 2.12 (m, 2H), 1.98 (m, 1H), 1.89 - 1.74 (m, 1H), 1.06 (m, 1H), 0.94 (m, 2H), 0.65 (m, 1H)43 526.251H NMR (400 MHz, DMSO-d6) 59.60 (d, J = 1.5 Hz, 1H), 8.23 (dd, J = 7.9, 1.6 Hz,1H), 7.79 - 7.67 (m, 1H), 7.53 - 7.28 (m, 4H), 5.14 (d, J = 6.9 Hz, 1H), 5.01 (d, J = 6.7 Hz, 1H), 3.30 - 3.24 (m, 1H), 2.60 - 2.53 (m, 4H), 2.25 (s, 2H), 1.45 (d, J = 1.6Hz, 6H)WSGR Docket No. 66412-713.601Ex. LCMS ¹H NMR (ppm)[M+H]+44 523.25 ¹H NMR (400 MHz, DMSO-d6) δ8.79 (d, J = 7.4 Hz, 1H), 8.41 (d, J = 1.8 Hz, 1H),8.23 (dd, J = 7.8, 1.7 Hz, 1H), 7.87 - 7.44 (m, 3H), 7.41 - 7.27 (m, 3H), 5.05 (dd, J = 21.6, 6.7 Hz, 2H), 3.97 (s, 3H), 3.35 (s, 1H), 2.51-2.54 (m, 1H), 2.33 (s, 2H), 1.45 (s, 6H)45 570.25 ’H NMR (400 MHz, DMSO-d6) 59.30 (s, 1H), 8.93 (dd, J = 7.3, 1.0 Hz, 1H), 8.22 (dd, J = 7.9, 1.6 Hz, 1H), 7.71 (dd, J = 2.2, 0.9 Hz, 1H), 7.64 - 7.30 (m, 3H), 7.20 (dd, J = 7.3, 2.1 Hz, 1H), 5.12 (d, J = 6.9 Hz, 1H), 5.03 (d, J = 6.6 Hz, 1H), 3.28 (s, 1H), 2.77 (d, J = 2.1 Hz, 2H), 2.68 - 2.61 (m, 2H), 2.55 (s, 1H), 1.47 (s, 3H)46 508.20 ’H NMR (400 MHz, DMSO-d6) 58.83 (s, 2H), 8.63 (d, J = 7.2 Hz, 1H), 8.13 (dd, J =5.5, 4.0 Hz, 1H), 7.63 - 7.15 (m, 3H), 6.86 (d, J = 7.2 Hz, 1H), 5.22 (d, J = 6.9 Hz, 1H), 5.04 (d, J = 6.7 Hz, 1H), 3.29 (m, 1H), 2.47 (s, 1H), 2.41 (s, 3H), 2.17 (s, 2H), 1.46 (s, 6H)47 496.30 ’H NMR (400 MHz, DMSO-d6) 59.07 (s, 2H), 8.86 - 8.73 (m, 1H), 8.49 - 8.41 (m,1H), 8.35 - 8.15 (m, 1H), 7.91 - 7.78 (m, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.35 - 7.15 (m, 1H), 5.05 (d, J = 6.8 Hz, 1H), 4.64 (d, J = 6.8 Hz, 1H), 3.29 - 3.19 (m, 1H), 2.73 - 2.65 (m, 1H), 2.47 (s, 1H), 1.47 (s, 5H), 1.39 - 1.12 (m, 4H)48 560.20 ¹H NMR (400 MHz, DMSO-d6) δ9.23 (d, J = 7.4 Hz, 1H), 8.95 (s, 1H), 8.24 (dd, J =7.4, 2.1 Hz, 1H), 7.58 - 7.20 (m, 4H), 5.11 (dd, J = 12.8, 6.8 Hz, 2H), 3.30 (d, J = 6.9 Hz, 1H), 3.26 - 3.19 (m, 2H), 2.68 (s, 3H), 2.67 - 2.57 (m, 2H), 2.54 (s, 1H), 2.32 - 2.26 (m, 2H), 1.72 (s, 3H)49 531.20 ¹H NMR (400 MHz, DMSO-d6) δ9.28 (s, 1H), 8.92 (d, J = 7.3 Hz, 1H), 8.33 (s, OH),8.23 (dd, J = 7.8, 1.6 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.66 - 7.19 (m, 4H), 5.08 (dd, J = 34.6, 6.8 Hz, 2H), 2.68 - 2.58 (m, 2H), 2.51 (d, J = 2.1 Hz, 2H), 2.15 (d, J = 7.4 Hz, 2H), 2.05 (ddd, J = 15.2, 9.9, 5.6 Hz, 1H), 1.84 (s, 1H)50 519.25 ’H NMR (400 MHz, DMSO-d6) 59.26 (s, 1H), 8.92 (d, J = 7.3 Hz, 1H), 8.28 - 8.18(m, 1H), 7.73 - 7.60 (m, 1H), 7.48 - 7.28 (m, 3H), 7.29 - 7.14 (m, 1H), 5.26 - 4.86 (m, 2H), 3.32 - 3.25 (m, 1H), 2.54 (s, 1H), 2.17 (s, 2H), 1.48 (s, 6H)51 547.20 ’H NMR (400 MHz, DMSO-d6) 58.79 (dd, J = 7.2, 0.9 Hz, 1H), 8.65 (s, 1H), 8.23 (dd, J = 7.8, 1.8 Hz, 1H), 7.71 - 7.24 (m, 4H), 7.01 (dd, J = 7.2, 2.0 Hz, 1H), 5.09 (d, J = 6.9 Hz, 1H), 5.03 (s, 1H), 5.00 (d, J = 6.6 Hz, 1H), 3.32 - 3.24 (m, 4H), 2.88 - 2.78 (m, 2H), 2.53 (s, 1H), 2.48 (s, 3H), 2.42 (s, 2H), 2.22 - 2.14 (m, 2H), 1.19 (s,3H)

[0189] Additional compounds of the invention were prepared by modifications of the methods exemplified herein. When chiral starting reactants were available, compounds were prepared and isolated as single stereoisomers having a known absolute configuration, as indicated by (R) and (S) labels on their structures. When racemic starting reactants were used, compounds were carried through synthesis as a mixture of diastereomers and then separated into single stereoisomers by an appropriate chiral preparative HPLC or SFC method before characterization and testing.Example A: HEK-Blue™ hTNFa reporter assay

[0190] Stimulation of HEK293 cells by TNFa leads to activation of the NF-KB pathway. The potency of compounds was examined in HEK-Blue™ hTNFa reporter cells (Invivogen, Cat# hkb-tnfdmyd).HEK-Blue™ TNFa cells were generated by stable transfection of HEK293 cell line with a SEAP reporter gene under the control of the IFN-P minimal promoter fused to NF-KB binding sites. Stimulation of HEK-Blue™ TNFa cells with TNFa triggers the activation of the NF-KB-inducible promoter and the production of SEAP. Levels of SEAP in the supernatant can be easily determined using QUANTI-Blue™WSGR Docket No. 66412-713.601Solution (Invivogen, cat# rep-qbs) by reading the OD at 620-655 nm. The compound inhibits TNF-a and prevents the production of SEAP in the cells.

[0191] HEK-Blue™ TNFa cells were cultured in DMEM supplemented with 10% FBS, lOOp / mL penicillin, 100 pg / mL streptomycin, 100 pg / mL normocin, Ipg / mL puromycin, and 100 pg / mL zeocin. The culture was maintained in culture incubator with 5% CO2 at 37 °C. When used for assay, the cells were gently rinsed twice with pre-warmed phosphate buffered saline (PBS) and detached in presence of PBS by tapping the flask or by using a cell scraper. The cells were spun to remove PBS and resuspended in fresh, pre-warmed test medium (DMEM supplemented with 10% FBS, lOOp / mL penicillin, and 100 pg / mL streptomycin). A serial dilution of work solution of tested compound was made in DMSO with 1000X of final concentration, and 40 nL of compound DMSO solution was transferred into 384-well plates (Coming 3764) by Echo, and incubated with 10 pL of recombinant hTNFa (R& D biosystem, Cat# 210-TA-020 / CF) for 1 h at 37 °C. The compound / hTNFa mixture well received 30pL HEK-Blue™ TNFa cell suspension at 10000 cells / well, and then incubated at 37 °C with 5% CO2 for 24 h. The final concentration of hTNFa is 120 pg / mL. After incubation, 5 pL of induced cell supernatant was transferred to a new 384-well plate well (Coring 3764) to mix with 45 pL of QUANTI-Blue Solution. After 1 h incubation at 37 °C, the plate was read using a spectrophotometer at 620 nm.

[0192] The percentage of inhibition was calculated by the following formula:

[0193] % inhibition = (positive control-Sample) / (positive control-negative control) * 100

[0194] Positive control: OD620 reading of cells with hTNFa stimulation.Negative control: OD620 reading of cells without hTNFa stimulation.Sample: OD620 reading of cells with compound at specific concentration and hTNFa stimulation

[0195] The % inhibition was plotted against compound concentration in logarithmic scale and the IC50 was rendered using 4-parameter nonlinear regression (GraphPad Prism).

[0196] The data is shown in Table 4.Table 4Ex. IC50 Ex. IC501 A 26 B2 A 27 B3 A 28 A4 A 29 A5 A 30 A6 A 31 A7 A 32 A8 A 33 A9 A 34 A10 A 35 A11 A 36 A12 B 37 A13 A 38 A14 A 39 A15 A 40 A16 A 41 A17 A 42 BWSGR Docket No. 66412-713.601Ex. IC50 Ex. IC50 18 A 43 B 19 B 44 A 20 A 45 A 21 A 46 B 22 B 47 A 23 A 49 A 24 A 50 A25 A

[0197] IC50 data are designated within the following ranges:IC50:A: 0 < IC50 < 25 nMB: 25 nM < IC50 < 100 nMC: 100nM< IC50< 1000 nM

Claims

1. WSGR Docket No. 66412-713.601CLAIMS WHAT IS CLAIMED IS:

1. A compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, that is selected from the group consisting of:WSGR Docket No. 66412-713.601WSGR Docket No. 66412-713.6012. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

3. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

4. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

5. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

6. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,WSGR Docket No. 66412-713.601wherein the compound is:

7. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:F8. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

9. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

10. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

11. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:WSGR Docket No. 66412-713.60112. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

13. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

14. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

15. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:F16. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

17. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,WSGR Docket No. 66412-713.601wherein the compound is:

18. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

19. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

20. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

21. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:F22. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:WSGR Docket No. 66412-713.60123. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

24. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

25. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

26. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

27. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

28. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,WSGR Docket No. 66412-713.601wherein the compound is:

29. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:F30. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

31. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

32. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

33. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:WSGR Docket No. 66412-713.60134. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

35. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

36. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

37. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

38. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:WSGR Docket No. 66412-713.60139. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

40. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:F41. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

42. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

43. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

44. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:WSGR Docket No. 66412-713.60145. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:F46. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

47. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

48. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

49. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:WSGR Docket No. 66412-713.60150. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

51. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

52. The compound of claim 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein the compound is:

53. A pharmaceutical composition comprising the compound of any one of claims 1-52, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.

54. A method for the treatment of disorders for which the administration of a modulator of TNF alpha function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1-52, or a pharmaceutically acceptable salt or solvate thereof.

55. A method for the treatment of an inflammatory or autoimmune disorder, a neurological, a neuro- degenerative disorder, pain, a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of any one of claims 1-52, or a pharmaceutically acceptable salt or solvate thereof.

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